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DIABETES TX CHARTS: Glycemic Management in T2DM (see also T2DM Overview & Approach, page 47)
©
www.RxFiles.ca – Mar 2015
Table 2: Individualization of Drug Therapy: Special Considerations Preferred Drugs to Consider Initiate Lifestyle Modifications:1 diet portion plate; exercise pedometer ; & Patient Education (important at all levels! 2,3,4) Patient Factor GLYCEMIC MANAGEMENT OF TYPE 2 DIABETES (T2DM) IN ADULTS If individualized BG goals not achieved in 2‐3 months reassess; consider initiation of pharmacotherapy
Antihyperglycemic Monotherapy: Metformin (MF) for most, esp. if obese/overweight; Start low dose & dose over 3‐4 weeks or longer if GI side effects; Individualize goals & treatment {In rare “young, thin T2DM,” a sulfonylurea (SU) at low‐moderate dose or metformin may be suitable for initial tx} Goal: pursue target A1C over 3‐
If A1C 8.5‐9%, consider initiating combination tx with metformin +2nd agent ?insulin 6 months; avoid hypoglycemia!
SMBG: 1‐2x/day (AC+2hrPC) to learn effects of lifestyle/new medications ; to 1‐2x/wk once BG targets met
If individualized BG goals not achieved in 2‐3 months reassess; consider addition of combination therapy
Combination Antihyperglycemic Agent (AHA) Therapy: Gradual loss of glycemic control occurs over time so many will eventually require combination tx (e.g. MF + SU or other agent ± insulin); numerous options available (consider benefits, risks, patient preferences, goals of treatment, etc.) SMBG: as above; especially important when AHAs known to cause hypoglycemia (e.g. SU, meglitinide) initiated If individualized BG goals not achieved in 2‐3 months reassess; consider addition of another agent or insulin Adding Insulin to Existing AHAs Regimen (**MF will limit wt gain & insulin dose required)
Varying insulin initation regimens are available; regardless of approach, whatever dose initiated will likely require adjustment; titration is key! Starting SMBG individualize; varies Check BG at least as often as insulin is given See: http://guidelines.diabetes.ca/BloodGlucoseLowering/InsulinPrescriptionTool Note: insulin temporarily indicated in any patient with metabolic decompensation, severe fasting hyperglycemia, or severe illness Option 1: Basal Insulin Lantus, Levemir, Humulin N, Novolin ge NPH added to daytime PO agents (e.g. metformin 4‐T Trial)
Starting dose: 5 to 10 units once daily HS (for lean pts [<50kg] 0.1 to 0.2 units/kg; for very obese ~15 units) Titration: by 1 unit every night until FBG target achieved (ensure target realistic; avoid hypoglycemia) **If FBG target not achieved at 30 units/day, or daytime BG , consider addition of bolus insulin before meal nd
rd
with highest PPG/largest meal as a starting point (bolus dose = 10% of basal dose); 2 & 3 bolus doses can be added similarly in succession See Option 3 SMBG: Check FBG once daily in AM until target achieved ? PO Agents: Continue metformin! Continue secretagogue (at reduced dose to daytime hypoglycemia risk)
Option 2: Premixed Insulin Humalog Mix25, Humalog Mix50, Novomix 30, Humulin 30/70, Novolin ge 30/70, Novolin ge 40/60, Novolin ge 50/50
Starting dose: 5 to 10 units (0.1 to 0.2 units/kg) BID before breakfast & supper Titration: breakfast dose by 1 unit each day until pre‐supper BG target achieved OR supper dose by 1 unit each day until FBG target achieved (adjust only 1 insulin dose at a time) SMBG: Check BG before meals & at HS until targets achieved; May frequency once stable **Beware of hypoglycemia post‐breakfast or post‐
supper; advisable to check BG once weekly at 3am to rule out nocturnal hypoglycemia ? PO Agents: Continue metformin; consider reducing or stopping secretagogue
Option 3: Basal‐Bolusmealtime/prandial Insulin (“split‐mixed regimen,” “multiple daily injections” [MDI])
Starting dose: Calculate total daily insulin = 0.1 to 0.5 units/kg/day (depends on patient, other drugs, etc; safer to start lower); distribute as: 40% as basal insulin HS + 20% as bolus insulin before each meal Alternative: 50% as basal insulin HS; 50% as bolus insulin divided TID before each meal BID dosing alternative: a) divide total daily insulin: 2/3 pre‐breakfast, 1/3 pre‐supper or b) divide each dose: 2/3 basal & 1/3 bolus (or 30/70 premix) Titration: dose by 5‐10%/week or 1 to 2 units at a time; adjust only 1 insulin at a time; start with the insulin dose that will correct the first problem BG reading of the day (fix the lows first, and highs later) SMBG: Check BG before meals & at HS; consider PPG reading(s) to assess bolus dose(s) ? PO Agents: Continue metformin; typically, stop secretagogue.
Individualize targets: More aggressive: young adult
with recent diagnosis STENO-2; Less aggressive in frail
A1C% q3-6mos (calibrate meter q-yr) 7(6.5% in some) 6 8.5 (8-9 VADT) elderly 32. ACCORD A1C arm halted due to death
NNH= 95 / 3.5yr in aggressive target group (A1C <6 Achieved=6.4)
7.5 (ADA’14: Type 1, age <18yr)
15
FBG (mmol/L) Pre‐meal
4-7 ADA : 4.4 ‐7.2 4-6
5-12 (avoid hypoG) vs standard target group (A1C: 7-7.9 Achieved=7.5); patients
~ 10 yr hx.
PPG (mmol/L) 2hr post
5-10
5-8 (consider if A1C not met) with established T2DM at high CV risk
TARGETS: GLUCOSE CDN13 Adult Target for many Normal Frail elderly3
BP 2014 Diabetes ≤130/80 [New USA Targets: BP ≤140/90 ADA’15 or BP ≤140/90 JNC 8]
LIPID 2012 Diabetes most LDL<2 or by ≥50% (alternate targets if treating: either Apo B 0.8 or non-HDL-C 2.6) [USA: mod-high dose statin if ≥ 40yr AHA’13]
RENAL
Normal
Microalbuminuria ? Start ACEI or ARB Macroalbuminuria Start ACEI or ARB
Albuminuria
<30mg/day (<20mcg/min)
30-300mg/day (20-200mcg/min) >300mg/day( >200mcg/min)
Male or Female 2-20
Male or Female >20
Albumin mg/Creatinine mmol Ratio Male or Female <2
Screen: if BP >135/80 USPSTF’08.; FBG: screen q3yr if risk factors or 40yrs old. Estimate average glucose eAG: 8.5mmol/l = an A1C 7%
A1C (Threshold ≥ 6.5%) or FPG/OGTT annually if very high diabetes risk; or screen A1C q3-5yr if high risk CTFPHC 2012 using FINDRISC / CANRISK.
Random PG > 11.1 without symptoms: may be used for diagnosis 2013 CDA, Grade D recommendation.
Diagnosis: A1C since fast, easy, non-fasting (Prediabetes: 6-6.4%; Diabetes: ≥6.5%) CDA’13,ADA ‘14; FBG≥7mmol/l; OGTT 2hr plasma glucose ≥ 11.1 mmol/l
Hepatic disease Hypoglycemia Insulin; Repaglinide; Acarbose (Caution: Glyburide, Metformin & TZDs) Consider risk of combos Table 3; &/or need to relax targets Also: Repaglinide; Gliclazide / Glimepiride less than long‐acting SUs; Acarbose IGT/IFG “Prediabetes” Irregular mealtimes Obese / Overweight PPG >10mmol/L & FBG minimally ’d Renal failure * Metformin; Metformin+Sitagliptin or other incretin agents; TZDs (Basal insulin: Glargine or Detemir less than intermediate e.g. NPH/ N) Lifestyle (diet/exercise)DPP, FDP; MF 850mg BID DPP; Orlistat Xendos; Acarbose Stop‐NIDDM Repaglinide (may be preferred over SU) Metformin DOC if no CIs; mortality (UKPDS‐34); (Acarbose; I‐Detemir; new agents?) Repaglinide (or Acarbose); Metformin + Sitagliptin; Diet fibre Rapid Acting Insulin (if PPG very high >10mmol/L) e.g. Lispro, Aspart, Glulisine Repaglinide; Insulin; TZD edema (Gliclazide,5 Lina‐ or Sita‐ gliptin.) Cohort
] /dysfx: note MF dose below [Lower A1Cs may improve renal outcomes but for mortality A1C <8‐9% & 6.5%.
* MAX MF Dose:6 if CrCl: 45‐60 ml/min , 1000‐1700mg/day; if 30‐45 ml/min, 500‐850mg/day; <30 ml/min may avoid Table 3: Combination Therapy +/- Insulin in Type 2 Diabetes 7,8,73
Drug combination
MF + SU dose-dependent
SU + TZD 10
MF + repaglinide 11
MF + DPP-4 sita/saxa/linaMF + TZD 12,13,14
MF + acarbose 15
MF+canagliflozin+SU
exenatide+MF+SU 70
liraglutide+MF+SU
Insulin monotherapy
Insulin + MF
(FINFAT STUDY 16)
Insulin + SU
(UKPDS 57 ultralente @ evening)
Insulin + acarbose
Insulin+ pioglitazone
Insulin+ repaglinide
Insulin basal +GLP-1
(e.g. exenatide, liraglutide)
Insulin + 3 orals*
in
A1C
Hypo
-glyc
Wt
Comments
(long-term clinical outcomes not studied!)
/
MF combos generally result in less weight gain than SU
-/
-/
-/
17
/ /
combinations
if MF initially, may add SU e.g. gliclazide or repaglinide
if SU initially, may add MF or TZD; SU+MF may further
A1C by 1.7%; 1 study mortality9; but ADVANCE neutral*
MF+ pioglitazone: positive lipid effects, but edema/HF
MF+ rosiglitazone: lower A1C but edema/HF
MF+ acarbose: wt & PPG, but GI AE
MF+ DPP-4 inhibitor: wt, PPG & hypoglycemia unless with SU
MF+ canagliflozin: wt, PPG & hypoglycemia unless with insulin/SU
tight BG control but hypoglycemia/weight gain
overcomes insulin resistance; MF has positive effect
on weight & lipids; preferred in obese patient; superior to
insulin+SU; insulin sparing ~20-25%
evening basal insulin; lower A1C & less hypoglycemia than
insulin alone; caution in elderly (hypoglycemia)
PPG diet high in Carbs; also wt & triglycerides
insulin resistance; but harms ( wt, edema & risk of HF 18)
option to PPG; wt more than metformin non-obese Lund’09
if A1C <8, initial insulin dose by 20%. N/V & diarrhea
ACCORD: >50% on 3 orals+insulin; A1C=6.4 vs 7.5% death *
*ACCORD: baseline A1C=8.3%, wt=93kg & very aggressive intervention (>50% on 3 orals + insulin); A1C to 6.4% but death
NNH=95 /3.5yr (& wt. & hypoglycemia). In ADVANCE: baseline A1C=7.5%, wt=78kg; most on SU gliclazide + MF; A1C to 6.5% &
microvascular NNT=67 /5yr (esp. nephropathy) but also severe hypoglycemia NNT=83 /5yr & hospitalizations NNH=42 /5yr.
Note: benefits for trials often given in relative numbers for multiple years (~10years in the case of the UKPDS); however
adverse events often only reported in absolute numbers over one year. This has the effect of minimizing the
quantification of harms and exaggerating the benefits.
Drug-induced Hyperglycemia: antipsychotic clozapine, olanzapine…, corticosteroid, cyclosporine, diuretic thiazide e.g. >25mg
HCT, estrogen, GnRH agonist, interferon alpha, nicotinic acid dose , pasireotide, phenytoin, sympathomimetic decongestant, siro, tacro-, temsiro-limus, statin, tesamorelin, & thyroid hormones
Hypoglycemia risk -UKPDS: risk of 1 MAJOR hypoglycemic events/yr (ITT): chlorpropamide=1%,
glyburide=1.4%, insulin 1.8%; risk of ANY hypoglycemic event/yr: chlorprop.= 16%, glyburide=21%, insulin 28%.
Note: β-blockers have minimal risk of altering glucose control but may alter/mask hypoglycemic response.
Consider: 55 Lifestyle: Quit Smoking; 5-10% Weight (fibre, fat, low glycemic index carbs, whole grains); Exercise (aerobic
150min/wk + resistance 3x/wk; but start with 5-10 minutes). Lipids/statin, orlistat 56, hypertension ACEI/ARB/thiazide, ASA ~81mg/d.
A1C=glycosylated hemoglobin AE=adverse effects BG=blood glucose FBG=fasting blood glucose HF=heart failure
MF=metformin OGTT=oral glucose tolerance test PPG=postprandial BG SU=sulfonylurea TZD=pioglitazone, rosiglitazone
36
ANTI‐HYPERGLYCEMIC AGENTS (AHA): Comparison Chart 19,20,21,22,23,24,25,26,27 ADA 2015 ,28,29,30 CDA 2013 ,31,32 Generic/TRADE/ Strength/Pregnancy INITIAL & (Max) DOSE USUAL DOSE RANGE L Regier BSP, B Jensen BSP, L Rutherford © www.RxFiles.ca May 2015 DRUG COMMENTS INTERACTIONS (DI) HDL TGs Wt EFFECTS ON KINETICS $ /100 day FBG PPG A1C% LDL Biguanides – hepatic glucose production; insulin sensitivity & cellular glucose uptake & utilization; morbidity & mortality NNT=14 /10yr (RRR 27%) in obese patients (UKPDS‐34) 500mg po BID
21 Onset – days Metformin 33 (MF) P L 250‐500mg daily First line agent . Possible wt loss; DOC for OBESE ! ‐/ Metformin DPP
34
850mg BID 24 to max effect (Max: 2550mg/day, GLUCOPHAGE, GLYCON, g 1‐1.5
Does not by itself cause hypoglycemia. Elderly: dose. 2.9kg EtOH & cimetidine ADOPT
35 DPP conc .
ADOPT 4yr
36
31 at 2weeks 1g po BID
850mg TID; but 500, 850mg tab Prevents NIDDM . Used in PCOS . Low breast milk effect of MF UKPDS
lipids & wt! +’ve effect
on
30 Peak = 3h usual max 1g BID) 1700mg am, 850mg pm AE: GI (dyspepsia, N/D): To avoid, start low dose & q2‐4wk;
contrast media Metformin ER tab (ghost tab) Renal : dose if CrCl 45‐60ml/min, 1000‐1700mg/day; Duration = GLUMETZA if 30‐45ml/min, 500‐850mg/day. May avoid if <30ml/min.
8‐12h see below for more info
500mg, 1000mg tabs Metformin Combination Products Combination Products,
NOT in Canada: **once daily dosing Metformin/Rosiglitazone AVANDAMET Metformin/Pioglitazone ACTOplus met 500/15mg, 850/15mg BID {ghost tab shell may be Metformin/Sitagliptin JANUMET (XR ) passed in stool after Canagliflozin/Metformin INVOKAMET 50 & 150/500 mg; 50 & 150/1000 mg tab po BID
Metformin/Saxagliptin KOMBOGLYZE releasing drug} Metformin/Linagliptin JENTADUETO Sulfonylureas (SU) – insulin secretagogue; cell insulin release; peripheral glucose Chlorpropamide DIABINESE, g 100mg daily (500mg daily) P L 100, 250mg tabs Gliclazide 100mg po daily
250mg po daily
40mg (160mg BID)
DIAMICRON, g 80mg tab 30mg MR DIAMICRON MR, g Advance
P L
) (120mg daily 30mg, 60mg tab 1‐2mg daily in AM Glimepiride AMARYL, g (8mg daily)
1,2,4mg tabs 1.25‐2.5mg daily Glyburide P L DIABETA, g 2.5, 5mg tabs placentatransfer (7.5‐10mg BID $37) Tolbutamide ORINASE, g 500mg tab P L 19 Peak = 6‐8h 19 Dur = 24‐72h 29‐72 80mg po BID
‐contract price varies 60mg MR po daily
120mg MR po daily
Peak = 4‐6h 34 Dur =10‐24h 57
1mg daily
2mg daily
4mg daily
67
Peak = 2‐3h 67
Dur = 24h 67
5mg po daily‐BID ADOPT
7.5mg BID
18‐26 Onset ≤ 33 60min Lactic acidosis <1:10,0007 watch Na bicarb. Anemia may occur
folate absorption may TSH in treated hypothyroid pts long-term due to Vit B12 absorption 7% - consider oral B12 Avoid: renal fx (<30 ml/min), acute/decompensated HF, liver dx Hold: in acute illness/dehydration , 48hr post iodinated contrast. Combo MF/Rosi A1C by ~2% but edema & hypoglycemia vs MF alone. ( #/sensitivity of insulin receptors?); hepatic gluconeogenesis; may stop if on insulin or ? DOC HNF1A/4A‐MODY chlorpropamide
not recommended due
to BP & retinopathy (UKPDS-33)
Total Wt gain with glyburide >4kg
vs >6kg insulin (UKPDS-33)10yr
kg
‐ ‐ ‐ 1.6
ADOPT 4YR
1‐1.5 Peak = 2‐4h Peds: 0.05‐0.45mg/kg/d by 2C9 inhibitors eg. Amiodarone, In general, SUs achieve ~75% of effect at 1/2 their max dose. Caution in elderly (hypoglycemia risk) & obese (wt gain). SMX/TMP, fluvastatin… Dose titration q1‐2 weeks. Failure rates ~5‐10%/year. Reduce dose if renal/hepatic dysfx or if hypoglycemia. nd
eg. + MF or TZD Many (~75%) require 2 agent for BG control Hypoglycemia with: cimetidine, clarithromycin, EtOH, Hypoglycemia: most: chlorpropamide & glyburide (see fluconazole, fluoxetine, note below); least: tolbutamide, gliclazide,37 glimepiride38,39 MAOIs, metronidazole, Require consistent food intake to avoid problems with NSAIDs, hypoglycemia (risk: elderly, debilitated, malnourished)
quinolones,salicylates AE: Wt gain, headache, dizziness, sulpha skin rx (rash/ & sulfonamides ~1%
1‐3%
kids‐glyburide
‐Blockers may mask photosensitivity ),GI AE , tooth discolour toxicity
+
Concern: cardiac
, hyperinsulinemia, Na & G6PD. hypoglycemia Disulfiram rxn with Breast milk conc likely minimal with glyburide & EtOH & chlorpropamide glipizide.Glatstein09
rifampin effect Dur = 12‐24h 500mg po BID
500mg po TID
250mg daily (1000mg TID) utilization
TID dosing option for larger doses to GI intolerance
(acute renal dysfn)
long‐term VitB12 & .
34 Peak = 3h 46 Dur = 6‐12h Combo agent in USA only: glimepiride/pioglitazone DUETACT Meglitinides (GTN) – short‐acting insulin secretagogue; bind to cell to stimulate insulin release at different site than SUs; (adjust dose at ~7days); usually D/C if on insulin (?Option: HNF1A‐MODY) st
3A4 effect
Restores 1 phase insulin release ‐ PPG 60mg po TID
194 O ≤ 20min CYP inhib : Nateglinide Navigator NS P L 60mg TID ac
Amiodarone, azole‐antifungal, Rapid, short duration May risk of hypoglycemia vs SUs 120mg po TID
P =
60‐120min
STARLIX 194
(180mg po TID) cipro, clari‐/ery‐thromycin, 60, 120mg tab Repaglinide GLUCONORM,g P L 0.5, 1, 2mg tab D ≈ 4h 0.5mg TID ac {if no prev tx or A1C <8%} (4mg QID) 0.5mg po TID
1‐2mg po TID
4mg po TID
}
O =15‐60min P =60‐90min 236/84 g D ≈ 4‐6h 0.5 115/44 g
1‐1.5 ‐ ‐ ‐ ‐/ cyclosporine, diltiazem,
gemfibrozil & PI HIV meds. CYP 3A4 inducer effect: barbs, CBZ & rifampin CYP 2C8 inhib: trimethoprim option in elderly; {Flexibility with food intake: skip dose if skip meal; take extra dose if add meal} If stopping other hypoglycemics, begin next day & watch for hypoglycemia. ROLE: alone or + MF, TZD, or insulin Agents lack outcome data on morbidity &mortality. Thiazolidinediones (TZDs) (aka “glitazones”) – Insulin Sensitizers: hepatic output of glucose & peripheral insulin uptake; ~4‐6+ weeks before effect (adjust dose at ~2 months) 15mg po daily
More effective in obese or hyperinsulinemia pts. 68 g,279 Delayed macular edema; FDA’11: >1yr use may bladder ca
15mg daily PERISCOPE
30mg daily
Doesn’t cause hypoglycemia by itself. action… P L
84 g
,379
ACTOS, g 3.6kg
Cholestyramine PROACTIVE premenopausal PCOS.
ACT NOW
‐ 45mg daily Onset ≥ 4 wks
Ovulation resumption possible in anovulatory
) (45mg/day
15, 30, 45 mg tab absorption ~70% PROACTIVE 3yr
111 g,555
?MF+SU+ TZDs. 2C8
Pioglitazone Rosiglitazone 1st approved 2000 AVANDIA 2, 4, 8mg tab P L Metformin/Rosiglitazone AVANDAMET 500mg/1mg, 500mg/2mg, 1000mg/2mg 500mg/4mg, 1000mg/4mg 4mg daily 4mg po daily
246 ADOPT
4mg po BID
462 Max effect in DREAM, RECORD 8mg daily
CDN 339 8‐16 wks Europe D/C Sep’10 Restricted FDA:REMS
{4mg max if with SU}
(4mg BID) (44) BID dose ~more effective pt consent required 1000mg/2mg po BID
1000mg/4mg po BID
<1 or 1‐1.5 284
377
45,46
47,48
‐/ Hepatic CYP by gemfibrozil & by rifampin Pioglit (not rosi‐) 3A4 / 4.8kg CYP weak/moderate ADOPT 4yr inducer so may OCPs ‐
?? May MI, CV risk Nissen, DREAM?, FDA; Macular edema; advise against using rosi ADA’08
CI: any HF; triple tx
~1% mild
(due to AE: Edema 4.8% (HF 2x 40,41;HTN);Wt; anemia hemodilution?);fractures esp ,2X;monitor liver fx (ALT) when indicated
/DPP if MF CI
ROLE: +MF/SU ; HF if with insulin. Rosi: MI risk??60 Rosiglitazone requires patient consent due to cardiac risk. 42,43
Pioglitazone may have more +ve lipid effect
Glucosidase Inhibitors –inhibit ‐glucosidases in brush border of small intestine; prevent hydrolysis & delay carbohydrate digestion (Tx hypoglycemia with glucose tablets Dex4, honey or milk; [sucrose not absorbed]) digoxin effect Acarbose AE: GI intolerance (flatulence >41%, diarrhea >28%); LFTs 3% & 50mg po TID cc
99 Meal‐time P L 25mg daily Cholestyramine & GLUCOBAY (prev Prandase) dosing; hepatic failure. Accumulation in renal fx . Avoid in chronic 100mg po TID cc
133 ~8 wks for ‐ ‐ ‐/ ‐/ cathartics effect 50, 100mg tabs 0.5‐
(100mg TID) STOP‐NIDDM
49
max. effect 0.8 acarbose minimally absorbed; monitor 2hr PPG
Enzymesamylase/pancreatic
GI disease. (Low hypoglycemia risk.) ++
dose q4‐8wks. ROLE minimal: if PPG; + SU, MF; (+Insulin?) effect; Fe ? 37
Generic/TRADE/ Strength/Pregnancy INITIAL & (Max.) DOSE USUAL DOSE RANGE $/100 day KINETICS EFFECTS ON FBG PPG A1C% LDL DRUG INTERACTIONS (DI) HDL TGs ANTI‐HYPERGLYCEMICS continued. www.RxFiles.ca May 2015 COMMENTS Wt Dipeptidyl peptidase‐4 (DPP‐4) inhibitors (aka “gliptins”): insulin secretion via incretin degradation/ GLP‐1 & GIP; glucagon secretion; lower FPG & PPG in glucose‐dependent manner. ROLE: mono tx, combo w/MF, SU, TZD sitagliptin/insulin saxa‐ & sita‐gliptin (linagliptin not indicated for use w/insulin or TZD) DPP-4 inhibitor outcome trials: no early CV benefit, some AEs; HF concerns?
Sitagliptin 1st approved 2008 100mg po daily JANUVIA P L 325
100mg po daily 325
25‐50mg po daily (100mg po daily) 25, 50, 100mg tab free base Metformin/Sitagliptin PM JANUMET (XR ) 2 x 50/1000mg XR daily 360
500mg/50mg tab XR formats to be 500mg/50mg po BID 360
850mg/50mg tab 360
given once daily 850mg/50mg po BID 1000mg/50mg tab 1000mg/50mg po BID 360
Saxagliptin1st approved 2010 2.5‐5mg po daily 2.5‐ 5mg po daily 267‐314
P L ONGLYZA (5mg po daily) **do not split/cut tabs 2.5, 5mg tab Metformin/Saxagliptin KOMBOGLYZE 500mg/2.5mg tab 500mg/2.5mg po BID 284
850mg/2.5mg tab 850mg/2.5mg po BID 284
1000mg/2.5mg tab 1000mg/2.5mg po BID 284
Linagliptin 5mg po daily 5mg po daily 280
P L TRAJENTA
5mg tab
(5mg po daily) Metformin/Linagliptin JENTADUETO 500mg/2.5mg po BID 500mg/2.5mg tab 297
850mg/2.5mg po BID 297
850mg/2.5mg tab 1000mg/2.5mg po BID 1000mg/2.5mg tab 297
alogliptin NESINA CDN,USA: DPP-4 Θ; 6.25,12.5, 25mg tab OD $310
0.7
‐/ (0.5‐1) Peak =1‐3h Onset 4wks; ~18 wks for max effect ‐ ‐/ 0.6
(0.4‐0.8)
‐/ ‐ minimal experience sitagliptin CYP 3A4/2C8 digoxin: small in dig levels ‐/? (AUC 11%; Cmax 18%); no dose adjustment req’d less CYP 3A4 DI caution than saxagliptin ‐/ ‐/? Savor-Timi
53 CV outcomes NS 2yr,
but
HF hospitalizations, ↔wt
saxagliptin CYP 3A4/5 linagliptin CYP 3A4/P‐gp: CYP3A4 inducers (e.g. carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin) AE:throat sore ,infection URTI, UTICochrane08; HA, arthralgia; nausea, diarrhea/constipation; LFT/SJS/pancreatitis rare (FDA caution); hypersensitivity reaction; less hypoglycemia but with SU; edema?, lymphocyte? class effect? Wt ↔ Avoid use in HF limited trial data AE: infection URTI, UTI; HA, arthralgia; constipation; anemia; SJS/ pancreatitis ? extrapolated from sitagliptin; hypersensitivity reaction; less hypoglycemia but with SU; edema?; lymphocyte? class effect? Avoid use in HF ‐ may worsen SAVOR‐TIMI { hospitalization for HF seen in those with prior HF, CKD, or natriuretic peptides} Peak =1.5h Onset: significant A1C seen at 4‐6 wks 0.6
(0.4‐0.8)
‐ ‐ ‐ ‐/? saxagliptin CYP 3A4/5: CYP3A4 inhibitors (e.g. clarithromycin) less CYP 3A4 DI caution with linagliptin AE: infection URTI, UTI nasopharyngitis/cough; HA, arthralgia; diarrhea/constipation; SJS/pancreatitis ? extrapolated from sitagliptin; but with SU
; edema?; hypersensitivity rxn; less hypoglycemia 1.4kg@2yr / neutral anemia; lymphocyte? class effect?; Wt
Avoid use in HF limited data; No dose : mild‐mod renal/liver dysfx. Concern with insulin: potential increase in CV risk (non‐sig. composite endpoint: MI, stroke, CVD mortality) ; alogliptin + metformin 12.5///500/850/1000mg BID $320: KAZANO; + pioglit.12.5///15/30/45mg; 25mg///15/30/45mg: OSENI. AE: hypersensitive rx, infection URTI, UTI, hypoglycemia but with SU, ?pancreatitis & wt. CV outcome Examine ~25mg NS; DI: 3A4 minimal Glucagon‐like peptide‐1 (GLP‐1) receptor agonists: insulin secretion as incretin mimetic; FBG & PPG in glucose‐dependent manner; glucagon secretion; delay GI emptying. ROLE: combo with MF/SU/basal insulin Exenatide BYETTA
250mcg/mL 1.2mL pre‐filled pen 2.4mL pre‐filled pen 5mcg SC BID P L 1 hr before two main meals of day, 6 hrs apart BYDUREON U SA only exenatide
extended-release dosage form
2mg cnce WEEKLY SC inj reconstitute dose after 4 wks prn (10mcg SC BID) Liraglutide VICTOZA 0.6mg SC daily 6mg/mL 3mL pre‐filled pen P L ↑ to 1.2mg [as SAXENDA FDA 2014 indication for wt] to ↓GI AE after 1wk (1.8mg SC daily) 5mcg SC BID ac 468 Peak = 2‐3h 10mcg SC BID ac 468 Onset: injection sites: abdomen, A1C seen with thigh, upper arm in 3‐4 months Each 1.2mL pre‐filled pen provides: (if not, stop) 60 doses x 5mcg Each 2.4mL pre‐filled pen provides: 60 doses x 10mcg Stable x 30 days once pen in use 0.6mg SC daily 1.2mg SC daily 1.8mg SC daily 747
826
[injection sites: abdomen, thigh, upper arm] Each pre‐filled pen provides: 30 doses x 0.6mg or 15 doses x Peak =8‐12h 1.2mg or 10 doses x 1.8mg. Stable x 30 days once pen in use.
Dur=24h ‐ ‐ ‐ 1.5‐
2.8kg 0.9‐
1.5 CI: hx/family hx medullary thyroid carcinomaMTC; multiple endocrine neoplasia syndrome type 2MEN2
‐/+
0.8‐
1.4 ‐ ‐ ‐ minimal experience potential gastric‐emptying so CAUTION with agents requiring rapid GI absorption or narrow therapeutic index space apart by ≥ 1 hr before or 4 hrs after exenatide (e.g. antibiotics, OCPs) AE: headache, dizziness; less hypoglycemiabut with SU, insulin GI: N&V, diarrhea, dyspepsia, constipation (dose‐related) start low & titrate after ≥ 4 weeks use Rare: HR, prolonged PR interval, pancreatitis acute CAUTION (see monograph): Mod-severe HF (NYHA class III),
significant hx of cardiac dx, active CV dx < 1 year
?thyroid cancer/thyroid C‐cell tumours in mice & rats (extrapolated from liraglutide data) minimal experience AE: headache; less hypoglycemia (but with SU, insulin) potential for gastric‐
GI: N&V, diarrhea, dyspepsia, constipation (dose‐related) caution emptying DIs (risk may start low & titrate ≥ q week be less than with exenatide) Rare: HR 2‐4 bpm, prolonged PR interval, pancreatitis n=7
Thyroid cancer/thyroid C‐cell tumours (in mice & rats ) 2.8kg If >3 missed doses: restart at 0.6mg daily and titrate (FDA) albiglutide TANZEUM USA’14: 30,50mg once/wk SC GLP-1 agonist powder: store in fridge, stable room temp x 4wk T2DM mono or + MF/SU/PIO/Insulin; AE: N/D, hypersensitivity; concern rodent thyroid C-cell tumors. pramlintide SYMLIN not CDN amylinomimetic; 15-60-120ug SC TID ac; AE: wt & N/V.
dulaglutide TRULICITY USA Sept/14 : 0.75-1.5mg once weekly SC injectable store in fridge, stable room temp x 14day GLP-1 agonist for Type 2 diabetes (mono tx or with metformin/SU/TZD/insulin ; AE: nausea, diarrhea, vomiting, abd pain, ↓appetite, wt , inj site reactions; concern thyroid cancer in rodents. Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors: renal glucose resorption; renal threshold for glucose; insulin‐independent urinary glucose excretion; ROLE: combo with MF/2nd‐line agents/insulin (official indications: combo w/ MF, SU, or both cana‐ & dapa‐ gliflozin, or MF & pioglitazonecanagliflozin, or combo with insulin; not studied in combination w/DPP‐4 inhibitor or incretin mimetic). Long‐term benefit vs risk unknown! 100mg po daily st
with 1 meal of INVOKANA P L
day 100, 300mg tab INVOKAMET (USA only) (300mg po daily) Canagliflozin/Metformin 50 & 150/500 mg; Canagliflozin approved 2014 50 & 150/1000 mg tab Dapagliflozin FORXIGA CDN/Europe
USA
5mg po daily in / FARXIGA AM 5, 10mg tab (10mg po daily) (available in Canada Feb’15) XIGDUO XR (USA only): Dapagliflozin/Metformin 5 & 10/500mg 5 & 10/1000mg 298
100mg po daily 300mg po daily 298 Peak =1‐2h Dur =24h reduced efficacy at O: Near max FPG eGFR <60mL/min @ 6 wks; max CI: eGFR <45mL/min
A1C @3‐6 mos. Combo bid 5mg po daily in AM 10mg po daily in AM CI: eGFR <60mL/min Combo daily 316 Peak =2‐3h 316 Dur =24h FPG,wt @1wk
A1C @4 wks, & max @ 6 mos.
0.7 (0.6‐0.8)
Dose‐
related 0.11‐
0.21 mmol/L Dose‐
related ‐/ 0.5 (0.4‐
0.6) ‐/ ‐/ ‐/
4kg CANTATA
‐SU
canagliflozin UGT 1A9/2B4: UGT1A9/2B4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, St John’s wort) AE: UTI, genital fungal infections (esp ♀), nausea/ constipation, urinary frequency/volume, dizzy/faint/BP diuresis, K+/Mg/PO4, Ca++,BUN/SCr; low hypoglycemia risk if monotx, systolic BP Concerns: CV events stroke in first 30 days of use CANVAS digoxin levels AUC 20%; Older adults: risk of intravascular volume K+: ACEI/ARB, K+‐sparing diuretic (hypotension, postural dizziness, syncope, dehydration) hypovolemia/ BP: furosemide dapagliflozin UGT 1A9: mefenamic acid: AUC 51%; Cmax 13% UGT1A9 inhibitor 2‐3kg no dose adjustment req’d hypovolemia/ BP risk with loop diuretic Minimal experience. Long‐term safety unknown! AE: UTI, genital fungal infections (esp ♀), nausea/constipation, urinary frequency/volume, dizzy/faint/BP diuresis, PO4/Mg, BUN/SCr; low hypoglycemia risk if monotx, systolic BP Concerns: liver injury?; fracture risk in moderate renal impairment?; prostate Ca?; bladder Ca?: (10/6045 vs 1/3512 placebo
); breast Ca?: (9/4287 vs. 0/1941 placebo) empagliflozin JARDIANCE USA Aug’14 : 10-25mg tabs daily in am ; SGLT-2 Θ Type 2 diabetes AE: UTI, genital fungal infection (esp ♀), nausea/ constipation, urinary frequency/volume, dizzy/faint/BP diuresis, K+/Mg/PO4/LDL/Hct/BUN/SCr,Ca++; low hypoglycemia risk if monotx,BP systolic = dose for renal dysfx =scored tab $=total cost in SK; = Exception Drug Status in SK = Non‐formulary in SK = prior approval for NIHB = not covered by NIHB = covered by NIHB; ‘+’ denotes combo options; A1C = glycosolated Hemoglobin (reflects glycemic control over prior 8‐10 weeks) BP= blood pressure DOC= drug of choice dysfx= dysfunction EtOH= alcohol FBG= fasting blood glucose GI= gastrointestinal HA= headache HDL= high density lipoprotein HF= heart failure HR= heart rate Ins.= Insulin KINETICS: O=onset P=peak D=duration; LDL=low density lipoprotein PPG=postprandial BG Wt=weight Cancer associations, observational data: MF: breast & prostate Ca, Ca overall; Other agents?: (e.g. incretin/GLP‐1 based tx) pancreatic/thyroid Ca; PIO: ? bladder Ca.
38
Extras – RxFiles.ca – Oral Hypoglycemics Hypoglycemics & Sulfa Allergy Articles: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1783707/?tool=pubmed Pharmacist’s Letter document (Canadian Pharmacist's Letter 2010; 26(6):260601). Summary & Overview: Warnings don’t always correspond with available evidence; there is little information to suggest cross‐
sensitivity among the different sulfa chemical classes, however, those who have experienced a previous allergic reaction (to any drug) are more likely to experience a subsequent allergic reaction (to a related or unrelated drug) Specific drugs Chlorpropamide (Diabinese) (Apo‐Chlorpropamide ‐ Canada) ‐ no warning Gliclazide (Diamicron) – Warning‐ (Contraindicated‐Health Canada) Glimepiride (Amaryl)‐ Warning‐ (Contraindicated‐Health Canada) Glipizide (Glucotrol)‐ no warning Glyburide (DiaBeta, others) ‐ Warning (Contraindicated‐Health Canada) Tolbutamide (Orinase) (Apo‐Tolbutamide ‐ Canada) ‐ Warning One case report of contact dermatitis with tolbutamide in a patient with sensitivity to sulfanilamide vaginal cream.
After discontinuation of tolbutamide, therapy was changed to chlorpropamide, which was tolerated without difficulty.
Another case report describes an allergic reaction to glyburide in a patient with a known allergy to sulfamethoxazole.
New Agents – Safety concerns awaiting trials Canagliflozin: ?CV risk: awaiting results of CANVAS (RCT, n~4500, T2DM at high risk of CVD; canagliflozin 100mg vs. 300mg vs. placebo; completion 2018) Dapagliflozin: ?CV risk: awaiting results of DECLARE (RCT, n~17,000 T2DM; CV events with dapagliflozin added to existing tx; completion 2019) Rosiglitazone: link to Health Canada's warning: http://www.healthycanadians.gc.ca/recall‐alert‐rappel‐avis/hc‐sc/2010/14591a‐eng.php
(This also contains the link to GSK's consent form to be completed RE patient approval.)
DC’d
Glimepiride/rosiglitazone AVANDARYL
(1,2,4/4mg tabs) daily with a meal ($325)
D/C 2011
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28 Treatment Guidelines: Drugs for Type 2 Diabetes. The Medical Letter: September, 2002; (1) pp. 1-6. Updated Aug 2011 & Updated Mar 2014.
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30 Canadian 2003 Diabetes Guidelines http://www.diabetes.ca/cpg2003/download.aspx
Canadian 2008 Guidelines (Sept 2008): http://www.diabetes.ca/files/cpg2008/cpg-2008.pdf
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31 Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005 Jan 18;172(2):213-26.
32 Krentz AJ, Bailey CJ. Oral antidiabetic agents : current role in type 2 diabetes mellitus. Drugs. 2005;65(3):385-411.
33 Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002 Jul 2;137(1):25-33.
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34 Lalau JD and Race JM. Metformin and lactic acidosis in diabetic humans. Diabetes, Obesity and Metabolism 2000;2:131-137.
35 Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403
(Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003 Apr;26(4):977-80. The primary analysis of the DPP demonstrated that
metformin decreased the risk of diabetes by 31%. The washout study shows that 26% of this effect can be accounted for by a pharmacological effect of metformin that did not persist when the drug was stopped. After the washout the incidence of diabetes was still reduced by 25%.) (Eddy DM, Schlessinger L, Kahn R. Clinical outcomes and costeffectiveness of strategies for managing people at high risk for diabetes. Ann Intern Med. 2005 Aug 16;143(4):251-64. Summary for patients in: Ann Intern Med. 2005 Aug 16;143(4):I22.) (Lindstrom J, et al. Finnish Diabetes Prevention Study Group. (FDPS) Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of
the Finnish Diabetes Prevention Study. Lancet. 2006 Nov 11;368(9548):1673-9. (InfoPOEMs: Diet and exercise are effective in delaying the diagnosis of diabetes in patients at increased risk. (LOE = 2b)) )
Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009 Nov
14;374(9702):1677-86.
36 Polycystic Ovary Syndrome (PCOS)Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 MarApr;11(2):125-34. http://www.aace.com/clin/guidelines/PCOSpositionstatement.pdf (Moll E, et al. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly
diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006 Jun 13; Epub ahead of print. Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women
with polycystic ovary syndrome.)( De Leo V, Musacchio MC, Morgante G, Piomboni P, Petraglia F. Metformin treatment is effective in obese teenage girls with PCOS. Hum Reprod. 2006 Jun 19; [Epub ahead of print] ) (Legro RS,
Barnhart HX, Schlaff WD, et al. Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66. Clomiphene is superior
to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. InfoPOEMs: Clomiphene is more effective than metformin for enhancing fertility in women with polycystic ovary syndrome (PCOS). This study did not find that the combination of clomiphene and metformin was more effective than clomiphene alone. (LOE = 1b) )
Legro RS, Zaino RJ, Demers LM, Kunselman AR, Gnatuk CL, Williams NI, Dodson WC. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. Am J Obstet Gynecol. 2007
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Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008 Jan 3;358(1):47-54.
Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev.
2010 Jan 20;(1):CD003053.
Vause TD, Cheung AP, Sierra S, Claman P, Graham J, Guillemin JA, Lapensée L, Steward S, Wong BC. Ovulation induction in polycystic ovary syndrome. J Obstet Gynaecol Can. 2010 May;32(5):495-502. Ovulation Induction in
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Vanky E, Stridsklev S, Heimstad R, et al. Metformin Versus Placebo from First Trimester to Delivery in Polycystic Ovary Syndrome: A Randomized, Controlled Multicenter Study. J Clin Endocrinol Metab. 2010 Oct 6.
Wilson Jennifer F.. In the Clinic: The Polycystic Ovary Syndrome. Ann Intern Med February 1, 2011 154:ITC2-1.
Roos N, Kieler H, Sahlin L, Ekman-Ordeberg G, Falconer H, Stephansson O. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study. BMJ 2011;343:d6309.
Ganie MA, Khurana ML, Nisar S, et al. Improved Efficacy of Low-Dose Spironolactone and Metformin Combination Than Either Drug Alone in the Management of Women With Polycystic Ovary Syndrome (PCOS):
A Six-Month, Open-Label Randomized Study. J Clin Endocrinol Metab. 2013 Sep;98(9):3599-607.
Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2013 Oct 22.
37 Graal MB, Wolffenbuttel HR. The use of sulphonylureas in the elderly. Drugs and Aging 1999;15(6):471-81.
38 Dills DG, Schneider J. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Glimepiride/Glyburide Research Group. Horm Metab Res. 1996 Sep;28(9):426-9.
39 Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev. 2001 Nov-Dec;17(6):467-73.
40 Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2003 Nov;26(11):2983-9.
41 Nesto RW, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004 Jan;27(1):256-63.
(Pharmacist’s Letter Sept 2006. The use of Glitazones in persons with congestive heart failure) (see also DREAM & PROACTIVE trial results) (Singh S, Loke YK, Furberg CD. Thiazolidinediones and Heart Failure: A Teleo-Analysis.
Diabetes Care. 2007 May 29; [Epub ahead of print] Our teleo-analysis confirms the increased magnitude of the risk of heart failure with thiazolidinediones. We estimate the Number-Needed-to-Harm with thiazolidinediones to be around
50 over 2.2 years.) (Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials. Lancet. 2007
Sep 29;370(9593):1129-36. Congestive heart failure in patients given TZDs might not carry the risk that is usually associated with congestive heart failure which is caused by progressive systolic or diastolic dysfunction of the left
ventricle. Longer follow-up and better characterisation of such patients is needed to determine the effect of TZDs on overall cardiovascular outcome.)
Winkelmayer WC, Setoguchi S, Levin R, Solomon DH. Comparison of Cardiovascular Outcomes in Elderly Patients With Diabetes Who Initiated Rosiglitazone vs Pioglitazone Therapy. Arch Intern Med. 2008 Nov 24;168(21):2368-75.
Our findings from a large population-based cohort of US seniors are compatible with an increased risk of all-cause mortality and congestive heart failure in patients initiating therapy with rosiglitazone compared with similar patients
initiating therapy with pioglitazone.
42 Gegick C, Altheimer M. Comparison of effect of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice. Endocr Pract 2001;7:162-169.
43 Blickle J. Thiazolidinediones: donnees cliniques et perspectives (French language). Diabetes Metab 2001;27:279-285.
44 Phillips LS, Grunberger G, Miller E, Patwardhan R, et al.. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care. 2001 Feb;24(2):308-15.
45 Lebovitz HE, Dole JF, Patwardhan R, et al. Rosiglitazone monothreapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86:280-8.
46 Chiquette E, Ramirez G, Defronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med. 2004 Oct 25;164(19):2097-104.
47 Yki-Jarvinen Hannele, Drug Therapy: Thiazolidinediones. N Engl J Med 2004;351:1106-18.
48 Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005 Jul;28(7):1547-54.
49 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the
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Bowker SL, et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006 Feb;29(2):254-8. (InfoPOEMs: Death due to cancer seems to be more prevalent in patients with type 2 diabetes treated with either
insulin or a sulfonylurea than in patients treated with metformin (Glucophage). It may be that hyperinsulinemia increases cancer risk, or that metformin is protective. Another explanation could be that, although cancer is related to certain medication use, it is not caused by their use. We need a controlled study to answer these
questions. (LOE = 2b) )
Bressler NM, Beck RW, Ferris FL 3rd. Panretinal photocoagulation for proliferative diabetic retinopathy. N Engl J Med. 2011 Oct 20;365(16):1520-6.
Bressler NM, Varma R, Doan QV, et al. Underuse of the health care system by persons with diabetes mellitus and diabetic macular edema in the United States. JAMA Ophthalmol. 2014;132(2):168-173.
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Buchleitner AM, Martínez-Alonso M, Hernández M, Solà I, Mauricio D. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007315. The included trials did not demonstrate significant differences for most of the
outcomes when targeting intensive perioperative glycaemic control compared with conventional glycaemic control in patients with diabetes mellitus. However, posthoc analysis indicated that intensive glycaemic control was associated with an increased number of patients experiencing hypoglycaemic episodes.
Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med. 2009 Feb;26(2):142-8. This meta-analysis found no evidence to support the contention that diabetes alone is a coronary
heart disease (CHD) risk equivalent to a history of prior myocardial infarction (MI). The blanket use of aspirin and statins for patients with type 2 diabetes, regardless of their lipid levels, is not supported by the evidence. (LOE = 2a)
Burant CF, Viswanathan P, Marcinak J, et al. TAK-875 (FFAR1) versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2012; online Feb 27.
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Buse JB et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009 Jul 4; 374:39.
Buse JB, Drucker DJ, Taylor KL, et al. for the DURATION-1 Study Group. DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks. Diabetes Care. 2010 Mar 9.
Buse JB, Sesti G, Schmidt WE, et al. for the Liraglutide Effect and Action in Diabetes (LEAD)-6 Study Group. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2
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Callahan Alfred; Amarenco Pierre; Goldstein Larry B.; et al. for the SPARCL Investigators. Risk of Stroke and Cardiovascular Events After Ischemic Stroke or Transient Ischemic Attack in Patients With Type 2 Diabetes or Metabolic
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Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database of Systematic Reviews 2012, Issue 6. Art. No.: CD007543. According to high-quality evidence, enhanced
glucose control significantly prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in type 1 diabetes mellitus. In type 2 diabetes mellitus, enhanced glucose control reduces the incidence of
clinical neuropathy, although this was not formally statistically significant (P = 0.06). However, enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities. Importantly, enhanced glucose control
significantly increases the risk of severe hypoglycemic episodes, which needs to be taken into account when evaluating its risk/benefit ratio.
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& behavioral modification, improves weight management in obese adolescents. No major safety issues were identified after 1 year, but further follow-up for sustained weight management and safety is important. (LOE = 1b) )
Charbonnel B, et al. Efficacy & safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43.
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Chatterton H, Younger T, Fischer A, Khunti K; on behalf of the Programme Development Group. Risk identification and interventions to prevent type 2 diabetes in adults at high risk: summary of NICE guidance. BMJ. 2012 Jul 12;345:e4624.
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Craig J. Currie, Chris D. Poole, Sara Jenkins-Jones, et al. Mortality After Incident Cancer in People With and Without Type 2 Diabetes: Impact of metformin on survival. Diabetes Care February 2012 35:299-304; published ahead of print Jan 20, 2012.
Creanga AA, Bradley HM, McCormick C, Witkop CT. Use of metformin in polycystic ovary syndrome. Obstet Gynecol 2008;111:959-968. {Info POEMs: Metformin induces ovulation in women with polycystic ovarian syndrome (PCOS). Metformin plus clomiphene induces ovulation and results in early
pregnancy for clomiphene-resistant women. Data are insufficient to determine whether metformin increases live births in women with PCOS. Future studies should compare metformin head-to-head with clomiphene as the primary treatment. (LOE = 1a-)}
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Dailey George. Early and Intensive Therapy for Management of Hyperglycemia and Cardiovascular Risk Factors in Patients With Type 2 Diabetes. Clinical Therapeutics, Volume 33, Issue 6, June 2011
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Danaei G, Finucane MM, Lu Y, et al, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes
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Davis CL, Pollock NK, Waller JL, et al. Exercise dose and diabetes risk in overweight and obese children: a randomized controlled trial. JAMA. 2012 Sep 19;308(11):1103-12.
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9;336(7649):doi:10.1136/bmj.39553.528299.AD. A 6-hour well-constructed educational intervention given to patients with newly diagnosed diabetes was no better than usual care in improving their overall glucose control over 1 year of evaluation. However, the intervention resulted in a greater average weight
loss and prompted more patients to quit smoking, though these results were not the primary goal of the intervention. (LOE = 1b-)
Davies MJ, Chubb BD, Smith IC, et al. Cost-utility analysis of liraglutide compared with sulphonylurea or sitagliptin, all as add-on to metformin monotherapy in Type 2 diabetes mellitus. Diabet Med. 2012 Mar;29(3):313-20.
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de Boer H, et al. Glycaemic control without weight gain in insulin requiring type 2 diabetes: 1-year results of the GAME regimen. Diabetes Obes Metab. 2006 Sep;8(5):517-23. All patients were treated with the GAME regimen, a
combination of glimepiride administered at 20:00 hours for nocturnal glycaemic control, insulin aspart three times daily for meal-related glucose control and metformin.
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Arch Intern Med. 2008 Sep 22;168(17):1867-73. Hyperglycemia is a risk factor for incident hypertension in type 1 diabetes, and intensive insulin therapy reduces the long-term risk of developing hypertension.
de Boer IH.; Rue Tessa C.; Cleary Patricia A.; et al.; for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term Renal Outcomes of Patients With Type 1 Diabetes Mellitus and
Microalbuminuria: An Analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Cohort DCCT/EDIC. Arch Intern Med. 2011;171(5):412-420.
de Boer IH., Rue Tessa C., Hall Yoshio N., et al. Temporal Trends in the Prevalence of Diabetic Kidney Disease in the United States. JAMA. 2011;305(24):2532-2539.doi:10.1001/jama.2011.861.
De Cosmo S, Copetti M, Lamacchia O, et al. Development and Validation of a Predicting Model of All-Cause Mortality in Patients With Type 2 Diabetes Mellitus. Diabetes Care. 2013 May 1.
de Ferranti SD, de Boer IH, Fonseca V, et al. Type 1 Diabetes Mellitus and Cardiovascular Disease: A Scientific Statement From the American Heart Association and American Diabetes Association. Diabetes Care. 2014 Oct;37(10):2843-2863.
DeFronzo RA, Tripathy D, Schwenke DC, et al. for ACT NOW. Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance. N Engl J Med 2011; 364:1104-1115. {progression to T2DM (incidence of 2.1 vs 7.6%/yr; NNT=19/yr) but weight (3.9 vs 0.77kg) & edema (12.9 vs 6.4%)}.
de Goffau MC, Fuentes S, van den Bogert B, et al. Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia. 2014 Jun 15.
de la Hera JM, García-Ruiz JM, Martínez-Camblor P, et al. Real Incidence of Diabetes Mellitus in a Coronary Disease Population. Am J Cardiol. 2012 Nov 17.
de Jager Jolien, Kooy Adriaan, Lehert Philippe et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010;340
de Vathaire F, El-Fayech C, Ben Ayed FF, et al. Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol. 2012 Aug 22.
de Vos CC, Meier K, Zaalberg PB, et al. Spinal cord stimulation in patients with painful diabetic neuropathy: A multicentre randomized clinical trial. Pain. 2014 Aug 29.
de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. (Beacon) N Engl J Med 2013. DOI: 10.1056/NEJMoa1306033.
Deeks ED. Linagliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs. 2012 Sep 10;72(13):1793-824.
Denig P, Schuling J, Haaijer-Ruskamp F, et al. Effects of a patient oriented decision aid for prioritising treatment goals in diabetes: pragmatic randomised controlled trial. BMJ. 2014 Sep 25;349:g5651.
Desai Shrey; Brinker Allen; Swann Joslyn; et al. Sitagliptin-Associated Drug Allergy: Review of Spontaneous Adverse Event Reports Arch Intern Med. 2010;170(13):1169-1171.
Despres, JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia (Rio-Lipids). N Engl J Med 2005;353:2121-34. (Weight loss: 6.7kg at 1yr by repeated-measures method)
Devries JH, Bain SC, Rodbard HW, et al. Sequential Intensification of Metformin Treatment in Type 2 Diabetes With Liraglutide Followed by Randomized Addition of Basal Insulin (detemir) Prompted by A1C Targets. Diabetes Care. 2012 May 18.
Dhatariya K. Should inpatient hyperglycaemia be treated? BMJ. 2013 Jan 17;346:f134.
Dhulkotia JS, Ola B, Fraser R, et al. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis. Am J Obstet Gynecol. 2010 Nov;203(5):457.e1-9.
Diamant M et al. Safety and efficacy of once-weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks. Diabetes Care [Epub ahead of print] 22 February 2012; doi:10.2337/dc11-1233.
Digman C, Klein AK, Pittas AG. Leukopenia and thrombocytopenia caused by thiazolidinediones. Ann Intern Med. 2005 Sep 20;143(6):465-6.
Dipietro L, Gribok A, Stevens MS, et al. Three 15-min Bouts of Moderate Postmeal Walking Significantly Improves 24-h Glycemic Control in Older People at Risk for Impaired Glucose Tolerance. Diabetes Care. 2013 Jun 11.
Dixon JB, le Roux CW, Rubino F, Zimmet P. Bariatric surgery for type 2 diabetes. Lancet. 2012 Jun 8.
Diamant Michaela, Van Gaal Luc, Stranks Stephen, et al., Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial, The Lancet, Volume
375, Issue 9733, 26 June 2010-2 July 2010
DiNicolantonio JJ, O'Keefe JH, Lucan SC. Added Fructose: A Principal Driver of Type 2 Diabetes Mellitus and Its Consequences. Mayo Clin Proc. 2015 Jan 26.
DiPersio JF. Diabetic stem-cell "mobilopathy". N Engl J Med. 2011 Dec 29;365(26):2536-8.
Dixon JB, O'Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008 Jan 23;299(3):316-23. Participants randomized to surgical therapy were more likely to achieve remission
of type 2 diabetes through greater weight loss.
Donin AS, Nightingale CM, Owen CG, et al. Regular Breakfast Consumption and Type 2 Diabetes Risk Markers in 9- to 10-Year-Old Children in the Child Heart and Health Study in England (CHASE): A Cross-Sectional Analysis. PLoS Med. 2014 Sep
2;11(9):e1001703
Donnelly LA, Doney AS, Hattersley AT, Morris AD, Pearson ER. The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes. Diabet Med. 2006 Feb;23(2):128-33.
Donner T, Muñoz M. Update on insulin therapy for type 2 diabetes. J Clin Endocrinol Metab. 2012 May;97(5):1405-13.
Donovan L, Hartling L, Muise M, et al. Screening tests for gestational diabetes: a systematic review for the u.s. Preventive services task force (USPSTF). Ann Intern Med. 2013 Jul 16;159(2):115-22. The OGCT and fasting plasma glucose level (at a threshold
of 4.7 mmol/L [85 mg/dL]) by 24 weeks' gestation are good at identifying women who do not have GDM. The OGCT is better at identifying women who have GDM. The OGCT has not been validated for the IADPSG diagnostic criteria.
Dormandy JA, Charbonnel B, Eckland DJ, et al. PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular
Events): a randomised controlled trial. (PROACIVE) Lancet. 2005 Oct 8;366(9493):1279-89. (Jarvinen H. The PROactive study: some answers, many questions. -more heart failures, weight gain & more edema. Lancet.
2005 Oct 8;366(9493):1241-2. ) INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events. (n=5328 34.5months follow-up,
Pioglitazone vs placebo, primary endpoint not significant, secondary endpoint of composite of all-cause mortality, non-fatal MI & stroke was 11.6 vs 13.6%, more to hospital with heart failure 6 vs 4%, 22% vs 13% edema, weight gain 3.6kg vs 0.4kg decrease) (InfoPOEMs: In patients
with type 2 diabetes and comorbid macrovascular disease, 3 years of intensive diabetes care using pioglitazone did not significantly prevent further complications or mortality compared with placebo. (LOE = 1b) )
Wilcox R, Kupfer S, and Erdmann E. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: Results from Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive 10). Am Heart J 2008;
DOI:10.1016/j.ahj.2007.11.029 In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.
Dormuth CR, Carney G, Carleton B, et al. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009; 169:1395-1402.
Douglas IJ, Evans SJ, Pocock S, Smeeth L. The risk of fractures associated with thiazolidinediones: a self-controlled case-series study. PLoS Med. 2009 Sep;6(9):e1000154. Epub 2009 Sep 29.
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired
fasting glucose: a randomised controlled trial. Lancet. 2006 Sep 23;368(9541):1096-105. Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed
heart failure (p=0.01). (InfoPOEMs: Patients at increased risk of developing diabetes were less likely to develop diabetes if taking rosiglitazone (Avandia) than if given a placebo. We don't know how well rosiglitazone compares with other interventions also known to delay diabetes: diet
and exercise, metformin, or acarbose. We also don't know if clinically relevant outcomes are improved. (LOE = 1b));
(Montori VM, Isley WL, Guyatt GH. Waking up from the DREAM of preventing diabetes with drugs. BMJ. 2007 Apr 28;334(7599):882-4.)
(Nathan DM, Berkwits M. Trials that matter: rosiglitazone, ramipril, and the prevention of type 2 diabetes. Ann Intern Med. 2007 Mar 20;146(6):461-3.)
Drucker DJ, et al. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006 Nov 11;368(9548):1696-705. (eg. exenatide, liraglutide, sitagliptin, vildagliptin)
Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2008 Dec 17. (VADT study) Intensive glucose control in patients with poorly controlled type 2
diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications.
Dumville JC, Deshpande S, O`Meara S, et al. Foam dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2011 Sep 7;9:CD009111. Currently there is no research evidence to suggest that foam wound dressings are more effective in
healing foot ulcers in people with diabetes than other types of dressing however all trials in this field are very small.
Dumville JC, Deshpande S, O`Meara S, et al. Hydrocolloid dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2012 Feb 15;2:CD009099. Currently there is no research evidence to suggest that any type of hydrocolloid wound dressing is
more effective in healing diabetic foot ulcers than other types of dressing.
Dumville JC, Hinchliffe RJ, Cullum N, et al. Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus. Cochrane Database Syst Rev. 2013 Oct 17;10:CD010318. There is some evidence to suggest that negative pressure
wound therapy is more effective in healing post-operative foot wounds and ulcers of the foot in people with DM compared with moist wound dressings. However, these findings are uncertain due to the possible risk of bias in the original studies.
Duncan GE. Prevalence of diabetes and impaired fasting glucose levels among US adolescents: National Health and Nutrition Examination Survey, 1999-2002. Arch Pediatr Adolesc Med. 2006 May;160(5):523-8.
Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014; online July 11.
Dunkler D, Dehghan M, Teo KKet al. Diet and Kidney Disease in High-Risk Individuals With Type 2 Diabetes Mellitus. JAMA Intern Med. 2013 Aug 12.
Dunstan DW, Kingwell BA, Larsen R, et al. Breaking up prolonged sitting reduces postprandial glucose and insulin responses. Diabetes Care. 2012 May;35(5):976-83.
Durso SC. Using clinical guidelines designed for older adults with diabetes mellitus and complex health status. JAMA. 2006 Apr 26;295(16):1935-40.
Eakin EG, Winkler EA, Dunstan DW, et al. Living Well With Diabetes: 24-Month Outcomes From a Randomized Trial of Telephone-Delivered Weight Loss and Physical Activity Intervention to Improve Glycemic Control. Diabetes Care. 2014 Mar 21.
Echouffo-Tcheugui JB, Simmons RK, Prevost AT, et al. Long-term effect of population screening for diabetes on cardiovascular morbidity, self-rated health, and health behavior. Ann Fam Med. 2015 Mar;13(2):149-57.
Eckel RH, et al. Preventing cardiovascular risk and diabetes. A call to action from the American Diabetes Association and the American Heart Association. Circulation 2006; DOI: 10.1161/CIRCULATIONAHA.106.176583. http://www.circulationaha.org
Edelman S, et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care. 2006 Oct;29(10):2189-95.
Edelman SV, Liu R, Johnson J, et al. AUTONOMY: The First Randomized Trial Comparing Two Patient-Driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes. Diabetes Care. 2014 Aug;37(8):2132-40.
Edwards J, Stapley S. Debridement of diabetic foot ulcers. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003556. There is evidence to suggest that hydrogel increases the healing rate of diabetic foot ulcers compared with gauze dressings or standard care and
larval therapy resulted in significantly greater reduction in wound area than hydrogel.
Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. N Engl J Med. 2014 Feb 27;370(9):794-7.
Egi M, Finfer S, Bellomo R. Glycemic control in the ICU. Chest. 2011 Jul;140(1):212-20.
Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005 Mar 24;352(12):1223-36.
Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012 Jul 13;2(4).
Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies (sitagliptin, exenatide). Gastroenterology. 2011 Jul;141(1):150-6.
Elder DA, Herbers PM, Weis T et al. β-cell Dysfunction in Adolescents and Adults with Newly Diagnosed Type 2 Diabetes Mellitus. J Pediatr. 2012 Jan 10.
EMA July/11 The European Medicines Agency (EMA) has reached a decision:pioglitazone (Actos, Takeda), opting to recommend new contraindications & warnings be added to the drug label, noting that there is a small increased risk of bladder cancer.
Emerging Risk Factors Collaboration, Diabetes mellitus, fasting blood glucose concentration, & risk of vascular disease: a collaborative meta-analysis of 102 prospective studies, Lancet, Volume 375, Issue 9733, 26 June 2010-2 July 2010, Pages 2215-2222.
Emerging Risk Factors Collaboration. Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death. N Engl J Med 2011; 364:829-841.
Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014; online Sept 12. http://dx.doi.org/10.1016/S0140-6736(14)61335-0.
Engebretson SP, Hyman LG, Michalowicz BS, et al. The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial. JAMA. 2013 Dec 18;310(23):2523-32
Eskicioglu P, Halas J, Sénéchal M, et al. Peer Mentoring for Type 2 Diabetes Prevention in First Nations Children. Pediatrics. 2014 May 12.
Esposito K., Maiorino M. I., Ciotola M., et al. Effects of a Mediterranean-Style Diet on the Need for Antihyperglycemic Drug Therapy in Patients With Newly Diagnosed Type 2 Diabetes: A Randomized Trial. Ann Intern Med 2009; 306-314.
Esposito K, Maiorino MI, Petrizzo M, et al. The Effects of a Mediterranean Diet on Need for Diabetes Drugs and Remission of Newly Diagnosed Type 2 Diabetes: Follow-up of a Randomized Trial. Diabetes Care. 2014 Apr 10.
Esposito K, Maiorino MI, Petrizzo M, et al. The Effects of a Mediterranean Diet on Need for Diabetes Drugs and Remission of Newly Diagnosed Type 2 Diabetes: Follow-up of a Randomized Trial. Diabetes Care. 2014 Apr 10.
Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005 Oct;28(10):2345-51.
Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 2007 Aug 30; [Epub ahead of print] Metformin was the only
antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies.
Eurich DT, Simpson S, Senthilselvan A, et al. Comparative safety and effectiveness of sitagliptin in patients with type 2 diabetes: retrospective population based cohort study. BMJ. 2013 Apr 25;346:f2267.
Evans JR, Michelessi M, Virgili G. Laser photocoagulation for proliferative diabetic retinopathy. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD011234. DOI: 10.1002/14651858.CD011234.pub2. This review provides evidence that laser photocoagulation is beneficial in
treating proliferative diabetic retinopathy. We judged the evidence to be moderate or low, depending on the outcome. This is partly related to reporting of trials conducted many years ago, after which panretinal photocoagulation has become the mainstay of treatment of proliferative diabetic
retinopathy. Future Cochrane Reviews on variations in the laser treatment protocol are planned. Future research on laser photocoagulation should investigate the combination of laser photocoagulation with newer treatments such as anti-vascular endothelial growth factors (anti- VEGFs).
Even JL, Crosby CG, Song Y, McGirt MJ, Devin CJ. Effects of epidural steroid injections on blood glucose levels in patients with diabetes mellitus. Spine (Phila Pa 1976). 2012 Jan 1;37(1):E46-50.
Evert AB, Boucher JL, Cypress M, et al. Nutrition Therapy Recommendations for the Management of Adults With Diabetes. Diabetes Care. 2013 Oct 9.
Exalto LG, Biessels GJ, Karter AJ, et al. Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: a cohort study. Lancet Diabetes Endocrinol. 2013 Nov;1(3):183-90.
Fagherazzi G, Gusto G, Clavel-Chapelon F, et al. ABO and Rhesus blood groups and risk of type 2 diabetes: evidence from the large E3N cohort study. Diabetologia. 2014 Dec 23.
Farias JM, Tinetti M, Khoury M, et al. Low Testosterone Concentration and Atherosclerotic Disease Markers in Male Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2014 Oct 16
Farmer A, Wade A, Goyder E, et al. Impact of self-monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial. BMJ 2007; DOI: 10.1136/bmj.39247.447431. Evidence is not convincing of an effect
of self monitoring blood glucose, with or without instruction in incorporating findings into self care, in improving glycaemic control compared with usual care in reasonably well controlled non-insulin treated patients with type 2 diabetes. (see also
Pharmacist’s Letter Sept 2007) (Peel E, Douglas M, Lawton J. Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients' perspectives. BMJ. 2007 Sep 8;335(7618):493. Epub 2007 Aug 30.)
O'Kane MJ, Bunting B, Copeland M, Coates VE; on behalf of the ESMON study group. Efficacy of self monitoring of blood glucose in patients with newly diagnosed type 2 diabetes (ESMON study): randomised controlled
trial. BMJ. 2008 Apr 17; [Epub ahead of print] In patients with newly diagnosed type 2 diabetes self monitoring of blood glucose concentration has no effect on glycaemic control but is associated with higher scores on a
depression subscale. Simon J, Gray A, Clarke P, Wade A, Neil A, Farmer A; on behalf of the Diabetes Glycaemic Education and Monitoring Trial Group. Cost effectiveness of self monitoring of blood glucose in patients with
non-insulin treated type 2 diabetes: economic evaluation of data from the DiGEM trial. BMJ. 2008 Apr 17; [Epub ahead of print] Self monitoring of blood glucose with or without additional training in incorporating the results
into self care was associated with higher costs and lower quality of life in patients with non-insulin treated type 2 diabetes. In light of this, and no clinically significant differences in other outcomes, self monitoring of blood
glucose is unlikely to be cost effective in addition to standardised usual care.
Gomes, Tara, Juurlink, David N, Shah, Baiju R, et al. Blood glucose test strips: options to reduce usage. CMAJ 2009 0: cmaj.091017.
Cameron, Chris, Coyle, Doug, Ur, Ehud, Klarenbach, Scott. Cost-effectiveness of self-monitoring of blood glucose in patients with type 2 diabetes mellitus managed without insulin. CMAJ 2009 0: cmaj.090765.
Farmer AJ, Perera R, Ward A, et al. Meta-analysis of individual patient data in randomised trials of self monitoring of blood glucose (SMBG) in people with non-insulin treated type 2 diabetes. BMJ. 2012 Feb 27;344:e486.
Farmer A. Use of HbA1c in the diagnosis of diabetes. BMJ. 2012 Nov 1;345:e7293.
Farid D, Rosenberg E, and Bartlett G. Importance of education in managing type 2 diabetes during Ramadan. Canadian Family Physician 60.6 (2014): 508-510.
Farkouh ME et al. for the FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012 Nov 4; [e-pub ahead of print]. (CABG vs PCI)
Fazeli Farsani S, Souverein PC, et al. Long term trends in oral antidiabetic drug use among children and adolescents in the Netherlands. Br J Clin Pharmacol. 2015 Feb 12.
FDA Aug/09 Patients with diabetes who take therapeutic products containing nonglucose sugars (e.g., peritoneal dialysis solution and some immunoglobulins) can have falsely elevated readings from blood glucose test strips that use glucose dehydrogenase
pyrroloquinoline quinone (GDH-PQQ) technology, according to an FDA public health notification. The strips are in wide use, and we have provided a link to a listing of the affected products. The FDA cites 13 deaths associated with hypoglycemia not
detected by the test strips, which cannot distinguish between lucose and other sugars such as maltose and xylose. Ten patients were receiving icodextrin peritoneal dialysis solution. The FDA advises physicians to avoid using GDH-PQQ test strips in health
care facilities and to rely, instead, on laboratory assays of glucose — especially in patients taking the therapeutic products listed in the alert. Interfering products containing nonglucose sugars include icodextrin peritoneal dialysis solution, certain
immunoglobulins, abatacept (Orencia, Bristol-Myers Squibb), tositumomab (Bexxar, GlaxoSmithKline), and any product containing or metabolized into maltose, galactose, or xylose. Several test strips and associated monitors use GDH-PQQ methodology:
ACCU-CHEK (Roche), FreeStyle (Abbott Diabetes Care), TRUEtest (Home Diagnostics), CoZmonitor blood glucose module (for use with the Deltec Cozmo insulin pump, Smiths Medical MD), and OmniPod insulin management system (Insulet).
FDA Sep/10 & Takeda, conducted a planned analysis of the study data at the five-year mark, and submitted their results to FDA. Overall, there was no statistically significant association between Actos exposure and bladder cancer risk. However, further analyses were
also performed looking at how long patients were on Actos and the total amount of the drug they received during that time. An increased risk of bladder cancer was observed among patients with the longest exposure to Actos, as well as in those exposed to the
highest cumulative dose of Actos. FDA notified healthcare professionals and patients that the Agency is reviewing data from an ongoing, ten-year epidemiological study designed to evaluate whether Actos (pioglitazone) is associated with an increased risk of
bladder cancer.
FDA May/11 Updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. May 18, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm
FDA June/11 Victoza (liraglutide [rDNA origin]) Injection: REMS - Risk of Thyroid C-cell Tumors, Acute Pancreatitis. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258826.htm
FDA June/11 drug safety communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer- use for more than 12 months linked to an increased risk of bladder cancer. http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm
FDA Mar/13 is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics
(glucagonlike peptide-1 (GLP-1) agonists and the DPP-4 inhibitors, or "gliptins). These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes.
FDA Aug/13 Nova Diabetes Care initiated a voluntary recall of 21 lots of the Nova Max Glucose Test Strips distributed both in the USA and outside the continental USA.
Fedewa MV, Gist NH, Evans EM, Dishman RK. Exercise and Insulin Resistance in Youth: A Meta-Analysis. Pediatrics. 2013 Dec 2.
Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010 Oct;33(10):2217-24.
Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med. 2014 Oct 16;371(16):1547-8.
Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA. 2005 Oct 12;294(14):1782-7. CONCLUSIONS: With regard to ESRD, the prognosis of type 1 diabetes has
improved during the past 4 decades. Children diagnosed as having diabetes before age 5 years have the most favorable prognosis. Overall, incidence of ESRD appears to be lower than previously estimated.
Finucane MM, Stevens GA, Cowan MJ. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million
participants. Lancet 2011; DOI: 10.1016/S0140-6736(10)62035-5.
Fitzgerald E, Mathieu S, Ball A. Metformin associated lactic acidosis. BMJ. 2009 Sep 16;339:b3660. doi: 10.1136/bmj.b3660.
Flory JH, Hennessy S. Metformin Use Reduction in Mild to Moderate Renal Impairment: Possible Inappropriate Curbing of Use Based on Food and Drug Administration Contraindications. JAMA Intern Med. 2015 Jan 5.
Fonseca VA, Lavery LA, Thethi TK, et al. Metanx (L-methylfolate, methylcobalamin, and pyridoxal-5`-phosphate) in Type 2 Diabetes with Peripheral Neuropathy: A Randomized Trial. Am J Med. 2012 Dec 5. pii: S0002-9343(12)00586-4.
Fonseca V, McDuffie R, Calles J, et al. Determinants of weight gain in the Action to Control Cardiovascular Risk in Diabetes (Acord) trial.Diabetes Care 2013 .
Fouqueray P, Pirags V, Diamant M, et al. The Efficacy and Safety of Imeglimin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Sitagliptin Monotherapy. Diabetes Care. 2014 Apr 10.
Foushee JA, Goodbar NH, Kelly JL, et al. Cerebrovascular Accident in a High-Risk Patient During the Early Initiation Phase With Canagliflozin. Ann Pharmacother. 2014 Apr 16;48(8):1066-1069.
Franco OH, de Laet C, Peeters A, Jonker J, Mackenbach J, Nusselder W. Effects of physical activity on life expectancy with cardiovascular disease. Arch Intern Med. 2005 Nov 14;165(20):2355-60.
Franciosi M, Lucisano G, Pellegrini F, et al. ROSES Study Group. Role of self-monitoring of blood glucose and intensive education in patients with Type 2 diabetes not receiving insulin. A pilot randomized clinical trial. Diabet Med. 2011 Jul;28(7):789-96.
Franks, Paul W., Hanson, Robert L., Knowler, William C., et al. Childhood Obesity, Other Cardiovascular Risk Factors, and Premature Death. N Engl J Med 2010 362: 485-493.
Frid A, Hirsch L, Gaspar R, et al. Scientific Advisory Board for the Third Injection Technique Workshop. New injection recommendations for patients with diabetes. Diabetes Metab. 2010 Sep;36 Suppl 1:S3-18.
Frei A, Senn O, Chmiel C, et al. Implementation of the Chronic Care Model in Small Medical Practices Improves Cardiovascular Risk But Not Glycemic Control. Diabetes Care. 2014 Feb 10.
Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014 Feb 15.
Fournier JP, Yin H, Yu OH, et al. Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus. CMAJ. 2014 Sep 22.
Fox CS, et al. Trends in the Incidence of Type 2 Diabetes Mellitus From the 1970s to the 1990s. The Framingham Heart Study. Circulation. 2006 Jun 19; [Epub ahead of print]
Fox CS. Weighty Matters: Balancing Weight Gain with Cardiovascular Risk among Patients with Type 1 Diabetes Mellitus on Intensive Insulin Therapy. Circulation. 2013 Jan 15;127(2):157-9.
Franciosi M, Lucisano G, Lapice E, et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One. 2013 Aug 2;8(8):e71583.
Franco M, Bilal U, Urduñez P, et al. Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980-2010: repeated cross sectional surveys and ecological comparison of secular trends. BMJ 2013;346:f1515.
Franks AS, Lee PH, George CM. Pancreatitis: a potential complication of liraglutide? Ann Pharmacother. 2012 Nov;46(11):1547-53.
Frederiksen B, Kroehl M, Lamb MM, et al. Infant Exposures and Development of Type 1 Diabetes Mellitus: The Diabetes Autoimmunity Study in the Young (DAISY). JAMA Pediatr. 2013 Jul 8. These results suggest the safest age to introduce solid foods in
children at increased genetic risk for T1DM is between 4 and 5 months of age. Breastfeeding while introducing new foods may reduce T1DM risk.
Frosch DL, Uy V, Ochoa S, Mangione CM. Evaluation of a behavior support intervention for patients with poorly controlled diabetes [published online October 10, 2011]. Arch Intern Med. doi:10.1001/archinternmed.2011.497.
Fullerton B, Jeitler K, Seitz M, et al. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2014 Feb 14;2:CD009122. Tight blood sugar control reduces the risk of developing microvascular
diabetes complications. The evidence of benefit is mainly from studies in younger patients at early stages of the disease. Benefits need to be weighed against risks including severe hypoglycaemia, and patient training is an important aspect in practice. The effects of tight blood sugar control
seem to become weaker once complications have been manifested. However, further research is needed on this issue. Furthermore, there is a lack of evidence from RCTs on the effects of tight blood sugar control in older patient populations or patients with macrovascular disease. There is
no firm evidence for specific blood glucose targets and treatment goals need to be individualised taking into account age, disease progression, macrovascular risk, as well as the patient's lifestyle and disease management capabilities.
Gallwitz B, Guzman J, Dotta F, et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet 2012; online June 9.
Gallwitz B, Rosenstock J, Rauch J, et al. Two-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomized, double-blind, noninferiority trial. Lancet 2012.
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(Aspartame, acesulfame-K, neotame, saccharin, and sucralose)
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Gellad WF, Zhao X, Thorpe CT, et al. Dual Use of Department of Veterans Affairs and Medicare Benefits and Use of Test Strips in Veterans With Type 2 Diabetes Mellitus. JAMA Intern Med. 2014 Nov 10.
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Geng DF, Jin DM, Wu W, Liang YD, Wang JF. Angiotensin converting enzyme inhibitors for prevention of new-onset type 2 diabetes mellitus: A meta-analysis of 72,128 patients. Int J Cardiol. 2012 Jul 16.
Gerich J, Raskin P, Jean-Louis L, Purkayastha D, Baron MA. PRESERVE-beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin. Diabetes Care. 2005 Sep;28(9):2093-9.
Gerstein HC, Ratner RE, Cannon CP, et al. the APPROACH Study Group. Effect of Rosiglitazone on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. The Assessment
on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History Trial. Circulation. 2010 Mar 1
Gerstein HC, Miller ME, Ismail-Beigi F, et al, for the ACCORD Study Group. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet 2014; online Aug 1.
Gillett M, Royle P, Snaith A, et al. Non-pharmacological interventions to reduce the risk of diabetes in people with impaired glucose regulation: a systematic review and economic evaluation. Health Technol Assess. 2012 Aug;16(33):1-236, iii-iv.
Gillies CL, Abrams KR, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ. 2007 Jan 19; [Epub ahead
of print] Lifestyle and pharmacological interventions reduce the rate of progression to type 2 diabetes in people with impaired glucose tolerance. Lifestyle interventions seem to be at least as effective as drug treatment. (InfoPOEMs: Diet, exercise, or diet and exercise changes, at
least those in study situations, will slow the progression of diabetes by approximately 50% in patients with impaired glucose tolerance. Drug therapy with either oral diabetes drugs or the weight loss drug orlistat (Xenical) will also slow progression. The preventive effect of the drugs is not
maintained when they are stopped, and research has not been conducted for long enough to determine whether diabetes onset is prevented or just delayed. (LOE = 1a) )
Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril. 2006 Sep;86(3):658-63. Epub 2006 Jul 31. On the basis of the limited data available today, there is no evidence
of an increased risk for major malformations when metformin is taken during the first trimester of pregnancy. Large studies are needed to corroborate these preliminary results.
Giovannucci, Edward, Harlan, David M., Archer, Michael C., et al. Diabetes and Cancer: A Consensus Report. CA Cancer J Clin 2010 0: caac.20078.
Glatstein MM, Djokanovic N, Garcia-Bournissen F, Finkelstein Y, Koren G. Use of hypoglycemic drugs during lactation. Can Fam Physician. 2009 Apr;55(4):371-3.
Glueck CJ, Salehi M, Sieve L, Wang P. Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome. J Pediatr. 2006 May;148(5):628-632.
Gokhale M, Buse JB, Gray CL, et al. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes Obes Metab. 2014 Dec;16(12):1247-56.
Goldberg RB, Holman R, Drucker DJ. Clinical decisions. Management of type 2 diabetes. N Engl J Med. 2008 Jan 17;358(3):293-7.
Goldberg R, Temprosa M, Otvos J, et al. Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program. J Clin Endocrinol Metab 2013.
Goldenberg RM, Cheng AYY, Punthakee Z, Clement M. CDA Position statement: use of glycated hemoglobin (A1C) in the diagnosis of type 2 diabetes mellitus in adults. Can J Diabetes 2011;35:247-9.
Goldfine AB, et al. Family history of diabetes is a major determinant of endothelial function. J Am Coll Cardiol. 2006 Jun 20;47(12):2456-61. Epub 2006 May 30.
Goldfine Allison B., Fonseca Vivian, Jablonski Kathleen A., Et al. and for the TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The Effects of Salsalate on Glycemic Control in Patients With
Type 2 Diabetes: A Randomized Trial. Ann Intern Med March 16, 2010
Goldfine AB, Phua EJ, Abrahamson MJ. Glycemic management in patients with coronary artery disease and prediabetes or type 2 diabetes mellitus. Circulation. 2014 Jun 17;129(24):2567-73.
Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA. 1971 Nov;218(9):1400-10.
Gonzalez-Perez A, Schlienger RG, Rodríguez LA. Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. Diabetes Care. 2010 Dec;33(12):2580-5.
Goring S, Hawkins N, Wygant G, et al. Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis. Diabetes Obes Metab. 2013 Nov 14.
Gough SC, Bode B, Woo V, Rodbard HW, et al. NN9068-3697 (DUAL-I) trial investigators. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3,
open-label, randomised, 26-week, treat-to-target trial in insulin-naïve patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014 Nov;2(11):885-93.
Groop PH, Cooper ME, Perkovic V, et al. Linagliptin Lowers Albuminuria on Top of Recommended Standard Treatment in Patients With Type 2 Diabetes and Renal Dysfunction. Diabetes Care. 2013 Sep 11.
Goto A, Arah OA, Goto M, et al. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ. 2013 Jul 29;347:f4533.
Goyder E, Irwig L, Payne N. Should we screen for type 2 diabetes? No. BMJ. 2012 Jul 9;345:e4516.
Greene JA, Riggs KR. Why is there no generic insulin? Historical origins of a modern problem. N Engl J Med. 2015 Mar 19;372(12):1171-5.
Gregg B, Connor CG, Ruedy KJ, et al; Pediatric Diabetes Consortium. Body mass index changes in youth in the first year after type 1 diabetes diagnosis. J Pediatr. 2015 May;166(5):1265-1269.e1.
Gregg EW, Cheng YJ, Saydah S, et al. Trends in death rates among US adults with and without diabetes between 1997 and 2006.Diabetes Care 2012; 35:1252-1257.
Gregg EW, Chen H, Wagenknecht LE, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. (Look Ahead) JAMA. 2012;308(23): 2489-2496.
Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014 Apr 17;370(16):1514-23.
Griebeler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful diabetic neuropathy. An umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med. 2014;161:639-49. doi:10.7326/M14-0511
Griffin SJ, Borch-Johnsen K, Davies MJ, et al. Eff ect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe):a cluster-randomised
trial. Lancet 2011; published online June 25
Grimaldi-Bensouda L, Cameron D, Marty M, et al. Risk of breast cancer by individual insulin use - an international multicenter study. Diabetes Care. 2013 Aug 15.
Gross Jorge L., Kramer Caroline K., Leitão Cristiane B., et al. , for the Diabetes and Endocrinology Meta-analysis Group (DEMA). Effect of Antihyperglycemic Agents Added to Metformin and a Sulfonylurea on Glycemic Control and
Weight Gain in Type 2 Diabetes: A Network Meta-analysis. Ann Intern Med May 17, 2011 154:672-679.
Grøntved A, Rimm EB, Willett WC, et al. A Prospective Study of Weight Training and Risk of Type 2 Diabetes Mellitus in Men. Arch Intern Med. 2012 Aug 6:1-7.
Grøntved A, Pan A, Mekary RA, et al. Muscle-Strengthening and Conditioning Activities and Risk of Type 2 Diabetes: A Prospective Study in Two Cohorts of US Women. PLoS Med. 2014 Jan;11(1):e1001587
Grover SA, Kaouache M, Rempel P, et al. Years of life lost and healthy life-years lost from diabetes and cardiovascular disease in overweight and obese people: a modelling study. Lancet Diabetes Endocrinol. 2014 Dec 4.
Grunberger G, Chang A, Garcia Soria G, et al. Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled
study. Diabet Med. 2012 Oct;29(10):1260-7.
Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006 Mar 21;47(6):1093-100. Epub 2006 Feb 23.
Grundy SM, et al. American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005 Oct 25;112(17):2735-52. Epub 2005 Sep 12. Erratum in: Circulation. 2005 Oct 25;112(17):e297. Circulation. 2005
Oct 25;112(17):e298.
Grøntved A, Hu FB. Television viewing and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a meta-analysis. JAMA. 2011 Jun 15;305(23):2448-55.
Gujral UP, Narayan KM, Pradeepa RG, et al. Comparing Type 2 Diabetes, Prediabetes, and Their Associated Risk Factors in Asian Indians in India and in the U.S.: The CARRS and MASALA Studies. Diabetes Care. 2015 Apr 15.
Gulliford MC, Charlton J, Latinovic R. Risk of Diabetes Associated With Prescribed Glucocorticoids in a Large Population. Diabetes Care. 2006 Dec;29(12):2728-2729. The researchers found that the adjusted odds ratio for diabetes
associated with 3 or more prescriptions for oral glucorticoids was 1.36. Such patients appeared to account for about 2% of incident cases of diabetes.
Gupta AK, Dahlof B, et al. Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes Trial--Blood
Pressure Lowering Arm and the relative influence of antihypertensive medication. (ASCOT) Diabetes Care. 2008 May;31(5):982-8. Epub 2008 Jan 30. Baseline FPG >5 mmol/l, BMI, and use of an atenolol +/- diuretic
regimen were among the major determinants of NOD in hypertensive patients. The model developed from these data allows accurate prediction of NOD among hypertensive subjects.
Habib G, Khazin F, Chernin M. Continuous blood glucose monitoring in a patient with type-2 diabetes treated with intra-articular betamethasone injection at the knee joint. Arthritis Rheum. 2013 Oct 7.
Hackam DG, Quinn RR, Ravani P, et al. Canadian Hypertension Education Program. The 2013 Canadian Hypertension Education Program (CHEP) Recommendations for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment
of Hypertension. Can J Cardiol. 2013 Mar 28.
Haidar A, Legault L, Dallaire M, et al. Glucose-responsive insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial. CMAJ. 2013 Mar 5;185(4):297-305.
Haidar A, Legault L, Messier V, et al. Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled
crossover trial. Lancet Diabetes Endocrinol. 2014 Nov 26.
Haidar A, Legault L, Messier V, et al. Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled
crossover trial. Lancet Diabetes Endocrinol. 2015 Jan;3(1):17-26.
Halperin F, Ding SA, Simonson DC, et al. Roux-en-Y Gastric Bypass Surgery or Lifestyle With Intensive Medical Management in Patients With Type 2 Diabetes: Feasibility and 1-Year Results of a Randomized Clinical Trial. JAMA Surg. 2014 Jun 4.
Handelsman Y, Mechanick JI, Blonde L, et al. AACE Task Force for Developing Diabetes Comprehensive Care Plan. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care
plan. Endocr Pract 2011 Mar-Apr;17(Suppl 2):1-53.
Hansen LJ, Siersma V, Beck-Nielsen H, de Fine Olivarius N. Structured personal care of type 2 diabetes: a 19-year follow-up of the study Diabetes Care in General Practice (DCGP). Diabetologia 2013, online 8 April.
Harder T, Roepke K, Diller N, et al. Birth weight, early weight gain, and subsequent risk of type 1 diabetes: systematic review and meta-analysis. Am J Epidemiol. 2009 Jun 15;169(12):1428-36. Epub 2009 Apr 10. This meta-analysis
indicates that high birth weight and increased early weight gain are risk factors for type 1 diabetes.
Harjutsalo V, Forsblom C, Groop PH. Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study. BMJ. 2011 Sep 8;343:d5364. doi: 10.1136/bmj.d5364.
Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin As Add-on to Metformin Plus Sulfonylurea in Patients With Type 2 Diabetes: A 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013 Aug 20.
Harris DL, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised, double-blind, placebo-controlled trial. Lancet 2013; published online Sept 25.
Hartling L, Dryden DM, Guthrie A, et al. Screening and diagnosing gestational diabetes mellitus. Evid Rep Technol Assess. 2012 Oct; 210:1-327.
Hartling L, Dryden DM, Guthrie A, et al. Benefits and Harms of Treating Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of
Research. Ann Intern Med. 2013 May 28.
HbA1c targets in type 2 diabetes: guidelines and evidence. Drug Ther Bull. 2013 Apr;51(4):42-5.
Health Canada Dec/05 Association of AVANDIA & AVANDAMET with new onset and/or worsening of macular edema http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2005/avandia_avandamet_hpc-cps_e.html
Health Canada Jan/06 & July/07 Association of AVANDIA & 6 reports of parotid gland enlargement http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v16n1_e.html#2
Health Canada Apr/07 is warning consumers from The Hong Kong Department of Health found Lanmei Keili Ji to be adulterated with gliclazide, a hypoglycaemic agent (lowers blood sugar).
Health Canada May/07 is advising consumers not to use Xiaokeshuping Jiangtangning Jiaonang capsules in Hong Kong to contain the undeclared pharmaceutical drugs phenformin, rosiglitazone, and glibenclamide, which may be used in diabetes to lower blood sugar.
Health Canada May& June/07 is advising consumers & health professionals about heart risks with Avandia http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/2007/avandia_pc-cp_3_e.html
Health Canada Sept/07 is advising consumers not to use foreign health products due to concerns about possible side-effects: Jacaranda, Queenmer Fat Loss, Li Da Dai Dai Hua Jiao Nang, J-minus and Jelimel Slimming Capsules. These products are promoted for
weight loss and have been found to be adulterated with the prescription drug sibutramine. Sibutramine is used for treating obesity and should only be taken under the supervision of a health professional. Junyu Jiaonanyihao has been found to contain the
undeclared prescription drugs sibutramine and dexamethasone, as well as phenolphthalein, which is currently prohibited in Canada.. Heng Tong Jiangtangning Jiaonang was found to contain the prohibited drug phenformin, and the prescription drug
glibenclamide (glyburide) which should only be taken under the supervision of a health professional.
Health Canada Nov/07 Rosiglitazone (AVANDIA®) is no longer approved as monotherapy for type 2 diabetes, except when metformin use is contraindicated or not tolerated. Rosiglitazone is no longer approved for use in combination with a sulfonylurea, except when
metformin is contraindicated or not tolerated. Treatment with all rosiglitazone products is now contraindicated in patients with any stage of heart failure (i.e., NYHA Class I, II, III or IV).
Health Canada April/08 warns that Singapore's Health Sciences Authority (HSA) advised the public not to use the product Power 1 Walnut, because it was found to contain the prescription drugs sildenafil and glibenclamide.
Health Canada April/08 is advising consumers not to use The Hong Kong Department of Health advised the public not to use the product Tian Sheng Yi Bao because it was found to contain two pharmaceutical products, glibenclamide and phenformin.
Health Canada June/08 Nangen Zengzhangsu (may also be known as Nangen or Nangeng), Sanbianwan, Jiu Bian Wang, Tian Huang Gu Shen Dan, Zui Xian Dan Gong Shi Zi, and Power Up. The Hong Kong Department of Health has warned consumers not to
use these herbal/proprietary Chinese medicine products promoted for erectile dysfunction because they have been found to contain sildenafil and/or glibenclamide.
Health Canada June/08 Zhong Hua Niu Bian. Zhong Hua Niu Bian is an herbal/proprietary Chinese medicine product promoted for erectile dysfunction. Singapore's Health Sciences Authority has warned against the use of this product because it has been found to
contain sildenafil, glibenclamide, tadalafil and sibutramine
Health Canada Nov/08 is advising consumers not to use foreign health products due to concerns about possible side-effects: The Hong Kong Department of Health warned consumers not to buy or use Lu Quan because it contains
undeclared glibenclamide and sildenafil.
Health Canada Nov/10 AVANDIA®/AVANDAMET®/AVANDARYL® is now indicated only in patients with type 2 diabetes mellitus for whom all other oral antidiabetic agents, in monotherapy or in combination, do not result in
adequate glycemic control or are inappropriate due to contraindications or intolerance. Prior to starting or renewing a prescription for AVANDIA®/AVANDAMET®/ AVANDARYL®, physicians should consider whether a
rosiglitazone-containing product is an appropriate therapeutic choice, and if so: Document the eligibility of patients to meet the above criteria; Counsel each patient on the risks and benefits of AVANDIA®/AVANDAMET®/
AVANDARYL®, including the cardiovascular risks; and Obtain the patient's written informed consent to take the drug.
Health Canada Nov/11 Pancre-Plus The Hong Kong Department of Health warned that this counterfeit Chinese medicine contains an unauthorized drug (phenformin) and a prescription drug (glyburide). Tian Ma Tu Chung Seven Leave
Ginseng, Vall-Boon Tongkat Al, and Pao Ni Kang The Singapore Health Sciences Authority warned that these traditional herbal products contain prescription and over-the-counter drugs (dexamethasone, ketoconazole,
repaglinide, pheniramine, and chlorpheniramine).
Health Canada Apr/12 has recently completed a safety assessment of the available data for rosiglitazone-ACTOS, an oral anti-diabetic drug, and the label was updated to reflect the potential risk of bladder cancer in treated patients.
Health Canada May/12 1. Jin Yu Tang Tai Han Kang Pai Pu Ling Jiao Nang; TangBaoKouFuYiDaoSuJiaoNang; Tangren 365 Kangxunpai sangge huoyisu jiaonang; Tong Ren Xiu Fu Kou Fu Yi Dao Su. The Hong Kong Department of Health warned
that these products contain a combination of prescription drugs (metformin, glibenclamide [also known as glyburide], rosiglitazone, glimepiride, hydrochlorothiazide) and unauthorized drugs (phenolphthalein, phenformin).
Health Canada Jan/13: informing Canadians of a labelling update for all cholesterol-lowering drugs (also known as statins) regarding the risk of increased blood sugar levels and a small increased risk of diabetes among patients already at risk for the disease.
Health Canada Apr/14: San Xiao Ping Tang Jin Qi Jiao Nang: The Hong Kong Department of Health warned consumers not to use this product after it was found to contain phenformin, pioglitazoneand glibenclamide.
HEALTHY Study Group, A School-Based Intervention for Diabetes Risk Reduction. N Engl J Med 2010 0: NEJMoa1001933.
Heianza Y, Hara S, Arase Y, et al. HbA(1c) 5.7-6.4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): a longitudinal cohort study. Lancet. 2011 Jun 24.
Heikes KE, et al. Diabetes Risk Calculator: a simple tool for detecting undiagnosed diabetes and pre-diabetes. Diabetes Care. 2008 May;31(5):1040-5. Epub 2007 Dec 10. The Diabetes Risk Calculator is the only currently available noninvasive screening tool designed
and validated to detect both pre-diabetes and undiagnosed diabetes in the U.S. population.
Heine RJ, Van Gaal LF, Johns D, et al.; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005 Oct 18;143(8):559-69.
Heisler Michele, Vijan Sandeep, Makki Fatima, et al. Diabetes Control With Reciprocal Peer Support Versus Nurse Care Management: A Randomized Trial. Ann Intern Med October 19, 2010 153:507-515.
Helminen O, Aspholm S, Pokka T, et al. HbA1c Predicts Time to Diagnosis of Type 1 Diabetes in Children at Risk. Diabetes. 2015 May;64(5):1719-27.
Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD008143. DOI:
10.1002/14651858.CD008143.pub2. The included trials did not show significant differences for all-cause mortality and cardiovascular mortality when targeting intensive glycaemic control compared with conventional glycaemic control. Targeting intensive glycaemic control reduced
the risk of microvascular complications while increasing the risk of hypoglycaemia. Furthermore, intensive glycaemic control might reduce the risk of non-fatal myocardial infarction in trials exclusively dealing with glycaemic control in usual care settings.
Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ. 2011 Nov 24;343:d6898.
Hemmingsen B, Christensen LL, Wetterslev J, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ. 2012 Apr 19;344:e1771.
Hemmingsen B, Schroll JB, Lund SS, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013 Apr 30;4:CD009008. There is insufficient evidence fromRCTs to support the decision as to whether to initiate sulphonylureamonotherapy.
Data on patientimportant outcomes are lacking.
Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013 Nov 11;11:CD008143. Although we have been able to expand the number of participants by 16%
in this update, we still find paucity of data on outcomes and the bias risk of the trials was mostly considered high. Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differences for all-cause mortality and cardiovascular mortality.
Targeting intensive glycaemic control seemed to reduce the risk of microvascular complications, if we disregard the risks of bias, but increases the risk of hypoglycaemia and serious adverse events.
Hemmingsen B, Schroll JB, Wetterslev J, et al. Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open. 2014 Jul 22;2(3):E162 75.
Heinemann L, Fleming GA, Petrie JR, et al. Insulin pump risks and benefits: a clinical appraisal of pump safety standards, adverse event reporting and research needs. A Joint Statement of the European Association for the Study of Diabetes and the
American Diabetes Association Diabetes Technology Working Group. Diabetologia. 2015 Mar 18.
Henry RR, Mudaliar S, Kanitra L, Woloschak M, Balena R; for the T-Emerge 3 Study Group. Efficacy and Safety of Taspoglutide in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Plus Pioglitazone over 24 Weeks: T-Emerge 3 Trial. J Clin Endocrinol Metab. 2012 Apr 26.
Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012 May;66(5):446-56.
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lentils, nuts, pasta, and briefly boiled rice were emphasised. Breads (including pumpernickel, rye pita, and quinoa and flaxseed) and breakfast cereals (including large-flake oatmeal and oat bran) were emphasised in the lowglycaemic diet. In patients with type 2 diabetes, 6-month treatment with a low-glycemic index diet resulted in moderately lower HbA(1c) levels compared with a high-cereal fiber diet.
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rosiglitazone, 21% with metformin, and 34% with glyburide. Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction
of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone
and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was
associated with more weight gain, edema and fractures than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). An editorialist criticizes the study's
use of fasting glucose rather than glycated hemoglobin to ascertain failure. When looked at from the latter standpoint, he writes, rosiglitazone shows "a clinically less impressive effect. "Given the modest glycemic benefit of rosiglitazone (with the risk of fluid
retention & weight gain) & higher cost (including the need for more statins and diuretics), metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes. (n=4360 median 4yrs) .Feb/07 Health Canada Avandia fracture warning:
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/avandia_hpc-cps_3_e.html & May/07 for Actos http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/actos_hpc-cps_2_e.html
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underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.
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ACEi were found to prevent new onset DKD and death in normoalbuminuric people with diabetes, and could therefore be used in this population. More data are needed to clarify the role of ARB and other drug classes in preventing DKD.
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evidence that SMBG affects patient satisfaction, general well-being or general health-related quality of life. More research is needed to explore the psychological impact of SMBG and its impact on diabetes specific quality of life and well-being, as well as the impact of SMBG on
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Margel D, Urbach DR, Lipscombe LL, et al. Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men With Diabetes. J Clin Oncol. 2013 Sep 1;31(25):3069-3075.
Margolis KL, O`Connor PJ, Morgan TM, et al. Outcomes of Combined Cardiovascular Risk Factor Management Strategies in Type 2 Diabetes: The ACCORD Randomized Trial. Diabetes Care. 2014 Mar 4.
Marshall SM, Flyvbjerg A. Prevention and early detection of vascular complications of diabetes. BMJ. 2006 Sep 2;333(7566):475-80.
Martin J, et al. Cromium Picolinate Supplementation Attenuates Body Weight Gain and Increases Insulin Sensitivity in Subjects With Type 2 Diabetes. Diabetes Care. Volume 29;8: 2006
Maruthur NM, Ma Y, Delahanty LM, et al; for the Diabetes Prevention Program Research Group. Early Response to Preventive Strategies in the Diabetes Prevention Program. J Gen Intern Med. 2013 Jul 17.
Mathieu C, Rodbard HW, Cariou B, et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON). Diabetes Obes Metab. 2014 Jan 20.
Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009 Jul 2;361(1):40-51. Early blockade of the renin-angiotensin system in patients with type 1
diabetes did not slow nephropathy progression but slowed the progression of retinopathy.
Mauras N, Beck R, Xing D, et al. A randomized clinical trial to assess the efficacy and safety of real-time continuous glucose monitoring in the management of type 1 diabetes in young children aged 4 to <10 years. Diabetes Care. 2012 Feb;35(2):204-10.
May AL, Kuklina EV, Yoon PW. Prevalence of Cardiovascular Disease Risk Factors Among US Adolescents, 1999-2008. Pediatrics. 2012 May 21. (14% increase in prediabetes/diabetes)
Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes. (CHICAGO) A randomized trial. JAMA 2006; 298:doi:10.1001/jama.296.21.joc60158.
Over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed progression of CIMT compared with glimepiride.
McAllister DA, Hughes KA, Lone N, et al. Stress hyperglycaemia in hospitalised patients and their 3-year risk of diabetes: a Scottish retrospective cohort study. PLoS Med. 2014 Aug 19;11(8):e1001708.
McAuley PA, Artero EG, Sui X, et al. Fitness, fatness, and survival in adults with prediabetes. Diabetes Care. 2014 Feb;37(2):529-36. CRF markedly modifies the relationship between adiposity and mortality in persons with prediabetes. Unfit individuals have a
higher and fit individuals have a lower mortality risk irrespective of adiposity level in this high-risk group.
McBrien K, Rabi DM, Campbell N, et al. Intensive and Standard Blood Pressure Targets in Patients With Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis. Arch Intern Med. 2012 Aug 6:1-8.
McCall KL, Craddock D, Edwards K. Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers on the Rate of New-Onset Diabetes Mellitus: A Review and Pooled Analysis. Pharmacotherapy.
2006 Sep;26(9):1297-306.
McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet. 2012 Jun 8.
McDonagh MS, Selph S, Ozpinar A, et al. Systematic Review of the Benefits and Risks of Metformin in Treating Obesity in Children Aged 18 Years and Younger. JAMA Pediatr. 2013 Dec 16
McMullan CJ, Schernhammer ES, Rimm EB, et al. Melatonin secretion and the incidence of type 2 diabetes. JAMA. 2013 Apr 3;309(13):1388-96.
McPherson R, Frohlich J, Fodor G, Genest J. Canadian 2006 Cardiovascular Society position statement -- Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol.
2006 Sep;22(11):913-27.
Medical Letter May 23,2005: Pramlintide for Diabetes.
Medical Letter Jan 30,2006: Pioglitazone/Metformin (Actoplus met)
Medical Letter Jan 1,2007: Sitagliptin (Januvia); Medical Letter. Sitagliptin/Metformin (Janumet) for Type 2 Diabetes. June 4,2007.
Medical Letter Jan 29,2007: Pioglitazone/glimepiride (Duetact)
Medical Letter. Liraglutide (Victoza) for Type 2 Diabetes. April 5,2010.
Medical Letter. Continuous Glucose Monitoring. May 2, 2011.
Medical Letter. Canagliflozin (Invokana) for Type 2 Diabetes. May 13, 2013.
Medical Letter. Dapagliflozin (Farxiga) for Type 2 Diabetes. February 17, 2014.
Megia A, Naf S, Herranz L, et al. The usefulness of HbA1c in postpartum reclassification of gestational diabetes. BJOG. 2012 Apr 24.
Melander O, Maisel AS, Almgren P, et al. Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality. JAMA 2012; 308:1469-1475.
Menard J, Payette H, Baillargeon JP, Maheux P, et al. Efficacy of intensive multitherapy for patients with type 2 diabetes mellitus: a randomized controlled trial. CMAJ. 2005 Nov 17; [Epub ahead of print]
Meneilly GS. Diabetes in the elderly. Med Clin North Am. 2006 Sep;90(5):909-23.
Menon V, Lincoff AM. Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus. Circulation. 2014 Jun 24;129(25):2705-13.
Menon V, Aggarwal B. Why are we doing cardiovascular outcome trials in type 2 diabetes? Cleve Clin J Med. 2014 Nov;81(11):665-71.
Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies. Diabetes Obes Metab. 2014 Jan 29.
Mesotten D, Gielen M, Sterken C, et al. Neurocognitive development of children 4 years after critical illness and treatment with tight glucose control: a randomized controlled trial [published online October 17, 2012]. JAMA. doi: 10.1001/jama.201212424.
MHRA Sep/12 There have been reports of acute pancreatitis associated with drugs in the dipeptidylpeptidase-4 (DPP-4) inhibitor class of antidiabetic agents (‘gliptins’).
Middleton P, Crowther CA, Simmonds L. Different intensities of glycaemic control for pregnant women with pre-existing diabetes. Cochrane Database Syst Rev. 2012 Aug 15;8:CD008540. In a very limited body of evidence, few differences in outcomes were seen between very tight and tightmoderate glycaemic control targets in pregnant women with pre-existing type 1 diabetes, including actual glycaemic control achieved. There is evidence of harm (increased pre-eclampsia, caesareans and birthweights greater than 90th centile) for `loose` control (FBG above 7 mmol/L).
Future trials comparing interventions, rather than glycaemic control targets, may be more feasible particularly for pregnant women with type 2 diabetes.
Miller ME, Bonds DE, Gerstein HC, et al. ACCORD Investigators. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD
study. BMJ. 2010 Jan 8;340:b5444. doi: 10.1136/bmj.b5444.
Miller ME, Williamson JD, Gerstein HC, et al.; ACCORD Investigators. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial. Diabetes Care 2014;37:634–43.
Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012. DOI: 10.1056/NEJMoa1200111.
Mitanchez D, Burguet A, Simeoni U. Infants Born to Mothers with Gestational Diabetes Mellitus: Mild Neonatal Effects, a Long-term Threat to Global Health. J Pediatr. 2013 Dec 10
Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care. 2011 Nov;34(11):2474-6. (May reduce fractures)
Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013 Jul 9.
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract 2009;15:1-17.
Moghissi ES, Korytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus
statement on inpatient glycemic control. Diabetes Care. 2009 Jun;32(6):1119-31. Epub 2009 May 8.
Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA. 2007 Aug 22;298(8):902-16.
Moin T, Li J, Duru OK, et al. Metformin prescription for insured adults with prediabetes from 2010 to 2012: a retrospective cohort study. Ann Intern Med. 2015 Apr 21;162(8):542-8.
Moll E, et al. Effect of clomifene citrate plus metformin & clomifene plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006 Jun 24;332(7556):1485. Epub 2006 Jun 12.
Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Obstet Gynecol. 2010 Jan;115(1):55-9.
Monami M, et al. Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes Metab Res Rev. 2006 Apr 24; [Epub ahead of print]
Monami M, Colombi C, Balzi D, et al. Metformin and Cancer Occurrence in Insulin-treated type 2 diabetic patients. Diabetes Care. 2010 Oct 27. [Epub ahead of print]
Monami M, Lamanna C, Desideri CM, Mannucci E. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther. 2012 Jan;29(1):14-25.
Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013 Apr 17.
Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16:457-466
Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013 Dec 5.
Montori VM, Fernández-Balsells M. Glycemic Control in Type 2 Diabetes: Time for an Evidence-Based About-Face?. Ann Intern Med. 2009 Apr 20.
Moore EM, Mander AG, Ames D, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013 Oct;36(10):2981-7.
Moran A, Brundy B, Becker DJ, et al. Interleukin-1 antagonism (canakinumab & anakinra) in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 2013; online April 5.
Moreland EC, et al. Use of a blood glucose monitoring manual to enhance monitoring adherence in adults with diabetes: a randomized controlled trial. Arch Intern Med. 2006 Mar 27;166(6):689-95.
Moreno-Castilla C, Hernandez M, Bergua M, et al. Low-Carbohydrate Diet for the Treatment of Gestational Diabetes: A randomized controlled trial. Diabetes Care. 2013 Apr 5.
Morey MC, Pieper CF, Edelman DE, et al. Enhanced fitness: a randomized controlled trial of the effects of home-based physical activity counseling on glycemic control in older adults with prediabetes mellitus. J Am Geriatr Soc. 2012 Sep;60(9):1655-62.
Morgan CL, Poole CD, Evans M, et al. What Next after Metformin? A Retrospective Evaluation of the Outcome of Second-Line, Glucose-Lowering Therapies in People with Type 2 Diabetes. J Clin Endocrinol Metab. 2012 Oct 17.
Morrison JA, Glueck CJ, Horn PS, et al. Childhood predictors of adult type 2 diabetes at 9- and 26-year follow-ups. Arch Pediatr Adolesc Med. 2010 Jan;164(1):53-60.
Morrison F, Shubina M, Turchin A. Encounter frequency and serum glucose level, blood pressure, and cholesterol level control in patients with diabetes mellitus. Arch Intern Med. 2011;171(17):1542-1550.
Moyer VA. Screening for Gestational Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2014 Jan 14
Mozaffarian D, Kamineni A, Prineas RJ, Siscovick DS. Metabolic syndrome and mortality in older adults: the Cardiovascular Health Study. Arch Intern Med. 2008 May 12;168(9):969-78. These findings suggest limited utility of MetS for predicting
total or CVD mortality in older adults compared with assessment of fasting glucose and blood pressure alone.
Mullan Rebecca J.; Montori Victor M.; Shah Nilay D.; et al. The Diabetes Mellitus Medication Choice Decision Aid: A Randomized Trial. Arch Intern Med. 2009;169(17):1560-1568.
Muraki I, Imamura F, Manson JE, et al. Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies. BMJ. 2013 Aug 28;347:f5001.
Murphy HR, Rayman G, Lewis K, et al. Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ. 2008 Sep 25;337:a1680. doi: 10.1136/bmj.a1680.
Continuous glucose monitoring during pregnancy is associated with improved glycaemic control in the third trimester, lower birth weight, and reduced risk of macrosomia.
Murphy CE. Review of the safety and efficacy of exenatide once weekly for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2012 Jun;46(6):812-21.
Nahas R, Moher M. Complementary and alternative medicine for the treatment of type 2 diabetes. Can Fam Physician. 2009 Jun;55(6):591-6. Chromium, and possibly gymnema, appears to improve glycemic control. Fibre, green tea, and fenugreek have other benefits but there is
little evidence that they substantially improve glycemic control. Further research on bitter melon and cinnamon is warranted. There is no complementary and alternative medicine research addressing microvascular or macrovascular clinical outcomes.
Naik Aanand D.; Palmer Nynikka; Petersen Nancy J.; et al. Comparative Effectiveness of Goal Setting in Diabetes Mellitus Group Clinics: Randomized Clinical Trial. Arch Intern Med. 2011;171(5):453-459.
Nansel TR, Iannotti RJ, Liu A. Clinic-integrated behavioral intervention for families of youth with type 1 diabetes: randomized clinical trial. Pediatrics. 2012 Apr;129(4):e866-73.
Nathan DM, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association
for the Study of Diabetes. Diabetes Care. 2006 Aug;29(8):1963-72.
Nathan DM, et al.; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
N Engl J Med. 2005 Dec 22;353(25):2643-53. (InfoPOEMs: This extension of the Diabetes Control and Complications Trial (DCCT) trial provides the first high-quality evidence that intensive treatment of Type 1 diabetes reduces the risk of adverse cardiovascular outcomes.
Although the relative risk reduction was greater than 50%, the absolute risk reduction (0.42 per 100 patient years; NNT=25 over 10years) was modest. Note that this effect has not been shown in patients with Type 2 diabetes, although many patients and physicians believe otherwise,
and data regarding all-cause mortality or adverse effects of intensive treatment (such as hypoglycemic episodes or traffic accidents) are not reported.. (LOE = 1b) ) Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)
Research Group. Modern-Day Clinical Course of Type 1 Diabetes Mellitus After 30 Years' Duration: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (19832005). Arch Intern Med. 2009;169(14):1307-1316.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy : A consensus statement from the American
Diabetes Association (ADA) and the European Association for the Study of Diabetes. Diabetologia. 2008 Oct 22. http://care.diabetesjournals.org/misc/MedicalManagementofHyperglycemia.pdf
Nau KC. Lorenzetti RC, Cucuzzela M et al. Glycemic control in Hospitalized Patents not in Intensive Care: Beyond Sliding Scale. American Family Pysician. May 1, 2010.
Nauck MA. A Critical Analysis of the Clinical Use of Incretin-Based Therapies: The benefits by far outweigh the potential risks. Diabetes Care. 2013 May 6.
Nauck M, Weinstock RS, Umpierrez GE, et al. Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5). Diabetes Care. 2014 Apr 17.
Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol. 2015 Jan;26(1):220-9.
NAVIGATOR Study Group, Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events. N Engl J Med 2010 0: NEJMoa1001122.
NAVIGATOR Study Group, Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events. N Engl J Med 2010 0: NEJMoa1001121.
Neugebauer R, Fireman B, Roy JA, O'Connor PJ. Impact of Specific Glucose-Control Strategies on Microvascular and Macrovascular Outcomes in 58,000 Adults With Type 2 Diabetes. Diabetes Care. 2013 Jul 22.
Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia. 2012 Mar 31.
NICE recommends liraglutide for diabetes triple therapy Feb/10 http://www.nice.org.uk/newsroom/news/newsdiabetes.jsp http://www.nice.org.uk/nicemedia/live/13248/51313/51313.pdf
NICE: National Collaborating Centre for Chronic Conditions. Type 2 diabetes. The management of type 2 diabetes. London (UK): National Institute for Health and Clinical Excellence ; 2009 May.
NICE Mar 2011 Clinical Guideline 119. Diabetic foot - inpatient management of people with diabetic foot ulcers and infection. http://www.nice.org.uk/nicemedia/live/13416/53556/53556.pdf
NICE: National Institute for Health and Clinical Excellence. Exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes. London (UK): National Institute for Health and Clinical Excellence
(NICE); 2012 Feb. http://www.nice.org.uk/nicemedia/live/13670/58205/58205.pdf
NICE: National Institute for Health and Clinical Excellence. Preventing type 2 diabetes: risk identification and interventions for individuals at high risk. PHG38. 2012. http://guidance.nice.org.uk/PH38 .
NICE: National Institute for Health and Care Excellence (NICE). Dapagliflozin in combination therapy for treating type 2 diabetes. London (UK): National Institute for Health and Care Excellence (NICE); 2013 Jun.
Nice-Sugar. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367:1108-18.
Nichols GA, et al. Normal fasting plasma glucose and risk of type 2 diabetes diagnosis. Am J Med. 2008 Jun;121(6):519-24. The strong independent association between the level of normal fasting plasma glucose and the incidence of diabetes after controlling for other risk factors
suggests that diabetes risk increases as fasting plasma glucose levels increase, even within the currently accepted normal range.
Nichols GA, Joshua-Gotlib S, Parasuraman S. Independent contribution of A1c, systolic blood pressure, and LDL cholesterol control to risk of cardiovascular disease hospitalizations in type 2 diabetes: An observational cohort study. J Gen Intern Med 2013.
Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and Risks of Oral Diabetes Agents Compared With Insulin in Women With Gestational Diabetes: A Systematic Review. Obstet Gynecol. 2009 Jan;113(1):193-205. No substantial maternal or
neonatal outcome differences were found with the use of glyburide or metformin compared with use of insulin in women with GDM.
Nicklas JM, Zera CA, England LJ, et al. A web-based lifestyle intervention for women with recent gestational diabetes mellitus: a randomized controlled trial. Obstet Gynecol. 2014 Sep;124(3):563-70.
Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol. 2014 Nov;2(11):894-900.
Nielsen RE, Laursen MF, Vernal DL, et al. Risk of diabetes in children and adolescents exposed to antipsychotics: a nationwide 12-year case-control study. J Am Acad Child Adolesc Psychiatry. 2014 Sep;53(9):971-979.e6.
Ning G, Bi Y, Wang T, Xu M, Xu Y, Huang Y, et al. Relationship of urinary bisphenol A concentration to risk for prevalent type 2 diabetes in Chinese adults. A cross-sectional analysis. Ann Intern Med. 2011;155:368-74.
Nissen SE, Wolski K, Topol EJ. Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus JAMA. 2005;294:(doi:10.1001/jama.294.20.joc50147). Oct/05
Nissen SE, Nicholls SJ, Wolski K, et al.;for the PERISCOPE Investigators. Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes: The PERISCOPE Randomized Controlled Trial. JAMA. 2008 Mar
31; [Epub ahead of print] In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride.
Nobis S, Lehr D, Ebert DD, et al. Efficacy of a Web-Based Intervention With Mobile Phone Support in Treating Depressive Symptoms in Adults With Type 1 and Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care. 2015 Feb 20.
Noble D et al. Risk models and scores for type 2 diabetes: systematic review. BMJ. 2011 Nov 28;343:d7163.
Noe A, Howard C, Thuren T, et al. Pharmacokinetic and Pharmacodynamic Characteristics of Single-Dose Canakinumab in Patients With Type 2 Diabetes Mellitus. Clin Ther. 2014 Sep 17.
Nordmann AJ, et al. Effects of low-carbohydrate vs low-fat diets on weight loss & cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Feb 13;166(3):285-93. (InfoPOEMs: People interested in weight loss can choose either a lowfat, reduced calorie diet or a low-carbohydrate, non-calorie-restricted diet to lose a small but sustained amount of weight. The effect on cardiovascular outcomes of either diet are not known, though each has different effects on lipid levels, which may or may not translate into an actual
effect on patient-oriented outcomes that matter. (LOE = 1a) )
Norris SL, Kansagara D, Bougatsos C, Fu R; U.S. Preventive Services Task Force. Screening adults for type 2 diabetes: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2008 Jun 3;148(11):855-68.
Review. Summary for patients in: Ann Intern Med. 2008 Jun 3;148(11):I30. Direct evidence is lacking on the health benefits of detecting type 2 diabetes by either targeted or mass screening, and indirect evidence also fails to demonstrate health benefits for screening
general populations. Persons with hypertension probably benefit from screening, because blood pressure targets for persons with diabetes are lower than those for persons without diabetes. Intensive lifestyle and pharmacotherapeutic interventions reduce the progression of prediabetes
to diabetes, but few data examine the effect of these interventions on long-term health outcomes.
Norwood P, Liutkus JF, Haber H, et al. Safety of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Treated With a Thiazolidinedione Alone or in Combination With Metformin for 2 Years. Clin Ther. 2012 Sep 29.
Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin a1c for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care. 2011 Jun;34(6):1306-11.
NPS – Australia – Sitagliptin / Januvia Review: http://www.nps.org.au/health_professionals/publications/nps_radar/issues/current/august_2008/sitagliptin
Nygren M, Carstensen J, Koch F, et al. Experience of a serious life event increases the risk for childhood type 1 diabetes: the ABIS population-based prospective cohort study. Diabetologia. 2015 Apr 14.
Ockrim Z, Yorston D. Managing diabetic retinopathy. BMJ. 2010 Oct 25;341:c5400. doi: 10.1136/bmj.c5400.
Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the community: The Hisayama Study. Neurology. 2011 Sep 20;77(12):1126-34.
Olansky L. Q: Do incretin drugs for type 2 diabetes increase the risk of acute pancreatitis? Cleve Clin J Med. 2010 Aug;77(8):503-5.
Olausson EA, Störsrud S, Grundin H, et al. A Small Particle Size Diet Reduces Upper Gastrointestinal Symptoms in Patients With Diabetic Gastroparesis: A Randomized Controlled Trial. Am J Gastroenterol. 2014 Jan 14.
Olson DE, Rhee MK, Herrick K, et al. Screening for diabetes and pre-diabetes with proposed A1C-based diagnostic criteria. Diabetes Care. 2010 Oct;33(10):2184-9.
Onady G, Stolfi A. Insulin and oral agents for managing cystic fibrosis-related diabetes. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004730.
Oram RA, McDonald TJ, Shields BM, et al. on behalf of the UNITED Team. Most People With Long-Duration Type 1 Diabetes in a Large Population-Based Study Are Insulin Microsecretors. Diabetes Care. 2014 Dec 17.
Orban T, Bundy B, Becker DJ, et al. the Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial.
Lancet. 2011 Jun 28.
Orchard TJ, et al.; Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005 Apr
19;142(8):611-9 & ACP Journal Club . Summary for patients in: Ann Intern Med. 2005 Apr 19;142(8):I46.
Orchard TJ, Nathan DM, Zinman B, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015 Jan 6;313(1):45-53.
ORIGIN trial investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012.
ORIGIN Trial Investigators. Basal insulin (glargine) and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012 Jun 11
Orozco LJ, Buchleitner AM, Gimenez-Perez G, Roqué i Figuls M, Richter B, Mauricio D. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD003054.
DOI:10.1002/14651858.CD003054.pub3. Interventions aimed at increasing exercise combined with diet are able to decrease the incidence of type 2 diabetes mellitus in high risk groups (people with impaired glucose tolerance or the metabolic syndrome). There is a need for studies
exploring exercise only interventions and studies exploring the effect of exercise and diet on quality of life, morbidity and mortality, with special focus on cardiovascular outcomes.
Oster RT, Johnson JA, Hemmelgarn BR, et al. Recent epidemiologic trends of diabetes mellitus among status Aboriginal adults. CMAJ. 2011 Sep 6;183(12):E803-8.
Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011 Nov;28(11):1352-61.
Padwal RS, Gabr RQ, Sharma AM, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011 Jun;34(6):1295-300.
Paisley A, Yadav R, Younis N, Rao-Balakrishna P, Soran H. Dapagliflozin: a review on efficacy, clinical effectiveness and safety. Expert Opin Investig Drugs. 2013;22(1):131-140.
Pal K, Eastwood SV, Michie S, Farmer AJ, Barnard ML, Peacock R, et al. Computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev2013;3:CD008776. Computer-based diabetes
self- management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control and the effect was larger in the mobile phone subgroup. There is no evidence to show benefits in other biological outcomes or any cognitive, behavioural or
emotional outcomes.
Palomba S, et al. A randomized controlled trial evaluating metformin pre-treatment and co-administration in non-obese insulin-resistant women with polycystic ovary syndrome treated with controlled ovarian stimulation plus timed
intercourse or intrauterine insemination. Hum Reprod. 2005 Jun 15.
Palomba S, Orio F Jr, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate & metformin as the first-line treatment for ovulation induction in nonobese anovulatory
women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005 Jul;90(7):4068-74. (InfoPOEMs: In nonobese women with polycystic ovary syndrome, metformin is more effective than clomiphene for improving the rate of conception. (LOE = 1b) )
Pan A, Schernhammer ES, Sun Q, et al. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLoS Med 2011;8:e1001141.
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vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy. (InfoPOEMs: Perindopril (Aceon) plus indapamide (Lozol) is better than
placebo in decreasing clinically relevant events in patients with type 2 diabetes who are at high risk of cardiovascular complications. Whether the combination is better than other medications -- like aspirin -- isn't addressed by this study. (LOE = 1b) )
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Pharmacist’s Letter May 2006: Byetta (Exenatide) for Weight Loss.
Pharmacist’s Letter July 2006: Sitagliptin (Januvia) and Vildagliptin (Galvus) for Diabetes. (see also Medical Letter Jan 1,2007 Sitagliptin) (see also Vildagliptin. Emerging Drug List CADTH Nov/06;
(FDA:concern of skin toxicity in primates http://cws.huginonline.com/N/134323/PR/200611/1087811_5_2.html )
Pharmacist’s Letter: Treatment of type 2 diabetes mellitus. Nov 2006
Pharmacist’s Letter. Treatment of Diabetes in women who are pregnant. Sept 2007.
Pharmacist’s Letter. Metformin-Induced Vitamin B12 Deficiency: Can it Lead to Peripheral Neuropathy? Aug,2009.
Pharmacist’s Letter. Fasting in the Patient with Diabetes. July 2011.
Pharmacist’s Letter. Comparison of GLP-1 Agonists (Bydureon, Byetta, and Victoza). March 2012.
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trial. JAMA. 2006 Feb 15;295(7):761-75. (InfoPOEMs: Rimonabant (Acomplia) is minimally effective for obese or overweight patients for achieving sustained weight loss. Less than half the subjects initially enrolled in this study completed the protocol at 1 year. Of those
remaining in the study, only one fourth lost a clinically significant amount of weight (10% or more) and, as with other weight-loss drugs, the patients who stopped taking the medicine after 1 year regained the weight. (LOE = 1b-) )
Pierce SA, Chung AH, Black KK. Evaluation of vitamin B12 monitoring in a veteran population on long-term, high-dose metformin therapy. Ann Pharmacother. 2012 Nov;46(11):1470-6.
Plosker G. Dapagliflozin: A Review of its Use in Type 2 Diabetes Mellitus. Drugs. 2012;72(17):2289-2312.
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Polonsky KS. The past 200 years in diabetes. N Engl J Med. 2012 Oct 4;367(14):1332-40.
Porepa, Liane, Ray, Joel G, Sanchez-Romeu, Paula, Booth, Gillian L. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. CMAJ 2010 0: cmaj.092144.
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 2011; 305:2556-2564. (New onset diabetes NNH=498, Cardiovascular events NNT=155 per year)
Pratley RE, Nauck M, Bailey T, et al. for 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallelgroup, open-label trial. Lancet. 2010 Apr 24;375(9724):1447-1456.
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Puar TH, Khoo JJ, Cho LW, Xu Y, Chen YT, Chuo AM, Poh CB, Ng JM. Association between glycemic control and hip fracture. J Am Geriatr Soc. 2012 Aug;60(8):1493-7.
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of Physicians. Ann Intern Med. 2012 Feb 7;156(3):218-231.
Qaseem A, Chou R, Humphrey LL, Shekelle P; for the Clinical Guidelines Committee of the American College of Physicians. Inpatient Glycemic Control: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians.
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Ramachandran A, Riddle MC, et al. Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial. Diabetes Care. 2012 Apr;35(4):749-53.
Ranc K, Jørgensen ME, Friis S, et al. Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment. Diabetologia. 2014 Mar 15.
Rascati KL et al. Progression to insulin for patients with diabetes mellitus using the Texas medicaid database. Clin Ther. 2011 Dec;33(12):2016-20. (slower progression with metformin/TZD than sulfonylurea/TZD)
Rawlings AM, Sharrett AR, Schneider AL, et al. Diabetes in midlife and cognitive change over 20 years: a cohort study. Ann Intern Med. 2014 Dec 2;161(11):785-93.
Ray JG, et al. Breast size and risk of type 2 diabetes mellitus. CMAJ. 2008 Jan 29;178(3):289-95. A large bra cup size at age 20 may be a predictor of type 2 diabetes mellitus in middle-aged women.
Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomized controlled trials. Lancet 2009; 373: 1765-72.
Raz I, Wilson PW, Strojek K, et al. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care. 2009 Mar;32(3):381-6. Treating diabetic survivors of AMI with prandial
versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.
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Reed M, Huang J, Graetz I, et al. Outpatient electronic health records and the clinical care and outcomes of patients with diabetes mellitus. Ann Intern Med 2012.
Reeds Dominic N., Patterson Bruce W., Okunade Adewole, et al. Ginseng and Ginsenoside Re Do Not Improve β-Cell Function or Insulin Sensitivity in Overweight and Obese Subjects With Impaired Glucose Tolerance or Diabetes.
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Retnakaran, Ravi, Shah, Baiju R. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ 2009 0: cmaj.090569
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type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab. 2014 Dec;16(12):1257-64.
Rewers A, Dong F, Slover RH, et al. Incidence of diabetic ketoacidosis at diagnosis of type 1 diabetes in Colorado youth, 1998-2012. JAMA. 2015 Apr 21;313(15):1570-2.
Reznik Y, Cohen O, Aronson R, et al; for the OpT2mise Study Group. Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet. 2014 Jul 2.
Rho YH, Lu N, Peloquin CE, et al. Independent impact of gout on the risk of diabetes mellitus among women and men: a population-based, BMI-matched cohort study. Ann Rheum Dis. 2014 Oct 2.
Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim Sh. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006063. Eighteen trials which randomised 3888 people to rosiglitazone treatment were
identified. Longest duration of therapy was four years with a median of 26 weeks. Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs
and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was
significantly raised (OR 2.27, 95% confidence interval (CI) 1.83 to 2.81). The single large RCT (ADOPT - A Diabetes Outcomes Progression Trial) indicated increased cardiovascular risk.
Richter B, Bandeira-Echtler E, et al.. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006060. Until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear.
Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.
Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. Dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin and vildagliptin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006739.
Rigby MR, Dimeglio LA, et al. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 2013 Dec;1(4):284-94.
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Roberts AL, Agnew-Blais JC, Spiegelman D, et al. Posttraumatic Stress Disorder and Incidence of Type 2 Diabetes Mellitus in a Sample of Women: A 22-Year Longitudinal Study. JAMA Psychiatry. 2015 Jan 7.
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Rosenstock J, Balas B, Charbonnel B, et al; T-emerge 2 Study Group. The Fate of Taspoglutide, a Weekly GLP-1 Receptor Agonist, Versus Twice-Daily Exenatide for Type 2 Diabetes: The T-emerge 2 trial. Diabetes Care. 2013 Mar;36(3):498-504.
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with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors,
thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.
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Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008 Feb;121(2):149-157.e2. Using metformin to treat patients at risk for diabetes decreases their
likelihood of developing diabetes over a 3-year period. Longer studies are needed to determine whether the likelihood of diabetes is truly decreased or simply delayed. We have no research to tell us whether, in the long run,
patients live longer or live better if they are treated at this stage of (pre)diabetes. (LOE = 1a)
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Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309 (23):2473-2479.
Zinman B, Harris SB, Neuman J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): A double-blind randomised controlled study.
Lancet 2010; DOI: 10.1016/S0140-6736(10)60746-5.
Zoungas S et al. Severe hypoglycemia and risks of vascular events and death (Advance). N Engl J Med 2010 Oct 7; 363:1410. During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose
control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group).
Zoungas S, Chalmers J, Neal B, et al; the ADVANCE-ON Collaborative Group. Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes. N Engl J Med. 2014 Sep 19.
Clinical Knowledge Summary - Diabetes – NHS – UK: Link http://www.cks.library.nhs.uk/diabetes_type_2
AHRQ-USA: Clinicians Summary: http://www.effectivehealthcare.ahrq.gov/ehc/products/155/720/ECBCM_Oral%20Meds%20T2%20Diab_Clinician06282011.pdf; Full Report: http://www.effectivehealthcare.ahrq.gov/ehc/products/155/644/CER27_OralDiabetesMeds_20110623.pdf
AHRQ-USA: Patients Summary: http://www.effectivehealthcare.ahrq.gov/ehc/products/155/721/OralMedT2Diab_consumer.pdf
Mayo Clinic – Shared Decision Making – diabetes tools: http://dev.shareddecisions.mayoclinic.org/decision-aids-for-diabetes/diabetes-medication-management/
Health Canada – Advisory on rosiglitazone (Avandia) (June 01, 2007) http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/avandia_hpc-cps_4_e.html
Important Advice for Managing Your Patients
In Canada, Avandia® is NOT approved for use:
- with insulin therapy
- with the combination of metformin AND a sulfonylurea
- in patients with pre-diabetes.
Avandia® is contraindicated in patients with NYHA Class III and IV cardiac status.
Avandia® should be used with caution in any patient with NYHA Class I and II cardiac status.
All patients should be monitored for signs and symptoms of fluid retention, edema, and rapid weight gain.
The dose of Avandia® used in combination with a sulfonylurea should not exceed 4mg daily.
More links, information and a RxFiles Q&A Summary available at: http://www.rxfiles.ca/Rosiglitazone-CV-Controversy.htm
ANTIDEPRESSANT COMPARISON CHART 1,2,3,4,5,6,7
NAME: Generic / TRADE
g=generic
availabilty
ς
ς
,20, 40mg scored tabs) abr=CC S(+)citalopram 10 -20 mg od ~$60
Fluoxetine
(10,20,40
PROZACg
mg cap & 4mg/ml soln) abr=F
Fluvoxamine
(50,100mg scored tabs)
Paroxetine
abr=X
PAXILg
(10ς,20ς, 30mg tab)(40mg tab
{Paxil CR 12.5,25,37.5mg tab
Sertraline
)
⊗
5HT
abr=P
}
Nefazodone
abr-Z
DESYRELg
(50;75 ;100mg scored tabs)
(150mg Dividose tab:50/75/100/150mg
Amitriptyline
(10, 25,50mg; 75mg
)
(blocks
dopamine at
high doses:P,S)
SARI 5HT
Selective
SSRI+5HT2
rec. antagonism
5HT & NE
EFFECTS
(10, 25, 50mg tab)
SINEQUANg
tertiary (3°)
amine TCA's
(10,25,50,75,100,150mg cap)
Imipramine
(10, 25, 50; 75
TOFRANILg
NORPRAMINg
(10,25,50,75,100mg tab) -imipramine derivative
(50mg tabs better price in SK)
Nortriptyline
(10, 25mg cap)
0
AVENTYLg
-amitriptyline derivative
+
++
NE > 5HT
secondary (2°)
amine TCA's
+
+
0
+
+++
++++
+++++
+++++
+++++
++++
+++
++
++++
+++
++
++
Desvenlafaxine ER Prestiq ⊗ 50-100mg po od
avail. USA; DI: Cyp 3A4 (?clarithromycin)
SNRI
(Reg 37.5,75mg scored tabs-Co D/C Jul04)
++
+
5HT & NE
(XR 37.5mg, 75mg, 150mg cap) g
(also some DA)
(contents of XR caps may be sprinkled)
Venlafaxine EFFEXOR g
Bupropion SR WELLBUTRINg
(100,150mg tab)
(150,300mg XLtab)
⊗
MAOIs: non-selective & irreversible;
Mirtazapine REMERONg
15ς,30ς,45mg tabs (RDg 15,30,45mg tab )
Moclobemide
MANERIXg
(100,150,300mg scored tabs)
(2x150mg tabs cheaper than 300mg tab)
NDRI
DA & NE
SSRIs SE in General
nausea {21%(F) - 36% (X)},
anxiety, insomnia {~14%},
agitation,anorexia,tremor
somnolence {11-26%},
sweating, dry mouth,
headache, dizziness,
diarrhea {12% (F,P)-17% (S)},
constipation {13-18%}, EPS
sexual dysfx. >30%8,9, SIADH
0
0
Oct 08
fewest drug interactions
?benefit heart dx pts11
most anorexic & stimulating
long half-life (5 wk washout)
90mg weekly avail. in USA
most nauseating, constipating
& sedating SSRI; ↑ DI's
most anticholinergic of SSRIs
most official anxiety indications
↑weight, D/C reaction possible &
↑ sexual dysfunction
14
Rare: hepatotoxicity17
↓↓ BP, dizzy, headache,
nausea; (α1 blockade);
priapism 1/6000, (Tx epi)
√dementia 50mg hs (insomnia,
sundowning, aggression); less
cardiac effects than TCAs
nausea,imbalance,sensory dist., hyper.}
As for SSRIs +: ↓ BP
General TCA SE:
↑HR, ↓BP (Tx: fluid+/Florinef), weight gain,
sexual dysfx, sweating,
rash, tremors, ECG
abnormalities, seizures
fatal in overdose 18
(≥2gm) due to cardiac &
neurologic toxicity.
rare: anticonvulsant
hypersensitivity cross reactions
2° amines generally
better tolerated then 3°
amines (less dry mouth,
dizziness & weight gain)
As dose↑: ↑BP , agitation,
tremor,sweating,nausea~37%,
headache, sleep disturbances
caution:withdrawal effects
&HR
agitation,insomnia,tremor,sweating,
↓appetite, GI upset, psychos.
INITIAL &
MAX. DOSE
(Bold indicates official indication in Canada)
most diarrhea & male sexual
dysfx of SSRIs ?benefit heart
pts15,few drug interactions16;?↑TG
least stimulating serotonergic
less wt gain;less sex dysfx,DI's
Sx's 'FINISH' flu,insomnia,
---------------------------------------------------------------
+++
Prepared by Brent Jensen, Loren Regier
COMMENTS & ADDITIONAL USES
OTHER
Toxicity can→depression
10
{D/C Syndrome →flu-like
+++
mg tab)
Desipramine
0
0
ELAVILg
tab)
Clomipramine ANAFRANILg
Doxepin
+
SSRI's
abr=S
SERZONE
Trazodone
+
0/+
ZOLOFTg
(25,50,100mg cap)
SED.
SELECTIVE
LUVOXg
www.RxFiles.ca
SIDE EFFECTS
ACH.
escitalopram CIPRALEX ⊗
Citalopram CELEXAg
(10
RECEPTOR
AFFINITY
©
+
often 10-30 mg hs for sleep,
IBS & chronic pain Cp
esp. effective for OCD≥10yrs
Most serotonergic TCA; Cp
higher risk of seizures
Most histamine block Cp Breastfeed concern
√ psychoneurotic/anxious dep.
Cp
√ Childhood enuresis (age 6+)
Most NE activity
Least ACH side effects
Cp (used in IBS irritable bowel syndrome)
Therapeutic Uses:
√ OCD (esp. F, P,S,X)
10-20mg am
√ Panic(esp. P,S;F,CC,X)
10-20mg od
12,13
√ GAD (P,ES);?others
√ Bulimia nervosa (F)
√Diabetic neurop.(CC)
& deter use of EtOH
√ PTSD(P,S),√PMDD(F,P,S)
√Social Phobia (P,S)
√ Pediatric (F,S,X)
+ve effect on headache?
flat dose response
(majority of depressed
pts respond at the lowest
effective dose)
↓anxiety/insomnia
{Still avail. in USA}
√ Panic, chronic pain
√ Sleep disorders:
50-100mg hs
Therapeutic Uses 19
√ IBS, Pain Syndromes20
& sleep disorders21
(amitriptyline; but
°
nortriptyline 2 TCA
useful & less SE)
√ Neuropathy
√ Agitation &
insomnia
√ Panic→ imipramine
√ Migraine
prophylaxis22
Least hypotensive TCA. √IBS
Cp (response may be higher at
low end ≈50mg of dose range23)
(esp. amitrip./nortriptyline)
√ Smoke D/C→nortrip.
√ ADD(ie. desipramine)
initial nausea; “clean TCA”
side effects similar to SSRIs;
√Generalized,Panic &
social anxiety disorder
√for BPAD depressed;
low wt gain; few drug interactions
↓renal fx adjust dose; overdoseconcern
relapse prevents & ↓ recurrence
↑’d risk of seizure ~0.4% 400mg/d
=ZYBAN
less sex dysfx, low wt. gain
√ BPAD & Seasonal AD
→D/C smoking;
60mg/d
80mg/d
25-50mg hs
300mg/d
10-20mg am
60mg/d
25-50mg am
200mg/d
50-100mg bid
600mg/d
50mg bid
600mg/d
10-25mg hs
300mg/d
10-25mg hs
300mg/d
10-25mg hs
300mg/d
10-25mg hs
300mg/d
10-25mg hs
300mg/d
10mg hs
150mg/d
Star*D <200mg/d
18.75-37.5mg
375mg/d
100mg od am
450mg/d
USUAL ADULT
DOSE RANGE
$
/Month
20mg po od
27
27
40mg po od Star*D~40-60mg/d
(10mg po od)
41
30
20mg po od am (Solution $90)
53
40mg po od am
100mg po hs
39
150mg po hs
54
50mg am & 150mg hs
70
44-32
10-20mg po od am
33
30mg po od am
57
40mg po od am
61-64
12.5-25mg CR od am ⊗
100mg po od cc
34
59
50mg am &100mg pmStar D
100mg po bid cc
61
100mg po bid DISCONTINUED
150mg po bid Canada NOV03
50mg po hs
14
100mg po bid pc
27
200mg po bid pc
48
50 mg po hs
200mg po hs
50 mg po hs
150mg po hs
200mg po hs
50 mg po hs
200mg po hs
50 mg po hs
150-200mg po hs
50 mg po hs
150mg po hs (3x50mg)
200mg po hs (4x50mg)
25mg po hs
50mg po hs
100mg po hs
75-100mg/d for
neuropathic pain
37.5mg XR po od
75mg XR po od
150mg XR od Star*D ~200mg/d
225mg XR od (if 2-3 cap)
Star*D~300mg/d
100-150mg bid
150-300mg XL po od
15
34
22
51
65
22
61
18
40-51
22
51
66
17
25
43
28
49
51
99-130
34-43
26-44
atypical/refractory depression; enzyme effect ~10days; many DIs & food cautions (tyramine-hypertensive crisis);phenelzine NARDIL 15mg tab bid-tid; tranylcypromine PARNATE 10mg tab bid-tid
NaSSA5HT & NE
RIMA
Selective &
Reversible
+++
++++
Dry mouth, sedation, edema,
arthralgias, DI-clonidine
↑appetite&weight ;↓sexual dysfx;
+
0
Dry mouth, dizzy,
headache, nausea, tremor,
restless, less sex dysfx
no dietary tyramine precaution
enzyme effect lasts ~24hrs
DI:meperidine,sympathomimetics,DM…
rare neutropenia; RD if difficulty swallowing
√Anxiety,Somatization
√Atypical,
√Anxious-phobic,
√Co-morbid anxiety
15-45mg/day
Star*D <60mg/d
100mg bid
600-900mg/d
15-30mg po hs(RD & reg)
Generic RD Novo-mirtaz OD is ↓$
150mg po bid pc
300mg am&150pm pc
300mg po bid pc
17-35
26
36
58
=↓ dose for renal dysfx ς=scored tab
EDS non-formulary in SK =prior approval NIHB =covered by NIHB ⊗=not NIHB COST=total cost 5HT=serotonin ACH=anticholinergic effects (dry mouth,constipation,urinary hesitancy,blurred vision) ADD=attention
deficit disorder BP=blood pressure Cp=plasma level avail DA=dopamine D/C=discontinuation DI=drug interactions epi =epinephrine GI=stomach HR=heart rate MAOI=monoamine oxidase inhibitors NE=norepinephrine OCD=obsessive compulsive dx
RIMA reversible inhibitor of MAO-A SE=side effect SED=sedation SSRI=selective 5HT reuptake inhibitor Sx=symptoms TCA=tricyclic antidepressant Tx=treatment wk=week wt=weight INITIAL DOSE -Lower initial dose for elderly/sensitive pts.
=initial dose lower than usual effective dose. Pregnancy: C agents: fluoxetine (most clinical experience), sertraline & bupropion but less clinical experience. Treatment Duration: at full dose for at least ≥6-12months after remission (if recurrence tx longer)
New: Duloxetine CYMBALTA (30,60mg cap) χ⊗ an SNRI 30-60mg/d $60-120 Max 120mg. SE: insomnia, somnolence, headache, nausea, diarrhea, ↓appetite, fatigue, ↑sweating,↑BP, ↑LFTs,↑DI's & dry mouth; urinary retentionFDA?. √depression adult, GAD, diabetic neuropathic pain, fibromyalgia & ?stress incontinence.
Augmentation→if partial responder: some evidence ECT,(esp. with TCA + lithium ~600-900mg/d or l-thyroxine ≤100ug/d; for buspirone Star*D, pindolol, olanzapine / risperidone & tryptophan with SSRI). Combo's bupropion Star*D or mirtazapine (with SSRI or venlafaxine). 93
Anxiety/Panic
Anxiety, Comorbid
Atypical*
Bipolar
SSRIs, venlafaxine, mirtazapine
moclobemide, mirtazapine, duloxetine, ? buspirone
moclobemide, MAOIs, SSRIs
*
mood stabilizer (+/- antidepressant)
e.g. lithium, valproic acid, carbamazepine
Cardiac Condition SSRIs (citalopram,sertraline), MAOIs, bupropion
Chronic Pain/Neuropathy29 TCAs: amitriptyline, nortriptyline; venlafaxine, duloxetine
Drug Induced 30,31
stop or reduce offending agent (see bottom)
Elderly 32,33 SSRI(CC,P,S,X,Z); venlafaxine; mirtazapine; RIMA; 2°TCA e.g. nortriptyline
Migraine34
Obsessive Compulsive
Orthostatic Hypotension
amitriptyline, nortriptyline
SSRI (high dose), clomipramine
venlafaxine( BP); nortriptyline,
SSRIs (ambulation, hydration, gradual dose titration)
Phobic
Psychotic
Seizure History
Sleep Disorders35
Smoking Cessation36
Weight Gain, Less37
moclobemide, MAOI, paroxetine?
+ antipsychotic (or amoxapine), ECT Navarro’08
trazodone,SSRIs,moclobemide,venlafaxine
trazodone, amitriptyline, other TCAs (nortriptyline)
bupropion ZYBAN 300mg/d, nortriptyline 25-75mg/d
bupropion, SSRIs, RIMA, venlafaxine, duloxetine
SSRIs: hepatic dysfunction (↑ levels & half-life), irritable bowel
41
syndrome, CNS overstimulation (e.g. serotonin syndrome)
especially if used in combination with other serotonergic drugs
(buspirone, dextromethorphan, lithium, MAOI, meperidine, mirtazapine, MDMA,
ondansetron,sibutramine,St. Johns Wort,sumatriptan,tramadol,tryptophan, TCA)42;
withdrawal syndrome: dizziness, GI upset, headache, sleep disturbance,
agitation/restlessness (usually mild & transient; less common with fluoxetine) 43
44
{e.g. HIGH → Unpasteurized cheese (cheddar, camembert, blue), yeast
extract, herring, aged unpasteurized meats, broad bean pods;
MODERATE→ avocado, meat extract, certain ales & beer, wine;
LOW→ fruit, cream & cottage cheese, distilled spirits, chocolate};
Contraindicated: cerebrovascular/heart disease, geriatric or debilitated,
pheochromocytoma, or history of severe headache.
Bupropion: avoid if hx of seizures, bulimia or anorexia nervosa
Pediatric Issues: Safety & efficacy not well established 45,46,47,48
(Concern→suicide ideas<25yr, aggression & agitation). Imipramine for enuresis kids≥6 yrs.
FDA:Fluoxetine depression (49) & OCD;clomipramine, fluvoxamine & sertraline OCD,50.
Pregnancy: Consider risk vs benefit! ECT & psychotherapy are
non-drug options. TCAs desipramine & SSRIs: most clinical safety data.
(Pregnancy: some C agents may be preferable: fluoxetine (most
experience, paroxetine (no active metabolites,but ?↑harm51), sertraline &
bupropion but less clinical experience). Use lowest dose & try to
taper off 5-10 days before delivery.52,53,54,55,56,57 Neonates may
experience withdrawal 58 & pulmonary hypertension with SSRIs. 59
Breast feeding: consider risk vs benefit; psychotherapy; levels
often <10% of maternal dose; esp. SSRI’s & also nortriptyline used
SWITCH
TO
New agent
(sertraline, paroxetine & fluvoxamine:↓ levels & no reported adverse
effects; fluoxetine, citalopram & venlafaxine: ↑ breast milk level). 60,61,62,63
Elderly: extra caution required; med dose: start low & go slow
Relative Seizure Risk:64
*Atypical depression defined as: mood reactivity; irritability; hypersomnia;
hyperphagia; psychomotor agitation & hypersensitivity to rejection.
DRUG INTERACTIONS: Various cytochrome P450 inhibition65 by SSRI's.
Drug
citalopram
fluoxetine
fluvoxamine
paroxetine
sertraline
CYP450 1A2
0
+
+++
+
+
CYP450 2C9
0
++
++
+
+
CYP450 2C19
0
+ to ++
+++
+
+
1
1
1
1
1
3
5
7
1-7
1
7
1
1
2
1+
7+
1+
1+
1+
7-14
1-7
1-7
1-7
3
5
7
!
!
35 7
2## 14
##
2 14
3
2
The more critical recommendations are in bold; risks of
toxicity are greater with higher dosage regimens and
inadequate washout period. Some urgent cases may
necessitate shorter delays in switching.
HIGH→ maprotiline, amoxapine, clomipramine, bupropion
LOW→amitripyline,imipramine,trimipramine,nortriptyline,desipramine,doxe
LOWEST→ trazodone, SSRI’S, MAOI’S, moclobemide, venlafaxine
Less DI's 66: citalopram, mirtazapine, moclobemide, sertraline & venlafaxine.
7
7
7
7
7
3
1
7
5
5
5
7
7
7
!
35
7!
35!
7
7
1#
7
10
7#
7
10
1#
3
7
1#
7
7
1#
14 10-14
14
14 10-14 14
1
1
7
2
2
2
bupropion
insomnia, restlessness, cardiac conduction delays, heart block; arrhythmias)
#
1-7
1
#
1 7-14
#
1-7
1
#
1-7
1
#
1-7
1
moclobemide
1*
1*
clomipramine
doxepin, imipramine
1*
desipramine
1*
nortriptyline
1*
mirtazapine
1#
duloxetine
7#
venlafaxine
7#
fluoxetine
35!
fluvoxamine
1-7
paroxetine
7
citalopram/sertraline 1-7
nefazodone
1-3
trazodone
1-7
phenelzine
10-14
tranylcypromine 10-14
bupropion
1-3
moclobemide
2
amitriptyline
tranylcypromine
Table 4: Individualizing Therapy Considerations28
FROM
phenelzine
DC causative agent; fluid restriction (1 liter/d)
Serotonin Syndrome27: excitement,anxiety,diaphoresis,rigidity,↑temp,tremor,clonus,
↑reflexes,↑HR&BP,delirium; D/C serotonergic meds; Tx: Periactin 4mg po q4h, diazepam
Discontinuation syndrome with abrupt withdrawal eg. paroxetine & venlafaxine a flulike syndrome x~10day(FINISH: flu, insomnia, nausea, imbalance, sensory disturbances &
hyperactivity) may occur. Tx: TAPER off original antidepressants slowly over several
days or give benztropine (for cholinergic rebound→nausea/vomiting, sweating),
lorazepam (for agitation/insomnia), propranolol (for akathisia) as necessary.
TCAs: benign prostatic hypertrophy, history of urinary retention,
uncorrected angle closure glaucoma, seizure history, post-MI acute recovery phase, cardiovascular disease, cholinergic
rebound upon withdrawal from high doses (dizziness, nausea, diarrhea,
Bleeding & ?↑Fractures: assoc. by SSRI inhibition; risk of bleeding<0.5%
MAOIs: hypertensive crisis can occur secondary to foods containing tyramine
Oct 08
Table 3: Switching Antidepressants: Washout
periods in DAYS for outpatients 67,68,69
fluoxetine, fluvoxamine, paroxetine
SIADH (syndrome of inappropriate antidiuretic hormone secretion esp in elderly):
associated with hyponatremia
Table 2: Precautions
Prepared by: Loren Regier, Brent Jensen
38,39,40
citalopram,sertraline,nefazodone,trazodone
check BP for orthostatic hypotension; mild symptoms may attenuate
over several weeks; ↓ dose or switch agent; encourage adequate fluid intake & avoid
excessive salt restriction; Florinef 0.1mg po od & titrate
Sedation/foggy may attenuate over 1-2weeks; give single dose 1-2 hr prior to
bedtime; ↓dose or choose alternative; select pts modafinil or methylphenidate
Peripheral anticholinergic effects tolerance may develop over several
weeks; switch to alternative agent; treatment options for some Sx:
blurry vision-pilocarpine eye drops;methylcellulose drops for dry eyes
urinary hesitancy - bethanechol 25-50mg po tid-qid
abdominal cramps, nausea, diarrhea - adjust dose
dry mouth - sugarless gum; saliva substitutese.g.ORAL balance Gel, Mouth Kote; pilocarpine
constipation - adequate hydration, activity, bulk forming laxatives
Sweating ↓dose or change antidepressant; benztropine, cyproheptadine, clonidine
Weight gain modify & monitor diet & activity; switch to alternate agent
Sexual dysfunction distinguish etiology (drug vs illness); switch to:
(bupropion,mirtazapine,moclobemide,venlafaxine↓dose);adjust dose;1day/wk drug holiday,amantadine;
Other: ↓ libido→ neostigmine 7.5-15mg 30min prior to intercourse
impaired erection → bethanechol 10mg po tid
anorgasmia → amantadine; cyproheptadine Periactin 4mg po qam, ?sildenafil in ♀
antidepressant induced erectile dysfunction → sildenafil may help 26
Myoclonus ?TCA toxicity; reassess dose/levels; clonazepam 0.25mg tid
Insomnia & anxiety (5HT related) ↓dose; administer in am; + short course
of trazodone 50-100mg hs; switch to alternate agent
Dizziness
© www.RxFiles.ca
amitriptyline,clomipramine
doxepin, Imipramine
desipramine,nortriptyline
mirtazapine,venlafaxine, duloxetine
Antidepressants – Supplementary Tables
Table 1:Adverse Effects: Management Options 24,25
* no washout required; use
equivalent dose;
taper first drug; start 2nd new drug at a low dose;
# taper first drug over 3-7day prior to initiating 2nd new drug;
## taper if high dose;ndmaintain dietary restriction for 10d;
! use lower doses of 2 new drug initially; longer tapering
(up to 8 week) may be required for high dose fluoxetine
paroxetine & venlafaxine tapered slowly ↓discontinuation rxs.
CYP450 2D6
+
+++
+
+++
+ to ++
CYP450 3A4
0
+ to ++
++
+
+
Antidepressant Drug
Interactions: page 94
Other non P450 reactions
possible (eg. Serotonin Sx)
Drug induced depression: ACEI, acetazolamide, amphetamine/ cocaine withdrawal, anticonvulsants, amantadine, barbiturates, BCPs, benzos, bromocriptine, caffeine, chemotherapy some, cimetidine, clonidine, dapsone, digoxin, disulfiram, efavirenz, ethambutol, ethanol, finasteride, griseofulvin,
Haldol, hydralazine, interferon, isoniazid, isotretinoin, levodopa, mefloquine, methyldopa, methylphenidate, methysergide, metoclopramide, metronidazole, nitrofurantoin, NSAIDs, opiates, physostigmine, procainamide, progestins, propranolol, reserpine, streptomycin, steroids, sulfas, tetracycline & thiazides.
General: Remission ~30%, Response ~50%, Eventually ~80% respond to drug (2-4 wk some & 6-8wk for major improvement). Psychotherapy, cognitive behavioral therapy (CBT) +/- drug tx also effective! ECT may be effective 6-12 txs over 2-4wk. Vagus nerve stimulation is a new option. 92
ANTIDEPRESSANT COMPARISON CHART
1
Jefferson J, Greist JH. Mood Disorders in Textbook of Psychiatry, 2nd Ed. Editors: Hales RE, Yudofsky SC, Talbot JA. American Psychiatric Press, Washington, 1994.
Micromedix Drug Information, 2008.
3
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artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA. 2007 Jan 24;297(4):367-79. (n=284 12weeks)Based on these results and those of previous
trials, citalopram or sertraline plus clinical management should be considered as a first-step treatment for patients with CAD and major depression.)
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Grady-Weliky TA. Clinical practice. Premenstrual dysphoric disorder. N Engl J Med. 2003 Jan 30;348(5):433-8.
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Pearlstein T. Selective serotonin reuptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard? Drugs. 2002;62(13):1869-85.
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Glassman AH, O'Connor CM, Califf RM, et al.; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA.
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Tollefson GD. Antidepressant treatment and side effect considerations. J Clin Psychiatry 1991;52(5-suppl):4-13.
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Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003 Jan 1;289(1):56-64. (Taylor MJ,
Strategies for managing antidepressant-induced sexual dysfunction: systematic review of randomised controlled trials. J Affect Disord. 2005 Nov;88(3):241-54. Epub 2005 Sep 12.)( Basson R. Clinical practice. Sexual desire
and arousal disorders in women. N Engl J Med. 2006 Apr 6;354(14):1497-506.) (Fava M, et al. Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a
randomized, double-blind, placebo-controlled trial.J Clin Psychiatry.2006Feb;67(2):240-6.)
Nurnberg HG, Hensley PL, Heiman JR, Croft HA, Debattista C, Paine S. Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial.JAMA. 2008 Jul 23;300(4):395-404.
In this study population, sildenafil treatment of sexual dysfunction in women taking SRIs was associated with a reduction in adverse sexual effects.
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Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17;352(11):1112-20. (Pharmacist’s Letter: Serotonin Syndrome Sept 2006)
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Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Physician. 2004 May 15;69(10):2375-82.
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Finkel SI. Efficacy and tolerability of antidepressant therapy in the old-old. J Clin Psychiatry 1996;57(suppl 5):23-8.
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Menting JEA, Honig A, Verhey FRJ, et. al. Int Clin Psychophamacology 1996;11:165-175.
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Pryse-Phillips WEM, Dodick DW, Edmeads JG. Guidelines for the diagnosis and management of migraine in clinical practice. Can Med Assoc J 1997;156:1273-87.
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Reite M, Ruddy J, Nagel K. Evaluation and management of sleep disorders, 2nd Ed. Am Psychiatric Press, Washington, 1997.
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Hughes J, Stead L, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD000031. Review.
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Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety
review. BMJ. 2005 Feb 19;330(7488):385.
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Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry. 2005 Feb;62(2):165-72.
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Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ. 2003 May 27;168(11):1439-42.
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Hansten, PD and Horn JR. Drug Interactions Analysis and Management. Applied Therapeutics Incorporated. Vancouver, WA. 2008.
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Stahl MM, Lindquist M, Pettersson M, et.al. Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. Eur J clin Pharmacol 1997;53(3-4):163-9.
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Bleeding: Meijer WE, Heerdink ER, Nolen WA, et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004 Nov 22;164(21):2367-70. (Benazzi F.
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Hemorrhages during escitalopram-venlafaxine-mirtazapine combination treatment of depression. Can J Psychiatry. 2005 Mar;50(3):184.) (Ziegelstein RC, Meuchel J, Kim TJ, et al. Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med. 2007
Jun;120(6):525-30. Epub 2007 Apr 30. Selective serotonin reuptake inhibitor use during a hospitalization for an acute coronary syndrome is associated with reduced rates of recurrent ischemia, heart failure, or cardiac enzyme elevation at the expense of increased bleeding in patients
receiving maximal conventional antiplatelet medications and heparin.) FRACTURES: Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007 Jan
22;167(2):188-94. Daily SSRI use in adults 50 years and older remained associated with a 2-fold increased risk of clinical fragility fracture after adjustment for potential covariates. Depression and fragility fractures are common in this age group, and the elevated risk attributed to
daily SSRI use may have important public health consequences. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM, Ensrud KE. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch
Intern Med. 2007 Jun 25;167(12):1240-5. Use of SSRIs but not TCAs is associated with an increased rate of bone loss at the hip in this cohort of older women. Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes
MM; for the Osteoporotic Fractures in Men Study Group. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007 Jun 25;167(12):1246-51. In this population of
men, BMD was lower among those reporting current SSRI use, but not among users of other antidepressants.
Loke YK, Trivedi AN, Singh S. Meta-analysis: Gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2007 Oct 5; [Epub ahead of print]) Upper gastrointestinal (GI) bleeding is
associated with the use of selective serotonin reuptake inhibitors (SSRIs); the risk is increased when patients are also taking nonsteroidal anti-inflammatory drugs (NSAIDS). The risk for each individual is still low; but given the number of people taking SSRIs, the impact across a
population may be noticeable. (LOE = 3a)
Schalekamp T, Klungel JH, Souverein PC, de Boer A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med. 2008 Jan 28;168(2):180-5. In users of coumarins, SSRI usage was associated with increased risk of
hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.
de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry. 2008
Jul;65(7):795-803. Antidepressants with a relevant blockade action on the serotonin reuptake mechanism increase the risk of upper gastrointestinal tract bleeding. The increased risk may be of particular relevance when these drugs are associated with nonsteroidal anti-inflammatory
drugs. Our study findings also provide evidence that use of acid-suppressing agents limits such increased risk.
Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents. BMJ. 2004 Apr 10;328(7444):879-83.
Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm. BMJ. 2004 Jul 3;329(7456):34-8.
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Whittington CJ, Kendall T, Fonagy P, Cottrell D, et al. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet. 2004 Apr 24;363(9418):1341-5.
Ryan ND. Treatment of depression in children and adolescents. Lancet. 2005 Sep 10-16;366(9489):933-40.
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The American Academy of Child and Adolescent Psychiatry: http://www.aacap.org/Announcements/pdfs/physiciansmedguide.pdf .
American College of Neuropsychopharmacology: SSRIs & Suicidal Behavior in youth Jan/04: http://www.acnp.org/exec_summary.pdf Final Nov/05 http://www.nature.com/npp/journal/vaop/ncurrent/pdf/1300958a.pdf
Sept/05 Nice:Depression in children & young people http://www.nice.org.uk/pdf/CG028NICEguideline.pdf ; (Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry. 2006
Jan;163(1):41-7. CONCLUSIONS: The risk of suicide during acute-phase antidepressant treatment is approximately one in 3,000 treatment episodes, and risk of serious suicide attempt is approximately one in 1,000. Available data do not indicate a significant increase in risk of
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suicide or serious suicide attempt after starting treatment with newer antidepressant drugs.)( Cheung AH, et al. The use of antidepressants to treat depression in children and adolescents. CMAJ. 2006 Jan 17;174(2):193-200.) & (Hammad TA, et
al. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006 Mar;63(3):332-9. CONCLUSION: Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality. InfoPOEMs: The use of antidepressant
medications in children is associated with an increased risk of suicidal ideation and suicide-related behaviors. It is uncertain what overall effect antidepressant medications have on the morbidity and mortality of treated children. Close monitoring of patients using these medications
regarding the risk of suicidality is recommended. (LOE = 1a-) ) (Glaxo May/06 Meta analysis: 8958 paroxetine & 5953 placebo pts; suicidal behavior aged 18-24yrs (2.19 vs 0.92%); all ages (0.32 vs 0.05%); all were nonfatal suicide attempts; 8 of 11 attempts were in aged 18-30yrs)
Emslie GJ, et al. Paroxetine Treatment in Children and Adolescents With Major Depressive Disorder: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial. J Am Acad Child Adolesc Psychiatry. 2006 Jun;45(6):709-719. Paroxetine was not shown to be more efficacious
than placebo for treating pediatric major depressive disorder. (Misri S, et al. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry. 2006 Jun;163(6):1026-32.) (Dubicka B, Hadley S, Roberts C. Suicidal behaviour in
youths with depression treated with new-generation antidepressants: meta-analysis. Br J Psychiatry. 2006 Nov;189:393-8. Self-harm or suicide-related events occurred in 71 of 1487 (4.8%) of depressed youths treated with antidepressants v. 38 of 1254
(3.0%) of those given placebo (fixed effects odds ratio 1.70, 95% CI 1.13-2.54, P=0.01).) (Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J
Psychiatry. 2006 Nov;163(11):1898-904. The aggregate nature of these observational data precludes a direct causal interpretation of the results. More SSRI prescriptions are associated with lower suicide rates in children and may reflect antidepressant efficacy, treatment
compliance, better quality mental health care, and low toxicity in the event of a suicide attempt by overdose.) (Juurlink DN, et al. The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry. 2006 May;163(5):81321. Initiation of SSRI therapy is associated with an increased risk of suicide during the first month of therapy compared with other antidepressants. The absolute risk is low, suggesting that an idiosyncratic response to these agents may provoke suicide in a vulnerable subgroup of
patients.) (Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study. Arch Gen Psychiatry. 2006 Aug;63(8):865-72. In these high-risk patients,
antidepressant drug treatment does not seem to be related to suicide attempts and death in adults but might be related in children and adolescents. These findings support careful clinical monitoring during antidepressant drug treatment of severely depressed young people.) (Tiihonen
J, et al. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry. 2006 Dec;63(12):1358-67. Among suicidal subjects who had ever used antidepressants, the current use of
any antidepressant was associated with a markedly increased risk of attempted suicide and, at the same time, with a markedly decreased risk of completed suicide and death. Lower mortality was attributable to a decrease in cardiovascular- and cerebrovascular-related deaths during
selective serotonin reuptake inhibitor use.) (Simon GE. The antidepressant quandary--considering suicide risk when treating adolescent depression. N Engl J Med. 2006 Dec 28;355(26):2722-3.)
(Bhatia SK, Bhatia SC. Childhood and adolescent depression. Am Fam Physician. 2007 Jan 1;75(1):73-80. ) (Bridge JA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled
rials. JAMA. 2007 Apr 18;297(15):1683-96. Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of
antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.) (Gibbons RD, Brown CH, Hur K, Marcus SM,
Bhaumik DK, Mann JJ. Relationship between antidepressants and suicide attempts: an analysis of the veterans health administration data sets. Am J Psychiatry. 2007 Jul;164(7):1044-9. These findings suggest that SSRI
treatment has a protective effect in all adult age groups. They do not support the hypothesis that SSRI treatment places patients at greater risk of suicide.)
Gibbons RD, Brown CH, Hur K, et al. Early Evidence on the Effects of Regulators' Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. Am J Psychiatry. 2007 Sep;164(9):1356-63. In both the
United States and the Netherlands, SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory agencies issued warnings about a possible suicide risk with antidepressant use in pediatric
patients, and these decreases were associated with increases in suicide rates in children and adolescents.
Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and
adolescents. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004851. There was also evidence of an increased risk of suicidal ideation and behaviour for those prescribed SSRIs (RR 1.80, 95% CI 1.19 to 2.72). Fluoxetine was
the only SSRI where there was consistent evidence from three trials that it was effective in reducing depression symptoms in both children and adolescents (CDRS-R treatment effect -5.63, 95% CI -7.38 to -3.88), and 'response' to treatment (RR 1.86, 95% CI 1.49 to 2.32). Where rates
of adverse events were reported, this was higher for those prescribed SSRIs. While untreated depression is associated with the risk of completed suicide and impacts on functioning, it is unclear whether SSRIs would modify this risk in a clinically meaningful way. (Cheung AH,
Zuckerbrot RA, Jensen PS, Ghalib K, Laraque D, Stein RE; GLAD-PC Steering Group. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): II. Treatment and ongoing management. Pediatrics. 2007 Nov;120(5):e1313-26.)
Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial.JAMA. 2008 Feb 27;299(8):901-13. For adolescents with depression not
responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as
a switch to venlafaxine and resulted in fewer adverse effects.
Wheeler BW, Gunnell D, Metcalfe C, Stephens P, Martin RM. The population impact on incidence of suicide and non-fatal self harm of regulatory action against the use of selective serotonin reuptake inhibitors in under 18s in the United Kingdom: ecological study. BMJ. 2008 Mar
8;336(7643):542-5. Epub 2008 Feb 14. The noticeable reduction in prescribing of antidepressants since regulatory action in 2003 to restrict the use of SSRIs in under 18s does not seem to have been associated with changes in suicidal behaviour in young people. Specifically, these data
for England do not indicate that reductions in antidepressant use have led to an increase in suicidal behaviour.
Biddle L, Brock A, Brookes ST, Gunnell D. Suicide rates in young men in England and Wales in the 21st century: time trend study. BMJ. 2008 Mar 8;336(7643):539-42. Epub 2008 Feb 14. Suicide rates in young men have declined markedly in the past 10 years in England and Wales.
Reductions in key risk factors for suicide, such as unemployment, might be contributing to lower rates.
Treatment for Adolescents with Depression Study (TADS). Fluoxetine, Cognitive-Behavioral Therapy, & their Combination for Adolescents with Depression. JAMA. 2004 Aug 18;292(7):807-820. (Kennard B, Silva S,
Vitiello B, et al. TADS Team. Remission and residual symptoms after short-term treatment in the Treatment of Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006 Dec;45(12):1404-11.
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The combination of FLX and CBT was superior to both monotherapy and PBO in terms of remission rates, but overall rates of remission remain low and residual symptoms are common at the end of 12 weeks of treatment.) (March JS, Silva S, Petrycki S, Curry J, Wells K, Fairbank J,
Burns B, Domino M, McNulty S, Vitiello B, Severe J. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry. 2007 Oct;64(10):1132-43. In adolescents with moderate to severe depression, treatment with
fluoxetine alone or in combination with CBT accelerates the response. Adding CBT to medication enhances the safety of medication. Taking benefits & harms into account, combined treatment appears superior to either monotherapy as a treatment for major depression in adolescents.)
Emslie GJ, Kennard BD, Mayes TL, et al. Fluoxetine Versus Placebo in Preventing Relapse of Major Depression in Children and Adolescents. Am J Psychiatry. 2008 Feb 15; [Epub ahead of print] Continuation treatment with
fluoxetine was superior to placebo in preventing relapse and in increasing time to relapse in children and adolescents with major depression.
Rohde P, Silva SG, Tonev ST, et al. Achievement and maintenance of sustained response during the Treatment for Adolescents With Depression Study continuation and maintenance therapy.Arch Gen Psychiatry. 2008
Apr;65(4):447-55. Most adolescents with depression who had not achieved sustained response during acute treatment did achieve that level of improvement during continuation and maintenance therapies. The possibility that CBT may help the subset of adolescents with
depression who achieve early sustained response maintain their response warrants further investigation.
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Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS)
randomized controlled trial. JAMA. 2004 Oct 27;292(16):1969-76.
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Paxil (Paroxetine) and Birth Defects Pharmacist's Letter October 2005. (First trimester: Paxil any malformations 4% vs ~3% general population; cardiac 2% vs ~1% general population ; most common cardiac malformation was ventricular septal
defects) See also: Hallberg P, Sjoblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects. J Clin Psychopharmacol. 2005 Feb;25(1):59-73. &
Health Canada warning Oct/05 http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/paxil_3_hpc-cps_e.pdf ( Preliminay report of retrospective epidemiological study of 3,581 pregnant women). Dec/05 Health
Canada update http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/paxil_4_hpc-cps_e.html (An independent epidemiological study of delivery outcome following maternal use of SSRI antidepressants in early
pregnancy has been conducted utilizing the Swedish national registry data (n=5,123 women). The findings show an approximate 2-fold increased risk of cardiac malformations in infants exposed to paroxetine, compared with
the total registry population (approximately 2% incidence vs. 1%, respectively). ) (Use of SSRI’s During Pregnancy Pharmacist’s Letter April 2006) (ACOG Publications: Committee Opinion No.
354: Treatment With Selective Serotonin Reuptake Inhibitors During Pregnancy Obstet Gynecol 2006 108: 1601-1604.) (Djulus J, Koren G, et al. Exposure to Mirtazapine During Pregnancy: A Prospective, Comparative
Study of Birth Outcomes. J Clin Psychiatry. 2006 Aug;67(8):1280-1284. Mirtazapine does not appear to increase the baseline rate of major malformations of 1% to 3%. However, the higher number of spontaneous abortions in the antidepressant groups confirms the
higher rates of spontaneous abortions in pregnant women taking antidepressant medications found in previous studies.) (Kristensen JH, et al. Transfer of the antidepressant mirtazapine into breast milk. Br J Clin Pharmacol. 2006 Sep 13; [Epub
ahead of print] Results Mean (95% confidence interval) relative infant doses for mirtazapine and desmethylmirtazapine (n = 8) were 1.5% (0.8, 2.2) and 0.4% (0.2, 0.6) respectively.) (Thormahlen GM. Paroxetine Use During Pregnancy: Is it Safe? (October).
Ann Pharmacother. 2006 Aug 22; [Epub ahead of print] ) (Wogelius P, et al. Maternal Use of Selective Serotonin Reuptake Inhibitors and Risk of Congenital Malformations. Epidemiology. 2006 Nov;17(6):701-704. The
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150,780 women with no SSRI prescriptions gave birth to 5112 (3.4%) children with congenital malformations. The 1051 women with SSRI prescriptions any time during early pregnancy gave birth to 51 (4.9%) children with congenital malformations.)
Einarson A, Pistelli A, Desantis M, Malm H, Paulus WD, Panchaud A, Kennedy D, Einarson TR, Koren G. Evaluation of the Risk of Congenital Cardiovascular Defects Associated With Use of Paroxetine During Pregnancy. Am J Psychiatry. 2008 Apr 1; [Epub ahead of print] Paroxetine
does not appear to be associated with an increased risk of cardiovascular defects following use in early pregnancy, as the incidence in more than 3,000 infants was well within the population incidence of approximately 1%.
American College of Obstetricians and Gynecologists (ACOG). Use of psychiatric medications during pregnancy and lactation. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2008 Apr. 20 p. (ACOG practice bulletin; no. 92). [245 references]
Kulin AK, Pastuszak A, Sage SR, et.al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA 1998;279:609-610.
Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 7th Ed. Williams & Wilkins, Media, Pennsilvania, 2005. (Loughhead AM, et al. Antidepressants in Amniotic Fluid: Another Route of Fetal Exposure. Am J Psychiatry. 2006
Jan;163(1):145-147. )
Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry. 2002 Dec;159(12):2055-61.
Ward RK, Zamorski MA. Benefits and risks of psychiatric medications during pregnancy. Am Fam Physician. 2002 Aug 15;66(4):629-36. (Cohen LS, et al. Relapse of major depression during pregnancy in women who
maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. CONCLUSIONS: Pregnancy is not "protective" with respect to risk of relapse of major depression. Women with histories of depression who are euthymic in the context of ongoing
antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation. (InfoPOEMs: Nearly 50% of women currently receiving antidepressant medication will experience a relapse of major depression during pregnancy. The risk is highest for
those discontinuing their medication (68% relapse rate). It is likely that this study sample consists of patients with a higher severity of illness than those found in a routine community practice, so the findings may not generalize to other settings. (LOE = 1b)) ) {Wen SW, et al. Selective serotonin reuptake
inhibitors and adverse pregnancy outcomes. Am J Obstet Gynecol. 2006 Apr;194(4):961-6. (InfoPOEMs: The use of selective serotonin reuptake inhibitors (SSRIs) in the year before giving birth is associated with increased risk of prematurity, fetal death, and neonatal seizures. However, these observational
data are weakened by the need to make difficult adjustments for other important factors thought to be causally related to the outcomes studied, such as poverty and drug dependence. (LOE = 2b) }
Altshuler LL, Cohen LS, Moline ML, et al. Expert Consensus Panel for Depression in Women. The Expert Consensus Guideline Series. Treatment of depression in women. Postgrad Med. 2001 Mar;(Spec No):1-107.
Nordeng H, Spigset O. Treatment with selective serotonin reuptake inhibitors in the third trimester of pregnancy: effects on the infant. Drug Saf. 2005;28(7):565-81. (Sivojelezova A, Shuhaiber S, Sarkissian L, et al.
Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol. 2005 Dec;193(6):2004-9. InfoPOEMs: Citalopram (Celexa) does not appear to be teratogenic. Exposure
near the time of birth, however, was associated with increased risk of a diagnosis of fetal distress in labor and neonatal admission to special care nursery. (LOE = 1b) )
O'Keane V, Marsh MS. Depression during pregnancy. BMJ. 2007 May 12;334(7601):1003-5. ( Alwan S et al. Use of selective serotonin- reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007 Jun 28;
356:2684-92.) (Louik C et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007 Jun 28;
356:2675-83.) (Dietz PM, Williams SB, Callaghan WM, Bachman DJ, Whitlock EP, Hornbrook MC. Clinically identified maternal depression before, during, and after pregnancies ending in live births. Am J Psychiatry. 2007 Oct;164(10):1515-20. n=4398. Among 4,398 continuously enrolled
women with eligible pregnancies ending in live births, 678 (15.4%) had depression identified during at least one pregnancy phase; 8.7%, 6.9%, and 10.4% had depression identified before, during, and/or after pregnancy, respectively. Approximately one in seven women was identified with and treated for
depression during 39 weeks before through 39 weeks after pregnancy, and more than half of these women had recurring indicators for depression.)
Emilio J Sanz, Carlos et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis Lancet 2005; 365: 482-87 & ALSO Moses-Kolko EL, Bogen D, Perel J, et al.
Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005 May 18;293(19):2372-83.(InfoPOEMs: Late third trimester exposure to maternal use of
SSRIs increases the risk of neonatal behavioral abnormalities. Since the symptoms and signs were relatively benign and short lived, it makes sense to individualize the risks and benefits of continuing SSRI treatment throughout pregnancy. (LOE = 2a-)) (Levinson-Castiel R,
Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med. 2006 Feb;160(2):173-6. ) (Oberlander TF, et
al. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry. 2006 Aug;63(8):898-906. With
linked population health data and propensity score matching, prenatal SE-D exposure was associated with an increased risk of low birth weight and respiratory distress, even when maternal illness severity was accounted for.)
59
Chambers CD, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006 Feb 9;354(6):579-87. (InfoPOEMs: The use of selective
60
serotonin-reuptake inhibitors (SSRIs) during the second half of pregnancy is associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). This type of study cannot establish causation, untreated depression is a serious condition, and 99% of women would give birth to
infants unaffected by PPHN, so the potential benefits and harms of continuing SSRIs in these patients should be carefully weighed. (LOE = 3b)) Health Canada Mar/06 warning http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2006/2006_11_e.html
Misri S, Burgmann A, Kostaras D. Are SSRIs safe for pregnant and breastfeeding women? Can Fam Physician. 2000 Mar;46:626-8, 631-3.
Spencer JP, Gonzalez LS 3rd, Barnhart DJ. Medications in the breast-feeding mother. Am Fam Physician. 2001 Jul 1;64(1):119-26.
62
Wisner KL, Parry BL, Piontek CM. Clinical practice. Postpartum depression. N Engl J Med. 2002 Jul 18;347(3):194-9. (Wisner KL, et al. Postpartum depression: a randomized trial of sertraline versus nortriptyline. J Clin
Psychopharmacol. 2006 Aug;26(4):353-60. n=95 24week Times to response and remission also did not differ. Breast-fed infant serum levels were near or below the level of quantifiability for both agents.)
63
Altshuler LL, Cohen LS, Moline ML, Kahn DA, et al; Expert Consensus Panel for Depression in Women. The Expert Consensus Guideline Series. Treatment of depression in women. Postgrad Med. 2001 Mar;(Spec No):1-107.
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Skowron DM, Stimmel GL. Antidepressants and the risk of seizures. Pharmacotherapy 1992;12(1):18-22.
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Clinical Guidelines for the Treatment of Depressive Disorders. The Canadian Journal of Psychiatry June 2001.
( Prescribing Antidepressants for Depression in 2005: Recent Concerns & Recommendations http://www.cpa-apc.org/Publications/Position_Papers/2004-23s-en.pdf )
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Clinically significant drug interactions with antidepressants in the elderly. Spina E, Scordo MG. Drugs Aging 2002;19(4):299-320.
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Product monographs 2004 & Pharmacists Letter: How to Switch Antidepressants June 2006.
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Bezchlibnyk-Butler K, Jeffries JJ, eds. Clinical handbook of psychotropic drugs, 13th ed. Toronto: Hogrefe & Huber, 2003.
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Bezchlibnyk-Butler K. Serotonergic antidepressants: Drug response and drug-drug interactions. Pharmacy Practice:National CE Program 1998;Aug:1-8.
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Additional references:
Adams SM, Miller KE et al. Pharmacologic Management of Adult Depression. American Family Physician 2008; 77 (6): 785-792,795-796.
Alexopoulos GS. Depression in the elderly. Lancet. 2005 Jun 4-10;365(9475):1961-70.
Almeida OP, Waterreus A, Hankey GJ. Preventing depression after stroke: Results from a randomized (sertaline NS) placebo-controlled trial. J Clin Psychiatry. 2006 Jul;67(7):1104-9.
Appelhof BC, et al. Triiodothyronine (T3) addition to paroxetine in the treatment of major depressive disorder. J Clin Endocrinol Metab. 2004 Dec;89(12):6271-6.
Barbui C, Hotopf M, Freemantle N, et al. Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug adherence. Cochrane Database Syst Rev. 2000;(4):CD002791.
Bambauer KZ, et al. Physician alerts to increase antidepressant adherence: fax or fiction? Arch Intern Med. 2006 Mar 13;166(5):498-504.
Beck CA, Williams JV, Wang JL, et al. Psychotropic medication use in Canada. Can J Psychiatry. 2005 Sep;50(10):605-13. RESULTS: Overall psychotropic drug utilization was 7.2%. Utilization was higher for women and with increasing age. With any lifetime
CIDI-diagnosed disorder assessed in the CCHS 1.2, utilization was 19.3%, whereas without such disorders, it was 4.1%. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly used antidepressants for those with a past-year major depressive episode (17.8%), followed by venlafaxine
(7.4%). Among people aged 15 to 19 years, antidepressant use was 1.8% overall and 11.7% among those with past-year depression; SSRIs made up the majority of use. Sedative-hypnotics were used by 3.1% overall, increasing with age to 11.1% over 75 years.
Boulenger JP, et al. A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients. Curr Med Res Opin. 2006 Jul;22(7):1331-41.
Braun UK, Pham C, Kunik ME. Recognizing and managing depression at end of life. Geriatrics. 2008 Jun;63(6):25-7.
Brown GK, Ten Have T, Henriques GR, Xie SX, Hollander JE, Beck AT. Cognitive therapy for the prevention of suicide attempts: a randomized controlled trial. JAMA. 2005 Aug 3;294(5):563-70.
Brunzell JD. Clinical practice. Hypertriglyceridemia. N Engl J Med. 2007 Sep 6;357(10):1009-17.
Canadian Anxiety Guideline July 2006 (Panic, PTSD, GAD, SAD, OCD & specific phobias)
http://www.cpa-apc.org/Publications/CJP/supplements/july2006/anxiety_guidelines_2006.pdf
Candy B Jones L Williams R Tookman A King M. Psychostimulants for depression. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006722. There is some evidence that in the short-term, PS reduce symptoms of depression.
Whilst this reduction is statistically significant, the clinical significance is less clear.
Choi-Kwon S, Han SW, Kwon SU, et al. Fluoxetine Treatment in Poststroke Depression, Emotional Incontinence, and Anger Proneness. A Double-Blind, Placebo-Controlled Study. Stroke. 2005 Nov 23; [Epub ahead of print]
Chun-Fai-Chan B, Koren G, Fayez I, et al. Pregnancy outcome of women exposed to bupropion during pregnancy: A prospective comparative study. Am J Obstet Gynecol 2005; 192:932-36. (InfoPOEMs: Bupropion is not associated
with increased rates of major malformations. It may be associated with an increase in spontaneous abortions. (LOE = 1b) )
Cipriani A, Brambilla P, Furukawa T, et al.Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev. 2005 Oct 19;4:CD004185. AUTHORS' CONCLUSIONS: There are statistically significant differences in terms
of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn. From a clinical point of view the analysis of antidepressants' safety profile (adverse effect and suicide risk) remains of
crucial importance and more reliable data about these outcomes are needed. Waiting for more robust evidence, treatment decisions should be based on considerations of clinical history, drug toxicity, patient acceptability, and cost. We need for large, pragmatic trials, enrolling heterogeneous populations
of patients with depression to generate clinically relevant information on the benefits and harms of competitive pharmacological options. A meta-analysis of individual patient data from the randomised trials is clearly necessary.
Coelho HF, Boddy K, Ernst E. Massage therapy for the treatment of depression: a systematic review. Int J Clin Pract. 2008 Feb;62(2):325-33. Epub 2007 Dec 11. This review found no robust evidence supporting a
recommendation for deep (Swedish) massage therapy as a sole or additive modality for treating unipolar depression. (LOE = 1a-)
Cohen LS, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. CONCLUSIONS: Pregnancy is not "protective" with respect to risk of relapse
of major depression. Women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation.{InfoPOEMs Mar 2006: Nearly 50% of women currently receiving
antidepressant medication will experience a relapse of major depression during pregnancy. The risk is highest for those discontinuing their medication (68% relapse rate). It is likely that this study sample consists of patients with a higher severity of illness than those found in a routine community practice,
so the findings may not generalize to other settings. (LOE = 1b). Women maintaining their medication during pregnancy relapsed significantly less often than those who discontinued medication (26% vs 68%; number needed to treat (NNT)= 2; 95% CI, 1.8 - 4).}
Coogan PF, Palmer JR, Strom BL, Rosenberg L. Use of selective serotonin reuptake inhibitors and the risk of breast cancer. Am J Epidemiol. 2005 Nov 1;162(9):835-8. Epub 2005 Sep 21.
Davidson J, et al. Treatment of Posttraumatic Stress Disorder With Venlafaxine Extended Release: A 6-Month Randomized Controlled Trial. Arch Gen Psychiatry. 2006 Oct;63(10):1158-1165. n=329
Dennis CL, et al. Psychosocial and psychological interventions for treating postpartum depression. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD006116. Although the methodological quality of the majority of trials was, in
general, not strong, the meta-analysis results suggest that psychosocial and psychological interventions are an effective treatment option for women suffering from postpartum depression.
Depression scales The PHQ-9 is the 9 item depression scale of the Patient Health Questionnaire. The PHQ-9 is a powerful tool for assisting primary care clinicians in diagnosing depression as well as selecting and monitoring
treatment. http://www.depression-primarycare.org/clinicians/toolkits/materials/forms/phq9/ PHQ-2 Patient Health Questionnaire 2 about depressed mood and anhedonia: http://www.aafp.org/afp/20040915/1101.html
Deshauer D, Moher D, Fergusson D, et al. Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials. CMAJ. 2008 May 6;178(10):1293-301. There is
a lack of classic randomized controlled trials of serotonin reuptake inhibitors lasting more than 1 year for the treatment of depression. The results of our systematic review support current recommendations for 6-8 months of
antidepressant treatment following initial recovery but provide no guidance for longer treatment.
Dhillon S, Scott LJ, Plosker GL. Escitalopram: a review of its use in the management of anxiety disorders. CNS Drugs. 2006;20(9):763-90. Nevertheless, available clinical data indicate that escitalopram is an effective first-line treatment option for the
management of GAD, SAD, panic disorder and OCD.
Eating Disorder Treatment. Pharmacist’s Letter. Aug 2006.
Eberhard-Gran M, Eskild A, Opjordsmoen S. Use of Psychotropic Medications in Treating Mood Disorders during Lactation : Practical Recommendations. CNS Drugs. 2006;20(3):187-98.
Elderly
[Baldwin RC, Anderson D, Black S, et al; Faculty of Old Age Psychiatry Working Group, Royal College of Psychiatrists. Guideline for the management of late-life depression in primary care. Int J Geriatr Psychiatry. 2003 Sep;18(9):829-38.
Charney et al. Depression and Bipolar Support Alliance. Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Arch Gen Psychiatry. 2003 Jul;60(7):664-72.
Cuijpers P, van Straten A, Smit F. Psychological treatment of late-life depression: a meta-analysis of randomized controlled trials. Int J Geriatr Psychiatry. 2006 Dec;21(12):1139-49.
Dombrovski AY, Mulsant BH. The evidence for electroconvulsive therapy (ECT) in the treatment of severe late-life depression. ECT: the preferred treatment for severe depression in late life. Int Psychogeriatr. 2007 Feb;19(1):10-4, 27-35; discussion 24-6.
Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000 May 18;342(20):1462-70.
Mottram P, Wilson K, Strobl J. Antidepressants for depressed elderly. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003491. Our findings suggest that SSRIs and TCAs are of the same efficacy. However, we have found some evidence suggesting that TCA
related antidepressants and classical TCAs may have different side effect profiles and are associated with differing withdrawal rates when compared with SSRIs.
Pinquart M, Duberstein PR, Lyness JM. Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. Am J Psychiatry. 2006 Sep;163(9):1493-501. Given that psychotherapy and pharmacotherapy did not
show strong differences in effect sizes, treatment choice should be based on other criteria, such as contraindications, treatment access, or patient preferences.
Reynolds CF 3rd, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA. 1999 Jan 6;281(1):39-45.
Sjösten N, Kivelä SL. The effects of physical exercise on depressive symptoms among the aged: a systematic review. Int J Geriatr Psychiatry. 2006 May;21(5):410-8.
Unützer J. Clinical practice. Late-life depression. N Engl J Med. 2007 Nov 29;357(22):2269-76.
Wilson K, Mottram P. A comparison of side effects of selective serotonin reuptake inhibitors and tricyclic antidepressants in older depressed patients: a meta-analysis. Int J Geriatr Psychiatry. 2004 Aug;19(8):754-62.]
Ensrud KE, et al. for Study of Osteoporotic Fractures Research Gp. Use of selective serotonin reuptake inhibitors and sleep disturbances in community-dwelling older women. J Am Geriatr Soc 2006 Oct;54(10):1508-15.
Fava M, et al. Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial.J Clin Psychiatry.2006Feb;67(2):240-6.
Fava M, Rush AJ, Wisniewski SR, et al. A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report. Am J Psychiatry. 2006
Jul;163(7):1161-72. Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second
step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). For mirtazapine, remission rates were 12.3% and 8.0% per the
Hamilton and QIDS-SR(16) scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively
FDA: Oct/06 Letter regarding venlafaxine overdose concern http://www.fda.gov/medwatch/safety/2006/effexor_DHCPletter.pdf
Fink M, Taylor MA. Electroconvulsive therapy: evidence and challenges. JAMA. 2007 Jul 18;298(3):330-2.
Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006 Oct;63(10):1121-9.
Gamble J, Creedy D, Moyle W, Webster J, McAllister M, Dickson P. Effectiveness of a counseling intervention after traumatic childbirth: A randomized trial. Birth 2005; 32:11-19. (InfoPOEMs: Women with trauma symptoms who
receive face-to-face counseling during their hospital stay and phone counseling at 4 to 6 weeks postpartum are less likely to have persistent trauma symptoms or postpartum depression at 3 months. (LOE = 1b-))
Gilbody S, Bower P, Fletcher J, Richards D, Sutton AJ. Collaborative Care for Depression: A Cumulative Meta-analysis and Review of Longer-term Outcomes. Arch Intern Med. 2006 Nov 27;166(21):2314-21.
Gilbody S, House A, Sheldon T, Gilbody S. Screening and case finding instruments for depression. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002792. AUTHORS' CONCLUSIONS: There is substantial evidence that routinely
administered case finding/screening questionnaires for depression have minimal impact on the detection, management or outcome of depression by clinicians. Practice guidelines and recommendations to adopt this strategy, in isolation, in order to
improve the quality of healthcare should be resisted. The longer term benefits and costs of routine screening/case finding for depression have not been evaluated. A two stage procedure for screening/case finding may be effective, but this needs to
be evaluated in a large scale cluster randomised trial, with a prospective economic evaluation.
Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004 Sep;161(9):1537-47.
Golden RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. 2005 Apr;162(4):656-62. (InfoPOEMs: The available published
research literature provides very weak evidence that light therapy is effective for seasonal affective disorder (SAD) or nonseasonal depression. There seems to be a large acute effect of light therapy on symptoms of SAD in the first week of treatment but this effect disappears quickly
thereafter. Light therapy has a moderate effect on patients with nonseasonal depression when studied for only 7 days. Light therapy does not produce an additional effect when combined with pharmacologic therapy. Light boxes are expensive and may not provide the results desired
by patients with SAD. (LOE = 1a-) )
Goodyer I, Dubicka B, Wilkinson P, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled
trial. BMJ. 2007 Jul 21;335(7611):142. Epub 2007 Jun 7. For adolescents with moderate to severe major depression there is no evidence that the combination of CBT plus an SSRI in the presence of routine clinical care contributes to an improved outcome by 28
weeks compared with the provision of routine clinical care plus an SSRI alone.
Gordon PR, et al. Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause. 2006 Jul-Aug;13(4):568-75.
Guaiana G, Barbui C, Hotopf M. Amitriptyline for depression. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004186. This present systematic review indicates that amitriptyline is at least as efficacious as other tricyclics or newer compounds. However,
the burden of side-effects in patients receiving it was greater. In comparison with selective serotonin reuptake inhibitors amitriptyline was less well tolerated, and although counterbalanced by a higher proportion of responders, the difference was not statistically significant.
Hansen RA, Gartlehner G, Lohr KN, et al. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med. 2005 Sep 20;143(6):415-26. CONCLUSIONS: Overall, second-generation
antidepressants probably do not differ substantially for treatment of major depressive disorder. Choosing the agent that is most appropriate for a given patient is difficult. (InfoPOEMs: When it comes to the new, nontricyclic antidepressants, the medical literature does not give us any clear guidance as to which one is more
effective, of faster onset, safer, or better tolerated. Sexual side effects are lower with bupropion and nausea seems to occur more often with venlafaxine. Other research has shown these new drugs to be no more effective or better tolerated than tricyclic antidepressants. For now, start your patient on your favorite antidepressant,
with the realization that most patients will need to switch to another drug at least once. (LOE = 1a) )
Hubbard R, Lewis S, et al. Bupropion and the risk of sudden death: a self-controlled case-series analysis using The Health Improvement Network. Thorax. 2005 Oct;60(10):848-50. Epub 2005 Jul 29.
Hunkeler EM, et al. Long term outcomes from the IMPACT randomised trial for depressed elderly patients in primary care. BMJ. 2006 Feb 4;332(7536):259-63. Epub 2006 Jan 20.
Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003 Oct;160(10):1823-9.
Johnson EM, et al. Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiatry. 2006 Sep;14(9):796-802.
Keller MB, Trivedi MH, Thase ME, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: Outcomes from the 2-year and combined maintenance phases. J Clin Psyc.
2007 Aug;68(8):1246-56. In this study, an additional 12 months of maintenance therapy with venlafaxine ER was effective in preventing recurrence of depression in pts who had been responders to venlafaxine ER after acute (10 weeks), continuation (6 months), and initial maintenance (12 months) therapy.
Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis. J Psychiatry
Neurosci. 2006 Mar;31(2):122-31. Erratum in: J Psychiatry Neurosci. 2006 Jul;31(4):228.
Kennedy SH, et al. Sexual function during bupropion or paroxetine treatment of major depressive disorder. Can J Psychiatry. 2006 Mar;51(4):234-42.
Kennedy GJ, Marcus P. Use of antidepressants in older patients with co-morbid medical conditions: guidance from studies of depression in somatic illness. Drugs Aging. 2005;22(4):273-87.
Kim H, et al. Monoamine transporter gene polymorphisms and antidepressant response in Koreans with late-life depression. JAMA. 2006 Oct 4;296(13):1609-18.
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of date submitted to the Food and Drug Administration. PLoS Med 2008;5:e45. (Limited or placebo like benefit)
Kisely S, Smith M, Lawrence D, Maaten S. Mortality in individuals who have had psychiatric treatment: Population-based study in Nova Scotia. Br J Psychiatry. 2005 Dec;187:552-558.
Kraus MR, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut. 2008 Apr;57(4):531-6. Epub 2007 Dec 13. The findings demonstrate clearly that
citalopram treatment is highly effective in HCV patients on interferon therapy, when initiated after the onset of clinically relevant depressive symptoms. This suggests that a general SSRI prophylaxis is not necessary in these patients.
Lam RW, et al. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry. 2006 May;163(5):805-12.
(InfoPOEMs: Light
therapy and fluoxetine (Prozac) are equally effective treatment options for patients with seasonal affective disorder (SAD). Patient preference and an individual assessment of risks and benefits should guide treatment selection. (LOE = 1b) )
Leverich GS, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers.
Am J Psychiatry. 2006 Feb;163(2):232-9.
Linehan MM, et al. Two-Yr Randomized Controlled Trial & Follow-up of Dialectical Behavior Therapy vs Therapy by Experts for Suicidal Behaviors & Borderline Personality Disorder. Arch Gen Psyc. 2006 Jul;63(7):757-66.
Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007 Nov 8;357(19):1939-45.
Lustman PJ, et al. Sertraline for Prevention of Depression Recurrence in Diabetes Mellitus: A Randomized, Double-blind, Placebo-Controlled Trial. Arch Gen Psychiatry. 2006 May;63(5):521-9.
Ma J, et al. Association between antidepressant use and prescribing of gastric acid suppressants. Can J Psychiatry. 2006 Mar;51(3):178-84.
Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA. 2005 Oct 26;294(16):2064-74. CONCLUSIONS: Physician education in depression recognition and treatment and restricting access to lethal methods reduce
suicide rates. Other interventions need more evidence of efficacy. Ascertaining which components of suicide prevention programs are effective in reducing rates of suicide and suicide attempt is essential in order to optimize use of limited resources.
Mann JJ. The medical management of depression. N Engl J Med. 2005 Oct 27;353(17):1819-34.
Marcy TR, Britton ML. Antidepressant-induced sweating.Ann Pharmacother. 2005 Apr;39(4):748-52. Epub 2005 Feb 22.
Mariappan P, Ballantyne Z, N'dow J, Alhasso A. Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004742.
MacMillan HL et al. Canadian Task Force on Preventive Health Care. Screening for depression in primary care: recommendation statement from the Canadian Task Force on Preventive Health Care.CMAJ.2005Jan 4;172(1):33-5.
Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder: a randomized trial. Ann Intern Med. 2007 Nov 6;147(9):593-602. n=274 6wks. Risperidone (up to 2mg/d)
augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures.
McGrath PJ, et al. Predictors of relapse in a prospective study of fluoxetine treatment of major depression. Am J Psychiatry. 2006 Sep;163(9):1542-8.
McGrath PJ, et al. Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report. Am J Psychiatry. 2006 Sep;163(9):1531-41. Remission rates
were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups. The lower side effect burden, lack of dietary restrictions, and ease of use of venlafaxine and mirtazapine
suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments.
Medical Letter, Duloxetine for Diabetic Neuropathic pain. Vol 47 (Issue 1215/1216) Aug 15/29,2005. p.67-68.
Medical Letter “Treatment Guidelines- Drugs for Psychiatric Disorders Vol 4 (Issue 46) June 2006.
Moja P, Cusi C, Sterzi R, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002919. CONCLUSIONS: Over 2 months of
treatment, SSRIs are no more efficacious than placebo in patients with migraine. In patients with chronic TTH, SSRIs are less efficacious than tricyclic antidepressants. In comparison with SSRIs, the burden of adverse events in patients receiving tricyclics was greater. These results
are based on short-term trials and may not generalise to longer-term treatment.
Montgomery SA, Baldwin DS, Blier P, et al. Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int Clin Psychopharmacol. 2007 Nov;22(6):323-329. Only escitalopram was found to have
definite superiority in the treatment of severe depression; probable superiority was identified for venlafaxine and possible superiority for milnacipran and clomipramine.
Murdoch D, Keam SJ. Escitalopram: a review of its use in the management of major depressive disorder. Drugs. 2005;65(16):2379-404.
Musters C, McDonald E, Jones I. Management of postnatal depression. BMJ. 2008 Aug 8;337:a736. doi: 10.1136/bmj.a736.
Nahas Z, Marangell LB, Husain MM, et al. Two-Year Outcome of Vagus Nerve Stimulation (VNS) for Treatment of Major Depressive Episodes. J Clin Psychiatry. 2005 Sep;66(9):1097-1104.
Navarro V, Gastó C, Torres X, et al. Continuation/maintenance treatment with nortriptyline (n=17) versus combined nortriptyline and ECT (n=16)in late-life psychotic depression: a two-year randomized study. Am J Geriatr
Psychiatry. 2008 Jun;16(6):498-505. This study supports the judicious use of combined continuation/maintenance ECT and antidepressant treatment in elderly patients with psychotic unipolar depression who are ECT remitters.
Nelson JC, et al. Mirtazapine orally disintegrating tablets in depressed nursing home residents 85 years of age and older. Int J Geriatr Psychiatry. 2006 Sep;21(9):898-901.
Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006 Sep;163(9):1519-30; quiz 1665.
Remission rates with lithium (up to 900mg/d) and T(3) augmentation (up to 50ug/d) for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of T(3)
augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.
Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry. 2003 Oct;60(10):978-82.
Olfson M, Marcus SC, Tedeschi M, Wan GJ. Continuity of antidepressant treatment for adults with depression in the United States. Am J Psychiatry. 2006 Jan;163(1):101-8.
O'reardon JP, et al. A randomized, placebo-controlled trial of sertraline in the treatment of night eating syndrome. Am J Psychiatry. 2006 May;163(5):893-8.
Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in
treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry. 2007 Dec 1;62(11):1217-27. Epub 2007 Jun 22.
Parashar S, et al. Time course of depression and outcome of myocardial infarction. Arch Intern Med. 2006 Oct 9;166(18):2035-43.
Perkins S, et al. Self-help and Guided Self-help for Eating Disorders. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004191.
Pharmacist’s Letter May 2006: Pharmacotherapy of Treatment-Resistant Depression
Rahimi-Ardabili B, et al. Finasteride-induced depression : A prospective study. BMC Clin Pharmacol. 2006 Oct 7;6(1):7 [Epub ahead of print]
Reynolds CF 3rd, et al. Maintenance treatment of major depression in old age. N Engl J Med. 2006 Mar 16;354(11):1130-8. CONCLUSIONS: Patients elderly 70 years of age or older with major depression who had a response to initial treatment with
paroxetine and psychotherapy were less likely to have recurrent depression if they received two years of maintenance therapy with paroxetine. Monthly maintenance psychotherapy did not prevent recurrent depression. (InfoPOEMs: Prolonged treatment with paroxetine (Paxil)
reduces the risk of recurrence of major depression in elderly patients. (LOE = 1b) )
Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007 Jan 22;167(2):188-94. Daily SSRI use in adults 50 years and older remained associated
with a 2-fold increased risk of clinical fragility fracture after adjustment for potential covariates. Depression and fragility fractures are common in this age group, and the elevated risk attributed to daily SSRI use may have important public health consequences.
Robinson RG, Jorge RE, Moser DJ, Acion L, Solodkin A, Small SL, Fonzetti P,
Hegel M, Arndt S. Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA. 2008 May 28;299(20):2391-400. In this study of nondepressed patients with recent stroke, the use of
escitalopram or problem-solving therapy resulted in a significantly lower incidence of depression over 12 months of treatment compared with placebo, but problem-solving therapy did not achieve significant results over placebo using the intention-to-treat conservative method of analysis.
Rosen R, et al.; Vardenafil Study Site Investigators. Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study.
Am J Psychiatry. 2006 Jan;163(1):79-87.
Rush AJ, et al. STAR*D Study. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs (citalopram) for depression. n=727 N Engl J Med. 2006 Mar 23;354(12):1231-42. CONCLUSIONS: After unsuccessful treatment with an
SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (InfoPOEMs: Bupropion SR (~283mg/d),
sertraline(~136mg/d) & venlafaxine XR (~194mg/d) are equally effective at inducing remission or response in patients with persistent symptoms of depression despite initial treatment with citalopram (Celexa ~41mg/d). Most patients will not go into remission, though, and this study
lacked a placebo control group. (LOE = 1b) )
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am J Psychiatry. 2006 Nov;163(11):1905-17. The QIDSSR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%.
Rush AJ, Wisniewski SR, Warden D, Luther JF, Davis LL, Fava M, Nierenberg AA,
Trivedi MH. STAR*D Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008 Aug;65(8):870-80. Clinical,
demographic, and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder. Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity, less social disadvantage, and
at least a response to citalopram in the first step.
Ryan D, Milis L, Misri N. Depression during pregnancy. Can Fam Physician. 2005 Aug;51:1087-93.
Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001 Mar 14;285(10):1299-307.
Saarto T, et al. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454.
Second generation Antidepressants: Drug Class Review Sept 2006 Oregon Health & Science University http://www.ohsu.edu/drugeffectiveness/reports/documents/SG%20Antidepressants%20Final%20Report%20u3.pdf
Shah NR, Jones JB, Aperi J, Shemtov R, Karne A, Borenstein J. Selective Serotonin Reuptake Inhibitors for Premenstrual Syndrome and Premenstrual Dysphoric Disorder: A Meta-Analysis. Obstet Gynecol. 2008
May;111(5):1175-1182. Selective serotonin reuptake inhibitors were found to be effective in treating premenstrual symptoms, with continuous dosing regimens favored for effectiveness.
Shirayama T, et al. Usefulness of paroxetine in depressed men with paroxysmal atrial fibrillation. Am J Cardiol. 2006 Jun 15;97(12):1749-51. Epub 2006 Apr 21.
Soomro G, Altman D, Rajagopal S, Oakley-Browne M. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev. 2008 Jan 23;(1):CD001765. SSRIs
are more effective than placebo for OCD, at least in the short-term, although there are differences between the adverse effects of individual SSRI drugs.
Steiner M, Hirschberg AL, Bergeron R, et al. Luteal phase dosing with paroxetine controlled release (CR) in the treatment of premenstrual dysphoric disorder. Am J Obstet Gynecol. 2005 Aug;193(2):352-60.
Stearns V, Slack R, Greep N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol. 2005 Oct 1;23(28):6919-30.
Tack J, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006 Aug;55(8):1095-103. Epub 2006 Jan 9. (InfoPOEMs: Citalopram in a dose of 20 mg daily for 3 weeks
(perhaps increasing to 40 mg at that time) modestly improves symptoms in patients with irritable bowel syndrome (IBS). Paroxetine showed a similar benefit in a previous study, so this is likely a class effect of serotonin specific reuptake inhibitors (SSRIs). (LOE = 1b))
TADS Team. The Treatment for Adolescents With Depression Study (TADS): Long-term Effectiveness and Safety Outcomes. Arch Gen Psychiatry. 2007 Oct;64(10):1132-1143. In adolescents with moderate to severe
depression, treatment with fluoxetine alone or in combination with CBT accelerates the response. Adding CBT to medication enhances the safety of medication. Taking benefits and harms into account, combined treatment
appears superior to either monotherapy as a treatment for major depression in adolescents.
Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action: Systematic Review and Meta-analysis. Arch Gen Psychiatry. 2006 Nov;63(11):1217-23.
Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6 weeks. (InfoPOEMs: Treatment of unipolar depression in adults with selective serotonin reuptake
inhibitors (SSRIs) significantly improves symptoms in as quickly as 1 week. (LOE = 1a-) )
Tenback DE, et al. Evidence that early extrapyramidal symptoms predict later tardive dyskinesia: a prospective analysis of 10,000 patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Am J
Psychiatry. 2006 Aug;163(8):1438-40.
Tew JD Jr, et al. Impact of Prior Treatment Exposure on Response to Antidepressant Treatment in Late Life. Am J Geriatr Psychiatry. 2006 Nov;14(11):957-965.
Thase ME, et al. A Double-blind Comparison Between Bupropion XL and Venlafaxine XR: Sexual Functioning, Antidepressant Efficacy, and Tolerability. J Clin Psychopharmacol. 2006 Oct;26(5):482-488. In conclusion, in this
patient population (ie, relatively young, sexually active outpatients), bupropion XL was at least as effective as venlafaxine XR and had a significantly more favorable sexual side effect profile. N=348 12 week
Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58 Suppl 13:23-9.
Thase ME, Friedman ES, Biggs MM, et al. Cognitive Therapy Versus Medication in Augmentation and Switch Strategies as Second-Step Treatments: A STAR*D Report. Am J Psychiatry. 2007 May;164(5):739-752. After an
unsatisfactory response to citalopram, patients who consented to random assignment to either cognitive therapy or alternative pharmacologic strategies had generally comparable outcomes. Pharmacologic augmentation was more rapidly effective than cognitive therapy
augmentation of citalopram, whereas switching to cognitive therapy was better tolerated than switching to a different antidepressant.
Timonen M, Liukkonen T. Management of depression in adults. BMJ. 2008 Feb 23;336(7641):435-9.
Treatment Guidelines from the Medical Letter. Pharmaceutical Drug Overdose. Sept 2006. (TCAs: sodium bicarbonate treatment)
Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Am J Psychiatry. 2006 Jan;163(1):28-40. The
mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR) n=2,876.
Trivedi MH, et al. STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. n=565 N Engl J Med. 2006 Mar 23;354(12):1243-52. CONCLUSIONS: Augmentation of citalopram (40-60mg/d) with either
sustained-release bupropion (~267mg/d) or buspirone (~41mg/d) appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms
and fewer side effects and adverse events. (InfoPOEMs: Buspirone and bupropion SR added to citalopram (Celexa) are similarly effective for patients with depression who do not initially respond to citalopram alone. Bupropion SR is somewhat better tolerated. The study was
limited by the lack of a placebo control group. (LOE = 1b) )
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008 Jan 17;358(3):252-60.
Urquhart D, et al. Antidepressants for non-specific low back pain. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD001703. There is no clear evidence that antidepressants are more effective than placebo in the management of patients with chronic lowback pain.
Vahedi H, Merat S, et al. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther. 2005 Sep 1;22(5):381-5.
Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003724.
Wagena EJ, Knipschild PG, Huibers MJ, et al. Efficacy of bupropion & nortriptyline for smoking cessation among people at risk for or with chronic obstructive pulmonary disease. Arch Intern Med. 2005 Oct 24;165(19):2286-92.
CONCLUSIONS: Bupropion SR treatment is an efficacious aid to smoking cessation in patients with COPD. Nortriptyline treatment seems to be a useful alternative.
Wagner KD, Jonas J, Findling RL, Ventura D, et al. A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression. J Am Acad Child Adolesc Psychiatry. 2006 Mar;45(3):280-8.
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nervosa following weight restoration.
Weissman MM, et al; STAR*D-Child Team. Remissions in maternal depression and child psychopathology: a STAR*D-child report. JAMA. 2006 Mar 22;295(12):1389-98.
Weissman MM, Wickramaratne P, Nomura Y, Warner V, Pilowsky D, Verdeli H. Offspring of depressed parents: 20 years later. Am J Psychiatry. 2006 Jun;163(6):1001-8.
Wernicke JF, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006 Oct 24;67(8):1411-20.
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Xiong GL, et al. Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol. 2006 Jul 1;98(1):42-7. Epub 2006 May 5.
Zarate CA Jr, et al. A randomized trial of an N-methyl-D-aspartate antagonist (ketamine) in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
Zelefsky JR, Fine HF, Rubinstein VJ, Hsu IS, Finger PT. Escitalopram-induced uveal effusions and bilateral angle closure glaucoma. Am J Ophthalmol. 2006 Jun;141(6):1144-7.
Pediatric Pain: Treatment Considerations, Q&As
Common Challenges in Pediatric Pain
Specific Therapeutic Considerations
• Myth: children do not feel pain as their nervous system is not developed 1
• Myth: Let’s get it over with quickly; he won’t remember, he’s scared.
• Failure to anticipate pain. (e.g. urethral caths, NG tube, labwork)
• Failure to assess2 or difficulty in assessing pain in very young
• Fear of masking signs of a more serious etiology ÆNo adverse outcome or
Abdominal acute Opioid does not delay surgical decision appendicitis23;
-consider pain, age, … Relaxed patientÖ better exam & better diagnosis!
Burns, Minor 24 Cold compress x20-30min before applying a dressing.
<5% TBSA in children
Chronic Daily
Headache 25,26
delays in diagnosis attributed to admin of narcotic analgesia in acute abdominal pain3,4,5
• Fear of adverse events & overdose (sedation, respiratory depression)6
• Tendency to underdose (lack of parent/caregiver understanding of toxicity; dosing without dose calculation)7
• Transitioning: maintaining pain control from Recovery to Ward to Home
Ear Ache
-acute otitis media
(AOM): always treat
pain whether
“watchful waiting” or
using antibiotics.
Pain Assessment in Pediatrics
• ↑documenting of pain score assoc. with ↑analgesic use & ↓pain 8
Self-report scales9: 0-10 Numerical age 8+; Faces Pain Scale-Revised FPS-R 10, age 4+
• Observational scales Observe changes from usual in these cues:
Vocal
crying, screaming, yelling, moaning, whimpering
Social
quietness, irritability, difficult to console
Facial
furrowed brow, grimace, clenched teeth, tightly closed eyes
Activity
less movement, agitated, guarding of a body part
Physical pallor, sweat, gasping/breathing change, tense/stiff
Other
changes in sleeping & eating patterns
Give oral analgesic (ibuprofen or acetaminophen)
e.g. tension-type or transformed migraine; see migraine
chart. TCAs, gabapentin, riboflavin, etc. Assess stressors & family hx!
- consider analgesic rebound/overuse (if use >4x/week)
Acetaminophen or ibuprofen (+/- codeine). Ensure
adequate dose, initiate quickly (1st dose in emerg
department/clinic!) Give round the clock x24-48hr.
Warm heat-pad or cloth often helps.
Ear drops: AURALGAN antipyrine & benzocaine: sensitizing; if
perforated ear drum, avoid! Minimally effective but option
Emergency
trauma (ex.
Musculoskeletal)
Heel poke
Immunization*
Reviews: 28,29
{pressure at site helps}
See also FLACC scale: Face/Legs/Activity/Cry/Consolability11; Reviews12,13:
Ibuprofen in musculoskeletal trauma (extremities,
back & neck) better than acetaminophen or
codeine for pain relief and length of relief 27
Opioids suitable if moderate to severe pain
Breastfeeding, sucrose & sucking to ↓ pain
25% oral sucrose & pacifier 2 minutes pre; effective 30
• Distraction/psychological techniques: Cochrane 14 very useful if age appropriate
o toys, books, bubbles, music, humour, TV, imagery, breathing, blowing pinwheel
o parent’s presence; breastfeed during immunization15,16; position for comfort!
• Neonate/infant: bundle, kangaroo care, breast-feed, sucrose + sucking
Toddler: distraction; Older child: preparation, explanation, distraction;
assist parent on how to be calm; non-procedural talk most helpful.
• Sucrose Cochrane 20: best for single painful procedure (infant <6 months5,11,21);
pharmacologic
techniques.
Explain steps if
appropriate
+ distraction. {Administer <2 minutes prior: 2ml of 25% sucrose solution e.g. TOOT Sweet 24%
by oral syringe/dropper into mouth; or allow infant to suck from pacifier/breast. OK if NPO}
: resp.depr <1%}36
Avoid mucous membrane contact or ingestion
AMETOP superior to EMLA for needles 35; Lipisomal
lidocaine MAXILENE effective, fast , less vasoactive
Vapocoolant Spray: PAIN EASE; effect ≤60seconds64
if appropriate regional block (e.g. chest tube), epidural.
*
Preventing pain may decrease analgesic requirement for future procedures!
CAUTION! Calculate doseÖ Öoverdose common - mix-ups e.g. formulation ! [Newborn 4-40wks: Max 60mg/kg/day; may give drops PR for doses ≤80mg]
NSAID: Ibuprofen >6mo 5-10mg/kg q6-8h; Max 40mg/kg/day
may give acetaminophen & NSAID together for pain, not fever
Naproxen
>2yrs
Opioid
Susp 25mg/ml; Tab 125mg
Codeine
Morphine
Soln: 1, 5 mg/mL; Supp: 5, 10mg
Tab: 5, 10mg; (also SR & ER tabs)
Hydromorphone
Fentanyl CAUTION! Adjuncts for Neuropathic
(Ibuprofen: available OTC or by Rx; Naproxen by Rx only.)
2.5-5mg/kg BID; Max 20mg/kg/day;
[PR: 25-49kg: 250mg/dose; ≥50kg: 500mg dose]
0.5-1mg/kg PO q4h (requires metab; ↑SEs)
0.2-0.4mg/kg PO q4h
[ IV: 0.05-0.1mg/kg IV/SC q2-4h]
0.04-0.08 mg/kg PO q3-4h
Alternatives in topical/local anaesthetic allergy?
• True allergy to local anesthetic is rare39; often due to preservative
• Repeated use also ↑’s potential for hypersensitivity reactions
• Consider formulation without preservative if available/suitable40
• If allergy to amide (e.g. lidocaine, bupivicaine, mepivicaine, prilocaine): try
an ester (procaine, tetracaine, benzocaine, cocaine) & vice versa.41
{Allergy to both amide & ester: diphenhydramine1% or benzyl alcohol; efficacy = to 1% lidocaine}
Extras: Drugs for Procedural Sedation (sedative/hypnotic adjuncts)
{↑ in cannulation rate NNT=5; less procedure time 34}
AcetaminophenTYLENOL W 10-15mg/kg q4-6h; Max 75mg/kg/day >40wks Caution if malnourished or dehydrated; ↑ hepatotoxiticy?
{Liquids, chew-tab 80, 160mg, {DropsInfant: 80mg/ml; Liquid: 160mg/5ml
{Loading dose x1: Emerg or post-op option; ≤30mg/kg po;
Tab 325mg;Supp 120mg, 325mg} Supp PR: 15-20mg/kg/dose Max 5 dose/24hr}OTC ≤40mg/kg rectal57; (Toxic single dose <6yrs: ≥200mg/kg)}
Susp 20 & 40mg/ml; Tab 100 & 200mg
Is alternating* acetaminophen with ibuprofen appropriate?
• Not recommended by the Canadian Paediatric Society
• Increased risk of adverse effects & potential for errors
• Monotherapy sufficient & preferred for vast majority38. If not
effective, may switch to or add the other. Mechanisms differ for
pain; may give one round the clock, with other PRN for breakthrough.
• Reassess if pain unresolved; combining analgesics an option in pain
Ketamine: see protocol(s)52; 0.5-2mg/kg IV; onset 1-5 min; duration 15-60min; SE:
nystagmus, disassociative (looks awake but is asleep; inform parents); vivid dreams
x48hrs {add low dose midazolam if ≥10 yrs to prevent nightmares}; ↑BP, HR,
salivation (co-administer atropine with 1st dose)53; rash common but transient.
Rare-Severe SE: laryngospasm, apnea, resp depression; recovery agitation,
Preserves pharyngeal & resp fx. CI: airway instability, URTI, ↑ICP, ↑BP, acute globe
injury, glaucoma, thyrotoxicosis, psych disorder. Age >1yr preferred
N2O:(50/50mix O2, demand valve)∴age >6yrs: quick 3 min,short acting good for IV starts; CI: pneumothorax, bowel obstruction
Fentanyl 1-4ug/kg IV x1 slow over 2 min.; may repeat after 30-60min; rigidity possible with midazolam
Propofol: CAUTION - SIGNIFICANT TOXICITY! Ömetabolic acidosis; ↑BP, ↑death in ICU!
Reserve for anaesthesia. {Procedural sedation: 1mg/kg IVx1 then 0.5mg/kg q3-5min. Age >3yr}
Table 1: Pain Medication in Pediatrics - Overview (See also RxFiles pain related charts at www.RxFiles.ca)
Drug
Dose in Peds [PO unless otherwise indicated] Comments
{Acetaminophen po: Max 90mg/kg/day some refs.}
(PO)
Q&As
purchase; apply prior to appointment. Useful: ↓ pain 40%; (Table 2)
{RCTn=83: infants ↓ pain 3.8 vs 4.8 @7min; return to baseline @ 9min}
Topical anaesthetics: offer option to parents; OTC
Post-op analgesia: Start pain management before child awakens
{Concurrent opioids via IV Multimodal approach: pr naproxen or acetaminophen;
& epidural
www.RxFiles.ca - May/08
– Monitor for Procedural Sedation [check institution or department protocols & be aware of
guidelines / liability implications. Should not be providing sedation & doing procedure.]
Midazolam: as adjunct prior to minor procedures; PO onset 20-40min, duration 1hr;
PO: <20kg: 0.5-0.75 mg/kg x1; ≥20kg: 0.3-0.5mg/kg/dose; Max 10-20mg PO;
Note IV midazolam dose is MUCH lower than PO dose!!! (1/10th the dose)
{IV: 0.05mg/kg/dose IV x1; repeat x1 prn; onset 10min}; SE: disinhibition, paradoxical
agitation, apnea; Caution: ↓ hepatic or renal fx; DIs: CNS depressants ↓ dose of both.
Lumbar puncture * Topical Ametop; po acetaminophen or ibuprofen,
may mix-in po midazolam 1yr +; sucrose if infant
NG Tube insertion Lidocaine jelly; or endotracheal spray if >2yrs (burns & dose caution!)
Open wound32 Anaesthetics: administer topically e.g. LET, direct
(Not near eye!)
local infiltration or regional nerve block. Tetanus status?
Explore to rule out
Tissue adhesive: ↓pain in simple laceration <3cm 33
retained foreign body!
Topical anaesthetics (Table 2): useful but pain
IV insertion*:
relief not complete; takes time to absorb. Place
Use nonin ≥ 2 sites over suitable vein. Use routinely!
Non-pharmacological Tips {↑ coping & pain threshold}
• Pressure on injured or injection sites (e.g. immunizations 10 seconds prior)
• Cold/hot compresses (e.g. cold for sprains, warmth for earache)
• Splinting, elevation, bandaging or dressing (immobilize area & ↓ pain)
• Information giving: brief description, what to expect feels cold/warm, little pinch, will help you!
• NEVER, NEVER use the word needle 22; don’t let them see the needle
Prepared by Loren Regier, Brent Jensen, Beth Kessler -
some concern: long-term use may restrict healing fractures
caution in ↓ renal fx, dehydration & ? bleeding disorder
celecoxib FDA approval: Juvenile RA >2yrs 10-25kg: 50mg po BID
codeine ineffective in ~ 1/3 of kids who can’t metabolize
addiction not an issue when used appropriately for pain
monitor respirations avoid meperidine (dysphoric, seizures)
{reassess/titrate dose; forms: syrup & tab; codeine not PR}
Patch officially CI: <18yrs & opioid naive; {potent; chest wall rigidity in neonates; alternative routes used for incidental pain}
Antidepressants (e.g. TCAs) & Anticonvulsants (e.g. gabapentin): limited evidence, off-label use.
Opioid Reversal: naloxone Narcan Benzo Reversal: Flumazenil (short acting, rarely needed) RA= rheumatoid arthritis SHR= Saskatoon Health
Region AEs= adverse events Crm=cream CI=contraindications PACU= post anesthesia care unit PCA=patient controlled analgesia SE=side effect
{Nasal limited study: faster onset but ↓sedation & duration than po; less effective than intranasal ketamine.51}
ÖRoute of administration: generally use IV, PO; but PR rarely
o Avoid the IM route (add to pain; erratic absorption)56
o PCA pump option in cancer pain for older children anaesthesia referral
o Epidural: option if AEs systemic meds; psychological prep important
ÖDosing: by weight mg/kg or /BSA and by the hour!!!
ÖBe prepared to treat drug side effects as soon as they happen, or
before {e.g. nausea, constipation & itch with opioids; dry mouth mouth care}
Table 2: Topical Anaesthetics** OTC $6; Rx $15 Comments: use only on intact skin; avoid middle ear ototoxic
AMETOP tetracaine (amethocaine) 4% Gel ⊗ 1.5g/ $6 - 15 Apply 30min prior; lasts 4hrs after removal; ?occlusion not required (if old enough to leave on);
[ester] {write time on patch & remove per instructions blistering}
Age: >1mo term infant; Vasodilation(erythema; edema); Refrigerate; 1month @room temp
EMLA lidocaine 2.5%*+ prilocaine 2.5%W: Crm 30g/ $43, Patch 2 / $6 60+ min prior; occlusion required! Age: term infant; vasoconstriction {Rare: risk of
[amide]
methemoglobinemia: ↑ if <3mo; & in <1yr if DI’s that ↑ Met-Hgb risk e.g. sulfonamides}
60+ min prior; occlusion required! {vasoconstriction: venous access more difficult.}
MAXILENE Liposomal* Lidocaine 4% ⊗30g/ $50; 5g/ $6-15 30+ min prior; occlusion not required; minimally vasoactive. (Available: 4% or 5%)
Lidocaine* Crm: 4% ⊗ LMX-4, ELA-Max. {also 5% ?}
Table 3: Other Local Anaesthetics** Comments: 45 minutes for good effect; Avoid mucous membranes 58
LET lidocaine 4% */ epinephrine 0.1% / tetracaine 0.5%
Epinephrine (E): ↑ hemostasis, ↑ anaesthetic duration;
AVOID: digits, nosetip, ear, penis (2° necrosis end artery).
Methylcellulose / epinephrine 0.05% / cocaine 11.8% (SHR)
topical anaesthetic for open wounds esp facial/scalp if <5cm in length; max 3mL
1) mix with cellulose form gel, apply to wound, cover - occlusive dressing
2) place LET soaked cotton ball into wound; apply pressure x20min
mixed solution with methylcellulose forms gel, preventing running; LET preferred!
Local Infiltration: 1) warm anaesthetic 37° C, 2) use smaller gauge needle (e.g. 27 or 30-gauge), 3) inject at slow rate, proximal borders 1st,
from inside wound edge, 4) pre-treat with topical anaesthetic, 5) consider buffering (sodium bicarb 9ml mix with 1ml 1mEq/ml bicarb), 6) pressure
Lidocaine (L): onset rapid; duration ½ hr local
- {duration 1-2hr if regional block}; Age 3yrs+ [ L: 0.5%, 1%, 2%; L+E: 1%, 2%; (L+E no preservative:1.5%)]
Mepivacaine: onset 6-10min; duration1-3hrs;
- if Age <3yrs or weight <13.6kg, use [0.5-1.5%};
- little vasodilation & epinephine seldom needed
Bupivacaine (B): onset 8-12min; duration 4-6hr;
Age 12yrs+ ; CI: sulfite allergy
[B: 0.25%, 0.5%; B+E: 1%, 2%]
*avoid if amide allergy (rare); ** systemic toxicity (cardiac & CNS) possible but rare with appropriate use: (careful with dose & site).
Rx coverage : =Exception Drug Status in SK =Non-formulary in SK =prior approval for NIHB ⊗=not covered by NIHB W=covered by NIHB (Indian Affairs)
Extras, Links & References:
AMETOP: tetracaine (amethocaine) 4% Gel : Adults (including geriatrics) & children over 1 month EMLA (lidocaine and prilocaine) - for intact skin, requires occlusion, needs to be
of age: Apply contents of the tube to the skin starting from the centre of the area to be anesthetized
applied for at least one hour Dose — To attain adequate anesthesia, 1 to 2 g of EMLA
cream should be applied per 10 sq cm (approximate size of a Canadian “toonie”) of skin and
& cover with an occlusive dressing. The contents expellable from 1 tube (approximately 1 g) will cover
2
& anesthetize an area of up to 30cm (6×5 cm {~ 3/4 area of a credit card}). Smaller areas of anesthetized
covered with an occlusive dressing for 45 to 60 minutes. The maximum application areas
recommended for children are Less than 10 kg —100 sq cm {~ 2.5x area of a credit card};10 to 20
skin may be adequate in infants & small children. Adequate anesthesia can usually be achieved for
kg — 600 sq cm; Greater than 20 kg — 2000 sq cm ; causes vasoconstriction.
venepuncture following a 30-minute application time, & for venous cannulation following a 45-minute
application time; after which the gel should be removed with a gauze swab & the site prepared with
an antiseptic wipe in the normal manner. It is not necessary to apply tetracaine gel for longer than
See www.usask.ca/pediatrics/services/pain for
the above times & anesthesia is maintained for 4 to 6 hrs in most patients after a single application.
[Clinical Trial in progress: Ametop vs Maxilene: http://www.druglib.com/trial/02/NCT00353002.html ]
information for parents on children’s pain
Benzocaine –in NG tube placement controversial10 Causes methemoglobinemia!!! AVOID!
Lidocaine iontophoresis {Numby Stuff}: mild electric current penetrates skin more quickly;
effective in 10-20min. 59 EMLA similar or slightly better.60,61 (Tingle may be bothersome.)
TAC tetracaine 0.5% / epinephrine 0.05% / cocaine ≤ 11.8%, AE: seizures, arrhythmias, fatal; requires
narcotic storage (LET preferred)
Cancer Pain: Reference 62
Urethral Catheterization: lidocaine gel 2 min prior to insertion while setting up
then use as the lubricant as well (video: http://www.uihealthcare.com/topics/medicaldepartments/urology/catheterization/index.html)
Acetaminophen vs ibuprofen: http://www.cps.ca/English/statements/DT/dt98-01.htm For fever:63
SHR Peds Pain Links: http://www.usask.ca/pediatrics/services/pain/
CADTH. Short-Acting Agents for Procedural Sedation and Analgesia in Canadian Emerg.:
A Review of Clinical Outcomes and Economic Evaluation http://cadth.ca/media/pdf/O0428_Short-Acting-Procedural-Sedation_to_e.pdf
References {RxFiles Pediatric Pain Chart: Treatment Considerations, Q&As}
Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987 Nov 19;317(21):1321-9. {Also: Finley, G.A., Franck, L.S., Grunau, R.E., & von
Baeyer, C.L. (2005). Why children's pain matters. International Association for the Study of Pain. Pain: Clinical Updates, XIII(4), 1-6. Online (PDF) available at http://www.iasppain.org/AM/Template.cfm?Section=Resources1&Template=/CM/ContentDisplay.cfm&ContentID=2265 ; Razzaq Q. The underuse of analgesia and sedation in pediatric
emergency medicine. Ann Saudi Med. 2006 Sep-Oct;26(5):375-81.}
2 Taylor EM, Boyer K, Campbell FA. Pain in hospitalized children: A prospective cross-sectional survey of pain prevalence, intensity, assessment and management in a Canadian
pediatric teaching hospital. Pain Res Manag. 2008 Jan-Feb;13(1):25-32.}
3 McHale PM, LoVecchio F. Narcotic analgesia in the acute abdomen--a review of prospective trials. Eur J Emerg Med. 2001 Jun;8(2):131-6.
4 Ann Emerg Med. 2007 Oct;50(4):371-8. Epub 2007 Jun 27.Efficacy and impact of intravenous morphine before surgical consultation in children with right lower quadrant pain
suggestive of appendicitis: a randomized controlled trial. Bailey B, Bergeron S, Gravel J, Bussières JF, Bensoussan A.
5 Thomas SH, Silen W. Br J Surg 2003;90(1):5-9.& J Fam Pract. 2003;52(6):435-6. Effect on diagnostic efficiency of analgesia for undifferentiated abdominal pain.
6 Zempsky WT, Cravero JP. Relief of pain and anxiety in pediatric patients in emergency medical systems. Pediatrics. 2004 Nov;114(5):1348-56.
7 Dlugosz CK, Chater RW, Engle JP. Appropriate use of nonprescription analgesics in pediatric patients. J Pediatr Health Care. 2006;20(5):316-25; quiz 326-8.
8 Drendel AL, Brousseau DC, Gorelick MH. Pain assessment for pediatric patients in the emergency department. Pediatrics. 2006 May;117(5):1511-8.
9 von Baeyer CL. Children's self-reports of pain intensity: scale selection, limitations and interpretation. Pain Research and Management 2006;11(3):157-62.
10 Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain
2001;93(2):173-83 Available online at: http://painsourcebook.ca/docs/pps92.html See thumbnail of scale at lower right of page.
11 Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997 May-Jun;23(3):293-7.
Accessible online: http://www.childcancerpain.org/content.cfm?content=assess08
12
Stinson JN, Kavanagh T, Yamada J, Gill N, Stevens B. Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use
in clinical trials in children and adolescents. Pain 2006;125(1-2):143-57.
13 von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children & adolescents aged 3 to 18 years. Pain 2007;127:140-50.
14 Uman LS, Chambers CT, McGrath PJ, Kisely S. Psychological interventions for needle-related procedural pain and distress in children and adolescents. Cochrane Database of
Systematic Reviews. 2006 Oct 18;(4):CD005179.0
15 Shah PS, Aliwalas L, Shah V. Breastfeeding or breastmilk to alleviate procedural pain in neonates: a systematic review. Breastfeed Med. 2007 Jun;2(2):74-82. Shah PS, Aliwalas
LI, Shah V. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004950
16 Efe E, Ozer ZC. The use of breast-feeding for pain relief during neonatal immunization injections. Appl Nurs Res. 2007 Feb;20(1):10-6.
20 Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev. 2004;(3):CD001069.
21 Acad Emerg Med. 2006 Jun;13(6):617-22. Epub 2006 Apr 24. A randomized, controlled trial of sucrose analgesia in infants younger than 90 days of age who require bladder
catheterization in the pediatric emergency department.Rogers AJ, Greenwald MH, Deguzman MA, Kelley ME, Simon HK.
22 Lakeside clinic medical staff: {Quote: “I usually tell them I'm going to have to pinch them for a second (again no need to know the pinch is a needle) and that I'm going to put some
magic potion on the cut so it doesn't hurt anymore. Parents can read to them from a BIG picture book if the wound is below their eyes, which also blocks their view of what I'm
doing. Also, when inserting a needle, the tissue edge of the wound has no pain receptors, so entering the tissue from the wound edge, rather than going through skin is helpful.
They still feel the burn of the local, but not the sharpness of the needle. Local kept in a warming cupboard or neutralized with bicarb is less painful too. Kids LOVE to talk about
themselves--so asking lots of questions about who they play with, what their favorite things are, etc is a big distraction.” }
23 Bailey B, Bergeron S, Gravel J, Bussières JF, Bensoussan A. Efficacy & impact of intravenous morphine before surgical consultation in children with right lower quadrant pain
suggestive of appendicitis: a randomized controlled trial. Ann Emerg Med. 2007 Oct;50(4):371-8.
24 Singer et al. Management of Local Burns in the ED. The Am J of Emerg Med 2007;25:666-71. Estimation of burn size for PDA: http://www.sagediagram.com/
25 Moore AJ, Shevell M. Chronic daily headaches in pediatric neurology practice. J Child Neurol. 2004 De c;19(12):925-9.http://www.medscape.com/viewarticle/501997_print
26 Gunner KB, Smith HD. Practice guideline for diagnosis & management of migraine headaches in children & adolescents: Part 2. J Pediatr Health Care 2008;22:52-9.
27Clark E, Plint AC, Correll R, Gaboury I, Passi B. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma.
Pediatrics. 2007 Mar;119(3):460-7. Comment in: Evid Based Med. 2007;12(5):144. Pediatrics. 2007;120(1):237; author reply 237-8.
28 Schechter NL, Zempsky WT, Cohen LL, McGrath PJ, McMurtry CM, Bright NS. Pain reduction during pediatric immunizations: evidence-based review and recommendations.
Pediatrics. 2007 May;119(5):e1184-98.
29 Taddio A, Manley J, Potash L, Ipp M, Sgro M, Shah V. Routine immunization practices: use of topical anesthetics & oral analgesics. Pediatrics 2007;120(3):e637-43.
30 Hatfield LA, Gusic ME, Dyer AM, Polomano RC. Analgesic properties of oral sucrose during routine immunizations at 2 and 4 months of age. Pediatrics. 2008;121.
32 O'Sullivan R, Oakley E, Starr M. Wound repair in children. Aust Fam Physician. 2006 Jul;35(7):476-9.
33 Farion KJ, Osmond MH, Hartling L, Russell KF, Klassen TP, Crumley E, Wiebe N. Tissue adhesives for traumatic lacerations: a systematic review of randomized controlled trials.
Acad Emerg Med. 2003 Feb;10(2):110-8. Review.
34
Taddio A, Soin HK, Schuh S, Koren G, Scolnik D. Liposomal lidocaine to improve procedural success rates and reduce procedural pain among children: a randomized controlled
trial. CMAJ. 2005 Jun 21;172(13):1691-5.
35 Lander JA, Weltman BJ, So SS. Cochrane Database 2006;19;3:CD004236.EMLA & amethocaine for reduction of children's pain associated with needle insertion.
36 Anghelescu DL, Ross CE, Oakes LL, Burgoyne LL. The Safety of Concurrent Administration of Opioids via Epidural and Intravenous Routes for Postoperative Pain in Pediatric
Oncology Patients. J Pain Symptom Manage. 2008 Feb 19; [Epub ahead of print] PMID: 18291619
38 Therapeutic Dilemma Alternating acetaminophen and ibuprofen. L Shortridge, V Harris February 2007, Volume 12 Issue 2: 127-128
39 1: Eggleston ST, Lush LW. Understanding allergic reactions to local anesthetics. Ann Pharmacother. 1996 Jul-Aug;30(7-8):851-7.
40 DeBoard RH, Rondeau DF, Kang CS, et al. Principles of basic wound evaluation & management in the emergency department. Emerg Med Clin North Am. 2007;25:23-39.
41 Therapeutic Choices 5th ed. Canadian Pharmacists Association 2007. Editor J Gray. (pg 201).
51 Nasal Midazolam for Sedation in Pediatric Patients Prior to Invasive Procedures. CADTH HTIS. Email: [email protected]
52 PA protocols - in PA Pearls January 1999. Accessed online at: http://www.erpearls.com/content/publications/01%20PA%20Pearls%20JAN%2099.pdf
53 Confirmed by Emergency Medicine: A Comprehensive Study Guide – 6th Ed(2004) through StatRef http://online.statref.com.cyber.usask.ca/document.aspx?fxid=80&docid=949
56 Acute Pain Management And Procedural Sedation In Children - Michael N. Johnston, Erica L. Liebelt (STAT REF)
57 Birmingham PK, Tobin MJ, Fisher DM, et al. Initial & subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations.
Anesthesiology. 2001;94:385-9. {See also: Kleiber C. Acetaminophen dosing for neonates, infants, & children. J Spec Pediatr Nurs. 2008;13:48-9. }
58 Emslander HC. Local and topical anesthesia for pediatric wound repair: a review of selected aspects. Pediatr Emerg Care. 1998 Apr;14(2):123-9.
59 UPTODATE reference on topical anaesthesia (2006) (http://www.uptodate.com/home/index.html)
60 Eur J Anaesthesiol. 2004 Mar;21(3):210-3.3 Comparison of EMLA and lidocaine iontophoresis for cannulation analgesia.Moppett IK, Szypula K, Yeoman PM
61 Galinkin JL, Rose JB, Harris K, Watcha MF. Lidocaine iontophoresis versus eutectic mixture of local anesthetics (EMLA) for IV placement in children. Anesth Analg. 2002;94:1484-8.
62 Pediatric Cancer Pain; Access: http://www.nccn.org/professionals/physician_gls/PDF/pediatric_pain.pdf ; National Comprehensive Cancer Network (NCCN) ; 2006
63 Sarrell EM, Wielunsky E, Cohen HA. Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch
Pediatr Adolesc Med. 2006 Feb;160(2):197-202
64 Farion KJ, Splinter KL, Newhook K, Gaboury I, Splinter WM. The effect of vapocoolant spray on pain due to intravenous cannulation in children: a RCT. CMAJ. 2008;179:31-6.
1
Pain Intensity Scoring:
Chose a scale that is age appropriate to patient & become familiar with using!
Interpret in light of any other pain related physical factors (e.g. heart rate)
Also interpret according to trends for improvement or worsening of pain control
Sherbrooke algorithm for acute pain in children (post-op): gave regular analgesic
according to pain scale: {0-3: acetaminophen; 3-6: naproxen + acetaminophen; 6-9: morphine +
naproxen + acetaminophen; 9-10: notify MD. Overall ↓ in pain scores & a ↓ in opioid requirement.}
Other links: Visual Analogue Scale: suitable for age 7+ {McGrath PA, Seifert CE, Speechley KN, et al. A new analogue scale for
assessing children's pain: an initial validation study. Pain. 1996 Mar;64(3):435-43.} Oucher Scale: age 3-12: http://www.oucher.org/history.html
FLACC SCALE – for assessing postop pain in very young children
Face
Legs
Activity
Cry
Consolability
No particular
expression or smile
Normal position or
relaxed
Lying quietly, normal
position, moves easily
No cry (awake or
asleep)
Content, relaxed
Occasional grimace or frown,
withdrawn, disinterested
Uneasy, restless, tense
Frequent to constant
quivering chin, clenched jaw
Kicking, or legs drawn up
Squirming, shifting back and forth,
tense
Moans or whimpers; occasional
complaint
Reassured by occasional touching,
hugging or being talked to, distractible
Arched, rigid or jerking
Crying steadily, screams or
sobs, frequent complaints
Difficult to console or
comfort
Each of the five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability is scored from 0-2, which results in a
total score between zero and ten.
From The FLACC: A behavioral scale for scoring postoperative pain in young children, by S Merkel and others, 1997,
Pediatr Nurse 23(3), p. 293-297. Copyright 1997 by Jannetti Co. University of Michigan Medical Center.
Faces Pain Scale – Revised (FPS-R) – age 4+
This is a thumbnail image. The full-size FPS-R with instructions is available on page 3 at
http://painsourcebook.ca/pdfs/pps92.pdf Numbers are not shown to children.
0
2
4
6
8
10
From: Hicks CL, von Baeyer CL, Spafford PA, Van Korlaar I, Goodenough B. The Faces Pain Scale – Revised. Toward a common metric in
pediatric pain measurement. Pain 2001;93:173-183. ©2001 International Association for the Study of Pain. Reprinted with permission.
Acknowledgements: External Contributors & Reviewers: K. Baerg BSN, MD (SHR-Peds), J. Cross MD, Carl L von Baeyer PhD, J. Rozdilsky RN
(Nurse Educator, RUH), S. Weins (SHR Ped Anesthesia), C. Bell (SDIS Drug Info, U of S), R. Siemens MD (SHR-Ped Emerg), F. Martino MD
(Brampton), the SHR Pediatric Pain Committee & the RxFiles Advisory Committee. Prepared by: L. Regier BSP, BA, B. Jensen BSP, B Kessler
DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region (SHR). Neither the authors nor Saskatoon
Health Region nor any other party who has been involved in the preparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or
omissions or for the result obtained from the use of such information. Any use of the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR, its employees, servants or agents. Readers are
encouraged to confirm the information contained herein with other sources. Additional information and references online at www.RxFiles.ca
Copyright 2008 – RxFiles, Saskatoon Health Region (SHR) www.RxFiles.ca
OPIOID ANALGESIC: COMPARISON CHART 1,2,3,4,5 ,6
Route
receptor
target
Morphine SR (12h)
PO
PR
Morphine Supp
Morphine Inj.
}
SC/IM/IV
mu
Fentanyl {50ug/hr=5mg total patch} Transdermal
{If skin irritation: steroid spray, or allow 1min for EtOH to evaporate}
Fentanyl / Sufentanil - SL
⊗
HYDROmorphone mu
PO
HYDROmorphone SR (12h) PO
MOS-SR
M-ESLON
KADIAN
Tab: 30,60mg
Cap: 10,15,30,60,100,200mg
STATEX supp
Supp: 5, 10, 20, 30mg
MORPHINE
Amp: 5,10,15,25,50 mg/ml
Syringe: 50ml X 50mg/ml
Patches:12,25,50,75,100 ug/hr
Cap: 10mgW,20,50,100mg
PO / PR
Methadone 1ς,5ς,10ς,25ςmg tab; 1mg/ml susp PO
mu & NMDA
Meperidine
PO
or
Meperidine Inj. Pethidine IM/SC/IV
HYDROMORPH- CONTIN DILAUDID,generic
DILAUDID
Cap: 3,6,12,18,24,30 mg
(may sprinkle contents)
Supp: 3mg
Inj: 2mg/ml; 10mg/ml;
20mg/ml; 50mg/ml;
Sterile Powder: 250mg
Tab: 5,10,20,40,80mg
Tab: 5ς,10ς,20ς mg
Tab:5ς,10ς,20ς mg; SuppW:10,20mg
DEMEROLW
642
DARVON-N
CODEINE
Amp:50,100mg/ml; (25,75 mg/ml)
⊗
⊗
Tab: 65mg
Cap: 100mg (=65mg propox.)
Tab: 15,30ς mg; Syrup: 5mg/ml
CODEINE CONTIN
Tab: 50,100ς,150ς,200ς mg
CODEINE
W
Amp: 30,60mg
Elix: A. 320mg+C. 16mg/10ml
Tab: A. 300mg+C. 8mg +Cf.15mg
Tab: A. 300mg+C. 15mg +Cf.15mg
Tab: A. 325mg+C. 15ς & 30ςmg
Tab: A. 300mg+C. 30mg +Cf.15mg
Tab: A. 300mg+C. 60mg
20mg po q4h
12 h
60mg po q12h
morphine: gold standard for opioids;
{M-6-G metabolite-↑SEs if renal dysfx
may sprinkle M-Eslon or Kadian
MS Contin may also be given pr
↑side effects in pts with renal failure
MS Contin,PMS & RATIO Morphine SR
are ONLY interchangeable SR products.
addiction to opioids rare when no
drug abuse hx & when used for pain
management; consider guidelines for
chronic pain & treatment agreements.
78g-120 25ug/hr ≅ 90mg oral morphine/dayDI 3A4
140g-230 not suitable for opioid naïve, acute pain, <18yrs
C/D
24 h
100mg po q24h
$76
$76
$78
$64
$71
$96
acute dosing)
4h
20mg pr q4h
$459
10mg Inj.
4h
in chronic
dosing
* (≤60mg in
(q8-12h)
10mg sc q4h
$197
(as high as 7.5mg;
wide variation in
po bioavailability
e.g. <30 - >90%)
2-3mg
(as low as 1.5mg)
12 h
12mg po q12h
$125
4h
3mg pr q4h
$460
4h
1.5-2mg sc q4h
$250
(q8-12h)
quick acting & very short duration
may have less SE's than morphine in
some patients (ie. sedation, nausea, const.)
"SC Pain Pump" option
Palladone XL not avail.,Kadian? & Avinza in USA:
(EtOH may dramatically ↑↑ levels)7
use laxatives (e.g. senna, lactulose)
to prevent constipation; consider shortterm/prn antinauseant in patients at risk.
375mg/30mg/30 mg; 375mg/15mg/30 mg
75mg
100mg?
150mg?
200mg
120mg
2-3 h
2-3 h
2-3 h
4h
12 h
4h
≤200mg C.
4+ h
≤200mg C.
4+ h
50mg im q3h
65mg po q4h
100mg po q4h
60mg po q4h
150mg po q12h
30mg sc q4h
20ml po q6h
ii tab po q4-6h
"
"
"
ii tab po q4-6h
$255
$30
$79
$40
$70
$210
$300
$25
$35
$35
$35
$75
$80
frequent dosing. Metabolites accumulate esp.
in ↓renal fx; ⇒ CNS toxicity: tremor, seizures
Max 390mg prop. plain/day; abuse risk
DIs!!: alcohol & CNS depressants.
Codeine: weak opioid; avoid doses over
800mg po; practical analgesic ceiling
≅200mg po or 120mg im /d where low
doses of stronger opioids may be more
effective & better tolerated than codeine
antitussive at dose of ≥15mg q4-6h
C/D
may cause ↑ constipation & GI upset;
caution with combination agents:
-risk of: hepatotoxicity with >4g/d of
acetaminophen; GI bleed with ASA
concern with breastfeeding in rapid p450 metabolizers
: 150, 200, 300 & 400mg tab od $60-140; TRIDURAL/RALIVIA: 100, 200, 300mg tab od $45-110, ⊗, Once daily dosing. (Not recommended for children <18yrs or pts with seizure history), {100mg ≈ 10-20mg po morphine?}
Low affinity for mu; also ↑serotonin & noradrenaline, Metabolized to active metabolite by CYP2D6
ς W
4h
Reassess regimens frequently when starting!
⇒
ZYTRAM XL
Oral
20-30mg
Oct 08
Comments
OXYCONTIN
$97 biphasic;↑abuse concern;↑SE if ultra-rapid 2D6 met.
10-15mg
8-12 h
20mg po q12h
=oxycodone 5mg + acetamin.325mg]
$86 [Percocet ςς W
OXY-IR
4-6h
15mg po q6h
[Percodan W=oxycodone 5mg + ASA 325mg]
Misuse/abuse? FDA Potential Risk List-Mar08
(cost based on 1½ x 10mg)
SUPEUDOL
tx of opioid dependence; useful for opioid rotation & pain+addiction; require special license; long-acting, complicated dosing; Resp depression,↑QT. {SK: Pall Care only} mu, δ, NMDA; ↑serotonin & noradrenalin
DEMEROLW 60 tabs/month;2 weeks Tab: 50ς mg (poorly absorbed!)
$85 not for chronic pain: short acting, requires
300mg
2-3 h
100mg po q3h
TYLENOL + C. Elixir
TYLENOL # 1 Non-Rx ⊗
+Codeine (C.) +/- Caffeine (Cf)
TYLENOL
#2 /Ratio#2
Codeine: morphine prodrug; requires CYP2D6 metabolism;
~10% genetically deficient; CYP inhibitors can ↓ analgesic ATASOL 15 & 30
effect (ie fluoxetine, paroxetine, Haldol). Ultra-rapid metabolizers TYLENOL # 3/Ratio #3
(ie Ethiopians39%, Saudi Arabians20%, Spaniards10%) have ↑ SE’s
TYLENOL # 4/Ratio #4
292 ς ; 282 ς Tabs W
ASA/Codeine/Caffeine
PO
Tramadol -long acting tablet:
~ duration
$
/30d
Weak Opioids
Propoxyphene
PO
Propoxyphene napsylate
PO
Codeine
PO
mu
Codeine SR (12h)
PO
Codeine Inj.
IM
Acetaminophen (A.)
PO
Dose
Comparative
Dose & Cost
Strong Opioids
mu & κ
Interval
DURAGESIC ,generic see comments
72 h
25ug/hr q72h
Patch; heat ↑absorption rate (Initial onset delayed ~12-24hr. Matrix Ratio; Reservoir Ran; Duragesic (q48-72h)
50ug/hr q72h
inj. form given SL for breakthrough/incidental pain (5min prior to transfers/position change); {USA: FENTORA bucal, ACTIQ lozenge}
$55
DILAUDID
Tab: 1,2,4,8ςmg
4-6mg
4h
4mg po q4h
Oral Liquid: 1mg/ml
$63
IV may be slightly more potent than SC
PO
PO
Equivalent
⇐
HYDROmorphone Supp
PR
HYDROmorphone Inj. SC/IM/IV
Oxycodone SR (12h)
Oxycodone regular
Oral Soln: 1,5,10,20,50Wmg/ml
Tab:5,10,20,25,30,40,50,60mg
MS CONTIN/PMS, RATIO SR,Novo Tab:(15,30,60) 1st 3 brands,100,200ς mg
PO
Morphine SR (24h)
Prepared by: Loren Regier - © www.RxFiles.ca
Dosage Forms
⇐
M.O.S;
MS-IR; STATEX
PO
mu
TRADE Name(s)
Pregnancy Category
Opioid
Generic name
Morphine
.
[Acetaminophen 325mg + Tramadol 37.5mg]=TRAMACET ⊗: New 2005. 2 tabs po q4-6h ~ $175/mo (Max 8 tabs/day).
Pentazocine TALWIN
- Tab: 50
mg (50mg po q4h $90
; Amp: 30mg (30mg im q4h $280
) less effective than NSAIDs & other opioids; agonist-antagonist (mu & κ): can cause withdrawal in pts on opioids.
Buprenorphine partial mu agonist/ κ antagonist + Naloxone mu, κ antagonist SUBOXONE 2 /0.5mg, 8 /2mg SL tab: Tx of opioid dependence; require special license; start 4 mg/day SL ≥4hr after last opiate; ↑or↓ by 2 - 4 mg to maintain patient & ↓withdrawal; range 4 to 24 mg/day. SE: sweat,GI,HA,↓BP; hepatic. DI: 3A4 inhibitors;BZDs,opiates,CNSdepressants C/B1
Max: 600mg/d
W
Max: 360mg/d
=dose listed not equivalent =EDS Sask =Non Formulary Sk Cost=to SK consumer ς=scored tab d=day =prior NIHB Wcovered NIHB CTZ=chemoreceptor trigger
zone OTC=over the counter. Adverse Rx's: nausea, constipation Tx: senna; methylnaltrexone 12mg sc EOD prn RELISTOR $40/dose,sedation, confusion/CNS effects, sweating, miosis, resp depression, myoclonus, urine retention, dry mouth, hormonal (e.g. ↓testosterone & cortisol, ↑prolactin) & pruritus.
* with chronic admin., equivalent po morphine dose is ~2-3X the inj. dose but in acute pain, it may be ≤ 6X;
Use short acting formulations PRN for breakthrough pain eg. 10-15% of total dialy dose. Chronic opioid therapy in pts with renal dysfx= may lead to accumulation of toxic metabolites (esp. meperidine); switching opioids or opioid rotation
strategies may be useful. Drug Interactions: CNS depressants (e.g. alcohol, sedatives, neuroleptics). Patients intolerant to the side effects of one opioid may be changed to a ≤ dose of another; True morphine allergy is very rare.
Switching opioids, often 25-50% less than equivalent is given to account for incomplete cross-tolerance. SC Pain Pumps available. Adjunct Options NSAIDs, antidepressantsTCA, anticonvulsants; dexamethasone 10mg sc/po bid.
Antinauseants: metoclopramide 10mg po/sc q4h prn, domperidone 5-10mg po tid ac (affect CTZ & GI motility); haloperidol 0.5-1mg po/sc bid prn (CTZ); prochlorperazine 5-10mg im/iv/po/pr q6h prn (effects CTZ but sedating); dimenhydrinate 25-50mg po/im/iv/sc/pr q6h prn
Opioid Immunoassay
Synthetics (meperidine, fentanyl series, propoxyphene, methadone) will be opiate negative and must be ordered independently. Semi-synthetics (hydrocodone, oxycodone, hydromorphone, oxymorphone,
(Urine):
buprenorphine) may be opiate positive or negative, depending on the threshold. Interpret false negatives with caution. Drug specific confirmatory testing may be required. Opiates may be detectable for a couple of days.
60
OPIOID ANALGESIC: COMPARISON CHART
1
Ballantyne JC, Mao J. Opioid Therapy for Chronic Pain. N Engl J Med. 2003 Nov 13;349(20):1943-1953.
Micromedex 2008
3
Hansten, PD and Horn JR. Drug Interactions Analysis and Management. Applied Therapeutics Incorporated. Vancouver, WA. 2008.
4
Drugs in Pregnancy & Lactation 8th edition, 2008.
5
Morrison, R. Sean, Meier, Diane E., Palliative Care. N Engl J Med 2004 350: 2582-2590.
6
Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005 Mar 31;352(13):1324-34. (InfoPOEMs: The combination of gabapentin &
2
morphine provides a small but clinically unimportant benefit over either drug alone. Tricyclic antidepressants have been shown in other studies to be as effective as gabapentin & much less expensive, but were not studied in this trial. (LOE = 1b) )
7
Health Canada Aug 2005 http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2005/2005_84_e.html (Long-Acting Opioids and a New Type of Alcohol Warning. Pharmacit's
Letter. Dec 2005).
8
Other Opioid Conversion (e.g. tramadol): http://databaseinnovationsdraft.com/OpioidConversionChart2007.pdf
Additional references:
Analgesic options for patients with allergic-type opioid reactions. Pharmacist’s Letter/Prescriber’s Letter 2006;22(2):220201.
Carise D, Dugosh KL, McLellan AT, et al. Prescription OxyContin Abuse Among Patients Entering Addiction Treatment. Am J Psychiatry. 2007 Nov;164(11):1750-6.
Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of
randomized controlled trials. JAMA. 2005 Jun 22;293(24):3043-52. CONCLUSIONS: Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies
demonstrate significant efficacy of opioids over placebo for neuropathic pain, which is likely to be clinically important. Reported adverse events of opioids are common but not life-threatening. Further RCTs are needed to establish their long-term efficacy, safety (including addiction
potential), and effects on quality of life.
Ehret GB, et al. Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone: High Frequency in Hospitalized Patients and Risk Factors. Arch Intern Med. 2006
Jun 26;166(12):1280-7.
Fiellin DA, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006 Jul 27;355(4):365-74. (InfoPOEMs: More intensive counseling and more
frequent medication dispensing does not improve outcomes for treatment of opioid dependence in the primary care setting. (LOE = 1b))
Finkel JC, et al. Ketamine as an adjuvant for treatment of cancer pain in children and adolescents. J Pain. 2007 Jun;8(6):515-21. Epub 2007 Apr 16. In many children with advanced stages of cancer, pain
control remains inadequate. We used subanesthetic doses of ketamine to treat 11 children & adolescents who were on high doses of opioids and had uncontrolled cancer pain. In the majority of patients, ketamine appeared to improve pain control and to have an opioid-sparing effect.
Foral PA, Malesker MA, Huerta G, Hilleman DE. Nebulized opioids use in COPD. Chest. 2004 Feb;125(2):691-4.
Fulda GJ, Giberson F, Fagraeus L. A prospective randomized trial of nebulized morphine compared with patient-controlled analgesia morphine in the management of acute thoracic
pain. J Trauma. 2005 Aug;59(2):383-8; discussion 389-90.
Gana TJ, et al. The 023 Study Group. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med
Res Opin. 2006 Jul;22(7):1391-401.
Gowing L, et al. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002022. Heavy sedation compared to
light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of commencement on naltrexone maintenance treatment. Given that the adverse events are potentially life-threatening, the value of antagonist-induced withdrawal under heavy
sedation or anaesthesia is not supported. The high cost of anaesthesia-based approaches, both in monetary terms and use of scarce intensive care resources, suggest that this form of treatment should not be pursued.
Green R, Bulloch B, Kabani A, Hancock BJ, Tenenbein M. Early analgesia for children with acute abdominal pain. Pediatrics. 2005 Oct;116(4):978-83. (InfoPOEMs: The immediate administration of
morphine in children aged 5 years to 16 years with acute abdominal pain does not obscure the diagnosis of appendicitis and does not affect the surgeon's confidence in his or her diagnosis. It also causes a small decrease in pain. As with adults, pain relief should not be withheld in
children until the cause of the pain is determined. (LOE = 2b) )
Jansson LM, Choo R, Velez ML, et al. et al. Methadone maintenance and breastfeeding in the neonatal period. Pediatrics. 2008 Jan;121(1):106-14. (n=8) Results contribute to the
recommendation of breastfeeding for methadone-maintained women.
Kokki H, Lintula H, Vanamo K, et al. Oxycodone vs placebo in children with undifferentiated abdominal pain: a randomized, double-blind clinical trial of the effect of analgesia on
diagnostic accuracy. Arch Pediatr Adolesc Med 2005;159:320-25. (InfoPOEMs: Giving analgesics to children with abdominal pain does not obscure the surgical diagnosis. We don't need to make kids suffer while waiting
for a surgeon to evaluate their abdominal pain. (LOE = 2b) )
Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006 Aug 19;368(9536):704.
Madadi P, Koren G, et al. Safety of codeine during breastfeeding. Canadian Family Physician. Vol 53 Jan 2007 p33-35..
Lynch M. A review of the use of methadone for the treatment of noncancer pain. Pain Res Manage 2005;10(3):133-44.
Marsch LA, et al. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch Gen Psychiatry. 2005 Oct;62(10):1157-64.
Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2008 Apr
16;(2):CD002207. Buprenorphine is an effective intervention for use in the maintenance treatment of heroin dependence, but it is less effective than methadone delivered at adequate dosages.
Medical Letter: Treatment guidelines. Drugs for Pain April 2007.
Methadone: a focus on safety. Pharmacist’s Letter Sept 2006. (FDA Nov/06 warning http://www.fda.gov/cder/drug/InfoSheets/HCP/methadoneHCP.htm )
Mora B, et al. Transcutaneous electrical nerve stimulation: an effective treatment for pain caused by renal colic in emergency care. J Urol. 2006 May;175(5):173741; discussion 1741. (InfoPOEMs: Local transcutaneous electrical nerve stimulation (TENS) is a rapid and effective nondrug treatment for pain caused by renal colic. TENS may be most useful in the difficult circumstance of out-of-hospital rescue. (LOE = 1b) )
Nicholson B. Morphine sulfate extended-release capsules (Kadian) for the treatment of chronic, moderate-to-severe pain. Expert Opin Pharmacother. 2008 Jun;9(9):1585-94.
Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003971.
Pharmacist’s Letter Oct 2006. Alternative or Off-label Routes of Drug Administration. (Rectal administration of: Ms Contin, OxyContin; Sublingual administration of: methadone,
fentanyl & buprenorphine; Inhalational use of morphine, hydromorphone & fentanyl)
Pharmacist’s Letter Suboxone (buprenorphine / naloxone 2/0.5mg & 8/2mg sl tabs) Dec 2007.
Patanwala AE, Duby J, Waters D, Erstad BL. Opioid conversions in acute care. Ann Pharmacother. 2007 Feb;41(2):255-66. Epub 2007 Feb 13. Review. Erratum in: Ann
Pharmacother. 2007 Mar;41(3):531. Access online at: http://www.theannals.com/cgi/content/abstract/41/2/255
Ranji SR, Goldman LE, Simel DL, Shojania KG. Do opiates affect the clinical evaluation of patients with acute abdominal pain? JAMA. 2006 Oct 11;296(14):1764-74.
(InfoPOEMs: Opiate analgesia for adults and children presenting with acute abdominal pain may alter the physical examination, but does not increase the risk of management errors. Since most patients prefer pain control, it makes sense to abandon the outdated and incorrect
practice of withholding opiate analgesia from patients with acute abdominal pain. (LOE = 1a) )
Reid CM, et al. Oxycodone for cancer-related pain: meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Apr 24;166(8):837-43.
Safdar B, et al. Intravenous morphine plus ketorolac is superior to either drug alone for treatment of acute renal colic. Ann Emerg Med. 2006 Aug;48(2):173-81, 181.e1.
(InfoPOEMs: Intravenous morphine 5 mg combined with ketorolac (Toradol) 15 mg provided greater pain relief than either drug alone. The combination did not increase the likelihood of nausea or vomiting. (LOE = 1b))
Schwartz RP, Highfield DA, Jaffe JH, et al. A randomized controlled trial of interim methadone maintenance. Arch Gen Psychiatry. 2006 Jan;63(1):102-9.
See also RxFiles Newsletter – Fall, 2005 - Opioids in Chronic Non-Malignant Pain Troubleshooting Drug Therapy Issues www.RxFiles.ca
Shirk MB, Donahue KR, Shirvani J. Unlabeled uses of nebulized medications. Am J Health Syst Pharm. 2006 Sep 15;63(18):1704-16.
Sinha M, et al. Evaluation of nonpharmacologic methods of pain and anxiety management for laceration repair in the pediatric emergency department. Pediatrics. 2006
Apr;117(4):1162-8.
Smith J, Owen E, Earis J, Woodcock A. Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2006
Apr;117(4):831-5. Epub 2006 Feb 7.
Srivastava A, Kahan M. Buprenorphine: a potential new treatment option for opioid dependence. CMAJ;2006;174(13). http://www.cmaj.ca/cgi/content/full/174/13/1835
Taddio A, et al. Intravenous morphine and topical tetracaine for treatment of pain in preterm neonates undergoing central line placement.JAMA. 2006 Feb 15;295(7):793-800.
Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008 May 29;358(22):2332-43. Subcutaneous
methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate
opioid withdrawal. {InfoPOEMs Aug2008: Methylnaltrexone (Relistor) is effective for the treatment of opioid-induced constipation in hospice patients. However, long-term safety is not known, so it should not be widely used for nonterminally
ill patients until longer studies have been performed. (LOE = 1b)}
Treatment Guidelines from the Medical Letter. Pharmaceutical Drug Overdose. Sept 2006. (Opiates: naloxone treatment)
Van den Brink W, Haasen C. Evidenced-based treatment of opioid-dependent patients. Can J Psychiatry. 2006 Sep;51(10):635-46.
Wilson JF. Strategies to stop abuse of prescribed opioid drugs. Ann Intern Med. 2007 Jun 19;146(12):897-900.
Fentanyl Patches: “Attempting to give 1/2 patch”
The rate of medication delivery from Duragesic® patches is in proportion to the surface area of drug reservoir in contact with the skin. Prior to the
availability of the 12.5 mcg/hr strength, the following procedure was occasionally used to achieve this rate:
1. An occlusive dressing like Opsite was put on the skin.
2. A 25 mcg/hr patch was then applied on top with half on the skin and half on the dressing.
This approach lacks documentation and can not be routinely recommended.
Opioid Intolerance:
• Pseudoallergy (COMMON! – may use non-opioid, lower opioid dose, alternate opioid even from same class, addition of H1 diphenhydramine +/- H2 ranitiidine blocker.
o Flushing, itching, hives, sweating, and/or mild hypotension
o Itching, flushing or hives at injection site only
• Potential true opioid allergy (RARE! - would require change to non-opioid or opioid from different chemical class – see below)
o Severe hypotension
o Skin reaction other than (Flushing, itching, hives)
o Breathing, speaking, swallowing difficulties
o Swelling of the face, lips, mouth, tongue, pharynx or larynx
Opioid Chemical Class
1. Phenylpiperidines: meperidine, fentanyl, sufentanil, remifentanil
2.
3.
Diphenylheptanes: methadone, propoxyphene
Morphine group: morphine, codeine, hydromorphone, nalbuphine, butorphanol, levorphanol, pentazocine
New Drugs {Not yet in Canada Feb 07)
• Oral Oxymorphone (Opana, Opana ER)
i. Potency is about 10x more potent than morphine! Caution!
ii. Immediate release: 5, 10mg tabs
iii. Extended release; 5, 10, 20, 40 mg tabs
NSAIDS & COXIB ANALGESICS: Drug Comparison Chart 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16 GENERIC/TRADE (Strengths & formulations) L
L
L
L
L
L
L
L
L
L
L
L
Acetylsalicylic Acid (ASA) ASPIRIN, ENTROPHEN, g OTC Tablet: Chew: 80mg, 81mg IR: (80, 325mg), 500mg Delayed release tablet: 80, 81, 162, 325, 650mg Enteric coated (EC) caplet/tablet: 80mg, 81mg, 325mg, 500mg, 650mg (Only 325 & 650mg EC tabs on SK Formulary) Suppository: 150, 650mg Diflunisal DOLOBID, g Tablet: 250, 500mg LOWEST ANTI‐INFLAMMATORY, USUAL RANGE & MAXIMUM DOSE $/30d
L Regier BSP BA, B Jensen BSP, L Kosar MSc BSP © www.RxFiles.ca May 2015 CLASS/COMMENTS GENERAL COMMENTS (also see comments on individual agents) CI: CKD (CrCL≤40mL/min, okay in dialysis), cirrhosis, GI ulcer, HF, MI, thrombocytopenia, transplant Caution: asthma, CVD, HTN AE: dyspepsia <20%, edema, GI bleed risk ~1‐4%/yr, N/V, phototoxic reaction, small bowel ulceration, Stevens Johnson Syndrome,? AF, ? ototoxic DI: ↓ an ‐HTN effect: ACEI, ARB, ‐blocker, diuretic; ↑ toxicity of: cotrimoxazole, lithium, methotrexate, tenofovir, warfarin. M: CBC, LFTs, lytes, SCr yearly (1‐2wks if CV/renal risk); BP, HF (e.g. edema,↑ weight), photosensitivity PREGNANCY: except ARTHROTEC P1,P2,P3 P L
Pre‐conception: query block implantation st
18
1 trimester: malformations, ? miscarriage nd
2 trimester: low dose PRN, if needed;?cryptorchism
rd
3 trimester: closes ductus arteriosus CARDIAC Risk: Concern with all NSAID/COX‐2 Most trials done in low CV risk patients. Select pts carefully; use lowest effective dose. ↑ CV risk: diclofenac, indomethacin, rofecoxib, valdecoxib, & potentially meloxicam. CV risk appears neutral: naproxen 750mg/day, celecoxib 200mg/day & ibuprofen 1200mg/day 16
GASTROINTESTINAL ULCER Risk: risk ~1‐4%/yr Risk Factors: history of ulcer complication odds ratio (OR) 13.5, multiple NSAIDs OR 9, high dose NSAID OR 7, concomitant anticoagulant OR 6.4, age 70yr OR 5.6, concomitant SSRI OR 4.8, age 60yr OR 3.1, concomitant steroid OR 2.2, history of heart disease OR 1.8. If risk factors, consider adding gastric protection: - PPI e.g. omeprazole 20mg/d $20/mon (see RxFiles pg 63‐64) - Misoprostol CYTOTEC 200g BID‐QID $35‐64/mon Combination Products for GI Protection: - ARTHROTEC‐50, g Diclofenac 50mg + Misoprostol 200mcg po BID ($31 g) - ARTHROTEC‐75, g Diclofenac 75mg + Misoprostol 200mcg po daily ($25 g) - VIMOVO: Naproxen 375/500mg & Esomeprazole 20mg ($75/month) {< $40 if separate naproxen + PPI} Suppository formulation is NOT safer for GI tract. Possible gastric bleeding; antiplatelet effects of NSAIDs may ↑ risk during anticoagulant therapy. RENAL Risk: Risk Factors: underlying volume depletion (e.g. pts on ACEI/ARB & diuretics esp. high‐dose loop), pre‐existing CKD, HF, cirrhosis, age 70, prior long‐term daily use of high dose NSAIDs/ASA. Can use in CKD stage 1‐2 & dialysis; avoid in CKD stage 3 if CrCl 40mL/min, stage 4, stage 5 unless dialysis, & transplant. SURGERY: Caution with NSAIDs for perioperative pain, post‐abdominal aortic aneurysm surgery (↑ AKI risk) & CABG surgery (↑AKI, MI & stroke risk). COX‐2 Inhibitors (likely safer if ASA induced asthma) Compared to conventional NSAIDS: similar renal/ CV toxicity, less GI ulcer/bleed in non‐ASA pts. 19,20,21 Minimal platelet effects; ↑ cardiac/serious events with celecoxib CELEBREX 400mg/d [& rofecoxib VIOXX 25mg/d & lumiracoxib TARGET 22,23, now off market]. SALICYLATES ASA: CV protection at low doses, irreversible platelet inhibition for ~7‐10 days DI: ? NSAIDs give NSAID 30min after/8hrs before IR ASA. Reye’s Syndrome: avoid in pediatrics with chickenpox, influenza or flu‐like Sx. CI: <12yr. CLASS
↑ GI ulcer risk with other NSAIDs/COXIBs Lowest Anti‐inflammatory: 250mg po BID $47 ASA induced asthma common. Cross‐reacts Usual: 250‐500mg po BID; Maximum: 1.5g/d with other NSAIDs, rarely with acetaminophen.17
Lowest Anti‐inflammatory: 25mg po TID $19 INDOLE ACETIC ACIDS Indomethacin INDOCID, g (SAP: 75mg cap ankylosing spondylitis) Usual Range: 25‐50mg po TID; Max: 200mg/d Indomethacin: ↑ AE esp CNS confusion in elderly
Capsule: 25, 50mg; Suppository: 50, 100mg - Post ERCP: 100mg pr supp x1 ↓ pancreatitis Sulindac CLINORIL, g Tablet: 150, 200 mg Lowest Anti‐inflammatory: 150mg po BID $35 Sulindac: pro‐drug; AE: ↑ LFTs Usual: 150‐200mg po BID; Max: 400mg/d $29 PHENYLACETIC ACIDS DI: 2C9 voriconazole,rifampin
Diclofenac Sodium VOLTAREN, g Lowest Anti‐inflammatory: 50mg po BID + $24‐29 Diclofenac K (e.g. VOLTAREN RAPIDE): faster‐acting
75‐100mg SR po daily Tablet: EC: 25, 50mg; SR: 75, 100mg CLASS, MEDAL
OTC
AE: 75mg po BID & gel LFTs AST >4% Usual: 25‐50mg po BID‐TID; Max: 100mg/day Supp: 50, 100mg; Topical soln: 1.5% PENNSAID, g 24,25
26
or $90 Topical Diclofenac: Effective in localized pain PENNSAID 1.5% apply 40 drops (16mg) QID
27
Diclofenac Potassium esp ≤2 wks, NNT=4.5. VOLTAREN: pain relief 50 drops TID x3 months to affected knee. Tablet: 50mg VOLTAREN RAPIDE, g Allow to dry. Allow at least 1wk for effect. associated with recent acute, localized Pwd for oral soln: 50mg/pack CAMBIA acute migraine tx VOLTAREN RAPIDE 1 tab po BID, max 100mg/d muscle/joint injury e.g. sprains, strains or sports $30 CAMBIA dissolve 1 pack in 30‐60mL water x 1 $22/pk
injury e.g. sprain of ankle, strain of shoulder or back muscles. Diclofenac Diethylamine Topical gel: 1.16% VOLTAREN EMULGEL OTC VOLTAREN EMULGEL 2‐4g (4‐8cm) TID‐QID x 7d $18/wk
~6% absorbed; contains propylene glycol. Lowest Anti‐inflammatory: 10mg po QID Ketorolac TORADOL, g (SPRIX USA: intranasal) $25/7d PYROLIZINE CARBOXYLIC ACID AE: ↑ GI bleed risk
Usual (po): 10mg QID x7d max; Max: 40mg/d Injectable: can give IM not into injured muscle or IV Tablet: 10mg IM injection: 10, 30mg/mL Maximum total duration (IM + po) = 5 days Usual (IM): 10‐30mg q4‐6hr x2d max; Max: 120mg
Etodolac ULTRADOL, g Capsule: 200, 300mg Lowest Anti‐inflammatory: 300mg po BID $60 PYRANOCARBOXYLIC ACIDS Usual Range: 200‐600mg po BID; Max: 1.2g/d Some COX‐2 selectivity Flurbiprofen ANSAID, g Tablet: 50, 100mg Lowest Anti‐inflammatory: 100mg po BID $30 PROPIONIC ACIDS Usual: 50‐100mg po TID‐QID; Max: 300mg/day Discontinuation rates were similar to COXIBs: Ibuprofen ADVIL, MOTRIN, g (SAP: 10mg/2mL injectable) Lowest Anti‐inflammatory: 400‐600mg po TID $15‐25 - CLASS: ibuprofen 800mg TID vs celecoxib 400mg BID
- VIGOR: naproxen 500mg BID vs rofecoxib 50mg daily,
Capsule/tablet: 100mg, 200mg, 300mg, 400mg, 600mg Usual: 200‐800mg po TID‐QID; Max: 2.4‐3.2g/d
including less D/C due to HTN (0.1 vs 0.7%) Chew tablet: 50mg, 100mg All caps/tabs OTC, except 600mg Pediatrics: pain/fever: 5‐10mg/kg q6‐8hr (max DI: ? ASA → give NSAID 30min a er or 8hrs 40mg/kg/day); Rheum.Arthritis: ≤50mg/kg/day
Oral suspension: 100mg/5mL, 200mg/5mL OTC before immediate release ASA. Injectable: 100mg/mL CALDOLOR CALDOLOR ≤400‐800mg IV q6h
$7/4mL & $10/8mL
Ketoprofen ORUDIS, g Lowest Anti‐inflammatory: 50mg po TID $43 Max labeled dose for OTC NSAIDs: lower than Rx dose to allow for greater safety.
, 100mg Usual: 25‐100mg po TID‐QID; Max: 300mg/day Tab: EC: 50, 100mg; SR: 200mg; Cap: 50mg; Supp: 50
Ibuprofen: Naproxen NAPROSYN, g $20 Lowest Anti‐inflammatory: 375mg po BID VIGOR
Caplets/capsule/tablet: 220mg ALEVE OTC $25 - ?? help FEV1 in Cystic Fibrosis patients 500mg po BID
Tablet: 125mg, 250mg, 375 mg, 500 mg Usual Range: 125‐500mg po BID; Max:1.5g/day
Naproxen: Tab: EC:250,375,500mg ; CR:375mg,500mg ,SR:750mg ALEVE 220mg po BID‐TID; Max: 440mg/day $8 - ? help ↓ cough for acute common cold, treat +
Naproxen Na tablet: 275mg, 550 mg ANAPROX ANAPROX 275‐550 mg po BID $35‐55
for 5 days +
Pediatrics (>2yr): 10mg/kg/d; Max: 20mg/kg/d
- Naproxen Na ANAPROX: faster acting Oral suspension: 25mg/mL; Suppository: 500mg Lowest Anti‐inflammatory: 600mg po daily $33 Oxaprozin: ‐long t½ = 50 hours Oxaprozin DAYPRO, g Caplet: 600mg Usual: 600‐1800mg po daily; Max: 1.8g/day FDA’14
Lowest Anti‐inflammatory: 200mg po BID $33 {Flurbiprofen: may be toxic to cats}
Tiaprofenic Acid SURGAM, g Tablet: 200, 300 mg Usual: 200‐300mg po BID; Max: 600mg/day Lowest Anti‐inflammatory: 20mg po daily $23 OXICAMS t½ >50 hrs; AE: Stevens Johnson Syndrome
Piroxicam FELDENE, g Cap: 10, 20mg; Supp: 10mg, 20mg Usual Range: 10‐20mg daily; Maximum: 20mg/d
Piroxicam: AE ↑ skin & GI reactions - not for short‐term pain/inflammation $20 Lowest Anti‐inflammatory: 7.5mg po daily Meloxicam MOBICOX, g Tablet: 7.5, 15 mg Meloxicam: lacks outcome data for significant Usual Range: 7.5‐15mg daily; Maximum: 15mg/d
SELECT, MELISSA
but well ↓ in GI ulcer/complica ons Lowest Anti‐inflammatory: 20mg po daily $40 Tenoxicam MOBIFLEX, g Tablet: 20mg tolerated at low doses. Some COX‐2 selectivity.
Usual Range: 20‐40mg po daily; Max: 40mg/d Lowest Anti‐inflammatory: 1g po daily $34 NAPHTHYLALKANONES long t½ >24hrs Nabumetone RELAFEN, g Tablet: 500, 750mg Usual Range: 1‐2g po daily; Maximum: 2g/day Prodrug; some COX‐2 selectivity. Lowest Anti‐inflammatory: 200mg po QID $65 ANTHRANILIC ACIDS Floctafenine IDARAC, g Tablet: 200, 400mg Mefenamic acid: used for dysmenorrhea; Usual: 200‐400mg po TID‐QID; Max: 1.2g/day other NSAIDs also effective. $24/7d
Lowest Anti‐inflammatory: 250mg po QID Mefenamic Acid PONSTAN, g Capsule: 250mg - Initial dose: 500mg po x1 Usual: 250mg po QID x7d max; Max: 1.25g/day
32 Celecoxib CELEBREX , g Lowest Anti‐inflammatory: 200mg po daily‐BID $54‐100 COX‐2 SELECTIVE INHIBITOR highly COX‐2 selective Capsule: 100, 200mg Usual: AS/OA: 100mg po BID, RA: 200mg po BID $22‐37 g Equal efficacy compared to other NSAIDs st
AE: rare SULPHA allergic type reactions Max: 600mg/d on 1 day, 400mg/d thereafter Pediatrics (2yr FDA approved) 10‐25kg: 50mg BID Off‐Label: familial adenomatous polyposis 400mg BID See On‐line Extras: acetaminophen, discontinued products Lowest Anti‐inflammatory: 650mg EC po QID Usual Range: 325‐975mg po q4‐6hr Maximum: 4g/day $18 L
L
L
L
L
L
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=Exceptional Drug Status in Sask =prior approval NIHB =non‐formulary Sask =not covered NIHB =scored tablet AS=ankylosing spondylitis AKI=acute kidney injury ASA=acetylsalicylic acid COX‐2=selective cyclooxygenase 2 inhibitor COXIB=cyclooxygenase enzyme inhibitor CR=controlled release CV=cardiovascular EC=enteric coated IR=immediate release NSAID=non‐steroidal anti‐inflammatory drug OA=osteoarthritis OTC=over the counter RA=rheumatoid arthritis SAP=Special Access Programme (phone: 613‐941‐2108) SR=sustained release 98 RxFiles On‐Line Extras: NSAIDs & COXIB ANALGESICS L Regier BSP, B Jensen BSP © www.RxFiles.ca Oct 14 GENERIC/TRADE (Strengths & formulations) Acetaminophen TYLENOL, g OTC (=paracetamol) Chewable tablet: 160mg P L
Rapid‐dissolving tablet: 80, 160mg Immediate release caplet/tablet: 160, 325, 500mg Extended release caplet: TYLENOL ARTHRITIS 650mg Gelcap: 500mg Drops: 80mg/mL Liquid: 16mg/mL, 80mg/mL, 32mg/mL Suppository: 120, 160, 325,650mg Max NIHB is 3600mg/day. Caution: ingredient of many products! Unintentional duplication of use sometimes with overdose is common! LOWEST ANTI‐INFLAMMATORY, USUAL RANGE &
Class/Comments MAXIMUM DOSE $/30d $20 NON‐ANTI‐INFLAMMATORY ANALGESIC Lowest Anti‐inflammatory: 650mg po QID $25 Compared to NSAIDs/COXIBs, lowest risk for CV events & GI ulcer/bleed 1,300mg ER po TID Option in osteoarthritis Usual Range: 325‐1000mg po TID‐QID DI: warfarin ↑ INR with scheduled chronic use of acetaminophen. Concurrent use of isoniazid, zidovudine, or barbiturates may promote Maximum: 4g/day. Consider limiting dose to ≤3250mg/day if elderly or chronic use, or hepatotoxicity. ≤2600mg/day if hepatic/renal disease or chronic M: LFTs with chronic use & if ↑ alcohol use Larson’05 alcohol use.
Acute Overdose: hepatotoxic (#1 cause of drug‐induced transplant) Pediatrics: 10‐15mg/kg q4‐6hr; Max: 75mg/kg/day >140mg/kg or >7.5g - Level within 24 hours predictive Rumack‐Matthew Nomogram 36 Combination Product to Reduce Dyspepsia: ASPIRIN STOMACH GUARD: ASA 325/500mg & Ca++ Carbonate 227.5/350mg OTC New Drugs/Formulations: low‐dose diclofenac submicron particles (ZORVOLEX) Not in Canada – 18, 35mg capsules. in particle size ’s surface area resulting in faster dissolution & absorption. No comparative evidence. Not in Canada low‐dose indomethacin submicron (TIVORBEX) – 20, 40mg capsules. in particle size ’s surface area resulting in faster dissolution & absorption. No comparative evidence. Potent NSAID & AEs. Discontinued Products: NSAIDs: Choline Mg++ Trisalicylate TRILISATE, Fenoprofen NALFON, Piroxicam BREXIDOL, Salsalate DISALCID, Tolmentin TOLECTIN. COX‐2 Inhibitors: Lumiracoxib PREXIGE 100mg daily. Discontinued October 2007. Rare severe hepatic toxicity at doses ≥200mg/day. Rofecoxib VIOXX 12.5mg (OA) to 25mg (OA/RA) daily. Discontinued September 2004. VIGOR: CV events NNH=83, GI NNT=129/8 months. Valdecoxib BEXTRA 10‐20mg daily (OA, RA). Discontinued April 2005 in Canada, USA. Rare severe skin reactions e.g. exfoliative dermatitis & Stevens Johnson Syndrome. Trials to watch: PRECISION: CV risk of celecoxib vs ibuprofen vs naproxen (estimated study completion date ‐ Sept 2015) http://clinicaltrials.gov/ct/show/NCT00346216?order=4 NSAIDS, COXIBs & OTHER ANALGESICS: Comparison Chart
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Micromedex 2013
Silverstein F, Faich G, Goldstein J, et al. Gastrointestinal toxicity with celecoxib versus non-steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib
Long-term Arthritis Safety Study. JAMA 2000;284:1247-55.
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Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J
Med 2000;343:1520-8. (Curfman GD, Morrissey S, Drazen JM. Expression of Concern: Bombardier et al., "Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and
Naproxen in Patients with Rheumatoid Arthritis," N Engl J Med 2000;343:1520-8. N Engl J Med. 2005 Dec 8; [Epub ahead of print] )
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Detailed study results for CLASS; FDA Feb 2001 - http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_01_searle.pdf & http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf Access verified, May 6, 2002.
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Detailed study results for VIGOR; FDA Feb, 2001 - http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_01_merck.pdf Access verified, May 6, 2002.
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Singh G, Ramey D, Triadafilopoulos G. Early experience with selective COX-2 inhibitors: safety profile in over 340,000 patient years of use [Abstract]. Arthritis Rheum 1999;42(Suppl 9):S296.
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Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-9.
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Singh G, Ramey D. NSAID-induced gastrointestinal complications: the ARAMIS perspective-1997. J Rheumatol 1998;25(suppl 51):8-16.
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Wolfe M, Lichtenstein D, Singh G. Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. N Engl J. Med 1999; 340:1888-99.
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Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002 Feb;46(2):328-46.
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Treatment Guidelines: Drugs for Rheumatoid Arthritis. The Medical Letter: January, 2003; (5) pp. 25-32 & Dec 2005.
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Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Br J Rheumatol 1998;37:937-45.
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Dequeker J, Hawkey C, Kahan A, et al. Improvement in gastrointestinal tolerbility of the selective cyclogenase (COX)-2 inhibitor meloxicam, compared with piroxicam: Results of the Safety and Efficacy Large-scale Evaluation
of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998;37:946-51.
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http://www.oregonrx.org/OrgrxPDF/NSAIDS%20review/NSAID%20Update%20Report/5-12-03%20NSAID%20update.pdf
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http://www.oregonrx.org/OrgrxPDF/NSAID%20Review.htm
Hunt RH, Barkun AN, Baron D, et al. Recommendations for the appropriate use of anti-inflammatory drugs in the era of the coxibs: defining the role of gastroprotective agents. Can J Gastroenterol. 2002 Apr;16(4):231-40.
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Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ. 2004 Feb 21;328(7437):434.
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Treatment Guidelines: Drugs for Rheumatoid Arthritis. The Medical Letter: January, 2003; (5) pp. 25-32 & Dec 2005.
Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011 Sep 6.
Edwards DV, Aldridge T, Baird D et al. Periconceptional OTC NSAID exposure and risk for spontaneous abortion. ObsGyn 2012; 120(1):113-122.
Daniel S, Koren G, Lunenfeld E, et al. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. 2014 Mar 18;186(5) (Concern with indomethacin)
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Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery. N Engl J Med. 2005 Feb 15; [Epub ahead of print]
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Bresalier RS, et al. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial (APPROVe). N Engl J Med 2005; 352:1092-102. (InfoPOEMs: For every 62 patients who take rofecoxib instead of placebo
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for 3 years, 1 additional patient will experience a serious cardiovascular event. Remember, there is no greater symptomatic relief with COX-2 inhibitors than with older drugs; acetaminophen is a very safe alternative. The decrease in risk of serious gastrointestinal complications is marginal
with COX-2 inhibitors and the cost is high. (LOE = 1b) )
Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention. (APC trial) N Engl J Med 2005; 352:1071-80. (InfoPOEMs: One additional
cardiovascular event or cardiovascular death occurs for every 126 patients treated for 1 year with celecoxib. There appears to be a dose response relationship. It is difficult to justify continued use of this and other coxibs, except in the most exceptional circumstances. (LOE = 1b) )
(Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. (APC study) N Engl J Med 2006; 355:873-884. Follow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The
estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77;
P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the lowdose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of
cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9). ) (Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. (PreSAP
trial) N Engl J Med 2006; 355:885-895. Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib 400mg od group who were
included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64;
95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated
serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62). (Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, Stanley A, Stokes JC,
Julier P, Iveson C, Duvvuri R, McConkey CC; VICTOR Trial Group. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med. 2007 Jul 26;357(4):360-9. Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular
events among patients with a median study treatment of 7.4 months' duration.)
Farkouh ME, Kirshner H., Harrington RA. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised
controlled trial. Lancet 2004;364:675-84. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events [0.65%]) and the non-steroidal anti-inflammatory drugs (50 events [0.55%]; hazard ratio 1.14 [95% CI 0.78-1.66], p=0.5074). Incidence of myocardial infarction
(clinical and silent) in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (ten) and 0.11% with lumiracoxib (five) versus 0.16% with ibuprofen (seven).
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Schnitzer TJ., Burmester GR., Mysler E., Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised
controlled trial. Lancet 2004;364:665-74. (18325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) in two substudies of identical design. Randomisation
was stratified for low-dose aspirin use and age. In patients not taking aspirin, the cumulative 1-year incidence of ulcer complications was 1.09% (95% CI 0.82-1.36) with non-steroidal anti-inflammatory drugs (64 events) versus 0.25% (95% CI 0.12-0.39) with lumiracoxib (14 events; hazard ratio 0.21 [95% CI 0.120.37], p<0.0001). Reductions in ulcer complications were also significant in the overall population (0.34 [0.22-0.52], p<0.0001) but not in those taking aspirin (0.79 [0.40-1.55], p=0.4876). In the overall population, 0.55% (50/9127) of those on non-steroidal anti-inflammatory drugs and 0.65% (59/9117) of those on
lumiracoxib reached the cardiovascular endpoint (1.14 [0.78-1.66], p=0.5074).) (see also Pharmacists Letter Dec/06) Hawkey CJ et al. Effect of risk factors on complicated and uncomplicated ulcers in the TARGET lumiracoxib outcomes study. Gastroenterology 2007 Jul; 133:57-64. Lumiracoxib was associated
with a reduced risk of ulcer complications compared with NSAIDs in all significant subgroups except aspirin users.
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Bookman AA, Williams KS, Shainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ. 2004 Aug 17;171(4):333-8.
Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004
Oct 11;164(18):2017-23.
28. Bjordal JM, Ljunggren AE, Klovning A, Slordal L. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ. 2004
Dec 4;329(7478):1317. Epub 2004 Nov 23. Conclusion NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious
adverse effects are associated with oral NSAIDs, only limited use can be recommended.
29. Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet. 2005 Mar 12;365(9463):965-73.
30. Savage R. Cyclo-oxygenase-2 inhibitors : when should they be used in the elderly? Drugs Aging. 2005;22(3):185-200.
31. Hippisley-Cox J, Coupland C. Risk of MI in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ.2005 Jun 11;330(7504):1366.
32. Hudson M, et al. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ. 2005 Jun 11;330(7504):1370.
33. Arrich J, Piribauer F, Mad P, et al. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ. 2005 Apr 12;172(8):1039-43. (InfoPOEMs: The evidence that intra-articular
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hyaluronic acid helps patients with knee osteoarthritis is of poor quality. Improvements in pain at rest and pain during exercise is seen in a minority of studies, and those studies were of lower quality than those showing no benefit. There is no evidence of functional improvement. Injections
like this have a potentially powerful placebo effect, so any benefit seen in unblinded studies without concealed allocation is likely represent the placebo effect rather than any effect of the drug. (LOE = 1a-) ) Petrella RJ, Petrella M. A prospective, randomized, double-
blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol. 2006 May;33(5):951-6.
34. Verhamme KM, Dieleman JP, Van Wijk MA, et al. Nonsteroidal anti-inflammatory drugs and increased risk of acute urinary retention. Arch Intern Med. 2005 Jul 11;165(13):1547-51.
35. Sudbo J, Lee JJ, Lippman SM, et al. Non-steroidal anti-inflammatory drugs and the risk of oral cancer: a nested case-control study. Lancet. 2005 Oct 15-21;366(9494):1359-66.
Long-term use of NSAIDs is associated with a reduced incidence of oral cancer (including in active smokers), but also with an increased risk of death due to cardiovascular disease. These findings highlight the need for a careful risk-benefit analysis when the long-term use of NSAIDs.
(Jan/06 The Norwegian daily newspaper Dagbladet reports that a number of statistical improbabilities were found in the data set of the cancer trial, published in the Lancet in October last year. Lancet editor Dr Richard Horton told the BBC he would be speaking to the coauthors
of the study to seek their permission to retract the paper. One example of the improbabilities" is the fact that of the 908 people in the trial, 250 shared the same birthday.)
36. Acetaminophen Overdose: Medscape article: http://www.medscape.com/viewarticle/459187_4 ; Merck Manual’s Online Medical Manual: http://www.merck.com/mmpe/sec21/ch326/ch326c.html {Rumack-Matthew nomogram for predicting (Caution with units of measure!) }
( 10ug/ml = 66.2umol/L) {Acetaminophen level: 4hrs post ingestion & repeat in 4hrs; if 150mg/kg and 8hr post, may start n-acetylcysteine while awaiting levels; TOXIC levels: 4hr level >993umol/L; 6hr >728umol/L; 8hr >496.5umol/L; 24hr >29.8umol/L } {LFTs: AST usually first}
Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008 Jul 17;359(3):285-92.
Ferner Robin E, Dear James W, Bateman D Nicholas. Management of acetaminophen/paracetamol poisoning. BMJ 2011;342:doi:10.1136/bmj.d2218 (Published 20 April 2011)
Hitchings AW, Wood DM, Dargan PI. Dissemination and uptake of a new treatment pathway for paracetamol poisoning in the UK: a survey of healthcare professionals. Br J Clin Pharmacol. 2013 Mar 14.
Bateman DN, Dear JW, Thanacoody HKR, et al. Reduction of adverse events from intravenous acetylcysteine treatment for paracetamol (acetaminophen) poisoning: a randomised controlled trial. Lancet 2013; online Nov 28.
This modified acetylcysteine regimen infused a total dose of 300 mg/kg over 12 hours, versus roughly 20 hours; it used a lower initial dose (100 mg/kg over 2 hours, vs. 150 mg/kg over 15 minutes in the U.K. and 1 hour in the U.S.).
MHRA Sept 2012: Paracetamol (acetaminophen) overdose: Simplification of the use of intravenous acetylcysteine
{There is some evidence for the use of fomepizole as a CYP2E1 inhibitor and for decreased hepatotoxicity in the setting of acetaminophen overdose... To date, the evidence is all animal models but when the patient will otherwise die, the potential benefit outweighs the lack of human evidence.}
Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2009 Oct;54(4):606-14. Epub 2009 Jun 25. It favored the 20-hour protocol for patients presenting early and favored
the 72-hour protocol for patients presenting late after acute acetaminophen overdose. Johnson Michael T, McCammon Craig A, Mullins Michael E, et al. Evaluation of a Simplified N-Acetylcysteine Dosing Regimen for the Treatment of Acetaminophen Toxicity. Articles Ahead of Print published on 1 June 2011, DOI
10.1345/aph.1P613. Ann Pharmacother ;45:713-720.
Blackford MG, Felter T, Gothard MD, Reed MD. Assessment of the Clinical Use of Intravenous and Oral N-Acetylcysteine in the Treatment of Acute Acetaminophen Poisoning in Children: A Retrospective Review. Clin Ther. 2011 Sep 2.
Bateman DN, Carroll R, Pettie J, et al. Effect of the UK's Revised Paracetamol Poisoning Management Guidelines on Admissions, Adverse Reactions, and Costs of Treatment. Br J Clin Pharmacol. 2014 Mar 26.
ADAPT Research Group. Cognitive Function Over Time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): Results of a Randomized, Controlled Trial of Naproxen and Celecoxib. Arch Neurol. 2008 May 12. [Epub ahead of print] Use of naproxen or celecoxib
did not improve cognitive function. There was weak evidence for a detrimental effect of naproxen.
Akbar A, Abu Dayyeh BK, Baron TH, et al. Rectal nonsteroidal anti-inflammatory drugs are superior to pancreatic duct stents in preventing pancreatitis after endoscopic retrograde cholangiopancreatography: a network meta-analysis. Clin Gastroenterol Hepatol 2013;11:778–783.
Al-Sukhun J, Koivusalo A, Tornwall J, Lindqvist C. COX-2 inhibitors and early failure of free vascular flaps. N Engl J Med. 2006 Aug 3;355(5):528-9.
Amendolia B, Lynn M, Bhat V, et al. Severe pulmonary hypertension with therapeutic L-lysine Ibuprofen in 2 preterm neonates. Pediatrics. 2012 May;129(5):e1360-3.
Amin AK, et al. Does obesity influence the clinical outcome at five years following total knee replacement for osteoarthritis? J Bone Joint Surg Br. 2006 Mar;88(3):335-40. (InfoPOEMs: In this study, obese patients undergoing primary knee arthroplasty had comparable long-term outcomes with
nonobese patients. (LOE = 1b-) )
Amin SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol. 2007 Nov;197(5):486.e1-10. Antenatal indomethacin may be associated with an increased risk of periventricular leukomalacia and necrotizing
enterocolitis in premature infants and therefore should be used judiciously for tocolysis.
Ananthakrishnan AN, Higuchi LM, Huang ES, et al. Aspirin, Nonsteroidal Anti-inflammatory Drug Use, and Risk for Crohn Disease and Ulcerative Colitis: A Cohort Study (NHS). Ann Intern Med. 2012 Mar 6;156(5):350-9.
Andersohn F, et al. Cyclooxygenase-2 Selective Nonsteroidal Anti-Inflammatory Drugs and the Risk of Ischemic Stroke. A Nested Case-Control Study. Stroke. 2006 May 25; [Epub ahead of print] Current use of rofecoxib (OR=1.71; 95% CI, 1.33 to 2.18), etoricoxib (OR=2.38; 95%
CI, 1.10 to 5.13), but not of celecoxib (OR=1.07; 95% CI, 0.79 to 1.44) was associated with a significantly increased risk of ischemic stroke. For rofecoxib and etoricoxib, ORs tended to increase with higher daily dose and longer duration of use and were also elevated in patients
without major stroke risk factors. "From the non-selective NSAIDs, diclofenac, but not ibuprofen or naproxen, was also associated with a slightly increased risk of ischemic stroke," Dr. Andersohn said.
Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs & risk of acute myocardial infarction. Circulation. 2006 Apr 25;113(16):1950-7. Epub 2006 Apr 17. Current use of etoricoxib was associated with
a 2.09-fold (95% confidence interval [CI], 1.10 to 3.97) risk of AMI compared with no use of NSAIDs during the prior year. Current use of rofecoxib (RR=1.29; 95% CI, 1.02 to 1.63), celecoxib (RR=1.56; 95% CI, 1.22 to 2.00), and diclofenac (RR=1.37; 95% CI, 1.17 to 1.59)
also significantly increased the AMI risk. For current use of valdecoxib, the RR was 4.60 (95% CI, 0.61 to 34.51). RRs appeared to increase with higher daily doses of COX-2 inhibitors and were also increased in patients without major cardiovascular risk factors.
Andrew T. Chan, MD, MPH; Edward L. et al. Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer JAMA. 2005;294:914-923. CONCLUSIONS: Regular, long-term aspirin use reduces risk of colorectal cancer. Nonaspirin NSAIDs
appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially
higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered. (InfoPOEMs: Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), especially more than 14 doses per week for at least 10 years, reduces
the risk of colon cancer while also increasing the risk of a major gastrointestinal bleeding event. All-cause mortality is not affected by regular use. We need additional methods (gene testing?) to determine who is at high risk of colorectal cancer before making specific recommendations for prevention. (LOE = 2b) )
Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs. An update for clinicians. A scientific statement from the American Heart Association. Circulation 2007; DOI:10.1161/CIRCULATIONAHA.106.181424. Available at: http://circ.ahajournals.org.
Anzellotti P, Capone ML, Jeyam A, et al. Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: Recommendations to minimize the functional consequences. Arthritis Rheum. 2010 Dec 2.
Are, Chaitanya, Turagam, Mohit, Aucar, John A., Greenberg, Eugene. Meloxicam-induced enteropathy of the small bowel. CMAJ 2011 183: 577-580
Asgari MM, Chren MM, Warton EM, Friedman GD, White E. Association Between Nonsteroidal Anti-inflammatory Drug Use and Cutaneous Squamous Cell Carcinoma. Arch Dermatol. 2010 Feb 15.
Ash Z, Gaujoux-Viala C, Gossec L, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis. 2011 Jul 28.
Aspirin for cancer: Rothwell PM, Price JF, Fowkes FGR, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefi ts in 51 randomised controlled trials. Lancet 2012; online March 21.
Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; online March 21. DOI:10.1016/S0140-6736(12)60209-8.
Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncology 2012; online March 21. DOI:10.1016/S1470-2045(12)70112-2.
Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010 Oct 21.
Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individualpatient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31-41.
Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study (WHS): a randomized controlled trial. JAMA 2005; 294: 47–55. (no effect)
Sturmer T, Glynn RJ, Lee IM, Manson JE, Buring JE, Hennekens CH. Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study (PHS). Ann Intern Med 1998; 128: 713–20. (no effect)
Babb, Malaika, Koren, Gideon, Einarson, Adrienne. Treating pain during pregnancy. Can Fam Physician 2010 56: 25-27.
Bäck M, Yin L, Ingelsson E. Cyclooxygenase-2 inhibitors and cardiovascular risk in a nationwide cohort study after the withdrawal of rofecoxib. Eur Heart J 2011. (increased risk of developing atrial fibrillation)
Bandolier. Avocado/soybean unsaponifiables for OA. April 2004;122-23. Web site: http://www.jr2.ox.ac.uk/bandolier/band122/b122-3.html. The limited data to date support the safety and possible efficacy of ASU for osteoarthritis of the knee. More and longer studies are needed
before we can recommend this to our patients without hesitation. (LOE = 1b-)
Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis. A systematic review and network meta- analysis. Ann Intern Med. 2015;162:46-54. doi:10.7326/M14-2636
Barkhuizen A, et al. Celecoxib is efficacious and well tolerated in treating signs and symptoms of ankylosing spondylitis. J Rheumatol. 2006 Sep;33(9):1805-12.
Bakkeheim E, Mowinckel P, Carlsen KH, Håland G, Carlsen KC. Paracetamol (acetaminophen) in early infancy: the risk of childhood allergy and asthma. Acta Paediatr. 2011 Jan;100(1):90-6. doi: 10.1111/j.1651-2227.2010.01942.x.
Barkin RL, Beckerman M, Blum SL, et al. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging. 2010 Oct 1;27(10):775-89. Prescribing
Barkun AN, Bardou M, et al. and for the International Consensus Upper Gastrointestinal Bleeding Conference Group. Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med January 19, 2010 152:101-113.
Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003 Mar 6;348(10):891-9.
Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008 Oct 13. [Epub ahead of print] Use of rofecoxib is associated with increased rates of APTC events. Study
data are compatible with an early increase in risk that persists for one year after stopping treatment.
Bateman DN, Carroll R, Pettie J, et al. Effect of the UK's Revised Paracetamol Poisoning Management Guidelines on Admissions, Adverse Reactions, and Costs of Treatment. Br J Clin Pharmacol. 2014 Mar 26.
Bavbek S, et al. Safety of Meloxicam in Aspirin-Hypersensitive Patients with Asthma and/or Nasal Polyps. A Challenge-Proven Study. Int Arch Allergy Immunol. 2006 Oct 2;142(1):64-69 [Epub ahead of print]
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Bellamy N, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD005321.
Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999 May 6;340(18):1377-82.
Bennell KL, Kyriakides M, Metcalf B, et al. Neuromuscular versus quadriceps strengthening exercise in people with medial knee osteoarthritis and varus malalignment: A randomised controlled trial. Arthritis Rheum. 2013 Dec 24.
Berman BM, et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med. 2004 Dec 21;141(12):901-10. Summary for patients in: Ann Intern Med. 2004 Dec 21;141(12):I20.
Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus
Documents. J Am Coll Cardiol. 2008; Circulation. 2008; DOI: DOI: 10.1161/CIRCULATIONAHA.108.191087. Available at: http://circ.ahajournals.org http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.108.191087
Bijlsma Johannes W J, Berenbaum Francis, Lafeber Floris P J G. Osteoarthritis: an update with relevance for clinical practice. Lancet 2011; 377: 2115–26.
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Biswal S, Medhi B, Pandhi P. Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: metaanalysis of randomized placebo controlled clinical trials. J Rheumatol. 2006 Sep;33(9):1841-4.
Blouin M, Rhainds M. Use of Nonsteroidal Anti-inflammatory Drugs in Colorectal Surgery: Do the Risks Cast a Shadow on the Benefits? Ann Pharmacother. 2014 Dec;48(12):1662-4.
Bowers LW, Maximo IX, Brenner AJ, et al. NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin-Aromatase Interactions. Cancer Res. 2014 Aug 15;74(16):4446-57.
Brandlistuen RE, Ystrom E, Nulman I, et al. Prenatal paracetamol/acetaminophen exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013 Oct 24
Braun J, van den Berg R, Baraliakos X, et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 2011;70:896-904 doi:10.1136/ard.2011.151027.
Burmester Gerd, Lanas Angel, Biasucci Luigi, et al. The appropriate use of non-steroidal anti-inflammatory drugs (NSAIDs )in rheumatic disease: opinions of a multidisciplinary European expert panel. Ann Rheum Dis 2011;70:818-822 Online: 10 Sept 2010.
Butler GJ, Neale R, Green AC, Pandeya N, Whiteman DC. Nonsteroidal anti-inflammatory drugs and the risk of actinic keratoses and squamous cell cancers of the skin. J Am Acad Dermatol. 2005 Dec;53(6):966-72. Epub 2005 Oct 19.
Calder LA, Balasubramanian S, Fergusson D. Topical nonsteroidal anti-inflammatory drugs for corneal abrasions: meta-analysis of randomized trials. Acad Emerg Med. 2005 May;12(5):467-73.
Cannon CP, et al.; MEDAL Steering Committee. Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study program: cardiovascular outcomes with etoricoxib versus
diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J. 2006 Aug;152(2):237-45.
Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet
2006: DOI:10.1016/S0140-6736(06)69666-9. Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.
Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005 Apr 19;45(8):1295-301.
Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials. 2006 Nov 17;1(7):e33 [Epub ahead of print] For celecoxib, ADAPT data do not show the same level of risk as those of the
APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk. (Nissen SE. ADAPT: The Wrong Way to Stop a Clinical Trial. PLoS Clin Trials. 2006 Nov 17;1(7):e35 [Epub ahead of print])
Carmo KB, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. J Pediatr. 2009 Dec;155(6):819-822.e1. Epub 2009 Jul 29.
Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001 Dec 20;345(25):1809-17.
Chan AT, et al. Nonsteroidal Antiinflammatory Drugs, Acetaminophen, and the Risk of Cardiovascular Events. Circulation. 2006 Mar 13; [Epub ahead of print]
Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009 Aug 12;302(6):649-58. Regular aspirin use after the diagnosis of colorectal cancer is associated with lower risk of colorectal cancer-specific and overall mortality, especially among individuals with tumors that
overexpress COX-2.
Chan FKL, et al Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding. N Engl J Med 2005;352:238-44. (InfoPOEMs: For patients with a history of bleeding peptic ulcer, the combination of aspirin and a proton pump inhibitor twice a day was safer in terms of
bleeding side effects than clopidogrel. While esomeprazole was used in this study, generic omeprazole 20 mg give twice a day provides nearly the same degree of acid suppression at a much lower cost. This study calls into question the overall safety of clopidogrel, which has been promoted as not increasing the risk of
bleeding significantly. (LOE = 1b))
Chan FK, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001 Mar 29;344(13):967-73. CONCLUSIONS: Among patients with H. pylori infection and a history of upper
gastrointestinal bleeding who are taking low-dose aspirin, the eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole is superior to the eradication of H. pylori in preventing recurrent bleeding in patients who are taking other NSAIDs.
Chan FK, Wong VW, Suen BY, et al. Combination of cyclo-oxygenase-2 inhibitor (celecoxib 200mg bid) and proton-pump inhibitor (esomeprazole 20mg bid) for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007 May
12;369(9573):1621-6. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). n=441 12months. Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive
combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.
Chan CC, Reid CM, Aw TJ, Liew D, Haas SJ, Krum H. Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? An updated meta-analysis. J Hypertens. 2009 Nov 2. [Epub ahead of print] However, this response was heterogeneous, with markedly raised BP
associated with rofecoxib and etoricoxib, whereas celecoxib, valdecoxib and lumiracoxib appeared to have little BP effect.
Chan Francis KL, Lanas Angel, Scheiman James, et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial, The Lancet, Online 16 June 2010, ISSN 0140-6736, DOI:10.1016/S0140-6736(10)60673-3.
Chang CH, Shau WY, Kuo CW, Chen ST, Lai MS. Increased Risk of Stroke Associated With Nonsteroidal Anti-Inflammatory Drugs. A Nationwide Case-Crossover Study. Stroke. 2010 Jul 29.
Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann Neurol. 2005 Dec;58(6):963-7.
Chen J, Shen P, Zhang XC, et al. Efficacy and Safety Profile of Celecoxib for Treating Advanced Cancers: A Meta-Analysis of 11 Randomized Clinical Trials. Clin Ther. 2014 Jul 9.
Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a
systematic review and economic evaluation. Health Technol Assess. 2008 Apr;12(11):1-278, iii.
Cho E, Curhan G, Hankinson SE, Kantoff P, Atkins MB, Stampfer M, Choueiri TK. Prospective evaluation of analgesic use and risk of renal cell cancer. Arch Intern Med. 2011 Sep 12;171(16):1487-93.
Cimbollek S, Quiralte J, Avila R. COX-2 inhibitors in patients with sensitivity to nonselective NSAIDs. N Engl J Med. 2009 Nov 26;361(22):2197-8.
Claridge LC, Eksteen B, Smith A, Shah T, Holt AP. Acute liver failure after administration of paracetamol (acetaminophen) at the maximum recommended daily dose in adults. BMJ. 2010 Dec 2;341:c6764. doi: 10.1136/bmj.c6764.
Clyman R, Wickremasinghe A, Jhaveri N, et al; Ductus Arteriosus Feed or Fast with Indomethacin or Ibuprofen (DAFFII) Investigators. Enteral Feeding during Indomethacin and Ibuprofen Treatment of a Patent Ductus Arteriosus. J Pediatr. 2013 Mar 5.
Colak T, Ipek T, Kanik A, Ogetman Z, Aydin S. Efficacy of topical nonsteroidal (diclofenac) antiinflammatory drugs in mastalgia treatment. J Am Coll Surg. 2003 Apr;196(4):525-30.
Colli A, Conte D, Valle SD, Sciola V, Fraquelli M. Meta-analysis: nonsteroidal anti-inflammatory drugs in biliary colic. Aliment Pharmacol Ther. 2012 Jun;35(12):1370-8.
Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study (WHS): a randomized controlled trial. JAMA. 2005;294:47-55.
Cooper K, Squires H, Carroll C, et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess. 2010 Jun;14(32):1-206. (Especially aspirin & celecoxib reviewed)
Corman SL, Fedutes BA, Ansani NT. Impact of nonsteroidal antiinflammatory drugs on the cardioprotective effects of aspirin. Ann Pharmacother. 2005 Jun;39(6):1073-9. Epub 2005 May 3.
Cox-2 inhibitors & NSAIDS: Drug Class Review Nov 2006 Oregon Health & Science University http://www.ohsu.edu/drugeffectiveness/reports/documents/NSAIDS%20Final%20Report%20Update%203.pdf
Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-infl ammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; online May 30.
Craig DG, Bates CM, Davidson JS, et al.. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol (acetaminophen)-induced hepatotoxicity. Br J Clin Pharmacol. 2011 Nov 22.
Cryer B, Li C, Simon LS, et al. GI-REASONS: Novel 6-Month, Prospective, Randomized, Open-Label, Blinded Endpoint (PROBE) Trial. Am J Gastroenterol. 2013 Feb 12. Celecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs.
Curhan SG, Eavey R, Shargorodsky J, Curhan GC. Analgesic use and the risk of hearing loss in men. Am J Med. 2010 Mar;123(3):231-7.
Curhan SG et al. Analgesic use and the risk of hearing loss in women. Am J Epidemiol 2012; 176(6):544-554.
Daniel S, Matok I, Gorodischer R, et al. Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy. J Rheumatol. 2012 Nov;39(11):2163-9.
Daniel S, Koren G, Lunenfeld E, et al. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. 2014 Mar 18;186(5)
Daniel S, Koren G, Lunenfeld E, et al. NSAIDs and spontaneous abortions - true effect or an indication bias? Br J Clin Pharmacol. 2015 Apr 6.
Dart RC, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Washington (DC): American Association of Poison Control Centers; 2005.http://www.aapcc.org/FinalizedPMGdlns/APAP%20-%20final%20guideline%209.9.05.pdf
Davidson BL, Verheijen S, Lensing AW, et al. Bleeding Risk of Patients With Acute Venous Thromboembolism (on warfarin) Taking Nonsteroidal Anti-Inflammatory Drugs or Aspirin. JAMA Intern Med. 2014 Apr 14.
Day RO, Graham GG. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ. 2013 Jun 11;346:f3195.
De Caterina Raffaele; Ruigomez Ana; Rodriguez Luis Alberto Garcia. Long-term Use of Anti-inflammatory Drugs (NSAIDS) and Risk of Atrial Fibrillation. Arch Intern Med. 2010;170(16):1450-1455.
De Silva V, El-Metwally A, Ernst E, et al. Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review. Rheumatology (Oxford). 2011 May;50(5):911-20.
den Hertog HM, van der Worp HB, et al.; on behalf of the PAIS investigators. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol. 2009 May;8(5):434-440. Epub 2009 Mar 16.
Derry S, Moore RA. Single dose oral aspirin for acute postoperative pain in adults. Cochrane Database Syst Rev. 2012 Apr 18;4:CD002067. Aspirin is an effective analgesic for acute pain of moderate to severe intensity. High doses are more effective, but are associated with
increased adverse events, including drowsiness and gastric irritation. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol.
Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD007400. DOI: 10.1002/14651858.CD007400.pub2. Topical NSAIDs can provide good levels of pain relief; topical diclofenac
solution is equivalent to that of oral NSAIDs in knee and hand osteoarthritis, but there is no evidence for other chronic painful conditions. Formulation can influence efficacy. The incidence of local adverse events is increased with topical NSAIDs, but gastrointestinal adverse events
are reduced compared with oral NSAIDs.
Derry S, Derry CJ, Moore RA. Single dose oral ibuprofen plus oxycodone for acute postoperative pain in adults. Cochrane Database Syst Rev. 2013 Jun 26;6:CD010289. The combination of ibuprofen 400mg + oxycodone 5mg provided analgesia for longer than oxycodone alone, but
not ibuprofen alone (at the same dose). There was also a smaller chance of needing additional analgesia over about eight hours, and with no greater chance of experiencing an adverse event.
Desjardins PJ, Olugemo K, Solorio D, et al. Pharmacokinetic Properties and Tolerability of Low-dose SoluMatrix Diclofenac. Clin Ther. 2014 Dec 8.
Diener HC, et al. Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalagia. 2006 May;26(5):537-47.
Din Farhat V N, Theodoratou Evropi, Farrington Susan M, Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut gut.2009.203000Published Online First: 15 September 2010 doi:10.1136/gut.2009.203000.
Doherty M, Hawkey C, Goulder M, et al.A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis. 2011 Sep;70(9):1534-41.
Dougados M, Baeten D. Spondyloarthritis. Lancet. 2011 Jun 18;377(9783):2127-37.
Douglas L, Akil M. Sodium in soluble paracetamol may be linked to raised blood pressure. BMJ. 2006 May 13;332(7550):1133. (some forms of acetaminophen may have high sodium content)
Drendel AL, Lyon R, Bergholte J, et al. Outpatient pediatric pain management practices for fractures. Pediatr Emerg Care. 2006 Feb;22(2):94-9. Most children with fractures have the "worst" pain in the first 48 hours after injury and used analgesia for 3 days after injury. There are
noteworthy functional limitations for both children and their caregivers. Ibuprofen and acetaminophen with codeine are the analgesics most commonly used, with no clear superiority.
Drendel AL, Gorelick MH, Weisman SJ, Lyon R, Brousseau DC, Kim MK. A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain. Ann Emerg Med. 2009 Oct;54(4):553-60.
Driver Jane A, Logroscino Giancarlo, Lu Linda, et al. Use of non-steroidal anti-inflammatory drugs (NSAIDs) and risk of Parkinson’s disease: nested case-control study. BMJ 2011;342:doi:10.1136/bmj.d198 (20 Jan 2011) –no association found
Drugs in Pregnancy and Lactation. 9th ed. Briggs GE, Freeman RK, Yaffe SJ, editors. Williams and Wilkins; Philadelphia, PA: 2011.
Eliassen AH, Chen WY, Spiegelman D, Willett WC, Hunter DJ, Hankinson SE. Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and risk of breast cancer among premenopausal women in the Nurses' Health Study II. Arch Intern Med. 2009 Jan
26;169(2):115-21; discussion 121. These data suggest that the use of aspirin, other NSAIDs, and acetaminophen is not associated with a reduced risk of breast cancer among premenopausal women.
Elmunzer BJ, Waljee AK, Elta GH, Taylor JR, Fehmi SM, Higgins PD. A meta-analysis of rectal NSAIDs in the prevention of post-ERCP pancreatitis. Gut. 2008 Sep;57(9):1262-7.
Elmunzer BJ, Scheiman JM, Lehman GA, et al. U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012 Apr 12;366(15):1414-22.
Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, Fitzgerald JM. Acetaminophen Use and the Risk of Asthma in Children and Adults: A Systematic Review and Metaanalysis. Chest. 2009 Aug 20. [Epub ahead of print]
European Medicines Agency (EMA), 2012. Agency finalises review of recent published data on cardiovascular safety of NSAIDs [online]. Available:http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/10/news_detail_001637.jsp&mid=WC0b01ac058004d5c1
FDA- Acetaminophen and Liver Injury: Q & A for Consumers 2009 http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM172664.pdf
FDA Dec/09 , Endo, & Novartis revised the Hepatic Effects section of the Prescribing Information to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products (including diclofenac gel) on diclofenac sodium. In
postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis,
jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
FDA June/12 cautioned late last week against using Reumofan Plus, a dietary supplement marketed as a "natural" pain reliever for arthritis, osteoporosis, and other conditions. The drug, which is made in Mexico but available online, contains unlabeled and potentially harmful
pharmaceutical ingredients: diclofenac, methocarbamol & sometimes dexamethasone. (Dec/12 FDA: Reumofan Plus is being relabeled and sold under the name “WOW.” )
FDA Aug/12 is issuing an updated alert that Reumofan Plus and Reumofan Plus Premium contain undeclared active ingredients found in prescription drugs that should be used only under the supervision of a health care professional. It contains Diclofenac Sodium and Methocarbamol.
FDA Aug/13 laboratory analysis confirmed that Ortiga contains the prescription drug ingredient, diclofenac.
FDA Jan/14 is recommending health care professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 milligrams (mg) of acetaminophen per tablet, capsule or other dosage unit.
FDA Feb/14 analysis of Arth-Q supplement contains hidden ingredient ibuprofen.
FDA Mar/14: Pain Free By Nature is recalling "Reumofan Plus" Tablets purchased through their website at www.painfreebynature.com, after FDA discovered that the product was distributed in packaging that did not reveal the presence of the active pharmaceutical ingredients
methocarbamol and diclofenac, making it an unapproved drug.
FDA Apr/14: Nano Well-being Health Inc. issued a voluntary recall of Super Arthgold, 500 mg capsules to the consumer level. FDA laboratory analysis has found the product to contain chlorzoxazone, diclofenac and indomethacin.
FDA Apr/15 is alerting pet owners, veterinarians, health care providers and pharmacists that pets are at risk of illness and death when exposed to topical pain medications containing the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen.
People using these medications should use care when applying them in a household with pets, as even very small amounts could be dangerous to these animals.
Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med. 2006 Feb 23;354(8):841-8.
Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007 May 12;369(9573):1603-13. Use of 300 mg or more of
aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years, which is consistent with findings from observational studies. Long-term follow-up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin.
Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007; 167:394-399. The frequency of nonnarcotic analgesic use is independently associated with a moderate increase in the risk of incident hypertension. Given the
widespread use of these medications and the high prevalence of hypertension, these results may have important public health implications.
Forestier R, Desfour H, Tessier JM, et al. Spa therapy in the treatment of knee osteoarthritis: a large randomised multicentre trial. Ann Rheum Dis. 2010 Apr;69(4):660-5. Epub 2009 Sep 3.
Fosbøl EL, Folke F, Jacobsen S, et al. Cause-Specific Cardiovascular Risk Associated With Nonsteroidal Antiinflammatory Drugs Among Healthy Individuals. Circ Cardiovasc Qual Outcomes. 2010 Jun 8. (Diclofenac & rofecoxib)
Foster NE, Thomas E, Barlas P, Hill JC, Young J, Mason E, Hay EM. Acupuncture as an adjunct to exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial. BMJ. 2007 Sep 1;335(7617):436. Epub 2007 Aug 15. The
addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores.
Fransen M, et al. HIPAID Collaborative Group. Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): randomised controlled trial. BMJ. 2006 Sep
9;333(7567):519. Epub 2006 Aug 2. These data do not support the use of routine prophylaxis with NSAIDs in patients undergoing total hip replacement surgery.
Friday JH, Kanegaye JT, McCaslin I, Zheng A, Harley JR. Ibuprofen provides analgesia equivalent to acetaminophen-codeine in the treatment of acute pain in children with extremity injuries: a randomized clinical trial. Acad Emerg Med. 2009 Aug;16(8):711-6. Epub 2009 Jul 14.
Acute pain relief from ibuprofen is equivalent to that of acetaminophen-codeine for children presenting to the emergency department with extremity injury. More than half the children in this study were consequently found to have fractures. (LOE = 1b)
Frithsen IL, Simpson WM Jr. Recognition and management of acute medication poisoning. Am Fam Physician. 2010 Feb 1;81(3):316-23.
Gatoulis SC, Voelker M, Fisher M. Assessment of the Efficacy and Safety Profiles of Aspirin 1gm and Acetaminophen With Codeine: Results From 2 Randomized, Controlled Trials in Individuals With Tension-Type Headache and Postoperative Dental Pain. Clin Ther. 2011 Dec 12.
Gauer RL, Semidey MJ. Diagnosis and Treatment of Temporomandibular Disorders. Am Fam Physician. 2015 Mar 15;91(6):378-386.
Gaujoux-Viala C, Dougados M, Gossec L. Efficacy and safety of steroid injections for shoulder and elbow tendonitis: a meta-analysis of randomized controlled trials. Ann Rheum Dis. 2009 Dec;68(12):1843-9. Epub 2008 Dec 3. In the first 3 months of tendinitis of either the elbow or shoulder,
injected corticosteroids are more effective than placebo or physical therapy, but no more effective than treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). In the longer term they are no more effective than any treatment. What hasn't been studied is the effectiveness of steroid injections in patients for whom NSAID treatment
isn't effective, since this is the usual progression of treatment of these painful conditions. (LOE = 1a-)
Gelber AC. In the Clinic: Osteoarthritis. Ann Intern Med. July1,2014. ITC1-2.
Gislason GH, et al. Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction. Circulation. 2006 Jun 19; [Epub ahead of print] For any use of rofecoxib,
celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk
of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. CONCLUSIONS: Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI
and should therefore be used with particular caution in these patients.
Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs) in chronic heart failure. Arch Intern Med. 2009 Jan 26;169(2):141-9.
Gleason JM, Slezak JM, Jung H, et al. Regular Nonsteroidal Anti-Inflammatory Drug (NSAIDs) Use and Erectile Dysfunction. J Urol. 2011 Feb 18.
Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet. 2015 Mar 3.
Gokmen T, Erdeve O, Altug N, et al. Efficacy and safety of oral versus intravenous Ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr. 2011 Apr;158(4):549-554.e1.
Goldstein JL, Johanson JF, et al. Healing of gastric ulcers with esomeprazole versus ranitidine in patients who continued to receive NSAID therapy: a randomized trial. Am J Gastroenterol. 2005 Dec;100(12):2650-7.
Goldstein JL, Cryer B, Amer F, Hunt B. Celecoxib plus aspirin versus naproxen and lansoprazole plus aspirin: a randomized, double-blind, endoscopic trial. Clin Gastroenterol Hepatol. 2007 Oct;5(10):1167-74. n=854 In patients with osteoarthritis taking low-dose aspirin, the use of
celecoxib or naproxen plus lansoprazole resulted in similar rates of gastroduodenal ulceration.
Goldstein LH, Berlin M, Berkovitch M, Kozer E. Effectiveness of oral vs rectal acetaminophen: a meta-analysis. Arch Pediatr Adolesc Med. 2008 Nov;162(11):1042-6. Among 4 small studies, oral and rectal acetaminophen for fever control were comparable in effectiveness.
The authors could only find 1 study comparing oral and rectal acetaminophen for pain. It appeared that oral administration was more effective, but the effect may not have been clinically meaningful. The authors don't report on adverse effects. (LOE = 1a-)
Goldstein JL, Chan FK, Lanas A, Wilcox CM, Peura D, Sands GH, Berger MF, Nguyen H, Scheiman JM. Haemoglobin decreases in NSAID users over time: an analysis of two large outcome trials. Aliment Pharmacol Ther. 2011 Aug 2.
González ELM et al. Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010 Jun; 62:1592.
Gouyon JB, Kibleur Y. Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants. Clin Ther. 2010 Sep;32(10):1740-8.
Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2011 Sep 27.
Graham GG, Scott KF, Day RO. Tolerability of paracetamol. Drug Saf. 2005;28(3):227-40.
Graham DJ, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005 Feb 5-11;365(9458):475-81.
Graham DY, Agrawal NM, Campbell DR, et al. NSAID-Associated Gastric Ulcer Prevention Study Group. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of
misoprostol vs lansoprazole. Arch Intern Med. 2002 Jan 28;162(2):169-75.
Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jove J, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol acetaminophen): the multinational case-population SALT study. Drug Saf 2013;36:135-44.
Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ. 2012 Oct 9;345:e6226.
Hakkarainen TW, Steele SR, Bastaworous A, et al. Nonsteroidal Anti-inflammatory Drugs and the Risk for Anastomotic Failure: A Report From Washington State's Surgical Care and Outcomes Assessment Program (SCOAP). JAMA Surg. 2015 Jan 21.
Hammerman C et al. Ductal closure with paracetamol (acetaminophen): a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011 Dec;128(6):e1618-21.
Harbin M, Turgeon RD, Kolber MR. Cardiovascular safety of NSAIDs. Can Fam Physician. 2014 Mar;60(3):e166.
Harnden A, Takahashi M, Burgner D. Kawasaki disease. BMJ. 2009 May 5;338:b1514. doi: 10.1136/bmj.b1514.
Harris RE, Beebe-Donk J, Alshafie GA. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer. 2006 Jan 30;6:27.
Hay EM, et al. Effectiveness of community physiotherapy and enhanced pharmacy review for knee pain in people aged over 55 presenting to primary care: pragmatic randomized trial. BMJ. 2006 Oct 20; [Epub ahead of print] Evidence based care for older adults with knee pain,
delivered by primary care physiotherapists and pharmacists, resulted in short term improvements in health outcomes, reduced use of non-steroidal anti-inflammatory drugs, and high patient satisfaction.
Hay AD, Costelloe C, Redmond NM, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ. 2008 Sep 2;337:a1302. doi: 10.1136/bmj.a1302. Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement
physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours.
Hawkey CJ, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med. 1998 Mar 12;338(11):727-34.
Hawton K, Bergen H, Simkin S, et al. Long term effect of reduced pack sizes of paracetamol (acetaminophen) on poisoning deaths and liver transplant activity in England and Wales: interrupted time series analyses. BMJ 2013;346:f403.
Health Canada Prohits sale of Bextra http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2005/2005_134_e.html
Health Canada June/06 two documents as part of its ongoing evaluation of COX-2-selective drugs: its official comments on the advice provided by the COX-2 Expert Advisory Panel and a report on the Department's scientific review of certain COX-2s.
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-consult/cox2/index_e.html
Health Canada Aug/07 reports that the Therapeutic Goods Administration (TGA), the federal regulatory authority in Australia, recently withdrew market authorization for Prexige due to eight reports of serious liver adverse events in Australia linked to the drug, including two deaths
and two liver transplants. These adverse events were primarily with use of 200 mg and 400 mg doses daily.
Health Canada Sept/07 reports that Qiangli Zhuanggutongbiling has reportedly been used for joint pain and stiffness. It was found to contain the undeclared prescription drugs prednisolone acetate, cortisone acetate, piroxicam, and diclofenac.
Health Canada Sept/07: Khun-Phra is a health product promoted for pain relief that has been found to contain the undeclared drugs dexamethasone, prednisolone, phenylbutazone, diazepam, cyproheptadine and mebhydrolin.. Asam Urat Flu Tulang, PJ Dewandaru is a health
product promoted to treat joint pain, rheumatism and arthritis. It has been found to contain the undeclared drugs dexamethasone, diclofenac and acetaminophen.
Health Canada Oct/07 Foreign Product Alerts: Zhen Feng Da Brand Xi Tong Wan is promoted as a pain reliever. Lot #060908 has been found to contain undeclared indomethacin, a prescription anti-inflammatory drug that should only be taken under the guidance of a health
professional. Wellring Brand Yin Qiao Jie Du is a health product promoted to treat cold and flu symptoms. Lot#51005 has been found to contain undeclared acetaminophen. Gu Ci Dan and Xu Log Bou are promoted as pain relievers and have been found to contain indomethacin.
Health Canada Oct/07 is advising consumers that it has stopped the sale of the anti-inflammatory drug Prexige (lumiracoxib) in Canada and will cancel the drug's market authorization due to the potential for serious liver-related adverse events. (2 new severe cases in Canada)
Health Canada July/08 is advising consumers not to use 2 foreign health products due to concerns about possible side-effects: 3rd Generation In Homoeopathy Arthrit Indica Tablet. The product is labelled for "intense joint pain." The Health Sciences Authority of Singapore has
warned consumers not to use the product because it contains nimesulide, a pharmaceutical ingredient that has been associated with liver damage.
Health Canada Aug/08 is advising consumers not to use foreign health products due to concerns against the use of AA Qu Feng Shu Jin Wan because it was found to contain the undeclared pharmaceutical ingredient dexamethasone. Obat Asam Urat and Asam Urat both contained
dexamethasone, phenylbutazone and piroxicam.
Health Canada June/09 is informing Canadian health care professionals and consumers of recent restrictions regarding the use of the prescription drug piroxicam. Health Canada has conducted a safety review and concluded that piroxicam should no longer be used to treat short-term
pain and inflammation due to an increased risk of serious skin reactions and gastrointestinal problems relative to other similar drugs.
Health Canada July/09 is warning consumers not to use the unauthorized health product labelled as Specific-Formula Arthro-Ace as it was found to contain undeclared dexamethasone and may cause serious health effects.
Health Canada July/09 is warning that the Singapore Health Sciences Authority (HSA) warned consumers to not buy or use Air Ikan Haruan after it was found to contain undeclared dexamethasone. The Hong Kong Department of Health warned consumers not to buy or use the
product Neovidan after it was found to contain undeclared prednisolone and mefenamic acid.
Health Canada Aug/09 is advising via Singapore Health Sciences Authority (HSA) that Delima Raja Urat contains undeclared dexamethasone, chlorpheniramine, pheniramine and sibutramine, while Cao Gen Bai Lin Wan contains undeclared dexamethasone and chlorpheniramine.
Health Canada Aug/10 Huo Luo Jing Dan The Singapore Health Sciences Authority warned consumers not to buy or consume Huo Luo Jing Dan after it was found to contain undeclared indomethacin, dexamethasone and prednisolone.
Health Canada Oct/11 Huo Li Bao and Ren Sem Tu Chon Chin Kuo Pill - The Singapore Health Sciences Authority warned that these Chinese pain-relief products contain prescription and/or over-the-counter drugs (furosemide, piroxicam, chlorpheniramine, and/or dexamethasone).
Health Canada Dec/11 is advising Canadians that Vita Health’s product, “Compliments Muscle and Back Pain Relief Regular Strength” contains a significant labelling error in the French dosing directions that may pose serious risks to children (less than 12 years of age).
Health Canada Apr/13 1. Diet Garcinia Forte; Shan Dian Shou; Aulura Energy Dietary Supplement The Hong Kong Department of Health has advised consumers not to use these products after they were found to contain sibutramine and phenolphthalein, drug ingredients that were
not declared on their product label. Shan Dian Shou also contains the undeclared prescription drug sildenafil. 2. Snake Powder Capsule for Rheumatism; Jia Rong Zhuang Gu Tong Bi Jiaonang; Long Ren Tang Fu She Gu Rang Jiao Nang The Hong Kong Department of
Health advised consumers not to use these products after they were found to contain multiple prescription and non-prescription drugs that were not declared on their product label. (prednisone, indomethacin, diclofenac, hydrochlorothiazide, cimetidine, prednisone, theophylline,
dexamethasone etc ). 3. Tinea Schwartz’s; Tiao Jing Bu Xue Pills; Yeung Ng Tong Tin Hee Pills The Hong Kong Department of Health advised consumers not to use these products after they were found to contain prescription drugs that were not declared on their product label
(prednisone, indomethacin, diclofenac). 4. Quan Xie Jin Gu Tong; Xinhuang Pian; Jin Gu Feng Shi Kang Jiao Nang The Hong Kong Department of Health advised consumers not to use these products after they were found to contain multiple prescription and non-prescription
drugs that were not declared on their product label. (prednisone, piroxicam, diclofenac, indomethacin, naproxen).
Health Canada Apr/14: Nano Well-being Health Inc. issued a voluntary recall of Super Arthgold, 500 mg capsules to the consumer level. FDA laboratory analysis has found the product to contain chlorzoxazone, diclofenac and indomethacin, making it an unapproved new drug.
Health Canada May/14 Ortiga contains diclofenac.
Health Canada June/14: Pro ArthMax contains diclofenac, ibuprofen, naproxen, indomethacin, chlorzoxazone.
Health Canada June/14: Zi Xiu Tang Pollen capsule and Zi Xiu Tang Beauty Face and Figure capsule: The Australian Therapeutic Goods Administration (TGA) warned consumers not to use these products after they were found to contain undeclared sibutramine, phenolphthalein,
diclofenac, and ibuprofen. The product, Zi Xiu Tang Beauty Face and Figure capsule, was also found to contain undeclared glibenclamide, and indomethacin.
Health Canada Sep/14: JIN LONG Snakes Bones Rheumatic Capsules- The Singapore Health Sciences Authority warned consumers not to use this product after it was found to contain betamethasone, piroxicam,oxethazaine, paracetamol (also known as acetaminophen) and furosemide.
Health Canada Oct/14 Diclofenac - Update to Heart and Stroke Related Safety Information and Decrease in the Maximum Recommended Daily Dose for Tablets and Suppositories - Novartis Pharma Canada Inc. and Pfizer Canada Inc. Diclofenac at 150 mg per day, is associated with an
increased risk of serious cardiovascular adverse events. The maximum recommended daily dose of systemic diclofenac is now 100 mg per day. Diclofenac is not recommended in patients with pre-existing cardiovascular or cerebrovascular disease.
Health Canada Dec/14: Joint-Soft: The Singapore Health Sciences Authority warned consumers not to use the product JOINT-SOFT after it was found to contain piroxicam anddexamethasone. The Singapore Health Sciences Authority warned consumers not to use the product
KEBIGUTAIJIAONANG after it was found to contain piroxicam, hydrochlorothiazide, and prednisone. The Singapore Health Sciences Authority warned consumers not to use the product Pil Raja Urat Asli after it was found to contain piroxicam and indomethacin.
Health Canada Mar/15 advises- Feng Shi Ling: undeclared diclofenac & indomethacin.
Health Canada Apr/15 is working with the Canadian manufacturers of prescription oral ibuprofen products to update the safety information regarding the risk of serious cardiovascular side effects (e.g., heart attack and stroke) when these products are used at high doses
(at or above 2400 mg/day). This risk increases with dose and duration of use.
Heard KJ, Green JL, Dart RC. Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers. Pharmacotherapy. 2010 Aug;30(8):818-22.
Helin-Salmivaara A, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J. 2006 Jul;27(14):1657-63. Epub 2006 May 26.
Hill KP, Ross JS, Egilman DS, Krumholz HM. The ADVANTAGE seeding trial: a review of internal documents. (Vioxx marketing trial) Ann Intern Med. 2008 Aug 19;149(4):251-8.
Hinz B, Brune K. Paracetamol and cyclooxygenase inhibition: is there a cause for concern? Ann Rheum Dis. 2012 Jan;71(1):20-5.
Hippisley-Cox J, Coupland C, Logan R. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005 Dec 3;331(7528):1310-6.
CONCLUSION: No consistent evidence was found of enhanced safety against gastrointestinal events with any of the new cyclo-oxygenase-2 inhibitors compared with non-selective non-steroidal anti-inflammatory drugs. The use of ulcer healing drugs reduced the increased risk of adverse gastrointestinal outcomes with all groups of
non-steroidal anti-inflammatory drugs, but for diclofenac the increased risk remained significant.
Ho JM, Juurlink DN. Considerations when prescribing trimethoprim-sulfamethoxazole. CMAJ. 2011 Oct 11. (NSAID DIs)
Hochberg, M. C., Altman, R. D., April, K. T., et al. American College of Rheumatology (ACR) 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. 2012 Arthritis Care Res, 64: 465–474.
Hochberg MC, Martel-Pelletier J, Monfort J, et al. on behalf of the MOVES Investigation Group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. 2015 Jan 14.
Holmes, Michelle D., Chen, Wendy Y., Li, Lisa, et al. Aspirin Intake and Survival After Breast Cancer. J Clin Oncol 2010 0: JCO.2009.22.7918.
Hooper L, Brown TJ, Elliott R, et al. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ. 2004 Oct 23;329(7472):948. Epub 2004 Oct 8. CONCLUSIONS: Misoprostol, COX-2
specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor
antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
Hudson N, Taha AS, Russell RI, et al. Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration. Gastroenterology. 1997 Jun;112(6):1817-22.
Huerta C, Varas-Lorenzo C, Castellsague J, Garcia Rodriguez LA. Non-steroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population. Heart. 2006 Nov;92(11):1610-5. Epub 2006 May 22.
Hughes GJ, Patel PN, Saxena N.. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011 June;31(6):591–597.
Husebo BS, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ 2011;343;d4065. (70% on 3g/day acetaminophen)
Irwin RS, et al. American College of Chest Physicians (ACCP). Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan;129(1 Suppl):1S-23S. http://www.chestjournal.org/cgi/content/full/129/1_suppl/1S
Iversen MD, Hammond A, Betteridge N. Self-management of rheumatic diseases: state of the art and future perspectives. Ann Rheum Dis 2010; 69: 955–63.
James LP, et al. Pediatric Acute Liver Failure Study Group. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006 Sep;118(3):e676-81.
James ND, Sydes MR, Mason MD, et al. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol 2012; online March 26.
Jaturapatporn D, Isaac MG, McCleery J, et al. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer`s disease. Cochrane Database Syst Rev. 2012 Feb 15;2:CD006378. Based on the studies carried out so far, the efficacy of aspirin, steroid
and NSAIDs (traditional NSAIDs and COX-2 inhibitors) is not proven. Therefore, these drugs cannot be recommended for the treatment of AD.
Jerschow E, Lin RY, Scaperotti MM, et al. Fatal anaphylaxis in the United States, 1999-2010: Temporal patterns and demographic associations. J Allergy Clin Immunol. 2014 Sep 26.
Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013 Sep;21(9):571-6.
Jick H, et al. Nonsteroidal antiinflammatory drugs and acute myocardial infarction in patients with no major risk factors. Pharmacotherapy. 2006 Oct;26(10):1379-87. Extensive use of rofecoxib, celecoxib, and diclofenac increases the risk of acute
myocardial infarction, but similar use of ibuprofen and naproxen does not.
Jickling G, Heino A, Ahmed SN. Acetaminophen toxicity with concomitant use of carbamazepine. Epileptic Disord. 2009 Dec 9.
Johannesdottir SA, Chang ET, Mehnert F, et al. Nonsteroidal anti-inflammatory drugs and the risk of skin cancer: A population-based case-control study. Cancer. 2012 May 29.
Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a Simplified N-Acetylcysteine Dosing Regimen for the Treatment of Acetaminophen Toxicity (June). Ann Pharmacother. 2011 May 17.
Jordan KM, Arden NK, Doherty M, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum
Dis 2003; 62: 1145–55.
Juhl C et al. Impact of exercise type and dose on pain and disability in knee osteoarthritis: A systematic review and meta-regression analysis of randomized controlled trials. Arthritis Rheumatol 2014 Mar; 66:622.
Kai S, Kondo E, Kawaguchi Y, et al. Flurbiprofen Concentration in the Soft Tissues Is Higher after Topical Application Than after Oral Administration. Br J Clin Pharmacol. 2012 Jul 24.
Kang EM, Lundsberg LS, Illuzzi JL, Bracken MB. Prenatal exposure to acetaminophen and asthma in children. Obstet Gynecol. 2009 Dec;114(6):1295-306.
Kastelein F et al. Probar-study Group. Nonsteroidal Anti-Inflammatory Drugs and Statins Have Chemopreventative Effects in Patients With Barrett's Esophagus. Gastroenterology. 2011 Dec;141(6):2000-8
Kearney PM, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006 Jun 3;332(7553):1302-8. Selective COX 2 inhibitors are associated with a
moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.
Kerry S. Kuehl, Review of the efficacy and tolerability of the diclofenac epolamine topical patch 1.3% in patients with acute pain due to soft tissue injuries, Clinical Therapeutics, Volume 32, Issue 6, June 2010, Pages 1001-1014.
Kim SY, Chang YJ, Cho HM, Hwang YW, Moon YS. Non-steroidal anti-inflammatory drugs for the common cold. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD006362.
Kiriakidou M, Cotton D, Taichman D, Williams S. Systemic Lupus Erythematosus. Ann Intern Med. 2013 Oct 1;159(7):ITC4-1.
Kirkley A, et al. A Randomized Trial of Arthroscopic Surgery for Osteoarthritis of the Knee. N Engl J Med. 2008 Sep 11;359(11):1097-1107. Arthroscopic surgery for osteoarthritis of the knee provides no additional benefit to optimized physical and medical therapy.
Klein M, Gögenur I, Rosenberg J. Postoperative use of non-steroidal anti-inflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data. BMJ. 2012 Sep 26;345:e6166. (diclofenac concerning)
Köhler O, Benros ME, Nordentoft M, et al. Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Psychiatry. 2014 Oct 15.
Konrad G, Katz A. Are medication restrictions before FOBT necessary?:Practical advice based on a systematic review of the literature. Can Fam Physician. 2012 Sep;58(9):939-48.
Kroon F, Landewe R, Dougados M, et al. Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis 2012.
Konstan MW, Schluchter MD, Xue W, Davis PB. Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1084-9. Epub 2007 Sep 13. Slower rates of FEV(1) decline are seen in children and adolescents with
cystic fibrosis who are treated with ibuprofen. The apparent benefits of ibuprofen therapy outweigh the small risk of gastrointestinal bleeding.
Krijthe BP, Heeringa J, Hofman A, et al. Non-steroidal anti-inflammatory drugs and the risk of atrial fibrillation: a population-based follow-up study. BMJ Open. 2014 Apr 8
Kuo HW, Tsai SS, Tiao MM, Liu YC, Lee IM, Yang CY. Analgesic use and the risk for progression of chronic kidney disease. Pharmacoepidemiol Drug Saf. 2010 Jul;19(7):745-51.
Kurmis AP, Kurmis TP, O'Brien JX, Dalén T. The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am. 2012 May 2;94(9):815-23.
Kurth T, Hennekens CH, Stürmer T, Sesso HD, Glynn RJ, Buring JE, Gaziano JM. Analgesic use and risk of subsequent hypertension in apparently healthy men. Arch Intern Med. 2005 Sep 12;165(16):1903-9.
Lackner JE, et al. Correlation of leukocytospermia with clinical infection and the positive effect of antiinflammatory (valdecoxib) treatment on semen quality. Fertil Steril. 2006 Sep;86(3):601-5. Epub 2006 Jun 16.
Lai KC, Chu KM, Hui WM, et al. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J Med. 2005 Nov;118(11):1271-8. (InfoPOEMs: In patients at high risk for recurrent peptic ulcer with nonsteroidal anti-inflammatory drug
therapy, celecoxib was no more effective than the combination of naproxen (Naprosyn) and lansoprazole (Prevacid) in preventing serious adverse effects and was more likely to cause dyspepsia symptoms. The benefit of COX-2 inhibitors in preventing serious gastrointestinal
adverse events is likely overstated. (LOE = 1b-) )
Lai KC, Lam SK, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002 Jun 27;346(26):2033-8.
Laine L, Kivitz AJ, Bello AE, et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol. 2012 Mar;107(3):379-86.
Laine L.NSAID-associated gastrointestinal bleeding: Assessing the role of concomitant medications. Gastroenterology 2014 Oct; 147:730.
Lamberts M, Lip GY, et al. Relation of Nonsteroidal Anti-inflammatory Drugs to Serious Bleeding and Thromboembolism Risk in Patients With Atrial Fibrillation Receiving Antithrombotic Therapy: A Nationwide Cohort Study. Ann Intern Med. 2014 Nov 18;161(10):690-8.
Lands LC, Milner R, Cantin AM, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr. 2007 Sep;151(3):249-54. Epub 2007 Jun 26.
Lane NE. Clinical practice. Osteoarthritis of the hip. N Engl J Med. 2007 Oct 4;357(14):1413-21.
Lanas A, Boers M, Nuevo J. Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatic diseases: the EVIDENCE study of European routine practice. Ann Rheum Dis. 2013 Dec 18.
Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009 Mar;104(3):728-38. Epub 2009 Feb 24.
Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs (NSAIDs) and risk of acute kidney injury: nested case-control study. BMJ 2013;346:e8525.
Larson AM, et al, and the Acute Liver Failure Study Group. Acetaminophen-Induced Acute Liver Failure: Results of a US Muticenter, Prospective Study. Hepatology; Dec 2005. (of 662 consecutive acute liver failure pts over 6yrs: 42% from acetaminophen liver injury; 48% were
unintentional overdoses; only 65% of pts survived) (Benson GD, Koff RS, Tolman KG. The therapeutic use of acetaminophen in patients with liver disease. Am J Ther. 2005 Mar-Apr;12(2):133-41. & Oviedo J, Wolfe MM. Alcohol, acetaminophen, & toxic effects on the liver.
Arch Intern Med. 2002 May 27;162(10):1194-5.) ( Mahadevan SB, McKiernan PJ, Davies P, Kelly DA. Paracetamol-induced hepatotoxicity in children. Arch Dis Child. 2006 Mar 17; [Epub ahead of print]) (Watkins PB, et al. Aminotransferase elevations in healthy adults
receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):87-93.) (Kuffner EK, Green JL, Bogdan GM, Knox PC, Palmer RB, Heard K, Slattery JT, Dart RC. The effect of acetaminophen (four grams a day for three consecutive days) on
hepatic tests in alcoholic patients--a multicenter randomized study. BMC Med. 2007 May 30;5:13. Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of
liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.) (Heard K, Green JL, Bailey JE, Bogdan GM, Dart RC. A randomized trial to determine the change in alanine
aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol. Aliment Pharmacol Ther. 2007 Jul 15;26(2):283-90. Therapeutic dosing of paracetamol administered for 10 days appears to elevate serum ALT
in moderate drinkers, but does not produce clinically evident liver injury.)
Latimer Nicholas, Lord Joanne, Grant Robert L, et al., on behalf of the National Institute for Health and Clinical Excellence Osteoarthritis Guideline Development Group. Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton
pump inhibitor for people with osteoarthritis. BMJ 2009;339:b2538, doi: 10.1136/bmj.b2538
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population (not to mention the thousands of cardiovascular deaths attributed to this class of drugs). Although physicians complain about prescribing restrictions, sometimes for good reason, in this case they seem to be of benefit. (LOE = 2c))
Marjoribanks J, Proctor M, Farquhar C, Derks RS. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001751.
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Masclee GM, Coloma PM, Spaander MC, et al. NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett's oesophagus: a population-based case-control study. BMJ Open. 2015 Jan 29;5(1):e006640.
Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev. 2010 Jun 16;6:CD007402. Topical NSAIDs can provide good levels of pain relief, without the systemic adverse events associated with oral NSAIDs, when used to treat acute musculoskeletal
conditions. NNT=4.5 (3.9-5.3) for 50% reduction in pain.
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McGettigan P, Henry D. Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2. JAMA. 2006 Sep 12; [Epub ahead of print] A doserelated risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment.
Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.161.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18). CONCLUSIONS: This review confirms the findings from
randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about
the safety of diclofenac, an older drug. (InfoPOEMs: Rofecoxib (Vioxx), diclofenac (Voltaren, Cataflam), and indomethacin (Indocin) are associated with a significant increased risk of CVD. It is likely that all NSAIDs carry some risk, but the
risks may vary between medicines. Current evidence does not point to an increased risk for low dose (over the counter) ibuprofen and this remains safe to use at recommended doses. (LOE = 2a-))
McGettigan P, Henry D. Cardiovascular risk with nonsteroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011; DOI:10.1371/journal.pmed.1001098. (High CV risk with rofecoxib & diclofenac)
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Medical Letter: Treatment guidelines. Drugs for Pain. April 2007; April 2010. April 2013.
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Mehlisch Donald R., Aspley Sue, Daniels Stephen E., et al., Comparison of the analgesic efficacy of concurrent ibuprofen and paracetamol with ibuprofen or paracetamol alone in the management of moderate to severe acute postoperative dental pain in adolescents and adults:
A randomized, double-blind, placebo-controlled, parallel-group, single-dose, two-center, modified factorial study, Clinical Therapeutics, Volume 32, Issue 5, May 2010, Pages 882-895.
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Messier SP, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum. 2004 May;50(5):1501-10.
Meurin Philippe, Tabet JY, Thabut Gabriel, et al. and for the French Society of Cardiology. Nonsteroidal Anti-inflammatory Drug Treatment for Postoperative Pericardial Effusion: Multicenter Randomized, Double-Blind Trial (POPE). Ann Intern Med Feb 2, 2010 152:137-143.
Miao XP, Li JS, Ouyang Q, et al. Tolerability of selective cyclooxygenase 2 inhibitors used for the treatment of rheumatological manifestations of inflammatory bowel disease. Cochrane Database Syst Rev. 2014 Oct 23;10:CD007744. The results for disease exacerbation and AEs between the
COX-2 inhibitors celecoxib and etoricoxib and placebo were uncertain. Thus no definitive conclusions regarding the tolerability and safety of the short term use of celecoxib and etoricoxib in patients with IBD can be drawn. The two included studies suggest that celecoxib and etoricoxib do not exacerbate IBD symptoms. However, it should be noted that both studies had
relatively small sample sizes and short follow-up durations. Clinicians need to continue to weigh the risks and benefits of these drugs when treating patients IBD patients with rheumatological manifestations in order to avoid disease exacerbation and other adverse effects. Further RCTs are needed to determine the tolerability and safety of celecoxib and etoricoxib in these
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Mindikoglu AL, Magder LS, et al. Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the united network for organ sharing database. Liver Transpl. 2009 Jul;15(7):719-29. The 4 leading implicated drug groups were acetaminophen
(n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), & antibiotics (n = 39; 6%). Being on life support, DIALF due to antiepileptics (at age < 18), and elevated serum creatinine were independent pretransplant predictors of poor survival after LT for DIALF.
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Moon KW, Kim J, Kim JH, et al. Risk factors for acute kidney injury by non-steroidal anti-inflammatory drugs in patients with hyperuricaemia. Rheumatology (Oxford). 2011 Oct 22. (Low GFR and low serum albumin)
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Ogilvie JD, Rieder MJ, Lim R. Acetaminophen overdose in children. CMAJ. 2012 Jun 4.
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PDA and reduces the risk of NEC and transient renal insufficiency.
Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010061. DOI: 10.1002/14651858.CD010061.pub2. Although a limited number of infants with a PDA
have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the
development of autism or autism spectrum disorder in childhood, long-term follow-up to at least 18 to 24 months postnatal age must be incorporated in any studies of paracetamol in the newborn population. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.
Olsen Anne-Marie Schjerning, Fosbøl Emil L., Lindhardsen Jesper, et al. Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction: A Nationwide Cohort Study.
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Pharmacist’s Letter Oct 2006. Alternative or Off-label Routes of Drug Administration. (Oral administration of: N-acetylcysteine Mucomyst)
Pharmacist’s Letter Oct 2006. Cardiovascular Risks of NSAIDs and Cox-2 Inhibitors.
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patients requiring analgesic/anti-inflammatory treatment, use of the combination of a NSAID and acetaminophen may increase the risk of GI bleeding compared with either agent alone.
Rangnekar AS, Ellerbe C, Durkalski V, et al. Quality of life is significantly impaired in long-term survivors of acute liver failure and particularly in acetaminophen-overdose patients. Liver Transpl. 2013 Jun 18.
Rother M, Conaghan PG. A randomized, double-blind, phase III trial in moderate osteoarthritis knee pain comparing topical ketoprofen gel with ketoprofen-free gel. J Rheumatol. 2013 Oct;40(10):1742-8.
Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes. 2009 May;2(3):155-63. Epub 2009 May 5. (Naproxen good CV safety)
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or with any specific group of major abnormalities.
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Ringdahl E, Pandit S. Treatment of Knee Osteoarthritis. Am Fam Physician. 2011;83(11):1287-1292.
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Ross Joseph S.; Madigan David; Hill Kevin P.; et al. Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data: Lessons for Postmarket Pharmaceutical Safety Surveillance. Arch Intern Med. 2009;169(21):1976-1985.
Ross Joseph S.; Madigan David; Konstam Marvin A.; et al. Persistence of Cardiovascular Risk After Rofecoxib Discontinuation. Arch Intern Med. 2010;170(22):2035-2036.
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Services Task Force. Ann Intern Med. 2007 Mar 6;146(5):376-89. Review. Summary for patients in: Ann Intern Med. 2007 Mar 6;146(5):I35. Cyclooxygenase-2 inhibitors and NSAIDs reduce the incidence of colonic adenomas. Nonsteroidal antiinflammatory drugs also reduce the incidence of CRC. However, these agents are associated with important cardiovascular events and gastrointestinal harms. The balance of benefits to risk does not favor chemoprevention in average-risk individuals. (InfoPOEMs: The US
Preventive Services Task Force recommends against routine use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer. The beneficial decrease in colorectal adenoma, cancer incidence, and possibly cancer-related mortality is more than offset by
the harm associated with their use. Ulcers leading to gastrointestinal bleeding, renal impairment, and an increase in cardiovascular events are the main problems. (LOE = 1a))
Rostom A, Muir K, Dube C, Jolicoeur E, Boucher M, Joyce J, Tugwell P, Wells GW. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol. 2007
Jul;5(7):818-28, 828.e1-5; quiz 768. Epub 2007Jun 6. COX-2s appear to offer greater upper GI safety and are better tolerated than nonselective NSAIDs. The co-administration of acetylsalicylic acid might reduce the safety
advantage of COX-2s over that of nonselective NSAIDs.
Rostom A, Moayyedi P, Hunt R; CAG Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther. 2009 Mar 1;29(5):481-96
{Recommendations based on personal opinion: Low GI & low CV risk traditional NSAID; low GI & high CV risk naproxen; high GI & low CV risk COXIB plus PPI standard dose; high GI & high CV risk careful assessment to priorize risks (consider alternatives) ; prescribe lowest dose for shortest time possible.}
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Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individualpatient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31-41.
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selective coxibs, rofecoxib and valdecoxib, also shown to increase cardiovascular risk. These results also provide some reassurance about other specific NSAIDs regarding stroke risk.
Sachs HC; COMMITTEE ON DRUGS. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013 Sep;132(3):e796-809. doi: 10.1542/peds.2013-1985.
Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Non-steroidal antiinflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst. 2012;XX(X):XXX-XXX.
Samii A, Etminan M, Wiens MO, Jafari S. NSAID use and the risk of Parkinson's disease: systematic review and meta-analysis of observational studies. Drugs Aging. 2009;26(9):769-79.
Savino, Francesco, Lupica, Maria Maddalena, Tarasco, Valentina, et al. Fulminant Hepatitis After 10 Days of Acetaminophen Treatment at Recommended Dosage in an Infant. Pediatrics 2011 127: e494-e497.
Sawhney MS, McDougall H, Nelson DB, Bond JH. Fecal Occult Blood Test in Patients on Low-Dose Aspirin, Warfarin, Clopidogrel, or Non-steroidal Anti-inflammatory Drugs. Dig Dis Sci. 2010 Mar 3. [Epub ahead of print] Anticoagulants and antiplatelet medications lower the
positive-predictive-value of FOBT for advance colonic neoplasia and should be stopped if clinically feasible prior to stool collection.
Sawitzke AD, Shi H, Finco MF, Dunlop DD, et al.. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis. 2010 Jun 4.
Scharf HP, et al. Acupuncture and knee osteoarthritis: a three-armed randomized trial. Ann Intern Med. 2006 Jul 4;145(1):12-20. Compared with physiotherapy and as-needed anti-inflammatory drugs, addition of either TCA or sham acupuncture led to
greater improvement in WOMAC score at 26 weeks.
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Schmidt M, Hovath-Puho E, Christiansen CF, et al. Preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs and 30-day stroke mortality. Neurology. 2014 Nov 5.
Schneider V, Levesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am J Epidemiol. 2006 Nov 1;164(9):881-9. Epub 2006 Sep
27. There was a significant association for both selective and nonselective NSAIDs with acute renal failure, but confirmatory studies are required.
Scott PA, Kingsley GH, Smith CM, et al. Non-steroidal anti-inflammatory drugs and myocardial infarctions: comparative systematic review of evidence from observational studies and randomized controlled trials. Ann Rheum Dis. 2007 Oct;66(10):1296-304. Epub 2007 Mar 7. {The comparative risk of
myocardial infarction (MI) with cyclo-oxygenase-2-specific drugs and traditional non-steroidal anti-inflammatory drugs (NSAIDs) was determined. METHODS: The results of studies of a suitable size in colonic adenoma and arthritis-that had been published in English and from which crude data about MIs could be extracted-were evaluated. Medline, Embase and Cinahl
(2000-2006) databases, as well as published bibliographies, were used as data sources. Systematic reviews examined MI risks in case-control and cohort studies, as well as in randomised controlled trials (RCTs). RESULTS: 14 case-control studies (74 673 MI patients, 368 968 controls) showed no significant association of NSAIDs with MI in a random-effects model (OR
1.17; 95% CI 0.99 to 1.37) and a small risk of MI in a fixed-effects model (OR 1.32; 95% CI 1.29 to 1.35). Sensitivity analyses showed higher risks of MI in large European studies involving matched controls. Six cohort studies (387 983 patient years, 1 120 812 control years) showed no significant risk of MI with NSAIDs (RR 1.03; 95% CI 1.00 to 1.07); the risk was higher
with rofecoxib (RR 1.25; 95% CI 1.17 to 1.34) but not with any other NSAIDs. Four RCTs of NSAIDs in colonic adenoma (6000 patients) showed an increased risk of MI (RR 2.68; 95% CI 1.43 to 5.01). Fourteen RCTs in arthritis (45 425 patients) showed more MIs with cyclo-oxygenase-2-specific drugs (Peto OR 1.6; 95% CI 1.1 to 2.4), but fewer serious upper
gastrointestinal events (Peto OR 0.40; 95% CI 0.31 to 0.53). CONCLUSION: The overall risk of MI with NSAIDs and cyclo-oxygenase-2-specific drugs was small; rofecoxib showed the highest risk. There was an increased MI risk with cyclo-oxygenase-2-specific drugs compared with NSAIDs, but less serious upper gastrointestinal toxicity.}
Shephard A, Smith G, Aspley S, et al. Randomised, double-blind, placebo-controlled studies on flurbiprofen 8.75 mg lozenges in patients with/without group A or C streptococcal throat infection, with an assessment of clinicians` prediction of strep throat. Int J Clin Pract. 2014 Oct 9.
Sherve K, Gerard CJ, Neher JO, et al. Cardiovascular effects of NSAIDs. Am Fam Physician. 2014 Aug 15;90(4):Online.
Silverstein FE, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995 Aug 15;123(4):241-9.
Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Physician. 2012 Jan 1;85(1):49-56.
Smith CA, Zhu X, He L, et al. Acupuncture for primary dysmenorrhoea. Cochrane Database Syst Rev. 2011 Jan 19;1:CD007854. Acupuncture may reduce period pain, however there is a need for further well-designed randomised controlled trials.
Smith CH, Goldman RD. Topical nonsteroidal anti-inflammatory drugs for corneal abrasions in children. Can Fam Physician. 2012 Jul;58(7):748-9.
Snyder MJ, Bepko J, White M. Acute pericarditis: diagnosis and management. Am Fam Physician. 2014 Apr 1;89(7):553-60.
Soininen H, West C, Robbins J, Niculescu L. Long-Term Efficacy and Safety of Celecoxib in Alzheimer's Disease. Dement Geriatr Cogn Disord. 2006 Oct 26;23(1):8-21 [Epub ahead of print] Celecoxib 200 mg bid did not slow the progression of AD in this study, and the
occurrence of adverse events was as expected for an elderly population with a complex chronic medical condition.
Solomon SD, et al.; APC and PreSAP Trial Investigators. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006 Sep 5;114(10):1028-35.
Solomon SD, Wittes J, Finn PV, et al.; for the Cross Trial Safety Assessment Group. Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials. The Cross Trial Safety Analysis. Circulation. 2008 Mar 31; [Epub ahead of print] We observed evidence of differential cardiovascular
risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition. The risk, which increased with dose regimen (P=0.0005), was
lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1).
Solomon Daniel H.; Rassen Jeremy A.; Glynn Robert J.; et al. The Comparative Safety of Analgesics in Older Adults With Arthritis. Arch Intern Med. 2010;170(22):1968-1978. The comparative safety of analgesics varies depending on the safety event studied. Opioid use exhibits an
increased relative risk of many safety events compared with nsNSAIDs.
Solomon Daniel H.; Rassen Jeremy A.; Glynn Robert J.; et al. The Comparative Safety of Opioids for Nonmalignant Pain in Older Adults. Arch Intern Med. 2010;170(22):1979-1986.
Sood BG, Lulic-Botica M, Holzhausen KA, et al. The risk of necrotizing enterocolitis after indomethacin tocolysis. Pediatrics. 2011 Jul;128(1):e54-62.
Sotoudehmanesh R, Khatibian M, Kolahdoozan S, Ainechi S, Malboosbaf R, Nouraie M. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol. 2007 May;102(5):978-83. Epub 2007 Mar 13. n=490.
Sperber SJ, et al. Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial. Ann Intern Med. 1992 Jul 1;117(1):37-41.
Strand V. Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet 2007; 370:2138-2151. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but
asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.
Strate LL, Liu YL, Huang ES, et al. Use of aspirin or nonsteroidal anti-inflammatory drugs increases risk for diverticulitis and diverticular bleeding. Gastroenterology. 2011 May;140(5):1427-33.
Stürmer T, Glynn RJ, Lee IM, et al. Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study (PHS). Ann Intern Med. 1998;128:713-20.
Sudano I, Flammer AJ, Périat D, et al. Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation. 2010 Nov 2;122(18):1789-96.
Suissa D, Delaney JA, Dial S, et al. Non-Steroidal Anti-Inflammatory Drugs and The Risk of Clostridium Difficile-Associated Disease. Br J Clin Pharmacol. 2012 Jan 29. (diclofenac increased risk of CDAD)
Taggart E, Doran S, Kokotillo A, et al. Ketorolac in the Treatment of Acute Migraine: A Systematic Review. Headache. 2013 Jan 8.
Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet. 2009 Jul 11;374(9684):119-25. Epub 2009 Jul 3.
Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med. 1996 May 30;334(22):1435-9.
Tanaka R, Ozawa J, Kito N, et al. Efficacy of strengthening or aerobic exercise on pain relief in people with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2013 Jul 4.
Tannenbaum H, Bombardier C, Davis P, Russell AS; Third Canadian Consensus Conference Group. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus Conference. J Rheumatol. 2006 Jan;33(1):140-57. Epub 2005 Dec 1.
Tarp S, Bartels EM, Bliddal H, et al. Effect of nonsteroidal antiinflammatory drugs on C-reactive protein (naproxen) in rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheum. 2012 Jul 25.
Taylor IC, Lindblad AJ, Kolber MR. Fracture healing and NSAIDs. Can Fam Physician. 2014 Sep;60(9):817.
Temple AR, Temple BR, Kuffner EK. Dosing and Antipyretic Efficacy of Oral Acetaminophen in Children. Clin Ther. 2013 Aug 22.
The “Triple Whammy”. Pharmaicst’s Letter Dec/06 (Impaired renal function while involving an ACE &/or ARB, an NSAID &/or a diuretic)
Towheed TE, et al. Acetaminophen for osteoarthritis (review). The Cochrane Database of Systematic Reviews 2006, Issue 1.
Treatment Guidelines from the Medical Letter. Pharmaceutical Drug Overdose. Sept 2006. (Acetaminophen: N-acetylcysteine treatment. Aspirin: sodium bicarbonate treatment)
Treatment guidelines from the Medical Letter. Drugs for Pain April 2007.
Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011 Jan 11;342:c7086. doi: 10.1136/bmj.c7086.
Ungprasert P, Srivali N, Wijarnpreecha K, et al. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford). 2014 Sep 24.
Unlu N, Kocaoglan H, Sayin F, et al. Penetration of topically applied diclofenac and ketorolac into the aqueous humour and subretinal fluid: randomized clinical trial. Can J Ophthalmol. 2010 Dec 8;45(6):1-6.
Uthman OA, van der Windt DA, Jordan JL, et al. Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. BMJ. 2013 Sep 20;347:f5555.
Valkhoff VE, van Soest EM, Mazzaglia G, et al. Adherence to gastroprotection during cyclooxygenase-2 inhibitor use and the risk of upper gastrointestinal events: A population-based study. Arthritis Rheum. 2012 Apr 16.
Van Marter LJ, Hernandez-Diaz S, Werler MM, et al. Nonsteroidal antiinflammatory drugs in late pregnancy and persistent pulmonary hypertension of the newborn. Pediatrics. 2013 Jan;131(1):79-87.
Vergara M, Catalán M, Gisbert JP, Calvet X. Meta-analysis: role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users. Aliment Pharmacol Ther. 2005 Jun 15;21(12):1411-8.
Voiriot G, Dury S, Parrot A, Mayaud C, Fartoukh M. Nonsteroidal antiinflammatory drugs may affect the presentation and course of community-acquired pneumonia. Chest. 2011 Feb;139(2):387-94.
Wallace JL, Syer S, Denou E, et al. Proton Pump Inhibitors Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis. Gastroenterology. 2011 Jul 13.
Walson PD, Halvorsen M, Edge J, et al. Pharmacokinetic Comparison of Acetaminophen Elixir Versus Suppositories in Vaccinated Infants (Aged 3 to 36 Months): A Single-Dose, Open-Label, Randomized, Parallel-Group Design. Clin Ther. 2013 Jan 22.
Wang SY, Olson-Kellogg B, Shamliyan TA, et al. Physical therapy interventions for knee pain secondary to osteoarthritis: a systematic review. Ann Intern Med. 2012 Nov 6;157(9):632-44.
Watanabe T, Tanigawa T, Nadatani Y, et al. Risk factors for severe nonsteroidal anti-inflammatory drug-induced small intestinal damage. Dig Liver Dis. 2013 Jan 17.
White WB, et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am J Cardiol. 2007 Jan 1;99(1):91-8. Epub 2006 Nov 10. These analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and
demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs.
Wilcox CM, Allison J, Benzuly K, et al. Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 enzyme inhibitors and aspirin. Clin Gastroenterol Hepatol. 2006 Sep;4(9):1082-9. Epub 2006 Jul 31.
Williams CM, Latimer J, Maher CG, et al. PACE--the first placebo controlled trial of paracetamol/acetaminophen for acute low back pain: design of a randomised controlled trial. BMC Musculoskelet Disord. 2010 Jul 23;11:169.
Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol/acetaminophen for acute low-back pain: a double-blind, randomized controlled trial. (PACE) Lancet. 2014 Jul 23. pii: S0140-6736(14)60805-9.
Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther. 2010 Dec;32(14):2348-69.
Witt CM, et al. Acupuncture in patients with osteoarthritis of the knee or hip: A randomized, controlled trial with an additional nonrandomized arm. Arthritis Rheum. 2006 Oct 30;54(11):3485-3493. These results indicate that acupuncture plus routine care is associated with marked
clinical improvement in patients with chronic OA-associated pain of the knee or hip.
Wong T, Stang AS, Ganshorn H, Hartling L, Maconochie IK, Thomsen AM, Johnson DW. Combined and alternating paracetamol and ibuprofen therapy for febrile children. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD009572. DOI: 10.1002/14651858.CD009572.pub2. There is
some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone.However, the evidence for improvements inmeasures of child discomfort remains inconclusive.
Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM. Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials. Rheumatology (Oxford). 2007 Jan;46(1):135-40. {InfoPOEMs – Feb07: In this short-term study emphasizing individual response, acetaminophen
and celecoxib (Celebrex) are virtually indistinguishable in improving pain, stiffness, and function in patients with clinically diagnosed degenerative joint disease (DJD). Since acetaminophen is less expensive and has fewer safety concerns, it should be the drug of first choice. (LOE = 1b).}
Zapata-Colindres JC,et al. The association of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in peptic ulcer disease. Can J Gastroenterol. 2006 Apr;20(4):277-80. The development of PUD was observed earlier in the combined H pylori and NSAID group than
in patients with only NSAID use. This suggests a synergic effect between the two risks factors in the development of PUD.
Zhang W, Doherty M, Arden N, et al. EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for
International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2005 May;64(5):669-81. Epub 2004 Oct 7 & ACP Journal Club .
Zhang J, Ding EL, Song Y. Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials. JAMA. 2006 Sep 12; [Epub ahead of print] In this comprehensive analysis of 114 randomized trials
with 116 094 participants, rofecoxib was associated with increased renal and arrhythmia risks. A COX-2 inhibitor class effect was not evident.
Zhang W, Doherty M, et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007; 66: 377–88.
Zayat AS, Conaghan PG, Sharif M, et al. Do non-steroidal anti-inflammatory drugs have a significant effect on detection and grading of ultrasound-detected synovitis in patients with rheumatoid arthritis? Results from a randomised study. Ann Rheum Dis. 2011 Oct;70(10):1746-51.
Zhou L, Maviglia SM, Mahoney LM, et al. Supratherapeutic dosing of acetaminophen among hospitalized patients. Arch Intern Med. 2012 Dec 10;172(22):1721-8.
-------------------------------New coxib - Etoricoxib (ARCOXIA) - NOT approved by FDA (April, 2007)
Lumiracoxib – hepatic toxicity – deregulation in Australia. http://www.medadnews.com/News/index.cfm?articleid=467159
26
Mazieres B, Rouanet S, Guillon Y, Scarsi C, Reiner V. Topical ketoprofen patch in the treatment of tendinitis: a randomized, double blind, placebo controlled study. J Rheumatol. 2005 Aug;32(8):1563-70.
Underwood M, Ashby D, Cross P, et al; on behalf of the TOIB study team. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial & patient preference study. BMJ. 2007 Dec 4; [Epub ahead of print] Advice to use oral or topical
preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs.
Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev. 2010 Jun 16;6:CD007402. Topical NSAIDs can provide good levels of pain relief, without the systemic adverse events associated with oral NSAIDs, when used to treat acute musculoskeletal
conditions.
Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD007400. DOI: 10.1002/14651858.CD007400.pub2. Topical NSAIDs can provide good levels of pain relief; topical
diclofenac solution is equivalent to that of oral NSAIDs in knee and hand osteoarthritis, but there is no evidence for other chronic painful conditions. Formulation can influence efficacy. The incidence of local adverse events is increased with topical NSAIDs, but gastrointestinal adverse
events are reduced compared with oral NSAIDs.
Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ. 2004 Aug 7;329(7461):324. (Towheed TE.
Pennsaid therapy for osteoarthritis of the knee: a systematic review and metaanalysis of randomized controlled trials. J Rheumatol. 2006 Mar;33(3):567-73. )
27
MIGRAINE:
Generic/
TRADE
AGENTS FOR ACUTE TREATMENT
INDICATIONS and
SIDE EFFECTS
PREGNANCY
CATEGORY
CONTRAINDICATIONS (CI)
1st line for severe attacks
C
Naratriptan
≤40% of all attacks & 25% of all
AMERGE
1
(1,2.5mg D shaped tab);OTC in UK patients do not respond ; high
recurrence rate (~40% @24hr IMITREX)
Rizatriptan
C
CI •cardiac or cerebrovascular
MAXALT
W
disease (or risk factors for same)
(5,10mg capsule shaped tab;
(risk of MI ~1/5,000,000 migraine
5,10mg wafer)
attacks treated 2,49)
Sumatriptan C -most used •uncontrolled hypertension
•?diabetes
IMITREX W
•hemiplegic or basilar migraine
(25,50,100mg DF tab;
Caution: decrease dose/avoid
-generic 25,50 & 100mg tabs •Renal dysfunction with nara/suma
5,20mg Nasal spray;
•Hepatic dysfn with all triptans
6mg/0.5ml SC inj);
•aspartame ZOMIG Rapimelt, MAXALT wafer
TRIPTANS
W
50mg OTC in the UK
(Treximet in USA, Suma 85mg & naproxen 500mg)
C
Zolmitriptan
W
ZOMIG
(2.5mg tab; 2.5mg
ZOMIG
Rapimelt tab);
⊗
(5mg Nasal spray )
Dihydroergotamine
DHE
X
MIGRANAL/generic
ERGOTS
(1mg/ml inj)
(4mg/ml nasal spray
= 0.5mg/spray)
NOTE: pump 4Xs into
the air to prime nasal
spray for 1st use.
X
caffeine (1/100 tabς ,supp)
Ergotamine/ W
CAFERGOT
NONSPECIFIC ANALGESICS
Ergodryl avail.; Ergomar SL &
Cafergot-PB Supp – DC’d by
the company.
NSAIDs
C/D
ie high dose ASA,
B/D
ibuprofen,
naproxen Na+ or
naproxen K+ ANAPROXW
Öcaution in PKU pts
EDS Criteria:Treat migraine
For all: (13 trials suggest no differences)65
Chest discomfort or tightness (or
tightness of neck/throat), nausea
facial flushing,tingling & paresthesia
Riza / Zolmi Ö dizziness,
fatique, somnolence ( 8-10%)
Almo/Elet/Nara/Suma:
Ö sulfa allergy ?
Differences generally not
clinically significant; trends:
•Almo/Nara =less adverse effects?
•Riza=more recurrence?
•Zolmi = more adverse effects?
•Suma = 50mg dose appears
as effective as 100mg & as
well tolerated as 25mg3
baseline cardiac evaluation/ECG
recommended for >40yr & >50yr
headache (Age >18yr )
Prepared by: L Regier BSP, B Jensen BSP, S Downey BSP © www.RxFiles.ca
DRUG (DI)
INTERACTIONS
•Serotonin syndrome
(e.g. agitation, excitement,
hypomania, myoclonus, tremor,
hyperreflexia, ataxia, motor
weakness, fever/chills, diarrhea)
with concurrent MAOIs,
SSRIs, TCAs or lithium.
MAOIs = stop at least 2 weeks
prior to triptans (except Nara);
caution with other agents
•Do NOT use within
24hr of DHE, other
ergot preps or other
triptans (risk of additive
vasoconstriction/
coronary vasospasm)
≤
•↑level of Zolmi use 5mg/24h
with cimetidine,
ciprofloxacin & fluvoxamine
Eletriptan RELPAX ⊗:20-40mg tab,
?sulfa allergy but ↑DI 3A4 with other meds; low recurrence $92/6 doses
Almotriptan AXERT W:6.25-12.5mg tab may repeat x1 in 2hr; similar to po sumatriptan; $100/6 doses.
Frovatriptan FROVA ⊗: 2.5mg; may repeat after 2hr, MAX 5mg/24hrs; long t½= 25hr ?-less effective but less
recurrence $94/6 doses. C
{Review:Med Letter Feb05, Treatment Guidelines Mar08}
1st line agent for severe & ultrasevere attacks (for status
Ö
migrainosus, pre-dose antiemetic,
e.g. metoclopramide, x2-3 days)
Metoclopramide MAXERAN,
REGLAN alone sometimes effective
Chest discomfort, tingling &
paresthesia, nausea, drowsiness,
dizziness, diarrhea, muscle cramp
Nasal spray = rhinitis, taste
disturbance but ↓ nausea
CI •cardiac or cerebrovascular
disease(or risk factors);uncontrolled
hypertension, ?diabetes, pregnancy
•hemiplegic or basilar migraine
baseline cardiac evaluation/ECG
Caution: renal/hepatic dysfunction
recommended for >40yr & >50yr
nd
2 line due to ↓ efficacy & ↑ toxicity
Chest discomfort/ pain,
CI •cardiac or cerebrovascular
tingling & paresthesia, nausea,
dx or risk factors, uncontrolled BP,
?diabetes, pregnancy/?breastfeeding vomiting, dizziness, drowsiness,
diarrhea, muscle cramps
•hemiplegic or basilar migraine
Chronic daily headache (overuse)
Caution: renal/hepatic dysfunction
Treatment of mild-moderate attack
•GI irritation/upset/bleed,
dizziness, fatigue, rash
CI •hypersensitivity to ASA/NSAID
(ie bronchospasm, nasal polyps)
•Renal impairment esp. if
Caution: if cardiovascular or renal
CrCl <30ml/min
•Do NOT use within
12hr of triptans or
24hrs for naratriptan6
(risk of additive
vasoconstriction/
coronary vasospasm)
•↑ toxicity (eg. severe
ischemia) of ergot preps:
with clarithromycin,
erythromycin,
itraconazole, propranolol,
protease inhibitors &
posa- & vori-conazole.
Sibutramine:↑ risk of
serotonin syndrome.
•↑ bleeding with warfarin
& antiplatelet agents
•Displaces DVA & older
sulfonylureas so↑ toxicity
•May blunt effect of some
antihypertensives •others
disease; GI ulcer risk.
{Also useful for tension-type headache}
Combo analgesics C/D Treatment of mild-moderate attack if: Drowsiness, dysphoria, nausea, •Products with ASA similar
constipation (esp. with codeine); to above
•not relieved with simple analgesics
(292s, TYLENOL #3,
•Additive effects with other
•vasoconstrictors are contraindicated
{Opioids may ↑ risk of chronic HA}
FIORINAL ⊗,others) acetaminophen TYLENOL W B : doses of ~1gram sometimes effective if taken early CNS depressants
Butorphanol ⊗ C/D Reserve for rescue treatment or
•↑ CNS depression:
Drowsiness, dysphoria, nausea
CNS depressants,
10mg/ml nasal spray
when DHE/triptans ineffective or
& vomiting, nasal irritation
MAOIs, alcohol
contraindicated
(previous STADOL) 1mg/spray
(Dose ~ 1mg/spray)
Oct 08
DOSING
COMMENTS
usual;
•Selective 5HT-1 receptor agonists
•Effective any time during an attack but
the sooner the better; for SC IMITREX
taking during aura phase may be too early
•If failure with one, can try another
•Triptan & NSAID: benefit some?↓recurrence, use≤2x/wk
•Frequent use of triptans can result in
rebound & chronic daily headache (MAX
weekly/monthly dose? Some clinicians suggest
12-18 doses per month; no supporting data2)
•Less nausea vs DHE but ↑ recurrence rate
-----------------------------------------------------------------------------------
MAX/24hr
1mg or 2.5mg;
may repeat in 4h
MAX=5mg/24h
5mg or 10mg;
may repeat in 2h
$ per
6 doses
109
109
MAX 20mg/24h
With Propranolol: 5mg; 15mg/24hr
25-50mg 72generic/
50-100mg PO;
111
may repeat in 2h
(MAX 200mg/24h)
SC IMITREX 4
•best bioavailability/fastest onset ~15min
versus oral onset 30 - 120min; (nasal also fast!)
5mg or 20mg in one
nostril; may rpt in 2h
Nasal IMITREX& DF(age >12yr5),MAXALT Wafer,
&/OR ZOMIG RAPIMELT or nasal 4 may be preferred if
• fast relief required ~15min and
• nausea &/or vomiting present
AMERGE 4 - slowest onset but
•better tolerability, less drug interactions
•longest duration, lowest recurrence rate
(MAX 40mg/24h)
6mg SC; may rpt x1in
1h; (MAX 12mg/24h)
1.25mg or 2.5mg ;
may repeat after 2hr
111
300
103
MAX 10mg/24h
{2.5mg less effective?: at 2hr vs riza 10mg & at 4hr vs suma 100mg}65
•Non-selective 5HT agonist
•More nausea than triptans but less chest pain
•May precede with 10mg metoclopramide, or
prochlorperazine 5-10mg esp. if severe attack
requiring repeat doses or if nausea present
•IV = rapid onset but more adverse effects so
reserve for severe attack6
•SC = slower response rate vs IMITREX but
longer acting & lower recurrence rate at 24hr 7
•Nasal spray =response rate similar to oral
triptans, or nasal IMITREX5
•Non-selective 5HT agonist
•Most nausea of all abortive preps; recent meta-
analysis ?'s efficacy as mainly appeared to ↑ N&V
8
With Propranolol ↓ zolmi dose.
5mg nasal
switch to oral
0.5-1mg q1h SC,
IM or IV;repeat q1h
198
34
to Max 3mg/24h 6mg/wk
{IV 1mg/50ml over ≥15min
1 spray into each
nostril stat;repeat in
15 minutes prn
MAX 4 spray/attack;
8 sprays/24h
2 tab SL stat, then
1 tab Q30-60min,
MAX 6tab/24h;10/wk
$ 44
per 1 pkg
( 3 bottles
X4 doses
per
bottle)
13
• Ergotism with overuse (vasoconstriction with
numbness, tingling, paresthesia, gangrene of extremities,
headaches, convulsion, abdominal/chest pain)
•Overuse (ie >3x/wk) leads to rebound
ASA 650-1300mg po q4h
headache & to medication-induced
X2 (MAX 4g/24h)
chronic daily headache; for short-term &
Ibuprofen 400-800mg po
intermittent use
q4-6h X2 (MAX 3.2g/24h)
•Enteric ASA too slow. Buffered ASA OK OTC
ANAPROX 275-550mg
po q4-6h X2 (MAX 1.65g/24h)
•Fast acting (e.g. ANAPROX) may be useful
•Ibuprofen effective & acetaminophen useful in kids5
•Overuse associated with rebound &
1-2 tabs/caps stat: may
medication induced headache (esp. caffeine
repeat 3-4h prn
combos); for short-term & intermittent use
MAX 6-8 tabs/caps per
may
mask
pain
without
affecting
•Dependency potential
24h
underlying pathophysiology
•Dependency potential
•Mixed agonist-antagonist so can precipitate
withdrawal in persons addicted to opiates
1 spray in 1 nostril;
may repeat in 3-5hr
$1
$1
OTC200mg
$ 15
T3=$ 7
292= $ 8
Fc½= $ 20
$55
(15 doses)
MAX 16 sprays/24h
CORONARY VASOSPASM Potential: still greatest concern; metaanalysis showed no clinically important differences between agents, thus one unlikely to be “safer” than others 9; Öpatient selection & counseling important! ( with aura ↑risk)
ADJUNCT AGENTS: metoclopramide 10mg SC/IV {IV: 10mg /50ml over ≥15min}; 5-10mg PO chlorpromazine 5-25mg IV (10-25mg PO) q4-6h {IV: pretreat with ≥ 500ml NS} domperidone 20-30mg PO (or 60mg PR) tid-qid prochlorperazine STEMETIL 5-10mg IV (25mg PR) q8h
trimebutine Modulon
200mg cap po x1
(may ↑ Tryptan efficacy with less nausea & photophobia.48) haloperidol HALDOL 5mg IV in 500ml normal saline or 5mg IV over 3mins
68
MIGRAINE:
AGENTS FOR PROPHYLAXIS
Generic/
TRADE
PREGNANCY
CATEGORY
TCAs
Amitriptyline
ELAVIL/generic
(10, 25, 50,75
W
C
mg tab)
C
Nortriptyline
AVENTYL/generic
INDICATIONS AND
CONTRAINDICATIONS CI
1st line especially if associated
depression, chronic pain, or
tension-type headache
•severe cardiac, kidney, liver,
prostate or thyroid disease; glaucoma,
hypotension •seizures •MAOI use
CI
(10,25mg cap)
β-BLOCKERS
Metoprolol
C/D
LOPRESOR/generic
(25
ς
,
ς
ς
50 ,100 mg tab;SR 100,200mg)
Atenolol (25,50ς,100ςmg tab)
Propranolol
C/D
INDERAL/generic
(10ς,20ς,40ς,80ς& 120ς mg tab;
LA 60,80,120,160mg)
CCBs
Flunarizine W
X
SIBELIUM (5mg cap)
Verapamil
C
ISOPTIN, others
ANTICONVULSANT
5HT-2
Reduce frequency but little effect
on intensity or duration
CI
•CHF, arrythmias,hypotension
(pregnancy with flunarizine)
Caution: β-blockers, Parkinsons
expert opinion
(120,180 ,240 SR tab/cap)
Divalproex (DVA)
EPIVAL/generic D
1st line for severe migraine
(↓ severity and duration) but little
effect on mild-moderate attacks;
useful for SSRI induced migraine
& prolonged atypical migraine aura
(125,250,500mg EC
χ⊗
tab;1000mg/10ml vial )
______________________________________
Gabapentin NEURONTIN
(100, 300, 400mg cap) C
________________________________________
Topiramate TOPAMAX
CI •liver disease
Caution: children → hepatotoxicity
Monitor: CBC, Platelets, LFT
(Level 350-830 umol/l – trough)
(25,100,200mg tab; C
-see comments column & antiepileptics chart p 73
15, 25mg sprinkle cap)
Pizotyline/pizotifen
SANDOMIGRAN C
(0.5mg, DS =1ς mg tab)
Methysergide
SANSERT
(2mg tab W)
X
Anticholinergic effects: dry
mouth, constipation, etc.;
dizziness, drowsiness, postural
hypotension, weight gain
Nortriptyline Öless drowsiness,
dry mouth & weight gain than
amitriptyline; but less evidence
Fatigue, bradycardia,
hypotension, coldness of
extremities, depression,
impotence, sleep disturbance,
bronchospasm
uncompensated heart failure,
peripheral vascular disease
st
ς
SIDE EFFECTS
CI •asthma, heart block or
Verapamil ~1 line option
ς
ERGOTS
1st line
Can reduce frequency and some
effect on intensity and duration
Prepared by S Downey BSP, L Regier BSP, B Jensen BSP © www.RxFiles.ca
2nd line (seldom used)
CI•?diabetes, heart disease, glaucoma,
Flunarizine: fatigue, weight
gain, depression, parkinson
like side effects (EPS)
Verapamil: bradycardia,
hypotension, constipation,
nausea, edema, headache
Nausea, tremor, weight gain,
alopecia, ↑ liver enzymes,
diarrhea (transient & can be
minimized by starting low &
titrating up); polycystic ovary
Rare: ↓ platelets (↓ dose
helps) & WBC, hepatotoxic,
skin rx's, pancreatitis
Neural tube defects→spina
bifida 1-2%.
Weight gain, fatigue,
weak anticholinergic effects
urinary retention, prostatic hypertrophy,
renal/hepatic dysfunction
3rd line - for prevention of severe
recurrent migraine unresponsive to
other agents (seldom used)
•hypertension, cardiac, liver,
kidney, lung & collagen diseases
•thrombophlebitis & pregnancy
CI
Retroperitoneal, cardiac &
pulmonary fibrosis
Ö do not use for >6 months
duration without weaning & a
1-2 month drug holiday!
Nausea, muscle cramps, ↑weight,
↓hair, claudication, hallucinations
DRUG (DI)
INTERACTIONS
COMMENTS
Avoid with MAOI,
cisapride, clonidine
↑ effects with MAOI,
anticholinergics, other
CNS depressants
↑ effect with CCBs, SSRIs
cimetidine,phenothiazines,
cipro (↓ TCA metabolism)
↑ levels of rizatriptan
(↓ dose of riza to 5mg)
↑ risk of peripheral
ischemia with ergots
↑ cardiovascular effects
with CCBs,clonidine
↑ levels of β-blocker with
cimetidine,fluoxetine
Altered hypo-glycemic
effect with sulfonylureas
•Central neuromodulator of noradrenaline &
serotonin (5HT) system
•Start low & titrate up to help ↓ side effects;
may give single dose at bedtime
↑ effect of CNS depressants
Verapamil = many DIs
ASA, barbs, β-blockers,
carbamazepine, cimetidine,
digoxin, erythromycin,
ketoconazole, lithium, statins
& theophylline
{nortriptyline ~2x more potent than amitriptyline}
•Caution in elderly Ö anticholinergic effects
•Modulation of central catecholaminergic system
& brain serotonin
•May be class effect however β-blockers with
intrinsic sympathomimetic activity may not be
effective (data from small/poorly designed trials) 10
•Timolol 20-30mg/day & nadolol also used
•Start low & titrate up
•If failure with one→ may try another β-blocker
•Taper slowly before stopping to prevent rebound
•? modulate transmitters rather than vasodilation
•Maximum effect may take several months
•Overall benefit similar to β-blockers
•Flunarizine seldom used (probably effective in
kids5); Verapamil often used but less studied
•Verapamil good prophylaxis→cluster headache
↑ ASA & warfarin effect
Anticonvulsants: effective NNT=3.8,SE’s common SEÖDC:NNH=2.4-33 19
↑ Valproic acid level by:
•Divalproex less GI effects than valproic acid
•Monitor LFTs initially: if ↑ enzymes, then ↓ dose;
if 2-3x normal→stop drug; Mech: Modulation of GABA receptors?
ASA, cimetidine, erythromycin,
fluoxetine, isoniazid & salicylates
↓ Valproic acid level by:
carbamazepine, cholestryramine,
lamotrigine, phenobarbital, phenytoin,
primidone, rifampin & topiramate
Oct 08
DOSING
range / typical
$
/month
30-150mg/d
100mg po hs
150mg po hs
21
27
10-150mg hs
50mg po hs
100mg po hs
25
43
Metopr 50-200mg/d
50mg po bid
100mg SR po od
14
15
Atenolol 50-150mg/d
100mg po od
24
Propran 80-320mg/d
80mg po bid
120mg LA po od
5-10mg/d
5mg po hs (>6yrs old)
10mg po hs starting dose
240-320mg/d
240mg SR po od
500-1500mg /d
125mg po bid cc
250mg po bid-tid cc
500mg bid cc with meals
12
39
26
45
31
15
22-28
35
_____________________________________________________
Gabapentin effective at 2,400mg/day
20
(Gabapentin & Topiramate are Peds options – see antiepileptic chart for dosing)
Valproic acid ↑'s levels of:
_____________________________________________________
amitriptyline, carbamazepine epoxide
(ie.↑ SE), clonazepam, diazepam,
lamotrigine lorazepam,
phenobarbital & warfarin
11,12,13,14
Topiramate
effective
; 100mg/day
equal to propranolol 160mg/day 15; no studies
compared to valproate; expensive but new generic avail;
SE’s common (e.g. paresthesias, cognitive); wt loss
Additive effects with:
CNS depressants,
anticholinergics
•Serotonin-2 receptor antagonist
•Somnolence so begin low & dose at bedtime
(ie 0.5mg hs).
•Do NOT use within 24hr
of triptans (risk of ↑
vasoconstriction/spasm)
↑ toxicity of ergots with
clarithromycin,erythromycin, propranolol &
protease inhibitors
•Serotonin-2 receptor antagonist with carotid
vasoconstrictor effect
•Active metabolite
•If no effect after 3 week trial,not likely to
{Initiate:300mg tid}
600-800mg po tid
___________________________________
{Initiate:25mg po hs ,
↑ by 25mg/wk}
50-100mg po bid
Start 0.5mg po hs
titrate to 0.5mg tid
(or 1.5mg po hs)
MAX 6 mg/day
115-135
32generic
100
20
44
--------------------------------------------------------------------
1mg tid
70
2-8mg/d
2mg po bid cc
2mg po tid cc
76
110
help
•Taper dose over 2-3 weeks before stopping!
OTHER: riboflavin (Vit B2) 400mg/d $10, magnesium ~500mg/d$10, feverfew TANACET 125mg/d, petasites (butterbur) extract PETADOLEX 100mg/d 16 BOTOX injection 25-100 IU –effective ~q3mons17 for some.Acupuncture?17
PROPHYLACTIC THERAPY should be considered if : migraines severe enough to impair quality of life or patient has > 3 severe attacks per month which fail to respond to abortive therapy.
TIPS : use one prophylactic agent at a time start low & titrate up; once effective dose reached, continue for minimum 3 month trial to evaluate effectiveness (benefits usually seen after 1-2 months) efficacy depends on
withdrawal of analgesics causing rebound or chronic daily headache if single agent ineffective, may try a combination (eg beta blocker + TCA); consider neuro consult if no response continue effective therapy for
9-12mon; discontinue gradually to prevent rebound before NSAID/triptan consider metoclopramide or domperidone in some long cycle continuous birth control pills can help ↓ migraines
Success of prophylaxis considered to be ↓ in severity or frequency of headache by 50% reassess in teens (eg nearly 40% of teens esp if no migraine family history, no longer had headaches 10 years later Monastero 2006)
CI =contraindication CNS=central nervous system DI=drug interaction LFT=liver function test SE=side effect SR=sustained release. χNon-formulary in SK
EDS status SK Wcovered NIHB
⊗not NIHB prior NIHB ς =scored tab
=↓dose for renal dysfx
69
References: RxFiles – MIGRAINE AGENTS
1
Diener Hc et al. Antimigraine drugs. J Neurol 1999;246:515-19.
Evans RW and Lipton RB. Topics in migraine management. Neurol Clinics 2001:19(1):1-21.
3
Smith MA and Ross MB. Oral 5HT1 receptor agonists for migraine: comparative considerations. Formulary 1999; 34:324-38.
4
Gawel MJ, et al. A systematic review of the use of triptans in acute migraine. Can J neurol Sci 2001;28:30-41.
2
5
Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Practice Parameter: Pharmacological treatment of migraine headache in children and adolescents: Report of the
American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004 Dec 28;63(12):2215-24.
6
Diener HC et al. A practical guide to the management and prevention of migraine. Drugs 1998;56:811-24.
Pryse-Phillips WE et al. Guidelines for the diagnosis and management of migraine in clinical practice. CAN Med Assoc J 1997;156(9): 1273-87.
8
Dahlof C. Placebo controlled trials with ergotamine in the acute treatment of migraine. Cephalgia 1993;13:166-71.
9
Ferrari MD et al. Oral triptans in acute migraine treatment: a meta analysis of 53 trials. The Lancet 2001;358: 1668-75.
10
Limmroth V and Michel M. The prevention of migraine: a critical review with special emphasis on B-adrenoceptor blockers. Br J Cin Pharmacol 2001;52:237-43.
11
Brandes J, Saper J, Diamond M, et al. Topiramate for Migraine Prevention: A Randomized Controlled Trial. JAMA 2004;291 965-973
7
12
Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004 Apr;61(4):490-5.
13
Storey JR et al …Headache 2001;41:968-1000.
14
Topiramate (Topamax) for prevention of migraine. Med Lett Drugs Ther. 2005 Jan 31;47(1201):9-10.
Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ, Neto W, Vijapurkar U, Doyle A, Jacobs D; MIGR-003 Study Group. Topiramate in migraine prophylaxis—
results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004 Aug;251(8):943-50.
16
Diener HC, Rahlfs VW, Danesch U. The first placebo-controlled trial of a special butterbur root extract for the
prevention of migraine: reanalysis of efficacy criteria. Eur Neurol. 2004;51(2):89-97. Epub 2004 Jan 28.
17
Blumenfeld A. Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders. Headache. 2003 Sep;43(8):853-60.
Chilson CN, Brown SJ. Role of botulinum toxin type a in the prophylactic treatment of migraine headaches. Ann Pharmacother. 2005 Dec;39(12):2081-5. Epub 2005 Nov 1.
Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type a and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache. 2008 Feb;48(2):21020. Epub 2007 Nov 28. Both BoNTA and DVPX significantly reduced disability associated with migraine; BoNTA had a favorable tolerability profile compared with DVPX.
15
Naumann M, So Y, Argoff CE, Childers MK, Dykstra DD, Gronseth GS, Jabbari B, Kaufmann HC, Schurch B, Silberstein SD, Simpson DM; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain
(an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008 May 6;70(19):1707-14. Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be
considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to
permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.
18
Linde K, Streng A, Jurgens S, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA. 2005 May 4;293(17):2118-25. . (InfoPOEMs: Acupuncture and sham acupuncture
RR, Kaufman JS, Kaptchuk TJ, et al. A
randomized, controlled trial of acupuncture for chronic daily headache. Headache. 2005 Oct;45(9):1113-23.
19
Chronicle E, Mulleners W. Anticonvulsant drugs for migraine prophylaxis. Cochrane Database Syst Rev. 2004;(3):CD003226.
20
Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001 Feb;41(2):119-28.
Jafarian S, et al. Gabapentin for prevention of hypobaric hypoxia-induced headache: randomized double-blind clinical trial. J Neurol Neurosurg Psychiatry. 2008 Mar;79(3):321-3.
Epub 2007 Oct 26.
are equally more effective than no treatment in patients with migraine headaches. These results defend the adage that doing something is better than doing nothing. (LOE = 1b) ). & Coeytaux
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43. Brandes JL. The influence of estrogen on migraine: a systematic review. JAMA. 2006 Apr 19;295(15):1824-30. Epidemiological, pathophysiological, and clinical evidence link
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of migraine with an angiotensin II receptor blocker (candesartan): a randomized controlled trial. JAMA. 2003 Jan 1;289(1):65-9.
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48. Rizatriptan vs risatriptan plus trimebutine for the acute treatment of migraine: a double blind, randomized, cross-over, placebo-controlled study. Cephalgia 2006;26:871-4.
49. Kurth T, et al. Migraine and risk of cardiovascular disease in women. JAMA. 2006 Jul 19;296(3):283-91. Erratum in: JAMA. 2006 Jul 19;296(3):1 p following 291. In this large,
prospective cohort of women, active migraine with aura was associated with increased risk of major CVD, myocardial infarction, ischemic stroke, and death due to ischemic CVD, as well as with coronary revascularization and angina. (InfoPOEMs: Women
suffering from active migraines with aura are at an increased risk of ischemic vascular events, including coronary heart disease and stroke. In general, this correlates to 18 additional cardiovascular events for every 10,000 women per year. Women with
active migraine without aura are not at an increased risk of ischemic vascular disease. (LOE = 2b-) )
50. van Ettekoven H, Lucas C. Efficacy of physiotherapy including a craniocervical training programme for tension-type headache; an RCT. Cephalalgia. 2006 Aug;26(8):983-91.
51. Rapoport A, et al. Long-term migraine prevention with topiramate: open-label extension of pivotal trials. Headache. 2006 Jul-Aug;46(7):1151-60.
52. Ahonen K, et al. A randomized trial of rizatriptan in migraine attacks in children. Neurology. 2006 Aug 30; [Epub ahead of print]
53. Ahonen K, et al. Nasal sumatriptan is effective in treatment of migraine attacks in children: A randomized trial. Neurology. 2004 Mar 23;62(6):883-7.
54. Cittadini E, et al. Effectiveness of Intranasal Zolmitriptan in Acute Cluster Headache: Randomized, Placebo-Controlled, Double-blind Crossover Study. Arch Neurol. 2006 Sep 11.
55. Detsky ME, et al. Does this patient with headache have a migraine or need neuroimaging? JAMA. 2006 Sep 13;296(10):1274-83. The best predictors can be summarized by the
mnemonic POUNDing (Pulsating, duration of 4-72 hOurs, Unilateral, Nausea, Disabling). The presence of 4 simple historical features can accurately diagnose migraine. Several
individual clinical features were found to be associated with a significant intracranial abnormality, and patients with these features should undergo neuroimaging. (InfoPOEMs: Useful clinical
criteria from the history and physical for distinguishing migraine from tension-type headache include: nausea, photophobia, phonophobia, and exacerbation by physical activity. Combined findings useful for distinguishing migraine can be summarized by
the mnemonic: POUNDing (Pulsatile quality; duration of 4 to 72 hOurs; Unilateral location; Nausea or vomiting; Disabling intensity). Patients with 4 or more of these criteria are most likely to have migraine headaches. Criteria increasing the risk of
intracranial pathology include: cluster-type headache; abnormal neurologic examination result; undefined headache; headache with aura; headache aggravated by exertion or valsalva-like maneuver; and headache with vomiting. No clinical features from
the history and physical are useful for significantly reducing the likelihood of intracranial pathology. (LOE = 3a))
56. Honkaniemi J, et al. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache. 2006 May;46(5):781-7.
57. Evers S, et al. Treatment of childhood migraine attacks with oral zolmitriptan and ibuprofen. Neurology. 2006 Aug 8;67(3):497-9. Epub 2006 Jun 14.
58. Kanai A, Saito M, Hoka S. Subcutaneous sumatriptan for refractory trigeminal neuralgia. Headache. 2006 Apr;46(4):577-82; discussion 583-4.
59. Tozer BS, Boatwright EA, David PS, et al. Prevention of migraine in women throughout the life span. Mayo Clin Proc. 2006 Aug;81(8):1086-91; quiz 1092.
60. Mellick LB, McIlrath ST, Mellick GA. Treatment of headaches in the ED with lower cervical intramuscular bupivacaine injections: a 1-year retrospective review of 417 patients.
Headache. 2006 Oct;46(9):1441-9.
61. Brighina F, Palermo A, Aloisio A, Francolini M, Giglia G, Fierro B. Levetiracetam in the Prophylaxis of Migraine With Aura: A 6-Month Open-label n=16 Study.
Clin Neuropharmacol. 2006 November/December;29(6):338-342.
62. Becker WJ, Christie SN, Ledoux S, Binder C. Topiramate prophylaxis and response to triptan treatment for acute migraine. Headache. 2006 Oct;46(9):1424-30. Although
topiramate prophylaxis did reduce migraine attack frequency, in this pilot study topiramate prophylactic migraine treatment did not increase the proportion of patients pain-free 2
hours after symptomatic triptan therapy.
63. Monastero R, Camarda C, Pipia C, Camarda R. Prognosis of migraine headaches in adolescents: A 10-year follow-up study. Neurology. 2006 Oct 24;67(8):1353-6.
64. Wammes-van der Heijden EA, et al. Risk of ischemic complications related to the intensity of triptan and ergotamine use. Neurology. 2006 Oct 10;67(7):1128-34. In general
practice, triptan overuse does not increase the risk of ischemic complications. Overuse of ergotamine may increase the risk of these complications, especially in those simultaneously
using cardiovascular drugs.
65. Membe S, McGahan L, Cimon K, et al. Tryptans for Acute Migraine. Technology Report 72. CADTH. March 2007. Accessed at:
http://www.cadth.ca/media/pdf/I4001_tr_Triptans_e.pdf .
66. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for the acute treatment of migraine: A randomized trial. JAMA 2007;297:1443-1454. {InfoPOEMs Jun07: A single-tablet combination
of sumatriptan (85 mg) plus naproxen sodium (500 mg) was better than either agent alone in the treatment of acute migraine. Outcomes measured included 2-hour headache relief and 24-hour sustained pain-free response. This fixed combination is
currently under FDA review and will be marketed under the trade name Trexima. This study used a single pill combination, but separate pills taken concurrently are likely to be equally efficacious (and potentially less expensive as generics). (LOE = 1b-)}
67. EFNS Migraine 2007 Guidelines http://www.efns.org/files/guideline_37.pdf
68. Tfelt-Hansen P, Steiner TJ. Over-the-Counter Triptans for Migraine : What are the Implications? CNS Drugs. 2007;21(11):877-83. In 2006, the triptans sumatriptan 50mg and naratriptan 2.5mg were
approved as over-the-counter (OTC) drugs in pharmacies in the UK and Germany, respectively. Both drugs have been used in a large number of patients with migraine and are considered to have good safety profiles.
69. Pascual J, Mateos V, Roig C, et al. Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability. Headache. 2007 Sep;47(8):1152-68.
70. Diener HC, et al. Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomised, double-blind, placebo-controlled trial. Lancet
Neurol. 2007 Dec;6(12):1054-62. Epub 2007 Nov 7. Sustained benefit was reported after discontinuation of topiramate, although number of migraine days did increase. These findings
suggest that patients should be treated for 6 months, with the option to continue to 12 months in some patients.
71. Loder E, Rizzoli P. Tension-type headache. BMJ. 2008 Jan 12;336(7635):88-92.
72. Dodick D, Freitag F. Evidence-based understanding of medication-overuse headache: clinical implications. Headache. 2006 Nov;46 Suppl 4:S202-11.
73. Silberstein S, Saper J, Berenson F, et al. Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study. Neurology. 2008 Feb 12;70(7):548-55. Overall,
oxcarbazepine was safe and well tolerated; however, oxcarbazepine did not show efficacy in the prophylactic treatment of migraine headaches.
74. Colman I, Friedman BW, Brown MD, et al. Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence.
BMJ. 2008 Jun 9. [Epub ahead of print] When added to standard abortive therapy for migraine headache, single dose parenteral dexamethasone is associated with a 26% relative
reduction in headache recurrence (number needed to treat=9) within 72 hours.
Donaldson D, et al. IV dexamethasone vs placebo as adjunctive therapy to reduce the recurrence rate of acute migraine headaches: a multicenter, double-blinded, placebo-controlled randomized clinical trial. Am J Emerg Med. 2008 Feb;26(2):124-30.
Kelly AM, Kerr D, Clooney M. Impact of oral dexamethasone versus placebo after ED treatment of migraine with phenothiazines on the rate of recurrent headache: a randomised controlled trial. Emerg Med J. 2008 Jan;25(1):26-9.
Rowe BH, Colman I, Edmonds ML, Blitz S, Walker A, Wiens S. Randomized controlled trial of intravenous dexamethasone to prevent relapse in acute migraine headache. Headache. 2008 Mar;48(3):333-40. Epub 2007 Nov 28.
Friedman BW, Greenwald P, Bania TC, et al. Randomized trial of IV dexamethasone for acute migraine in the emergency department. Neurology. 2007 Nov 27;69(22):2038-44. Epub 2007 Oct 17.
75. Kurth T, Schürks M, Logroscino G, Gaziano JM, Buring JE. Migraine, vascular risk, and cardiovascular events in women: prospective cohort study. BMJ. 2008 Aug 7;337:a636.
doi: 10.1136/bmj.a636. The association between migraine with aura and cardiovascular disease varies by vascular risk status. Information on history of migraine and vascular risk
status might help to identify women at increased risk for specific future cardiovascular disease events.
hyaluronic acid helps patients with knee osteoarthritis is of poor quality. Improvements in pain at rest and pain during exercise is seen in a minority of studies, and those studies were of lower quality than those showing no benefit. There is no evidence of functional improvement. Injections
like this have a potentially powerful placebo effect, so any benefit seen in unblinded studies without concealed allocation is likely represent the placebo effect rather than any effect of the drug. (LOE = 1a-) ) Petrella RJ, Petrella M. A prospective, randomized, double-
blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol. 2006 May;33(5):951-6.
34. Verhamme KM, Dieleman JP, Van Wijk MA, et al. Nonsteroidal anti-inflammatory drugs and increased risk of acute urinary retention. Arch Intern Med. 2005 Jul 11;165(13):1547-51.
35. Sudbo J, Lee JJ, Lippman SM, et al. Non-steroidal anti-inflammatory drugs and the risk of oral cancer: a nested case-control study. Lancet. 2005 Oct 15-21;366(9494):1359-66.
Long-term use of NSAIDs is associated with a reduced incidence of oral cancer (including in active smokers), but also with an increased risk of death due to cardiovascular disease. These findings highlight the need for a careful risk-benefit analysis when the long-term use of NSAIDs.
(Jan/06 The Norwegian daily newspaper Dagbladet reports that a number of statistical improbabilities were found in the data set of the cancer trial, published in the Lancet in October last year. Lancet editor Dr Richard Horton told the BBC he would be speaking to the coauthors
of the study to seek their permission to retract the paper. One example of the improbabilities" is the fact that of the 908 people in the trial, 250 shared the same birthday.)
36. Acetaminophen Overdose: Medscape article: http://www.medscape.com/viewarticle/459187_4 ; Merck Manual’s Online Medical Manual: http://www.merck.com/mmpe/sec21/ch326/ch326c.html {Rumack-Matthew nomogram for predicting (Caution with units of measure!) }
( 10ug/ml = 66.2umol/L) {Acetaminophen level: 4hrs post ingestion & repeat in 4hrs; if ≥150mg/kg and 8hr post, may start n-acetylcysteine while awaiting levels; TOXIC levels: 4hr level >993umol/L; 6hr >728umol/L; 8hr >496.5umol/L; 24hr >29.8umol/L } {LFTs: AST usually ↑ first}
Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008 Jul 17;359(3):285-92.
ADAPT Research Group. Cognitive Function Over Time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): Results of a Randomized, Controlled Trial of Naproxen and Celecoxib. Arch Neurol. 2008 May 12. [Epub ahead of print] Use of naproxen or celecoxib
did not improve cognitive function. There was weak evidence for a detrimental effect of naproxen.
Al-Sukhun J, Koivusalo A, Tornwall J, Lindqvist C. COX-2 inhibitors and early failure of free vascular flaps. N Engl J Med. 2006 Aug 3;355(5):528-9.
Amin AK, et al. Does obesity influence the clinical outcome at five years following total knee replacement for osteoarthritis? J Bone Joint Surg Br. 2006 Mar;88(3):335-40. (InfoPOEMs: In this study, obese patients undergoing primary knee arthroplasty had comparable long-term outcomes with
nonobese patients. (LOE = 1b-) )
Amin SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol. 2007 Nov;197(5):486.e1-10. Antenatal indomethacin may be associated with an increased risk of periventricular leukomalacia and necrotizing
enterocolitis in premature infants and therefore should be used judiciously for tocolysis.
Andersohn F, et al. Cyclooxygenase-2 Selective Nonsteroidal Anti-Inflammatory Drugs and the Risk of Ischemic Stroke. A Nested Case-Control Study. Stroke. 2006 May 25; [Epub ahead of print] Current use of rofecoxib (OR=1.71; 95% CI, 1.33 to 2.18), etoricoxib (OR=2.38; 95%
CI, 1.10 to 5.13), but not of celecoxib (OR=1.07; 95% CI, 0.79 to 1.44) was associated with a significantly increased risk of ischemic stroke. For rofecoxib and etoricoxib, ORs tended to increase with higher daily dose and longer duration of use and were also elevated in patients
without major stroke risk factors. "From the non-selective NSAIDs, diclofenac, but not ibuprofen or naproxen, was also associated with a slightly increased risk of ischemic stroke," Dr. Andersohn said.
Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs & risk of acute myocardial infarction. Circulation. 2006 Apr 25;113(16):1950-7. Epub 2006 Apr 17. Current use of etoricoxib was associated with
a 2.09-fold (95% confidence interval [CI], 1.10 to 3.97) risk of AMI compared with no use of NSAIDs during the prior year. Current use of rofecoxib (RR=1.29; 95% CI, 1.02 to 1.63), celecoxib (RR=1.56; 95% CI, 1.22 to 2.00), and diclofenac (RR=1.37; 95% CI, 1.17 to 1.59)
also significantly increased the AMI risk. For current use of valdecoxib, the RR was 4.60 (95% CI, 0.61 to 34.51). RRs appeared to increase with higher daily doses of COX-2 inhibitors and were also increased in patients without major cardiovascular risk factors.
Andrew T. Chan, MD, MPH; Edward L. et al. Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer JAMA. 2005;294:914-923. CONCLUSIONS: Regular, long-term aspirin use reduces risk of colorectal cancer. Nonaspirin NSAIDs
appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially
higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered. (InfoPOEMs: Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), especially more than 14 doses per week for at least 10 years, reduces
the risk of colon cancer while also increasing the risk of a major gastrointestinal bleeding event. All-cause mortality is not affected by regular use. We need additional methods (gene testing?) to determine who is at high risk of colorectal cancer before making specific recommendations for prevention. (LOE = 2b) )
Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs. An update for clinicians. A scientific statement from the American Heart Association. Circulation 2007; DOI:10.1161/CIRCULATIONAHA.106.181424. Available at: http://circ.ahajournals.org.
Bandolier. Avocado/soybean unsaponifiables for OA. April 2004;122-23. Web site: http://www.jr2.ox.ac.uk/bandolier/band122/b122-3.html. The limited data to date support the safety and possible efficacy of ASU for osteoarthritis of the knee. More and longer studies are needed
before we can recommend this to our patients without hesitation. (LOE = 1b-)
Barkhuizen A, et al. Celecoxib is efficacious and well tolerated in treating signs and symptoms of ankylosing spondylitis. J Rheumatol. 2006 Sep;33(9):1805-12.
Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003 Mar 6;348(10):891-9.
Bavbek S, et al. Safety of Meloxicam in Aspirin-Hypersensitive Patients with Asthma and/or Nasal Polyps. A Challenge-Proven Study. Int Arch Allergy Immunol. 2006 Oct 2;142(1):64-69 [Epub ahead of print]
Bellamy N, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD005321.
Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999 May 6;340(18):1377-82.
Berman BM, et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med. 2004 Dec 21;141(12):901-10. Summary for patients in: Ann Intern Med. 2004 Dec 21;141(12):I20.
Bingham CO 3rd, Eet al. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology (Oxford). 2006 Aug 27.
Biswal S, Medhi B, Pandhi P. Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: metaanalysis of randomized placebo controlled clinical trials. J Rheumatol. 2006 Sep;33(9):1841-4.
Butler GJ, Neale R, Green AC, Pandeya N, Whiteman DC. Nonsteroidal anti-inflammatory drugs and the risk of actinic keratoses and squamous cell cancers of the skin. J Am Acad Dermatol. 2005 Dec;53(6):966-72. Epub 2005 Oct 19.
Cannon CP, et al.; MEDAL Steering Committee. Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study program: cardiovascular outcomes with etoricoxib versus
diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J. 2006 Aug;152(2):237-45.
Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet
2006: DOI:10.1016/S0140-6736(06)69666-9. Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.
Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005 Apr 19;45(8):1295-301.
Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials. 2006 Nov 17;1(7):e33 [Epub ahead of print] For celecoxib, ADAPT data do not show the same level of risk as those of the
APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk. (Nissen SE. ADAPT: The Wrong Way to Stop a Clinical Trial. PLoS Clin Trials. 2006 Nov 17;1(7):e35 [Epub ahead of print])
Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001 Dec 20;345(25):1809-17.
Chan FKL, et al Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding. N Engl J Med 2005;352:238-44. (InfoPOEMs: For patients with a history of bleeding peptic ulcer, the combination of aspirin and a proton pump inhibitor twice a day was safer in terms of
bleeding side effects than clopidogrel. While esomeprazole was used in this study, generic omeprazole 20 mg give twice a day provides nearly the same degree of acid suppression at a much lower cost. This study calls into question the overall safety of clopidogrel, which has been promoted as not increasing the risk of
bleeding significantly. (LOE = 1b))
Chan FK, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001 Mar 29;344(13):967-73. CONCLUSIONS: Among patients with H. pylori infection and a history of upper
gastrointestinal bleeding who are taking low-dose aspirin, the eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole is superior to the eradication of H. pylori in preventing recurrent bleeding in patients who are taking other NSAIDs.
Chan AT, et al. Nonsteroidal Antiinflammatory Drugs, Acetaminophen, and the Risk of Cardiovascular Events. Circulation. 2006 Mar 13; [Epub ahead of print]
Chan FK, Wong VW, Suen BY, et al. Combination of cyclo-oxygenase-2 inhibitor (celecoxib 200mg bid) and proton-pump inhibitor (esomeprazole 20mg bid) for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007 May
12;369(9573):1621-6. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). n=441 12months. Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive
combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.
Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann Neurol. 2005 Dec;58(6):963-7.
Corman SL, Fedutes BA, Ansani NT. Impact of nonsteroidal antiinflammatory drugs on the cardioprotective effects of aspirin. Ann Pharmacother. 2005 Jun;39(6):1073-9. Epub 2005 May 3.
Cox-2 inhibitors & NSAIDS: Drug Class Review Nov 2006 Oregon Health & Science University http://www.ohsu.edu/drugeffectiveness/reports/documents/NSAIDS%20Final%20Report%20Update%203.pdf
Dart RC, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Washington (DC): American Association of Poison Control Centers; 2005.http://www.aapcc.org/FinalizedPMGdlns/APAP%20-%20final%20guideline%209.9.05.pdf
Diener HC, et al. Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalagia. 2006 May;26(5):537-47.
Douglas L, Akil M. Sodium in soluble paracetamol may be linked to raised blood pressure. BMJ. 2006 May 13;332(7550):1133. (some forms of acetaminophen may have high sodium content)
Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med. 2006 Feb 23;354(8):841-8.
Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007 May 12;369(9573):1603-13. Use of 300 mg or more of
aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years, which is consistent with findings from observational studies. Long-term follow-up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin.
Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007; 167:394-399. The frequency of nonnarcotic analgesic use is independently associated with a moderate increase in the risk of incident hypertension. Given the
widespread use of these medications and the high prevalence of hypertension, these results may have important public health implications.
Foster NE, Thomas E, Barlas P, Hill JC, Young J, Mason E, Hay EM. Acupuncture as an adjunct to exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial. BMJ. 2007 Sep 1;335(7617):436. Epub 2007 Aug 15. The
addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores.
Fransen M, et al. HIPAID Collaborative Group. Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): randomised controlled trial. BMJ. 2006 Sep
9;333(7567):519. Epub 2006 Aug 2. These data do not support the use of routine prophylaxis with NSAIDs in patients undergoing total hip replacement surgery.
Gislason GH, et al. Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction. Circulation. 2006 Jun 19; [Epub ahead of print] For any use of rofecoxib,
celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk
of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. CONCLUSIONS: Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI
and should therefore be used with particular caution in these patients.
Goldstein JL, Johanson JF, et al. Healing of gastric ulcers with esomeprazole versus ranitidine in patients who continued to receive NSAID therapy: a randomized trial. Am J Gastroenterol. 2005 Dec;100(12):2650-7.
Goldstein JL, Cryer B, Amer F, Hunt B. Celecoxib plus aspirin versus naproxen and lansoprazole plus aspirin: a randomized, double-blind, endoscopic trial. Clin Gastroenterol Hepatol. 2007 Oct;5(10):1167-74. n=854 In patients with osteoarthritis taking low-dose aspirin, the use of
celecoxib or naproxen plus lansoprazole resulted in similar rates of gastroduodenal ulceration.
Graham GG, Scott KF, Day RO. Tolerability of paracetamol. Drug Saf. 2005;28(3):227-40.
Graham DJ, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005 Feb 5-11;365(9458):475-81.
Harris RE, Beebe-Donk J, Alshafie GA. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer. 2006 Jan 30;6:27.
Hay EM, et al. Effectiveness of community physiotherapy and enhanced pharmacy review for knee pain in people aged over 55 presenting to primary care: pragmatic randomized trial. BMJ. 2006 Oct 20; [Epub ahead of print] Evidence based care for older adults with knee pain,
delivered by primary care physiotherapists and pharmacists, resulted in short term improvements in health outcomes, reduced use of non-steroidal anti-inflammatory drugs, and high patient satisfaction.
Hay AD, Costelloe C, Redmond NM, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ. 2008 Sep 2;337:a1302. doi: 10.1136/bmj.a1302. Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement
physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours.
Health Canada Prohits sale of Bextra http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2005/2005_134_e.html
Health Canada June/06 two documents as part of its ongoing evaluation of COX-2-selective drugs: its official comments on the advice provided by the COX-2 Expert Advisory Panel and a report on the Department's scientific review of certain COX-2s.
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-consult/cox2/index_e.html
Health Canada Aug/07 reports that the Therapeutic Goods Administration (TGA), the federal regulatory authority in Australia, recently withdrew market authorization for Prexige due to eight reports of serious liver adverse events in Australia linked to the drug, including two deaths
and two liver transplants. These adverse events were primarily with use of 200 mg and 400 mg doses daily.
Health Canada Sept/07 reports that Qiangli Zhuanggutongbiling has reportedly been used for joint pain and stiffness. It was found to contain the undeclared prescription drugs prednisolone acetate, cortisone acetate, piroxicam, and diclofenac.
Health Canada Sept/07: Khun-Phra is a health product promoted for pain relief that has been found to contain the undeclared drugs dexamethasone, prednisolone, phenylbutazone, diazepam, cyproheptadine and mebhydrolin.. Asam Urat Flu Tulang, PJ Dewandaru is a health
product promoted to treat joint pain, rheumatism and arthritis. It has been found to contain the undeclared drugs dexamethasone, diclofenac and acetaminophen.
Health Canada Oct/07 Foreign Product Alerts: Zhen Feng Da Brand Xi Tong Wan is promoted as a pain reliever. Lot #060908 has been found to contain undeclared indomethacin, a prescription anti-inflammatory drug that should only be taken under the guidance of a health
professional. Wellring Brand Yin Qiao Jie Du is a health product promoted to treat cold and flu symptoms. Lot#51005 has been found to contain undeclared acetaminophen. Gu Ci Dan and Xu Log Bou are promoted as pain relievers and have been found to contain indomethacin.
Health Canada Oct/07 is advising consumers that it has stopped the sale of the anti-inflammatory drug Prexige (lumiracoxib) in Canada and will cancel the drug's market authorization due to the potential for serious liver-related adverse events. (2 new severe cases in Canada)
Health Canada July/08 is advising consumers not to use 2 foreign health products due to concerns about possible side-effects: 3rd Generation In Homoeopathy Arthrit Indica Tablet. The product is labelled for "intense joint pain." The Health Sciences Authority of Singapore has
warned consumers not to use the product because it contains nimesulide, a pharmaceutical ingredient that has been associated with liver damage.
Health Canada Aug/08 is advising consumers not to use foreign health products due to concerns against the use of AA Qu Feng Shu Jin Wan because it was found to contain the undeclared pharmaceutical ingredient dexamethasone. Obat Asam Urat and Asam Urat both contained
dexamethasone, phenylbutazone and piroxicam.
Helin-Salmivaara A, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J. 2006 Jul;27(14):1657-63. Epub 2006 May 26.
Huerta C, Varas-Lorenzo C, Castellsague J, Garcia Rodriguez LA. Non-steroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population. Heart. 2006 Nov;92(11):1610-5. Epub 2006 May 22.
Hill KP, Ross JS, Egilman DS, Krumholz HM. The ADVANTAGE seeding trial: a review of internal documents. (Vioxx marketing trial) Ann Intern Med. 2008 Aug 19;149(4):251-8.
Hippisley-Cox J, Coupland C, Logan R. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005 Dec 3;331(7528):1310-6.
CONCLUSION: No consistent evidence was found of enhanced safety against gastrointestinal events with any of the new cyclo-oxygenase-2 inhibitors compared with non-selective non-steroidal anti-inflammatory drugs. The use of ulcer healing drugs reduced the increased risk of adverse gastrointestinal outcomes with all groups of
non-steroidal anti-inflammatory drugs, but for diclofenac the increased risk remained significant.
Hooper L, Brown TJ, Elliott R, et al. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ. 2004 Oct 23;329(7472):948. Epub 2004 Oct 8. CONCLUSIONS: Misoprostol, COX-2
specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor
antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
Irwin RS, et al. American College of Chest Physicians (ACCP). Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan;129(1 Suppl):1S-23S. http://www.chestjournal.org/cgi/content/full/129/1_suppl/1S
James LP, et al. Pediatric Acute Liver Failure Study Group. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006 Sep;118(3):e676-81.
Jick H, et al. Nonsteroidal antiinflammatory drugs and acute myocardial infarction in patients with no major risk factors. Pharmacotherapy. 2006 Oct;26(10):1379-87. Extensive use of rofecoxib, celecoxib, and diclofenac increases the risk of acute
myocardial infarction, but similar use of ibuprofen and naproxen does not.
Kearney PM, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006 Jun 3;332(7553):1302-8. Selective COX 2 inhibitors are associated with a
moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.
Konstan MW, Schluchter MD, Xue W, Davis PB. Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1084-9. Epub 2007 Sep 13. Slower rates of FEV(1) decline are seen in children and adolescents with
cystic fibrosis who are treated with ibuprofen. The apparent benefits of ibuprofen therapy outweigh the small risk of gastrointestinal bleeding.
Kurth T, Hennekens CH, Stürmer T, Sesso HD, Glynn RJ, Buring JE, Gaziano JM. Analgesic use and risk of subsequent hypertension in apparently healthy men. Arch Intern Med. 2005 Sep 12;165(16):1903-9.
Lackner JE, et al. Correlation of leukocytospermia with clinical infection and the positive effect of antiinflammatory (valdecoxib) treatment on semen quality. Fertil Steril. 2006 Sep;86(3):601-5. Epub 2006 Jun 16.
Lai KC, Chu KM, Hui WM, et al. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J Med. 2005 Nov;118(11):1271-8. (InfoPOEMs: In patients at high risk for recurrent peptic ulcer with nonsteroidal anti-inflammatory drug
therapy, celecoxib was no more effective than the combination of naproxen (Naprosyn) and lansoprazole (Prevacid) in preventing serious adverse effects and was more likely to cause dyspepsia symptoms. The benefit of COX-2 inhibitors in preventing serious gastrointestinal
adverse events is likely overstated. (LOE = 1b-) )
Lai KC, Lam SK, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002 Jun 27;346(26):2033-8.
Lands LC, Milner R, Cantin AM, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr. 2007 Sep;151(3):249-54. Epub 2007 Jun 26.
Lane NE. Clinical practice. Osteoarthritis of the hip. N Engl J Med. 2007 Oct 4;357(14):1413-21.
Larson AM, et al, and the Acute Liver Failure Study Group. Acetaminophen-Induced Acute Liver Failure: Results of a US Muticenter, Prospective Study. Hepatology; Dec 2005. (of 662 consecutive acute liver failure pts over 6yrs: 42% from acetaminophen liver injury; 48% were
unintentional overdoses; only 65% of pts survived) (Benson GD, Koff RS, Tolman KG. The therapeutic use of acetaminophen in patients with liver disease. Am J Ther. 2005 Mar-Apr;12(2):133-41. & Oviedo J, Wolfe MM. Alcohol, acetaminophen, & toxic effects on the liver.
Arch Intern Med. 2002 May 27;162(10):1194-5.) ( Mahadevan SB, McKiernan PJ, Davies P, Kelly DA. Paracetamol-induced hepatotoxicity in children. Arch Dis Child. 2006 Mar 17; [Epub ahead of print]) (Watkins PB, et al. Aminotransferase elevations in healthy adults
receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):87-93.) (Kuffner EK, Green JL, Bogdan GM, Knox PC, Palmer RB, Heard K, Slattery JT, Dart RC. The effect of acetaminophen (four grams a day for three consecutive days) on
hepatic tests in alcoholic patients--a multicenter randomized study. BMC Med. 2007 May 30;5:13. Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of
liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.) (Heard K, Green JL, Bailey JE, Bogdan GM, Dart RC. A randomized trial to determine the change in alanine
aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol. Aliment Pharmacol Ther. 2007 Jul 15;26(2):283-90. Therapeutic dosing of paracetamol administered for 10 days appears to elevate serum ALT
in moderate drinkers, but does not produce clinically evident liver injury.)
Levesque LE, Brophy JM, Zhang B. Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. CMAJ. 2006 May 23;174(11):1563-9. Epub 2006 May 2. A small proportion of patients using rofecoxib for the first time had their first MI shortly after starting the drug.
This risk did not increase with the length of treatment and returned to baseline shortly after treatment was discontinued. More research is needed to identify those most susceptible to cardiotoxicity mediated by COX-2 inhibitor therapy.
Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ. 2003 Aug 16;327(7411):368.
Liccardi G, et al. Safety of celecoxib in patients with adverse skin reactions to acetaminophen (paracetamol) and other non-steroidal anti-inflammatory drugs. J Investig Allergol Clin Immunol. 2005;15(4):249-53.
Loke YK, Trivedi AN, Singh S. Meta-analysis: Gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory
drugs. Aliment Pharmacol Ther. 2007 Oct 5; [Epub ahead of print]
Mamdani M, Warren L, Kopp A, Paterson JM, Laupacis A, Bassett K, Anderson GM. Changes in rates of upper gastrointestinal hemorrhage after the introduction of cyclooxygenase-2 inhibitors in British Columbia and Ontario. CMAJ. 2006 Dec
5;175(12):1535-8. (InfoPOEMs: Although COX-2 inhibitors may be slightly less likely to cause gastrointestinal (GI) complications, the overall increase in the use of nonsteroidal anti-inflammatory drugs (NSAIDs) seen after their introduction appears to have led to an overall increase in the number of GI complications in the
population (not to mention the thousands of cardiovascular deaths attributed to this class of drugs). Although physicians complain about prescribing restrictions, sometimes for good reason, in this case they seem to be of benefit. (LOE = 2c))
McGettigan P, Henry D. Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2. JAMA. 2006 Sep 12; [Epub ahead of print] A doserelated risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment.
Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.161.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18). CONCLUSIONS: This review confirms the findings from
randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about
the safety of diclofenac, an older drug. (InfoPOEMs: Rofecoxib (Vioxx), diclofenac (Voltaren, Cataflam), and indomethacin (Indocin) are associated with a significant increased risk of CVD. It is likely that all NSAIDs carry some risk, but the
risks may vary between medicines. Current evidence does not point to an increased risk for low dose (over the counter) ibuprofen and this remains safe to use at recommended doses. (LOE = 2a-))
Messier SP, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum. 2004 May;50(5):1501-10.
NICE Guidelines for the care and management of Osteoarthritis in Adults Feb, 2008. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11926
Ofori B, et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol. 2006 Aug 23; [Epub ahead of print] Our study suggests that women
prescribed NSAIDs during early pregnancy may be at a greater risk of having children with congenital anomalies, specifically cardiac septal defects.
Pharmacist’s Letter Oct 2006. Alternative or Off-label Routes of Drug Administration. (Oral administration of: N-acetylcysteine Mucomyst)
Pharmacist’s Letter Oct 2006. Cardiovascular Risks of NSAIDs and Cox-2 Inhibitors.
Psaty BM and Potter JD. Risks and benefits of celecoxib to prevent recurrent adenomas. N Engl J Med 2006; 355:950-952.
Psaty BM, Weiss NS. NSAID trials and the choice of comparators--questions of public health importance. N Engl J Med. 2007 Jan 25;356(4):328-30.
Rebordosa C, Kogevinas M, Horváth-Puhó E,et al. Acetaminophen use during pregnancy: effects on risk for congenital abnormalities. Am J Obstet Gynecol. 2008 Feb;198(2):178.e1-7. Acetaminophen is not associated with an increased prevalence of congenital abnormalities overall
or with any specific group of major abnormalities.
Rahme E, Barkun A, Nedjar H, Gaugris S, Watson D. Hospitalizations for Upper and Lower GI Events Associated With Traditional NSAIDs and Acetaminophen Among the Elderly in Quebec, Canada. Am J Gastroenterol. 2008 Apr;103(4):872-82. Epub 2008 Mar 26. Among elderly
patients requiring analgesic/anti-inflammatory treatment, use of the combination of a NSAID and acetaminophen may increase the risk of GI bleeding compared with either agent alone.
Roddy E, Zhang W, Doherty M. Aerobic walking or strengthening exercise for osteoarthritis of the knee? A systematic review. Ann Rheum Dis. 2005 Apr;64(4):544-8 & ACP Journal Club .
Rostom A, et al; U.S. Preventive Services Task Force. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive
Services Task Force. Ann Intern Med. 2007 Mar 6;146(5):376-89. Review. Summary for patients in: Ann Intern Med. 2007 Mar 6;146(5):I35. Cyclooxygenase-2 inhibitors and NSAIDs reduce the incidence of colonic adenomas. Nonsteroidal antiinflammatory drugs also reduce the incidence of CRC. However, these agents are associated with important cardiovascular events and gastrointestinal harms. The balance of benefits to risk does not favor chemoprevention in average-risk individuals. (InfoPOEMs: The US
Preventive Services Task Force recommends against routine use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer. The beneficial decrease in colorectal adenoma, cancer incidence, and possibly cancer-related mortality is more than offset by
the harm associated with their use. Ulcers leading to gastrointestinal bleeding, renal impairment, and an increase in cardiovascular events are the main problems. (LOE = 1a))
Rostom A, Muir K, Dube C, Jolicoeur E, Boucher M, Joyce J, Tugwell P, Wells GW. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol. 2007
Jul;5(7):818-28, 828.e1-5; quiz 768. Epub 2007Jun 6. COX-2s appear to offer greater upper GI safety and are better tolerated than nonselective NSAIDs. The co-administration of acetylsalicylic acid might reduce the safety
advantage of COX-2s over that of nonselective NSAIDs.
Roumie CL, Mitchel EF Jr, Kaltenbach L, Arbogast PG, Gideon P, Griffin MR. Nonaspirin NSAIDs, cyclooxygenase 2 inhibitors, and the risk for stroke. Stroke. 2008 Jul;39(7):2037-45. Epub 2008 Apr 24. Our results indicate an increased risk of stroke with current use of two highly
selective coxibs, rofecoxib and valdecoxib, also shown to increase cardiovascular risk. These results also provide some reassurance about other specific NSAIDs regarding stroke risk.
Scharf HP, et al. Acupuncture and knee osteoarthritis: a three-armed randomized trial. Ann Intern Med. 2006 Jul 4;145(1):12-20. Compared with physiotherapy and as-needed anti-inflammatory drugs, addition of either TCA or sham acupuncture led to
greater improvement in WOMAC score at 26 weeks.
Scheiman JM, et al. Prevention of Ulcers by Esomeprazole in At-Risk Patients Using Non-Selective NSAIDs and COX-2 Inhibitors. (Venus & Pluto) Am J Gastroenterol. 2006 Feb 22; [Epub ahead of print]
CONCLUSIONS: For at-risk patients, esomeprazole was effective in preventing ulcers in long-term users of NSAIDs, including COX-2 inhibitors.
Schneider V, Levesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am J Epidemiol. 2006 Nov 1;164(9):881-9. Epub 2006 Sep
27. There was a significant association for both selective and nonselective NSAIDs with acute renal failure, but confirmatory studies are required.
Scott PA, Kingsley GH, Smith CM, et al. Non-steroidal anti-inflammatory drugs and myocardial infarctions: comparative systematic review of evidence from observational studies and randomized controlled trials. Ann Rheum Dis. 2007 Oct;66(10):1296-304. Epub 2007 Mar 7. {The comparative risk
of myocardial infarction (MI) with cyclo-oxygenase-2-specific drugs and traditional non-steroidal anti-inflammatory drugs (NSAIDs) was determined. METHODS: The results of studies of a suitable size in colonic adenoma and arthritis-that had been published in English and from which crude data about MIs could be extracted-were evaluated. Medline, Embase and
Cinahl (2000-2006) databases, as well as published bibliographies, were used as data sources. Systematic reviews examined MI risks in case-control and cohort studies, as well as in randomised controlled trials (RCTs). RESULTS: 14 case-control studies (74 673 MI patients, 368 968 controls) showed no significant association of NSAIDs with MI in a random-effects
model (OR 1.17; 95% CI 0.99 to 1.37) and a small risk of MI in a fixed-effects model (OR 1.32; 95% CI 1.29 to 1.35). Sensitivity analyses showed higher risks of MI in large European studies involving matched controls. Six cohort studies (387 983 patient years, 1 120 812 control years) showed no significant risk of MI with NSAIDs (RR 1.03; 95% CI 1.00 to 1.07); the
risk was higher with rofecoxib (RR 1.25; 95% CI 1.17 to 1.34) but not with any other NSAIDs. Four RCTs of NSAIDs in colonic adenoma (6000 patients) showed an increased risk of MI (RR 2.68; 95% CI 1.43 to 5.01). Fourteen RCTs in arthritis (45 425 patients) showed more MIs with cyclo-oxygenase-2-specific drugs (Peto OR 1.6; 95% CI 1.1 to 2.4), but fewer
serious upper gastrointestinal events (Peto OR 0.40; 95% CI 0.31 to 0.53). CONCLUSION: The overall risk of MI with NSAIDs and cyclo-oxygenase-2-specific drugs was small; rofecoxib showed the highest risk. There was an increased MI risk with cyclo-oxygenase-2-specific drugs compared with NSAIDs, but less serious upper gastrointestinal toxicity.}
Silverstein FE, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995 Aug 15;123(4):241-9.
Soininen H, West C, Robbins J, Niculescu L. Long-Term Efficacy and Safety of Celecoxib in Alzheimer's Disease. Dement Geriatr Cogn Disord. 2006 Oct 26;23(1):8-21 [Epub ahead of print] Celecoxib 200 mg bid did not slow the progression of AD in this study, and the
occurrence of adverse events was as expected for an elderly population with a complex chronic medical condition.
Solomon SD, et al.; APC and PreSAP Trial Investigators. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006 Sep 5;114(10):1028-35.
Solomon SD, Wittes J, Finn PV, et al.; for the Cross Trial Safety Assessment Group. Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials. The Cross Trial Safety Analysis. Circulation. 2008 Mar 31; [Epub ahead of print] We observed evidence of differential cardiovascular
risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.
Sotoudehmanesh R, Khatibian M, Kolahdoozan S, Ainechi S, Malboosbaf R, Nouraie M. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol. 2007 May;102(5):978-83. Epub 2007 Mar 13. n=490.
Sperber SJ, et al. Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial. Ann Intern Med. 1992 Jul 1;117(1):37-41.
Strand V. Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet 2007; 370:2138-2151. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but
asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.
Tannenbaum H, Bombardier C, Davis P, Russell AS; Third Canadian Consensus Conference Group. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus Conference. J Rheumatol. 2006 Jan;33(1):140-57. Epub 2005 Dec 1.
The “Triple Whammy”. Pharmaicst’s Letter Dec/06 (Impaired renal function while involving an ACE &/or ARB, an NSAID &/or a diuretic)
Towheed TE, et al. Acetaminophen for osteoarthritis (review). The Cochrane Database of Systematic Reviews 2006, Issue 1.
Treatment Guidelines from the Medical Letter. Pharmaceutical Drug Overdose. Sept 2006. (Acetaminophen: N-acetylcysteine treatment. Aspirin: sodium bicarbonate treatment)
Treatment guidelines from the Medical Letter. Drugs for Pain April 2007.
White WB, et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am J Cardiol. 2007 Jan 1;99(1):91-8. Epub 2006 Nov 10. These analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and
demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs.
Wilcox CM, Allison J, Benzuly K, Borum M, Cryer B, Grosser T, Hunt R, Et al. Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 enzyme inhibitors and aspirin. Clin Gastroenterol
Hepatol. 2006 Sep;4(9):1082-9. Epub 2006 Jul 31.
Witt CM, et al. Acupuncture in patients with osteoarthritis of the knee or hip: A randomized, controlled trial with an additional nonrandomized arm. Arthritis Rheum. 2006 Oct 30;54(11):3485-3493. These results indicate that acupuncture plus routine care is associated with marked
clinical improvement in patients with chronic OA-associated pain of the knee or hip.
Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM. Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials. Rheumatology (Oxford). 2007 Jan;46(1):135-40. {InfoPOEMs – Feb07: In this short-term study emphasizing individual response,
acetaminophen and celecoxib (Celebrex) are virtually indistinguishable in improving pain, stiffness, and function in patients with clinically diagnosed degenerative joint disease (DJD). Since acetaminophen is less expensive and has fewer safety concerns, it should be the drug of first choice. (LOE = 1b).}
Zapata-Colindres JC,et al. The association of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in peptic ulcer disease. Can J Gastroenterol. 2006 Apr;20(4):277-80. The development of PUD was observed earlier in the combined H pylori and NSAID group than
in patients with only NSAID use. This suggests a synergic effect between the two risks factors in the development of PUD.
Zhang W, Doherty M, Arden N, et al. EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for
International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2005 May;64(5):669-81. Epub 2004 Oct 7 & ACP Journal Club .
Zhang J, Ding EL, Song Y. Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials. JAMA. 2006 Sep 12; [Epub ahead of print] In this comprehensive analysis of 114 randomized trials
with 116 094 participants, rofecoxib was associated with increased renal and arrhythmia risks. A COX-2 inhibitor class effect was not evident.
-------------------------------New coxib - Etoricoxib (ARCOXIA) - NOT approved by FDA (April, 2007)
Lumiracoxib – hepatic toxicity – deregulation in Australia. http://www.medadnews.com/News/index.cfm?articleid=467159
LIPID LOWERING THERAPY: DYSLIPIDEMIA Comparison Chart 1,2,3,4,5,6,7,8
LDL2,7
Generic/TRADE/
g=generic avail.
HDL2
TG2
Pregnancy (dose effect)
SIDE EFFECTS /CONTRAINDICATIONS (CI)
/COMMENTS/MONITOR (M)
Prepared by: Brent Jensen BSP, L Regier BSP © www.RxFiles.ca
DRUG
INTERACTIONS
SE≤10%;Generally better tolerated than other agents ↑ effect of: digoxinATO↑20%,
FLU,LOV,ROS,SIM
warfarin
Common: upper GI, muscle pain not ↓ by coenzyme Q10 Young’07,
Amlodipine//atorvastatin CADUET
FOR: LOV, SIM, ATOless effect
headache, rash & sleep disturbances
5 & 10mg//10 & 20 & 40 & 80mg tabs ⊗ $95-120 Rare: peripheral neuropathy, lupus like Sx, impotence9 ↑ toxicity with HMG &:
amiodarone, amprenavir,
?↑hemorrhagic stroke, pancreatitis
↓ 20 - 35%
clarithromycin, cyclosporine,
↑ LFT (AST & ALT >3X Normal in < 2%)4,7; dose danazol, daptomycin, diltiazem,
dependent high vs low dose NNH=96; reversible if stop statin ethinyl estradiol, erythromycin,
fenofibrate, fluoxetine, fusidic
↓ 25 - 40%
Myopathy10: <1%; concern esp. if muscle pain &
acid, gemfibrozil, grapefruit
↓ 7 - 30%
↑ 5 - 15%
(concern
if
CK>3-5x).
weakness present; check CK
juice, ketoconazole, indinavir,
Rhabdomyolysis <0.2%6 (CK>10x , darkened urine, renal failure) itraconazole, nelfinavir, niacin,
May 08
USUAL Dose Range (Max dose/day) $
Studied doses in 1° or 2° prevention / Month
THERAPEUTIC
BENEFITS/USES
67
10mg po hs 1 ASCOT, CARDS, TNT, ASPENNS
20mg po hs 4DNS80mg/d $87 AVERT MIRACL PROVE IT, 81
TNT,IDEAL,SPARCL,LEADe
87
40mg po hs
NS
↓ Atherosclerosis
S (10,20,40,80 elipitcal mg tablet)
20mg
po
hs
35
ATO,FLU,LOV,PRA,SIM,ROS
Fluvastatin
X
T
40mg po hs
46
↓ Coronary Heart Disease
LESCOL FLU
A (20 & 40mg cap)(80mgXLW)
(80mg/d)
86
ATO,FLU,LOV,PRA,SIM 40mg po bid cc LIPS
Diabetes ↓ heart & stroke ATO CARDS,SIM 20-40mg po hs 1 AFCAPS (Approved 1987)
T Lovastatin LOV
34 - 79
American Diabetes 2008 consider statin if age >10yr & LDL >4
151
40mg po bid cc → 40-80mg/d POST CABG
I MEVACORg X
↓ Stroke
ATO,PRA,SIM (cc=with meals ↑ absorption) (80mg/d)
N (20 scored ,40mg tab) ? in red yeast
Pediatric FDA approval
20mg po hs
(80mg/d)
nefazodone, raltegavir, ritonavir
36
-risk ↑10 fold 11,39 with combo/DI's; perioperative cautious use
ATO,FLU,LOV,PRA,SIM
S Pravastatin PRA ↓ 20 - 35%
telithromycin & verapamil.
ATO
,
ROS
ROS
40mg po hs 1 WOSCOPS; 2 → CARE,LIPID,PROSPER 42
PRAVACHOLg X
↓ CNS SE: ATO,FLU,PRA due to↓ CNS penetration ↓ effect of HMG by:
Effective in secondary
& SIM
& SIM
/ (10,20 & 40mg tablet)
{Adjust for severe
renal impairment 7}
cholestyramine & colestipol
causes such as diabetes
CI: Active Liver Dx, ↑ alcohol intake & Pregnancy
-Heart Failure- NS po od
5-10mg
53-56
may ↓ TGs
H Rosuvastatin ROS ↓ 40 - 65% may ↑ HDLs
CORONA
(space by ≥ 2hr); carbamazepine,
8,12
3,12,15
M: Routine LFT's & CK not indicated for all pts 23,30 efavirenz,phenytoin,pectin,phenobarb & in nephrotic syndrome 20mg po od
68
most
most
M CRESTOR X
(LFT: 0,3,6,12 months & annually if high dose/combo or at risk) St. Johns Wort & rifampin. In general doubling the statin 40mg po od
78
(5,10,20,40mg tablet)
(40mg/d)
dose ↓LDL by a further 6%
G
ROS: potent;↑levels in Asians; lacks outcome data12,13; PRA & ROS: appears to
14
41
20-40mg
po
hs
2 4S, IDEAL
Simvastatin SIM ↓ 35 - 50%
High vs low dose:ACS NNT=80/2yr death
postmarketing safety concerns relative to other statins have few interactions
41
40mg
po
hs
2
MRC/BHP:
HPS
ZOCORg
X
Pravastatin & Rosuvastatin few DIs-some transplant meds like cyclosporin & GEM. Fluvastatin less DIs→ still with glyburide, phenytoin,rifampin & warfarin.
41
80mg po hs A to Z
(80mg/d)
(5,10,20,40, 80 rectangle mg tab)
Atorvastatin similar DIs but less dramatic. {Primary Mechanisms3,11 of DI: PRAÖsulfation; ATO/LOV/SIMÖCYP-3A4; FLUÖCYP-2C9}
↑
toxicity/levels
with:
Common:
GI
upset,
rash
&
abdominal
pain
70
↓Cholesterol & ↓TG; ↑HDL 200mg po bid cc
F Bezafibrate U
LDL shifts to larger
cyclosporin, furosemide,
W 102
3
Less common: headache, pruritis, ↓ libido, dizzy,
200mg po tid cc
(600mg/d)
Combo with HMG/Niacin
I BEZALIPg BEZ W more buoyant forms
MAOI's, probenecid, & statins.
drowsy, arthralgia, ↑glucose, sleep/vision changes
64
(to ↑ HDL & ↓ TG) 400mg SR po od 2 BIP
(200mg tab;400mg SR tab)
B Fenofibrate C ↓ 5-20%
↓ effect by :
NS
Rare: ↓ renal fx, anemia, ↑ LFT’s, myopathy,
↓ Atherosclerosis
FIELD
3
(LDL may ↑ if ↑ 10-20% ↓ 20-50%
pancreatitis, impotence reversible & ↑gallstones by 1-2% cholestyramine & colestipol Type III dyslipidemia
200mg MICRO po od cc DAIS (200mg/d)
R LIPIDIL MICRO g
46
TG very high
(space by ≥ 2hrs); rifampin May be useful if :
(160mg/d) W 35
160mg SUPRA po od cc
67W& 200mg cap
CI
:
severe
hepatic
&
renal
Dx
&
?smoking
(↑
in
initially)
BIP, HHS
A LIPIDIL SUPRA g
VA-HIT
↑ effect of: chlorpropamide, ♦TG >2.3mmol/l
cardiac events in smokers + gemfibrozil
)
3,7
-virtually all clinical
(Lipidil EZ 48 & 145mg tab W$20-40)
T (W→ 100 & 160mg tab) -fenofibrate may ↓ LDL & ↓TG more than GEM M: CBC,Scr (↓ dose if ↑ Scr),Glucose, LFT's (?CK's) furosemide, homocysteine,
benefits in patients with
pioglitazone, repaglinide,
C & with statin combo may have ↓rhabdo than GEM
28
(ac=before meals)
300mg
po bid ac
7
E Gemfibrozil
Criteria: if gemfibrozil/fenofibrate intolerance or rosiglitazone, sulfonylureas diabetes & ↑ insulinemia
-current outcome evidence best with gemfibrozil
LOPIDg GEM
61
600mg
bid
ac
(1500mg/d)
WHO
1
HHS
,
2
VA-HIT
- lack all-cause mortality ↓
ineffective « bezafibrate
& warfarin.
S (300mg cap, 600mg tablet) -clofibrate was associated with ↑ mortality
Atorvastatin
LIPITOR ATO
X
↓ 35 - 60%
1997 approved
R
E
S
I
N
S
Ezetimibe16 2003 approved
INCREASE
C
EZETROL 10mg tab rectangle ↓18%
5mg ↓16%
↑ 1.3%
↓ 6%
O
T Nicotinic acid 17,18 ↓5-25%-shifts to
↓ 20-50%
(50 ,100,500mg tab); larger buoyant forms3 ↑ 15-35%
H NIACIN
NIASPAN (500&750mg,1g ER tab);
~2g
niacin/day
helps
HDL
& TG, but
E Advicor (500&1g/20mg LOV tab) ;
only higher doses affect LDL3,7
SR
/
No-flush
niacin:
non-Rx
in
R
NICOTINAMIDE-NOT EFFECTIVE !!
W
⊗
⊗
.
Canada,less effective; better
tolerated?; ↑ hepatic SE? C
,
ATO,FLU,LOV,PRA,SIM,ROS
,
Mix →juice/milk/water/applesauce M:LFT's,TGs
Space other meds ( by ≥ 2hrs)
with resins since ↓ absorption
of: amiodarone, cyclosporin,
digoxin, diuretics, fat soluble vitamins
(A,D,E,K), folate, HMG's, lthyroxine, methotrexate, NSAIDS,
propranolol, raloxifene, steroids,
sulfonylureas, valproate, warfarin,
mycophenolate
↓ Cholesterol & ↓ LDL
(Questran:pregnancy & age >2yr)
Combo with HMG
(to ↓ LDL)
Pruritus esp. with certain
biliary/liver dx
Bile acid induced diarrhea
↓’s intestinal cholesterol absorption; synergistic ↓ in
LDL when added to statin CI: hepatic M:LFT's
levels ↑’d by cyclosporine, fibrates
resins interfere with absorbtion
↓Cholesterol(+/-Statinor fenofibrate) 10mg od (with or without meals) ENHANCENS
-lacks outcome data approved 2003 {when added to statin, may allow ↓ statin dose}
64
Low dose or 325mg/d ASA:
useful on initiating/↑ niacin dose
to ↓ flushing; some pretreat X3d.
ASA may also ↑ niacin levels.
HMG's:
? ↑ myopathy if with lovastatin19
Start 50-100mg bid-tid (↑ tolerability)
(increase weekly by ~100mg/week)
9
↓Cholesterol & ↓TG; ↑HDL
Combo with HMG/Fibrate
(to ↑ HDL & ↓ TG)
Niacin deficiency (Pellagra)
nausea & bloating
Option:mix with metamucil & orangejuice/lemonade Common(<30%): constipation,
Rare:hyperchloremic acidosisCME in peds/↓renal fx 3
the night before; refrigerate & give next day,
QUESTRANg CME B
½ before breakfast & ½ before supper (shake well) CI: biliary obstruction, dysbetalipoproteinemia,
(4gram regular,4gram light)
TG >4.6 mmol/l (Caution TG >2.3 mmol/l);
NO
Colestipol
phenylketonurics (”light” & “orange granules”)
↑ 3-5%
Change or
COLESTID
B ↓ 15-30%
↑ fluid & bulk in diet→ metamucil may be required
(5g granules; 7.5g orange
Possible
Cholestyramine
granules; 1gm tab)
↓ Cholesterol (esp ↓ LDL)
Flushing (↓ by ASA/Advil 1/2hr pre),dry eyes, pruritus,
headache,GI upset,↑ LFT’s,↑uric acid & ↑ glucose
CI: severe peptic ulcer Dx, chronic liver Dx,
overt diabetes & severe gout
M: LFT's, glucose, uric acid
4g po bid ac → +/- 8g/day POST CABG
8g po bid ac
(16-24g/d)
Start 4g od-bid to ↑ tolerability
100
190
2g po bid ac
4g po bid ac
(20-30g/d)
Start 2-5g od-bid to ↑ tolerability
42
77
500mg po tid (all with meals/snack)
1500mg po bid 1 ADMIT
1g po tid cc 2 CDP
(3-6g/d)
Niaspan ER 500-750mg hs (Max 2g hs)
Advicor 500mgER/20mg (2gER/40mg hs)
12
16
16
⊗
80
⊗
48(53)
Major RISK Factors1,2,22: Diabetes most,Smoking,Hypertension(≥140/90/BP meds),Low HDL≤ 1, Family hx ~2x 10yr CAD Risk 1st degree relative (Age: <55, <65) CAD, Age( ≥45, ≥55); MODIFIABLE ↑BP,↑Lipid/LDL,Obesity: BMI>25,Waist( >102cm,40”; >88cm,35”), Diet,
Smoking, Alcohol & sedentary lifestyle. Screen: q1-3yr ≥40, ≥50 or postmenopausal;pts with CAD/PVD/atherosclerosis,diabetes,xanthomata or other stigmata of dyslipidemia;HTN;obesity;dyspnea;family hx of dyslipidemia/CAD even for kids;smokers;erectile dysfx; Lupus or if CKD renal.
DRUG INDUCED HYPERLIPIDEMIA20,21: amiodarone, beta-blockers non ISA, carbamazepine, clozapine, cyclosporin, danazol, contraceptives esp. levonorgestrel, efavirenz, phenytoin, phenobarbital, protease inhibitors, progestins, retinoids, steroids, temsirolimus & thiazides≥50mg/d.
CHOICE of AGENT: ↑↑LDLÖHMG +/- resin +/-ezetimibe; ↑↑LDL & ↑TGÖHMG; ↑↑LDL & ↓HDLÖHMG +/- fibrate/niacin; Normal LDL & ↑↑TGÖfibrate/niacin/salmon oil 22 or combo; Normal LDL & ÈHDLÖfibrate/niacin or combo
TARGETS 2006 23: HIGH Risk (10yr CAD risk ≥20% Target LDL <2.0 <2.5# & Total Chol/HDL <4 +Apo B <0.85) {High risk→ ALL pts with CAD,CVD,PAD; most with DIABETES older with risk factors & chronic renal dx GFR <30ml/min }
& Total Chol/HDL ≥5 +Apo B <1.05)High risk pts: treat medication & lifestyle changes concomitantly.
Lifestyle: DIET, EXERCISE, moderate alcohol
for patients at: MODERATE Risk(10yr CAD risk 10-19% Treat LDL ≥3.5
(Primary target: LDL)
use & stop SMOKING! (these will also ↑ HDL)
LOW Risk*(10yr CAD risk <10% Treat LDL ≥5.0
& Total Chol/HDL ≥6 +Apo B <1.2) Lower risk pts: treat with meds after 3-6 months of lifestyle changes
*If family hx of premature CAD or risk factors such as abd obesity,↑glucose, ↑hsCRP>3 mg/l or Lp(a)>0.3g/l→may intervene at a lower LDL. Low/Mod risk: suggest ↓LDL by 40-50% but simv 40mg , ator 10mg & prav 40mg has strong outcome data.
Consider ASA ~81mg/d. Highest risk benefit most!
#
An LDL <2.5 may be adequate control if high risk by Framingham risk score or some stable CAD without diabetes or saphenous vein bypass grafts. (Metabolic Sx 3 or more of: Abd obesity >102cm, >88cm; TG ≥1.7; HDL <1, <1.3; BP>130/85;Glucose fasting5.7-7)
EDS Sask. Non-formulary SK prior NIHB ⊗not covered NIHB Wcovered NIHB Indication/Use DI=Drug Interaction Dx=disease dysfx=dysfunction GI=stomach HDL=high density lipoprotein HMG CoA reductase inhib→STATINS
Caution: High statin dose in lower risk pts. Unclear if benefit solely from achievement of targets eg. ↓LDL alone 24 & page12
LDL=low density lipoprotein SE=side effect TG=triglycerides
=↓dose for renal dysfx +Apo B: useful, esp. if ↑TG/metabolic syndrome/on statin. Optimal TG<1.5mmol/l If >10mmol/l → ↑pancreatitis;Tx: ↓refined carbohydrates & ↑omega-3 fatty acids.
Rhabdomyolysis Statin Risk Factors NNH=22,700/yr but ↑ if: ↓ renal function, drug interactions e.g. fibrates NNH=1670/yr, cyclosporine, macrolides & niacin, high statin dosages, patients with diabetes, Asians, elderly & hypothyroidism.
Mortality ~10%.
13
All‐Cause Mortality (%) MAJOR STATIN TRIALS: All‐Cause Mortality Outcomes L Regier BSP BA, B Jensen BSP, K Krahn © www.RxFiles.ca Oct 2014 20
ALL‐CAUSE MORTALITY Graph/chart illustrates risk reduction for comparator vs statin tx. Not all trials powered/able to show all‐
cause mortality benefit. Note: 1) there is greater absolute benefit for 2 vs 1 prevention; 2) there is only STATIN OUTCOMES small absolute benefit for high‐dose vs low dose statins in active control trials (with very high risk 2 In Major Trials
Placebo
Placebo
14.6 Simva
prevention); 3) benefits seen even though very few trials have achieved LDLs <2mmol/L or 50% in LDL.
14.1
15
Compar at or
12.9
Prava
Placebo
11.5
S t at i n Tx
11
Placebo
Simva Atorva
Simva
9.4 Prava
10
Atorva 8.6
8.4 8.2
8.2
Placebo
80mg 10mg
Placebo
5.8
5.7
5.6
Atorva
Prava
Atorva Placebo Prava
Placebo
4.3
4.1
4.1
5
3.6
Atorva
Placebo Lova
Rosuva
3.2
3.2
Diet Diet + 2.8
2.3 2.4
2.2
2.2
2 Prava
1.4
0
WOSCOPS AFCAPS
LIPID
HPS (1 & 2) PROVE‐IT
JUPITER
4S
TNT
MEGA ASCOT
CARE
IDEAL
CARDS
RRR=22%
RRR=22%
RRR=12%
RRR=29%
RRR=21%
Trial 4S LIPID Drug & Pravastatin Simvastatin 1,2
3,4
Dose 20‐40mg daily 40mg daily 3.1% 3.3% ARR all death (p=0.0003) (p<0.001) NNT mortality 31 33 SECONDARY (2) PREVENTION (history of CHD) PROVE‐IT TNT IDEAL CARE HPS 1 & 2 Prevention Note: active control trials of high dose atorvastatin Pravastatin 40mg daily 5 Atorva 80mg vs Simvastatin Atorva 80mg vs Atorvastatin 10mg Simva 20‐40mg 40mg daily 6,7,8,9,10 Prava 40mg daily 11 vs 80mg daily 12 daily 13 1.7% NS (p<0.001) NS 59 5.4 years 6.1 years 5 years 5 years Duration Treat 31 pts for Treat 59 pts for 5 All‐Cause Treat 33 pts for 5.4 yrs to 6.1 yrs to prevent Not statistically yrs to prevent 1 Mortality significant death prevent 1 death 1 death in English (The 1 ENDPOINT) (A 1 ENDPOINT) n (+ ) 3583 + 576 15454 + 5082 3617+827 7498 + 1516 Publication yr 1994 1998 1996 2002 Comparator/ Statin {NNT for mean trial duration above) Comment MI/death CHD 8.3%/ 13.2%/ mortality above 10.2% prava 2:CHD: 28% vs 6.4% prava 19.4 % NNT=12 NNT=53 RRR=23% NNT=34 RRR=23% Impact after ~2 years; 10 yr data NNT=42 vascular
NS; *0.9%
(p=0.051) NS NS NS NS NS NS 2 years 4.9 years 4.8 years 4 years 3.3 yrs 3251 + 911 2004 8099 + 1902 2005 death/ MI/ angina/ stroke 25.2%/ 19.8% simva NNT=19 RRR=21% 26.3% prava/ 22.4% atorv NNT=26 RRR=15% Most benefit in Benefits similar in / LDL & CRP & LDL f/u: 11 yrs: CV benefit, baseline no cancer Pravastatin
40mg daily 16
NS, 11yr follow‐up NNT=36/11yrs Not statistically significant 7187 + 1701 2005 CV event
NS 10.4% simva/ 9.3% atorv 3.02.1 30% (3.2 vs 2.5%) LFTs NNH=100 3.42.3 32% 1st CHD Event MI/death CHD
4.9 years NS NS 5.2 years NS; *0.5% (p=0.052) NS JUPITER http://www.rxfiles.ca/rxfiles/uploads/docume
nts/Lipid-Jupiter-trial-overview.pdf
Rosuvastatin 20mg daily 19 0.6% (p=0.02) *176 (p=0.052)
167 (projected to compare: 64/5.4yr)
5.3 years 1.9 years 54.1 18% MI/death CHD
3.93 23% 11001 + 6801 2008 to mod risk pts, CRP 2mg/L; no CHD/ stroke/ DM; ave age 66 (≥50 & ≥60 ), BMI=28, Metabolic syn.41% 4.13.3 20% st
1st CV event 1 CHD Event
2.5% diet / 10.9%/ 1.7% diet&prava
9.0%/ 3%/ 7.9%/ 5.8% atorva 1.9% atorva 5.5% prava 6.8% lova NNT=119
RRR=34%
NNT=32 RRR=36% NNT=91 RRR=37% NNT=42 RRR=30% NNT=25 RRR=38% HR: ,=0.71, 0.63
non‐CV death *112 (p=0.051)
Lovastatin Prava 10‐20mg
20‐40mg daily daily + diet vs 17
diet alone 18 1929 + 909 8363 + 1942
6595 5608 + 997 2476 + 5356
2004 2003 1995 1998 2006 T2DM & 1 3 risk factors Scotland. HDL but LDL Japan. risk factor; no CHD; TC 6.5 with TC 7; & TC normal; no CHD or CHD/CVD, & HTN (24% stroke hx; 44% smokers; & ave age 58 LDL4.14; DM); average age 40‐70; (45‐73 & ave 55yo average age age 63 ave age 58. 55‐73 ) (45‐65) 62 (40‐75) (40‐79) True low risk.
Atorva 10mg: Simvastatin: 3.92.6 33% 3.12.616% Atorva 80mg: Atorvastatin: 3.92.0 49% 3.22.134% NNT=46 RRR=20% *Trend: Tx 112
*Trend: Tx 176 Not statistically Trial halted early;
Treat 167 pts for Not statistically pts over 4.9 Not statistically pts over 5.3 yrs
significant; trial death in 11yr
1.9 yrs to prevent significant significant yrs to prevent to prevent halted early follow up 1 death 1 death 1 death Pts with clinically Pts with hx of evident CHD and acute MI; hx of revasc.; age 80 age 35‐75 1st CHD Event 10.9% atorva 10mg/
8.7% atorva 80mg
Atorvastatin
NS Not statistically significant 10mg daily 15 NS fatal & non‐fatal Atorvastatin
10mg daily 14 http://www.rxfiles.ca/rxfiles/uploads/do
cuments/Lipid-QandA-ASCOT.pdf
NS UK. 32145 pts at 4 Scandinavia. Recent hx of Recent hx of Pts with an ACS wk run‐in; High risk Pts with angina within prior 10 acute MI or acute MI & avg 1 & 2 pts: MI, CHD, or previous MI days stable at PVD, DM, HTN, unstable angina;
LDL; & TC >5.5, 24hr, ± controlled stroke; TC3.5; age 31‐75 age 40‐80 (age in years) age 35‐70 DM; age 18 age 40‐80 3.62.5 31% Pravastatin: LDL (mean) 3.32.3 4.9 3.235%
If LDL <3.2, no 2.72.5 7% 30% initialend MI/death 3.92.9 26% CV benefit with Atorvastatin: 20
(adjusted ~3.9)
& % LDL prava 2.71.6 41% death CHD http://www.rxfiles.ca/rxfiles/uploads/do
cuments/Lipid-QandA-CARDS.pdf
PRIMARY (1) PREVENTION (no history of CHD) ASCOT WOSCOPS MEGA AFCAPS NS Patients Studied 1 Endpoint 1: total CARDS 2.81.4 50% 1st CV event 2.8%/ 1.6% rosuva NNT=83 RRR=43% Limitations: LFTs NNH=112 Benefit even in LDL <2 Lowest risk RCT; Benefit only , higher risk ; Serious adverse trial stopped early, events 34% benefit most; ?CRP role, >89,000 {10 yr follow‐up}
esp >60yr both groups
low potency. screened, mod risk 1 D/C NNH=53 1=primary 2=secondary =women =men ACS=acute coronary syndrome AE=adverse event ARR=% absolute risk reduction atorva=atorvastatin avg=average BMI=body mass index CHD=coronary heart disease CKD=chronic kidney disease CRP=C‐reactive protein CV=cardiovascular CVD=cardiovascular death & disease d/c=discontinuation DM=diabetes hx=history EF=ejection fraction HF=heart failure hr=hour HTN=hypertension LFT=liver function tests Lipid Values in mmol/L (HDL= high density lipoprotein LDL=low density lipoprotein TC=total cholesterol TG=triglycerides) MI=myocardial infarction n=number NNH=# needed to harm one additional pt NNT= # needed to treat to benefit one (e.g. in 4S trial, treating 30patients for 5.4yr would prevent 1 death) NS= not statistically significant NYHA=New York Heart Association prava=pravastatin pts=patients PVD=peripheral vascular disease RRR= relative risk reduction simva=simvastatin sx=symptom T2DM=type 2 diabetes mellitus yr=year NOTE: This data is from different studies of varying patient groups and with varying methodology; it demonstrates qualitative trends but can not be used for direct quantitative comparison. *Calculation for NS Trend provided for demonstration purposes only
SPECIAL CONSIDERATIONS: Patient Population Specific Evidence SUMMARY OF ALL‐CAUSE MORTALITY EVIDENCE (many studies not powered to evaluate this endpoint; of published trials, only the 4S & HPS "overall" had this as the 1 endpoint)
RENAL: statin+ezetimibe‐marginal benefit ischemic stroke, coronary revasc in CKD 67% non‐dialysis SHARP; INSUFFICIENT DATA to assess risk vs benefit in: 1) age >82 yrs 2) combo therapy 3) 1 prevention in low risk pts esp. 4) aggressive pursuit of targets in low‐mod risk pts. CV benefit in CKD ~51% stage 3/4 pts when combo with simvastatin 20mg daily vs placebo SHARP: major atherosclerotic event NNT=48/4.9yr, no effect on total mortality despite ~25% death overall , n=9270
STATINS 21,22 strong evidence for 2 prevention (incl. dose atorva 80mg in post MI, stable CHD & ACS 23); some evidence for 1 prevention in DM & at CHD risk. ; statins lack benefit (CV death, MI, stroke; all‐cause mortality) in dialysis only pts 4D, AURORA Trials show statins beneficial for CV risk rather than TC or LDL; no treat to target trials. HIGH‐DOSE STATIN mortality benefit in risk ACS, but liver & muscle AE. HEART FAILURE: statins lack benefit (CV death, MI, stroke; all‐cause mortality) in heart FIBRATES no evidence yet for in 1 or 2 all‐cause mortality24; possible benefit in pts with HDL, TG’s >2.3 &/or pts with DM. Clofibrate chance of mortality WHO‐CLOF 25
failure NYHA II,III,IV, EF~32% CORONA,GISSI‐HF Management of statin intolerance ‐ NIACIN some evidence mortality (no difference at 6yr; but at 15yr NNT=25, ) CDP, but NIASPAN no CV events Aim‐High 93
AORTIC STENOSIS: statins lack benefit ASTRONOMER STROKE PREVENTION: statins beneficial SPARCL Q&A:http://www.rxfiles.ca/rxfiles/uploads/
documents/Lipid‐Statin‐Intolerance.pdf
DIABETES: statins benefit; but combining simvastatin + fenofibrate lacked benefit ACCORD‐LIPID EZETIMIBE EZETROL no outcome data showing any benefit for ezetimibe alone or when adding to statin vs statin alone. 25 TOBACCO / SMOKING CESSATION PHARMACOTHERAPY-never too late to quit 1,2 Prepared by L. Regier, B. Jensen, W. Chan; Reviewer: Dr. J. Taylor
Generic/TRADE
Class /
Side Effects (SE) - common
√ = Advantages / :=Disadvantages; Comments
(Strength & forms)
Pregnancy
Contraindications CI 3
{NNT: number needed to treat for one patient to be
1,3
g=generic avail.
category
Monitor M
successful at 1 year based on systematic review}
NRT- assist in
NICOTINE
REPLACEMENT (NRT):
reducing craving.
Lack of trials; but
nicotine levels
generally lower
than with smoking;
Patch, Gum or Inhaler
OTC.
{USA: nasal inhaler also available}
↑’d malformations
musculoskeletal with
nicotine substitutes4
(General NRT comments;
more information below)
General NRT SE: arthralgias/back pain ≥5%,
GI – flatulence 4%, diarrhea, nausea, taste
change, etc.; acne 3%; dysmenorrhea 3%;
ÖIndividualize dose: ↑ if withdrawal, ↓ if SE
5
CI caution in post MI or angina/CAD
(however some would suggest safer than smoking);
hypersensitivity to components, eczema
NRT: ↑ in abstinence rates by 30-80% compared to Pl; NNT~10 6
[Abstinence rate vs Pl @12 months: N ≤11% vs 5.5% NNT=18;
I 17% vs 9%, NNT=13; G ≤27% vs 16.5 %, NNT=9] 7
M if no response in 4wks, stop, reassess, reinitiate?
Combos: NRT+ Bupropion may be better than either alone9,10;
NRT+CBT, no added benefit to adding bupropion11
√ Convenient once daily dosing, slow constant release rate, more
tolerable SE; fewer CV events, option after MI officially if >2 wks.5
: no spikes in concentrations to correspond with cravings
Individualize dosing regimen; recommendations serve as
guideline; two patches may be required in heavy smokers.
Smoking with patch: may ↑nicotine risks, but not CI
√ Quick delivery via buccal mucosa; Park & Chew Strategy –
chew gum few times, then hold in side of mouth x1min; repeat
: Patient compliance: unpleasant taste; but high abstinence rate
: Not advised for ↑risk cardiac pts : Risk of dependence13
30 minute chew: peak level 5→10ng/ml (for the 2mg→4mg gum)
Reduce to quit ↓ smoking 50% between 6-16wk or Stop to quit after 3mon→ ↓ ≥1 gum q4-7days
√ Quick delivery of high dose convenient for severe cravings
habitual hand-to-mouth motion (max absorption with ~20min
short continuous frequent puffing) √ Flexible dosing schedule
: Not recommended for high risk cardiac patients
Peak: N/H 6-12 hrs, I 15 min;
Nicotine Patch(clear or flesh color)
NICODERM
Max 70 patch/yr}
HABITROL
g
PATCH
=H
7,14,21mg patch χ{
Nicotine Gum {
SE: skin irritations 32%{May Tx with ICS}, headache ~20%;
insomnia & nightmares (if worn at night)
NOT contraindicated in pts with CV disease 12
If insomnia/disturbing dreams, remove patch
@HS; if morning craving, keep patch on 24hrs
or consider adding gum or inhaler.
N= D
=N
7,14,21mg/d patchχ{
Max 84 patch/yr}
{Unlabeled use: Ulcerative Colitis ~21 mg/day}
Max 945 pieces/yr}
G= C
NICORETTE Gum =G
2mg gum; PLUS=4mg χ
GUM
(g; sugar free; Flavors:
Pregnancy?: Some prefer
original, freshmint, orange) g
acute source (gum or inhaler)
THRIVE 2,4mg gum sucrose free;mint over a constant source (patch).
Nicotine Oral Inhaler
NICORETTE Inhaler =I
I= D
4mg {10mg cartridge gives
4mg nicotine}
⊗
INHALER
LOZENGE
⊗
Nicotine Lozenges
Nicorette SF, cherry, mint g 2,4mg; Thrive mint 1,2mg
Bupropion SR
TABLET
=B
ZYBAN
Antidepressant
150mg tab {Indication:
smoking cessation}; 1-800-489-8424
WELLBUTRIN {Not officially indicated
for smoking cessation}
100,150mg SR tab g
150,300mg tab XL
Varenicline
T½: N/H 4hrs, I 1-2 hrs
;
B
⊗
{ Max 165 tab/yr}
CHAMPIX CHANTIX
↓ dopamine
reuptake mesolimibic system
www.zybannet.com
=V activate nicotinic
USA 18
{2wk Starter Pack; 2wk Continuous Pack}
Nortriptyline
AVENTYL g (10, 25mg cap)
C
receptors α4β 2
D CAPSULE
Antidepressant
(Full formulary in SK)
SE: cough, throat irritation - usually mild
(absorb ~1/2 the nicotine in the gum)3;
CI dental problems, TMJ temporomandibular joint syndrome
DI: coffee & acidic beverages e.g. juice, pop
impair absorption; space by ≥15minutes
SE: throat irritation 66%, cough 32% , rhinitis 23%,
dyspepsia 18%
10 puffs =1 puff from cigarette: cartridge has
20min continuous puffing; once punctured,
cartridge viable for 24 hrs; buccal absorption
SE: soreness in gums, teeth, throat, hiccups &
heartburn/indigestion. {More potent than gum}
SE: insomnia, agitation, tremor, ↓ appetite &
GI upset, dry mouth, seizures 1/1000 at 300mg/d
CI personal/family hx of seizures, ↑risk for
seizures (eg. eating disorders); head trauma,
pts on MAO inhibitors within 14 days
{ Zyban not covered for smoking cessation in SK}
SE: nausea 30%, sleep/dream 18%, taste disturbance; aggression?
{↑Weight @12wks: Pl 3kg >V 2.6kg >B 2kg}. Less SEs requiring DC than B NNT >15
DI: NRT-↑nausea. CI: end stage renal?;epilepsy?; suicidal?n=39 FDA
SE: dry mouth, dizziness, drowsiness, ↑weight;
↓SE’s than amitriptyline
Note: an option when breastfeeding 22,23
CI ECG abnormalitiesrare, suicidal/seizure risk
No statistical difference between formulations. Choose specific
formulation based on SE’s, CI’s & patient preferences.
{Some real-life studies have found long-term results no better than placebo. 8
Effectiveness may depend on co-interventions &/or highly motivated patients!}
©
www.RxFiles.ca
Jun 08
$ ~12
weeks
Dosing
Schedule
N&H Smoking Hx
<10cig/d, <45kg &/or
CHD: 14mg od x 6wk;
7mg od x 2wk
N Smoking Hx
>10cig/d:21mg od x 6wk;
14mg od x 2wk;
7mg od x 2wk
H Smoking Hx
>20cig/d:21mg od x 3-4wk;
14mg od x 3-4wk;
7mg od x 3-4wk
$300-$360
g = ~$300
(~$30/7 patches)
Apply new patch
to clean, dry,
non-hairy area
every day.
Tapering not
always
necessary
Manufacturer recommendations; no
difference between N & H. Individualize tx
~1piece/hr PRN; max
20 pieces/d; ave 1016/d. individual taper.
{Use 4mg if ≥15cigs/d}
May use prn while on patch
~$140-$250
g=~$160-240
($35/2mg105pcs;
$45/4mg 105pcs)
Use 4 mg if hx of
smoking within
30min of waking!
6-16 cartridges/d x12 wk;
indiv. taper; max 16 cart/d.
Use 12 wks then taper
over 6-12 wks
~$550-$900
√ Convenient, inconspicuous √ Flexible dosing schedule Strength depends on
time to first craving upon awakening (<30minÖuse 4mg; >30minÖuse 2mg)
Park & Suck: suck until strong taste, then park, & repeat; lozenge lasts ~30min,don’t chew/drink
1 loz. q1-2hr x6 wk,
q2-4hr x3wk, q4-8hr x3wk
~$100-$350
Abstinence Rate at 12 months: 18.5% vs 6.6% Pl, NNT=8 14
$190 Zyban
150mg SR od x3 days,
150mg SR bid x7-12wks
{$135 300mg od
Begin 1 week before
Wellbutrin XL}
cessation of smoking.
For SR: allow at least 8hrs between doses;
take 2nd dose early pm to minimize insomnia
{Observational study found 21% abstinent @12mo; 29% stopped due to SE’s}15
May combine bupropion & NRT in patients with ↑↑cravings/withdrawal symptoms
no significant difference between 150mg/d & 300mg/d at 12 mo?14
: slower onset (1-2 weeks) √ option in concomitant depression
√ may delay weight gain & cravings post-smoking cessation
√ not CI in pts with hx of cardiovascular disease16 or on SSRIs17
Abstinence Rate continuous @12 months: V: 22% vs B: 15% vs Pl: 9% 19,20; 1of 2 trials NS
with 12 wk tx {NNT=14 vs B; NNT=8 vs Pl}; additional 12wks may ↑ success in
1/15 pts. 21 Start 1wk before quit; total 12wks tx ± 12wks if successful.
Abstinence Rate 12 months: 17% vs 7% Pl, NNT=10
24
CBT + (Bupropion300mg/d vs Nortriptyline75mg/d vs Pl): NS 42%vs31%vs22%; 6mo; n=156. 25
Consider if also: Pain, Migraine, depression, neuropathy, insomnia.
Max:15 x 2mg lozenges
0.5mg tab od x3days,
0.5mg bid x4days; then
1mg tab bid {2 wk Starter Pack avail.}
25–50-75mg po hs
(25mg-75mg/d for ~2wks before
quit-date; continue ≥12wks after)
(start kit $40;
$30/30 cart’s)
($29 g -45/2mg 96pcs;
$31 g -50/4mg 96pcs)
$390
{with food & H20}
(FAA pilot ban May/08)
$51-81-110
/14 wks
1 pack/day
($900) 12wk
Quit smoking advice from a clinician, even brief, can increase cessation rates by 30%.26 Some attempt 10 x before successfully quitting!
cost–savings⇒
(Cigarette Trivia: 1-3mg nicotine/cigarette; ~4000 chemicals/cigarette; 1pack/day = 20-40mg nicotine; 1pack= ~25 cigarettes)3 Withdrawal Sx better after 1-3 wks.
Tobacco – all forms
=↓dose for renal dysfx χ=Non-form Sk =Exception Drug Status Sk ⊗=not covered NIHB =covered NIHB :=Disadvantage CBT=cognitive behavioral therapy CI=contraindication CV=cardiovascular DI=drug interaction g=generics avail. HA=headache Hx=history
MI=myocardial infarction NS=not statistically significant Pl = placebo Pt=patient Sx=symptom SE=side effect T½=half life wk=weeks NICE: http://www.nice.org.uk/page.aspx?o=PHI001 Health Canada: www.gosmokefree.ca Smokers’ Helpline 1-877-513-5333 fax referral option
SMOKING /
New
Drugs:
Rimonabant ACOMPLIA –(not yet in Canada) cannabinoid receptor 1 blocker; 36% complete smoking cessation in final 4 wks of a 10 wk trial Dose: 20mg/d SE: nausea, depression, anxiety & ↓ weight.
27,28,29
Anti-nicotine vaccines (investigational): Celtic, Nabi, Cytos: reducing nicotine distribution to brain, ↓reinforcing effect of nicotine. Herbal: RESOLVE lozenge: CESTEMENOL-350 150 mg Passiflora incarnate, Abies balsamea L: lacks efficacy data & may↑ toxicity.
Non-Drug Measures: 5,30, 31,32 Consider exercise, counseling & support groups; avoid situations that trigger smoking urge. Behavioral therapy best in pts with a hx of depression. DI: if stop smoking drug level ↑ for caffeine, clozapine, fluvoxamine, haloperidol, olanzapine & theophylline.
yet ~18% CND’s smoke
HARMS/Reasons to Stop: 27,33,34 Leading cause of preventable death (45,000 CND/yr); ~50% of long-term smokers die prematurely from cancer, heart, stroke & lung disease
. Smokers die ~10-17yrs
younger than non-smokers. Quitting gives a 36% relative reduction in total mortality & ↓ cardiac events in CHD pts by ~50%.35 Cost: 1 pk/d cost ~$3600/yr. Other: impotence, osteoporosis & SIDS sudden infant death syndrome
st
Weight Gain: Average <5 kg/1 yr; ↑ exercise to lessen; health benefits persist despite weight gain (RRR 15-61% in mortality after MI). Consider strategies to avoid weight gain as part of the “Quit Plan”.
visits, phone
5 A’s to Smoking Cessation: ASK – about tobacco use at every visit; ADVISE - to quit; ASSESS - willingness to quit; ASSIST -implement plan; ARRANGE - follow-up
; & cessation counseling. 89
TOBACCO / SMOKING CESSATION PHARMACOTHERAPY
Cochrane Reviews – Other Therapies Summary (http://www.update-software.com/publications/cochrane )
1. Acupuncture: lack evidence for acupuncture, acupressure or electrostimulation.
2. Exercise: Most trials too small to reliably associate any effect of intervention.
One trial offered evidence for exercise aiding smoking cessation.
3. Anxiolytics: Lack evidence but possible effect.
4. Mecamylamine (nicotine antagonist): Limited data (2 small studies); not effective
alone, may enhance effectiveness of NRT
5. Opioid antagonist (naltrexone): -limited data ( 2 studies), not possible to confirm
or refute whether it helps smokers quit; need larger trials
6. Silver acetate: little evidence to support, may be reflective of poor compliance
7. Lobeline: no evidence from long-term trials that it can aid smoking cessation
8. Other Antidepressants: moclobemide trial showed significant effect at 6 months, none @12 months;
SSRI’s no evidence of clinically important benefits; venlafaxine trial failed to show significant increase in
cessation compared to nicotine patch & counseling alone, but confidence intervals do not exclude effect
9. Nicotine: the different forms of NRT were all significantly more effective than control
10. Clonidine: some evidence for being efficacious, but appropriateness not well defined & needs more trials.3
11. Topiramate: potential to be useful in smoking cessation, especially in those with alcohol dependence, but
more data is required before conclusions should be drawn. 36
12. Other references of interest: 37,38,39,40,41,42,43,44,45,46,47; Tools to assess dependence. E.g. Fagerstrom Tolerance Scale 48
CHAMPIX / Varenicline – for Smoking Cessation
Perspective – at 52wks
Ö note: most of the industry ad claims look a bit more impressive due to analysis of the 52 week trials at their 12 week mark {e.g. at
12 weeks, company states 4x better than placebo and 2x better than Zyban}. Cessation success rates decline steadily throughout
the 1 year period. An analysis at 52 weeks is more realistic and helpful in predicting long-term success:
2.8x better than Placebo
NNT= 8
(95% CI: 6, 11)
1.6x better than Bupropion (Zyban)
NNT= 14
(95% CI: 9, 34)
Additional 12 wks: NNT=15
(1 extra success for every 15 people who take an extra 12 weeks.)
Considerations:
Funding by maker of Champix
Relatively new drug – limited safety data
Cost: $390/12 weeks
$200 more per 12wk course than Zyban
SE:
naus ea 30%;
wt gain (12 wk) 2.6kg vs 2kg for Zyban
behavior & mood changes?
FDA MedWatch Feb/08; 491 suicidal reports; 39 completed
Jorenby, D. E. et al. JAMA 2006;296:56-63.
Summary: Compared to ZYBAN, 12 weeks of varenicline (Champix) offers:
Advantages:
- one extra person successfully quitting at 1 year for every 14 patients treated. based on 2 RCTs
Disadvantages:
- more nausea, weight gain, and potentially mood/behavior changes
- relatively new drug with some potential unknowns (in terms of adverse reactions, drug interactions, etc)
- $200 more per person (not bad for 1/14 who might get extra benefit, but not good for the other 13 people.)
Qualifier:
- above based on studies, all funded by the manufacturer with the potential for associated bias
References:
1
MicroMedex 2006; Lexi Drugs 2006
Therapeutic Choices 2003
Henningfield J, Reginald V, August R, et al. Pharmacotherapy for Nicotine Dependence. CA Cancer J Clin 2005;55:281-299
4
Morales-Suarez-Varela MM, Bille C, Christensen K, Olsen J. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol. 2006 Jan;107(1):51-7.
5
Ludvig J, Miner B, Eisenberg M. Smoking Cessation in patients with coronary artery disease. AHJ 2004;149(4):565-570.
6
Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation.Cochrane Database Syst Rev. 2004;(3):CD000146.
7
Silagy C, Lancaster T, Stead L, et al. Nicotine replacement therapy for smoking cessation. The Cochrane Database of Systemic Reviews 2004;3
8
Lam W, Sze PC, Sacks HS, Chalmers TC. Meta-analysis of randomised controlled trials of nicotine chewing-gum. Lancet. 1987 Jul 4;2(8549):27-30.
9
Jorenby DE, A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med. 1999 Mar 4;340(9):685-91. .
10
Chatkin JM, Mariante de Abreu C, Haggstram FM, et al.. Abstinence rates and predictors of outcome for smoking cessation: do Brazilian smokers need special strategies? Addiction. 2004 Jun;99(6):778-84.
11
Simon JA, Duncan C, Carmody TP, Hudes ES. Bupropion for smoking cessation: a randomized trial. Arch Intern Med. 2004 Sep 13;164(16):1797-803.
12
Joseph AM, Norman SM, Ferry LH, et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med. 1996 Dec 12;335(24):1792-8. (n=584, 14 wks)
13
http://heartdisease.about.com/cs/riskfactors/a/rimonabant_p.htm
14
Hughes J, Stead L, Lancaster T. Antidepressants for Smoking Cessation. The Cochrane Database of Systemic Reviews 2004;4. Hughes JR, Stead LF, Lancaster T.
Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD000031.
15
Paluck EC, McCormack JP, Ensom MH, Levine M, Soon JA, Fielding DW. Outcomes of bupropion therapy for smoking cessation during routine clinical use. Ann Pharmacother. 2006 Feb;40(2):185-90.
16
Tonstad S, Farsang C, Klaene G, et al. Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study. Eur Heart J. 2003 May;24(10):946-55.(n=629, 52 wks)
17
Regier L, Jensen B. Can Zyban be given with SSRIs in RxFiles Q&A Summary. Accessed at: http://www.rxfiles.ca/acrobat/zyban%2Dssri%2Dq%26a.pdf
18
Medical Letter 2006. 48;66-68.
19
Gonzales D, Rennard SI, Nides M, et al; Varenicline Phase 3 Study Group. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist,
vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):47-55. (InfoPOEMs: Varenicline (Chantix) therapy for 12 weeks is significantly more effective than placebo at maintaining smoking abstinence at 52
weeks. Varenicline may also be marginally more effective than bupropion SR. Reported success rates are likely to be higher than real-world settings. (LOE = 1b))
20
Jorenby DE, Hays JT, Rigotti NA, et al.; Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor
partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):56-63.
21
Tonstad S, Tonnesen P, Hajek P, et al. Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):64-71.
22
Wisner KL, Hanusa BH, Perel JM, Peindl KS, et al. Postpartum depression: a randomized trial of sertraline versus nortriptyline. J Clin Psychopharmacol. 2006 Aug;26(4):353-60.
23
Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004 Jun;161(6):1066-78.
24
Wagena E, et al. Efficacy of Bupropion & Nortriptyline for Smoking Cessation Among People at Risk for or with Chronic Obstructive Pulmonary Disease. Arch Intern Med 2005;165:2286-2292 (n=225; 12 wks).
25
Haggstram FM, Chatkin JM, et al. A controlled trial of nortriptyline, bupropion SR & placebo for smoking cessation: preliminary results. Pulm Pharmacol Ther. 2006;19(3):205-9. Epub 2006 Mar 6.
26
Henningfield J, Reginald V, August R, et al. Pharmacotherapy for Nicotine Dependence. CA Cancer J Clin 2005;55:281-299.
27
Critchley J, Capewell S. Mortality Risk Reduction Associated with Smoking Cessation in Patients with Coronary Heart Disease. JAMA 2003; 290(1):86-97.
28
http://heartdisease.about.com/cs/riskfactors/a/rimonabant_p.htm; http://www.docguide.com/news/content.nsf; http://www.uc.edu/news/NR.asp?id=1417; http://psychiatriymmc.com/displayArticle.cfm?article.cfm?articleID=article105
29
Acomplia (rimonabant) and OTC orlistat for weight loss. Pharmacist’s Letter 2006;22(3):220313.
30
Critchley J, Capewell S. Mortality Risk Reduction Associated with Smoking Cessation in Patients with Coronary Heart Disease. JAMA 2003; 290(1):86-97.
31
Weblinks: http://www.healthknowledgecentral.org/onepagers/smoking.pdf; http://www.quitnet.com/Library/Guides/NRT/lozenge_specifics.jtml
32
Ranney L, Melvin C, Lux L et al. Systematic Review: Smoking cessation Intervention Strategies for adults and adults in special populations. Ann Intern Med. 2006 Sep 5; [Epub ahead of print] Early Release – Accessed online at
http://www.annals.org/cgi/content/full/0000605-200612050-00142v1
33
Godtfredsen N, Prescott E, Osler M. Effect of Smoking Reduction on Lung Cancer Risk. JAMA 2005;294:1505-1510(n=19,714; 31 yrs)
34
Doll R, Peto R, Boneham J. Mortality in relation to smoking:50 years observations on male British doctors.BMJ 2004;328:1519-1529 (n=34,439, 50yrs)
35
Wilson K, Gibson N, Willan A, Cook D. Effect of Smoking Cessation on Mortality After Myocadial Infarction: Meta-analysis of Cohort Studies. Arch Intern Med 2000; 160; 939-944
36
Johnson BA, Ait-Daoud N, Akhtar FZ, Javors MA. Use of oral topiramate to promote smoking abstinence among alcohol-dependent smokers: an RCT. Arch Intern Med. 2005 Jul 25;165(14):1600-5.
37
An LC, et al. Benefits of telephone care over primary care for smoking cessation: a randomized trial.Arch Intern Med. 2006 Mar 13;166(5):536-42. (InfoPOEMs: A telephone-based counseling program is effective
at helping self-selected older men quit smoking. The men in this study were veterans who had smoked for an average of 40 years, and 1 in 8 was able to quit for at least 6 months. (LOE = 1b) )
38
Chaudhuri R, et al. Effects of Smoking Cessation on Lung Function and Airway Inflammation In Smokers with Asthma. Am J Respir Crit Care Med. 2006 Apr 27; [Epub ahead of print] Six weeks after smoking cessation, smokers with asthma achieved considerable improvement in lung
function and a fall in sputum neutrophil count compared to smokers who continued to smoke. These findings highlight the importance of smoking cessation in asthma.
39
Houston TK, et al. Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. BMJ. 2006 May 6;332(7549):1064-9. Epub 2006 Apr 7.
40
Lancaster T, Hajek P, Stead LF, West R, Jarvis MJ. Prevention of relapse after quitting smoking: a systematic review of trials. Arch Intern Med. 2006 Apr 24;166(8):828-35
41
Zhu SH, et al. Evidence of real-world effectiveness of a telephone quitline for smokers.N Engl J Med. 2002 Oct 3;347(14):1087-93.
42
Healton CG, et al. Smoking, obesity, & their co-occurrence in the USA: cross sectional analysis. BMJ. 2006 May 12; 23.5% of adults were obese, 22.7% smoked, and 4.7% smoked and were obese.
43
Tobacco Use: Prevention, Cessation, and Control. Agency for Healthcare Research and Quality; US Department of Heath and Human Services http://www.ahrq.gov/clinic/tp/tobusetp.htm
44
Shaw LJ, Raggi P, Callister TQ, Berman DS. Prognostic value of coronary artery calcium screening in asymptomatic smokers and non-smokers. Eur Heart J. 2006 Apr;27(8):968-75. Epub 2006 Jan 27.
45
Teo KK, et al.; behalf of the INTERHEART Study Investigators. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet. 2006 Aug 19;368(9536):647-58.
46
Wen W, et al. Environmental tobacco smoke and mortality in Chinese women who have never smoked: prospective cohort study. BMJ. 2006 Aug 19;333(7564):376. Epub 2006 Jul 12.
47
Anthonisen NR, et al; Lung Health Study Research Group. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005 Feb 15;142(4):233-9. Summary for patients in: Ann Intern Med. 2005 Feb 15;142(4):I12.
48
Heatherton, TF, Kozlowski LT, Frecker, RC, Fagerstrom KO. The Fagerstrom Test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. Brit J Add. 1991; 86:1119-1127. {Fagerstrom KO, Schneider NG. Measuring nicotine dependence: a review
of the Fagerstrom tolerance questionnaire. J Behav Med. 1989;12:159-82.}
2
3
TOBACCO / SMOKING CESSATION PHARMACOTHERAPY Extra articles:
Aldington S, Williams M, Nowitz M, Weatherall M, Pritchard A, McNaughton A,Robinson G, Beasley R. THE EFFECTS OF CANNABIS ON PULMONARY STRUCTURE, FUNCTION AND SYMPTOMS. Thorax. 2007 Jul 31; [Epub ahead of print] Smoking cannabis was
associated with a dose-related impairment of large airways function resulting in airflow obstruction and hyperinflation. In contrast, cannabis smoking was seldom associated with macroscopic emphysema. The 1:2.5 to 5 dose equivalence between cannabis joints and
tobacco cigarettes for adverse effects on lung function is of major public health significance.
Aveyard P, West R. Managing smoking cessation. BMJ. 2007 Jul 7;335(7609):37-41.
Aveyard P, Johnson C, Fillingham S, Parsons A, Murphy M. Nortriptyline plus nicotine replacement versus placebo plus nicotine replacement for smoking cessation: pragmatic randomised controlled trial. BMJ. 2008 Apr 27; [Epub ahead of print] Nortriptyline and nicotine
replacement therapy are both effective for smoking cessation but the effect of the combination is less than either alone and evidence is lacking that combination treatment is more effective than either alone.
Bartecchi C, et al. Reduction in the incidence of acute myocardial infarction associated with a citywide smoking ordinance. Circulation. 2006 Oct 3;114(14):1490-6. Epub 2006 Sep 25. (InfoPOEMs: This observational study found that a citywide smoking ban was associated with a
reduction in the incidence of acute myocardial infarction (AMI) by approximately 70 per 100,000 person-years (that is, approximately 1 fewer AMI for every 1400 persons per year). Share this information with local politicians and other community leaders who are resisting curbs on smoking. Another
study by the Centers for Disease Control and Prevention found that a smoking ban in El Paso, Texas, had no negative economic consequences for bars and restaurants.* *http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5307a2.htm (LOE = 4) )
Bjerregaard BK, et al. The effect of occasional smoking on smoking-related cancers : In the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control. 2006 Dec;17(10):1305-9.
Burstein AH, et al. Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers. J Clin Pharmacol. 2006 Nov;46(11):1234-40. Thus, no dose adjustment is necessary based on age alone.
Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD006103. DOI: 10.1002/14651858.CD006103.pub2. Varenicline increased the odds of successful long-term smoking
cessation approximately threefold compared with pharmacologically unassisted quit attempts.In trials reported so far, more participants quit successfully with varenicline than with bupropion. The effectiveness of varenicline as an aid to relapse prevention has not been clearly established. The main
adverse effect of varenciline is nausea, but this is mostly at mild to moderate levels and tends to reduce with habituation.There is a need for independent trials of varenicline versus placebo, to test the early findings. There is also a need for direct comparisons with nicotine replacement therapy, and for
further trials with bupropion, to establish the relative efficacy of the treatments.Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.
Campbell R, Starkey F, Holliday J, et al. An informal school-based peer-led intervention for smoking prevention in adolescence (ASSIST): a cluster randomised trial. Lancet. 2008 May 10;371(9624):1595-602. The results suggest that, if implemented on a population basis, the
ASSIST intervention could lead to a reduction in adolescent smoking prevalence of public-health importance.
Cesaroni G, Forastiere F, Agabiti N, et al. Effect of the Italian smoking ban on population rates of acute coronary events. Circulation 2008; DOI: 10.1161/circulationaha.107.729889.
Christakis NA, Fowler JH. The collective dynamics of smoking in a large social network. N Engl J Med. 2008 May 22;358(21):2249-58. Network phenomena appear to be relevant to smoking cessation. Smoking behavior spreads through close and distant social ties, groups of
interconnected people stop smoking in concert, and smokers are increasingly marginalized socially
Etter JF. Cytisine for smoking cessation: a literature review and a meta-analysis. Arch Intern Med. 2006 Aug 14-28;166(15):1553-9.
FDA Chantix/Champix Warning Feb/2008: 491 suicide reports; 39 completed. Canada: 46 psychiatric adverse reactions reported from April 1-Nov23/07
Freedman R. Exacerbation of schizophrenia by varenicline. Am J Psychiatry. 2007 Aug;164(8):1269.
Gunnell AS, et al. Synergy between Cigarette Smoking and Human Papillomavirus Type 16 in Cervical Cancer In situ Development. Cancer Epidemiol Biomarkers Prev. 2006 Oct 20; [Epub ahead of print]
Hall SM, Humfleet GL, Reus VI, Muñoz RF, Cullen J. Extended nortriptyline and psychological treatment for cigarette smoking. Am J Psychiatry. 2004 Nov;161(11):2100-7.
Harvard Study Confirms Rise in Nicotine Delivery of Cigarettes A reanalysis of data released last summer confirms that the nicotine yield from cigarettes increased about 11% from 1998 to 2005. A Harvard School of Public Health review of the data, which are annually
reported to the Massachusetts Department of Public Health by cigarette manufacturers, was released online. It found the nicotine increase across brands from the four major manufacturers and in all categories of cigarettes, such as menthol and ultralight.
The report said the nicotine boost was accomplished both by increasing the amount of nicotine in the cigarettes and by redesigning them to burn more slowly, so users take more puffs per cigarette. http://www.hsph.harvard.edu/nicotine/trends.pdf
Haslemo T, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006 Nov 7; [Epub ahead of print] A daily consumption of 7-12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine
metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.
Health Canada July/07 Unauthorized Smoking Cessation Product Resolve May Pose Health Risk - Consumer Information. The product contains an unacceptable amount of an ingredient labelled as "CESTEMENOL-350." Consuming excessive amounts of this ingredient might
result in damage to the kidney, liver or red blood cells.
Keating GM, Siddiqui MA. Varenicline : A Review of its Use as an Aid to Smoking Cessation Therapy. CNS Drugs. 2006;20(11):945-960.
Kenfield SA, Stampfer MJ, Rosner BA, et al. Smoking and smoking cessation in relation to mortality in women. JAMA 2008; 299: 2037-2047.
Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry. 2007 Aug;164(8):1269-70.
Kwok MK, Schooling CM, Ho LM, Leung S, Mak KH, McGhee SM, Lam TH, Leung GM. Early life second hand smoke exposure and serious infectious morbidity during the
first eight years: evidence from Hong Kong's "Children of 1997" birth cohort. Tob Control. 2008 May 27. [Epub ahead of print]
Maisonneuve P, et al. Impact of smoking on patients with idiopathic chronic pancreatitis. Pancreas. 2006 Aug;33(2):163-8.
Mennella JA, Yourshaw LM, Morgan LK. Breastfeeding and smoking: short-term effects on infant feeding and sleep.Pediatrics. 2007 Sep;120(3):497-502. An acute episode of smoking by lactating mothers altered infants' sleep/wake patterning.
Menzies D, et al. Respiratory symptoms, pulmonary function, and markers of inflammation among bar workers before and after a legislative ban on smoking in public places. JAMA. 2006 Oct 11;296(14):1742-8.
Mirkhel A, et al. Frequency of aspirin resistance in a community hospital. Am J Cardiol. 2006 Sep 1;98(5):577-9. Epub 2006 Jun 30. In conclusion, this study estimates aspirin resistance prevalence and shows a strong association of smoking with platelet hyperactivity in a diverse
community hospital population. Nonresponders to 81 mg/day frequently responded to 325 mg/day or to the addition of clopidogrel.
Moshammer H, et al. Parental smoking and lung function in children: an international study. Am J Respir Crit Care Med. 2006 Jun 1;173(11):1255-63. Epub 2006 Feb 16.
Mohiuddin SM, Mooss AN, Hunter CB, et al. Intensive smoking cessation intervention reduces mortality in high-risk smokers with cardiovascular disease. Chest. 2007 Feb;131(2):446-52. At 24 month, continuous abstinence smoking cessation rate was 33% in the intensivetreatment group and 9% in the usual-care group (p < 0.0001). Over the 2-year follow-up period, 41 patients in the usual-care group were hospitalized compared to 25 patients in the intensive-treatment group (relative risk reduction [RRR], 44%; 95% confidence interval
[CI], 16 to 63%; p = 0.007). The all-cause mortality rate was 2.8% in the intensive-treatment group and 12.0% in the usual-care group (RRR, 77%; 95% CI, 27 to 93%; p = 0.014). The absolute risk reduction in mortality was 9.2% with a number needed to treat of 11.
Monuteaux MC, Spencer TJ, Faraone SV, et al. A randomized, placebo-controlled clinical trial of bupropion for the prevention of smoking in children and adolescents with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2007 Jul;68(7):1094-101.
While bupropion was not associated with a lower rate of smoking in youth with ADHD, post hoc analyses suggest that stimulant treatment was. Future controlled studies should investigate the role of stimulants in the prevention of smoking in children and adolescents with ADHD.
Muramoto ML, Leischow SJ, Sherrill D, Matthews E, Strayer LJ. Randomized, double-blind, placebo-controlled trial of 2 dosages of sustained-release bupropion for adolescent smoking cessation. Arch Pediatr Adolesc Med. 2007 Nov;161(11):1068-74. Sustained-release
bupropion hydrochloride, 300 mg/d, plus brief counseling demonstrated short-term efficacy for adolescent smoking cessation. Abstinence rates were lower than those reported for adults, with rapid relapse after medication discontinuation.
National Institutes of Health State-of-the-Science Conference Statement: Tobacco Use: Prevention, Cessation, and Control. Ann Intern Med. 2006 Sep 5; [Epub ahead of print]
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Approximately 1 in 7 highly motivated patients will not be smoking 1 year after taking varenicline (Chantix) 1 mg twice daily for 6 weeks. Lower doses did not work. Side effects will be common and will not be tolerated by some patients. (LOE = 1b-) )
Oncken C, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med. 2006 Aug 14-28;166(15):1571-7.
Okuyemi KS, Nollen NL, Ahluwalia JS. Interventions to facilitate smoking cessation. Am Fam Physician. 2006 Jul 15;74(2):262-71. Review. Summary for patients in: Am Fam Physician. 2006 Jul 15;74(2):276.
O'Malley SS, et al. A controlled trial of naltrexone augmentation of nicotine replacement therapy for smoking cessation. Arch Intern Med. 2006 Mar 27;166(6):667-74.
Parkes G, Greenhalgh T, Griffin M, Dent R. Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial. BMJ. 2008 Mar 6; [Epub ahead of print] Telling smokers their lung age significantly improves the likelihood of them quitting
smoking, but the mechanism by which this intervention achieves its effect is unclear.
Pharmacists Letter. New Regimen for Nicorette Gum: Reduce-to-Quit (RTQ). Aug 2007.
Pletcher MJ, et al. Menthol cigarettes, smoking cessation, atherosclerosis, and pulmonary function: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Arch Intern Med. 2006 Sep 25;166(17):1915-22.
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Prochazka AV, Weaver MJ, Keller RT, Fryer GE, Licari PA, Lofaso D. A randomized trial of nortriptyline for smoking cessation. Arch Intern Med. 1998 Oct 12;158(18):2035-9.
Ranney L, Melvin C, Lux L, McClain E, Lohr KN. Systematic Review: Smoking Cessation Intervention Strategies for Adults and Adults in Special Populations. Ann Intern Med. 2006 Sep 5; [Epub ahead of print]
Retnakaran R, et al. Cigarette smoking and cardiovascular risk factors among Aboriginal Canadian youths. CMAJ. 2005 Oct 11;173(8):885-9.
Rigotti NA, et al. Bupropion for smokers hospitalized with acute cardiovascular disease. Am J Med. 2006 Dec;119(12):1080-7. Bupropion improved short-term but not long-term smoking cessation rates over intensive counseling and appeared to be safe in hospitalized smokers with acute
cardiovascular disease.
SDIS – Guidelines for NRT during pregnancy and lactation. Available at: http://www.usask.ca/pharmacy-nutrition/services/sdis.shtml
Smoking Cessation benefits: Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977 Jun 25;1(6077):1645-8.
Soria R, et al. A randomised controlled trial of motivational interviewing for smoking cessation. Br J Gen Pract. 2006 Oct;56(531):768-74. (InfoPOEMs: In this study with several biases favoring the intervention, motivational interviewing appears to be more effective than brief advice in
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Stapleton JA, Watson L, Spirling LI, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction. 2008 Jan;103(1):146-54. Epub 2007 Nov 19. (n=412 over
6weeks) In this setting and with group support varenicline appears to improve success rates over those achieved with NRT, and is equally effective and safe in those with and without a mental illness.
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quit tobacco use.
Stead LF, Perera R, Bullen C, Mant D, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD000146. All of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges)
can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50-70%, regardless of setting.The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual.
Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT.
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ACID SUPPRESSION: Drug Comparison Chart CAG 2004, CADTH B Schuster PharmD, L Regier BSP BA, B Jensen BSP © www.RxFiles.ca May 2015 GENERIC/TRADE COMMENTS / ADVERSE EVENTS AE / DOSE & DURATION BY INDICATION (Strength & formulation) DRUG INTERACTIONS DI $/30 days PROTON PUMP INHIBITORS (PPIs) listed in alphabetical order give 30 minutes before meal NIHB: Max 400 tablets or capsules/180days Dexlansoprazole DEXILANT, previously KAPIDEX P L PPIs superior efficacy vs H2RA incl. double dose esp. for daytime GERD: 60mg po daily ac x 4‐8 weeks 30mg, 60mg dual release* capsule Step‐down: 30mg po daily ac use lowest effective dose, on‐demand or intermittent; taper $87 or meal related acid secretion, except for functional dyspepsia. Moderate‐severe hepatic impairment: maximum 30mg/day Chronic PPI tx if ZES, likely Barrett’s or severe esophagitis. Esomeprazole NEXIUM, g NEXIUM 24HR 20mg USA AE: headache, dizziness, somnolence, diarrhea, constipation, GERD: 40mg po daily ac x 4‐8 weeks NSAID GU: 20mg po daily ac x 4‐8 weeks 20, 40mg delayed release tablet
$75g nausea, pruritis, sweating. Rare: interstitial nephritis, rash & P L Step‐down: 20mg po daily ac use lowest effective dose, on‐demand or intermittent; taper 10mg sachet for oral solution allergy. Long‐Term AE based on observational studies: ↓B12 ZES: 40‐80mg po BID ac S‐isomer of omeprazole:↑ bioavailability especially elderly, ↓ serum Mg++ if K+ low Mg++ likely low; may $82NEXIUM 3,4
Combination products: VIMOVO $75/month ↑pneumonia, C. difficile & hip fracture ↓alendronate effect. Severe hepatic impairment: maximum 20mg po daily ac 1‐11yrs: Reflux: 10mg (<20kg) or 10‐20mg (≥20kg) po daily ac x 8 weeks Esomeprazole 20mg + naproxen 375mg or 500mg DI with all PPIs: ↓level of drugs with low pH‐dependent ENRD: 10mg po daily ac x 8 weeks ++ ++
absorption (e.g. Ca carbonate, Fe , dasa‐/erlo‐/nilo‐tinib, 12‐17 yrs: Reflux: 20‐40mg po OD ac 4‐8 wks; ENRD: 20mg po OD ac 2‐4 wks atazanavir, keto‐/itra‐conazole, thyroxine, vismodegib); ok GERD: 30mg po daily ac x 4‐8 weeks Lansoprazole PREVACID, g OTC USA P L with antacids. All PPIs metabolized by CYP450 to some PUD: 15mg po OD ac, DU x 4 weeks, GU x 4‐8 weeks, NSAID 30mg ≤8 weeks $27g 15, 30mg delayed release capsule extent, especially CYP2C19 & CYP3A4. May ↑ Step‐down: 15mg po daily ac use lowest effective dose, on‐demand or intermittent; taper for capsule 15, 30mg oral disintegrating tab PREVACID FASTAB methotrexate, digoxin & tacrolimus levels. Additional DI: ZES: 30‐90mg po BID ac - Lansoprazole: ↓theophylline levels by 10% ? clinical concern, Hepatic impairment or elderly: maximum 30mg po daily ac $76 for FASTAB ? ↓ mycophenolate 1‐11yrs: GERD: 15mg (≤30kg) ‐ 30mg (>30kg) po daily ac x 12 weeks & PREVACID ≥12yrs: GERD: use adult dose - Omeprazole/esomeprazole: ↑levels of carbamazepine, GERD: 20mg po daily ac x 2‐8 weeks citalopram, diazepam, mycophenolate, phenytoin, $24 20mg Omeprazole LOSEC, g P L PUD: 20mg po daily ac, DU x 4 weeks, GU x 4‐8 weeks, NSAID x 4‐8 weeks triazolam, warfarin; ↓ clopidogrel see below. 10mg, 20mg delayed release tablet/capsule Step‐down: 10mg po daily ac use lowest effective dose, on‐demand or intermittent; taper $37 10mg OTC 14 tabs=~$14
- Pantoprazole & rabeprazole: least likely to have DI 20mg delayed release tablet OLEX
ZES: 60mg po daily up to 120mg po TID ac (less CYP450 & non‐enzymatic metabolism) - Clopidogrel: omeprazole & esomeprazole may ↓ clopidogrel’s Hepatic Impairment or elderly: maximum 20mg po daily ac ≥1yr:USA 0.7‐3.3mg/kg/day ac conversion to active drug. Some evidence suggests not +
$22g Pantoprazole Na PANTOLOC, g GERD: 40mg po ac daily x 2‐8 weeks clinical signficance. May consider pantoprazole or ? rabeprazole. P L 20mg, 40mg enteric coated tablet PUD: 40mg po daily ac, DU x 4 weeks, GU x 4‐8 weeks RxFiles Q&A http://www.rxfiles.ca/rxfiles/uploads/documents/Clopidogrel‐PPI‐interaction‐QandA.pdf Step‐down: 20mg po daily ac use lowest effective dose, on‐demand or intermittent; taper $35TECTA 40mg/10mL injectable (IV po) Alternative Formulations & Administration: see On‐Line Extras ZES: 40‐120mg po BID ac; 80mg IV BID‐TID ($30/dose) Pantoprazole Mg++ TECTA - Capsules: dexlansoprazole, lansoprazole, omeprazole Severe hepatic impairment: maximum 20mg po daily ac 40mg enteric coated tablet Open capsules & sprinkle intact granules onto soft, cold GI Bleed: 80mg IV bolus, then 8mg/hr x 72hrs, then 40mg IV daily ($15/dose) Na+ vs Mg++: Mg++ slower dissolution, but no clinical difference food. Swallow immediately; do not crush/chew granules. GERD: 20mg po daily ac x 4‐8 weeks Rabeprazole PARIET, g ACIPHEX USA P L - Suspension from solid dosage form for po or NG tube: PUD: 20mg po daily ac, DU x 4 weeks, GU x 6 weeks 10, 20mg enteric coated tablet $15‐18
dexlansoprazole, esomeprazole (tablet NEXIUM & some generics, Step‐down: 10mg po daily ac use lowest effective dose, on‐demand or intermittent; taper
granules), lansoprazole (capsule granules, FASTAB) ZES: 30‐60mg po BID ac USA
omeprazole (capsule, tablet), pantoprazole ≥12yrs: for GERD H2‐RECEPTOR ANTAGONISTS (H2RAs) listed in alphabetical order Higher dosages may be suitable for some patients/conditions GERD: 600mg po BID Cimetidine TAGAMET, g P L Useful for: dyspepsia (initial or maintenance), GERD especially mild, PRN PUD: 800mg po HS, DU x 4‐8 weeks, GU x 8 weeks
for dietary indiscretion; Not for NSAID‐induced ulcer prophylaxis 200 , 300, 400, 600, 800 mg tablet $17‐22 Step‐down: 200mg po daily use lowest effective dose, OD or PRN; taper Nocturnal symptoms: effective; may dose at HS with a daytime PPI, but 3‐16 yrs: GERD: 40‐80mg/kg/day, PUD: 15‐20mg/kg/day tachyphylaxis may develop ≥7 days; limited efficacy in GERD. $19‐27 Famotidine PEPCID, g Few significant differences between H2RAs; ranitidine may be a preferred GERD: 20mg po BID P L PUD: 40mg po HS, DU x 4‐8 weeks, GU x 8 weeks H2RA due to comparable safety, efficacy & lower cost 20, 40mg tablet; 10, 20mg tablet OTC Step‐down: 10mg po OD FAMOUS 20mg HS ↓PUD on ASA 75‐325mg/day
20mg, 40mg (10mg/mL) injectable - consider avoiding cimetidine in the elderly or those at ↑ risk of DI AE: Uncommon: diarrhea, constipation, headache, fatigue, confusion (risk ZES: 20mg IV q12h ($5/dose) 1‐16yrs max 40mg/d:USA GERD: 0.5mg/kg/day, PUD: 1mg/kg/day ↑in elderly & in pts with ↓renal func on). Rare: thrombocytopenia, Nizatidine AXID, g P L ↓B12. AE: Cimetidine slightly higher AE risk seen with higher doses for a GERD: 150mg po BID PUD: 300mg po HS, DU x 4‐8 weeks, GU x 8 weeks 150, 300mg capsule prolonged time; reversible gynecomastia <1% & impotence (weak $18‐24 Step‐down: 150mg po HS use lowest effective dose, HS or PRN; taper antiandrogenic effect); may transiently ↑ in SCr & LFTs. <12yrs:USA GERD: 5‐10mg/kd/d max 300mg/d, ≥12 yrs: adult dose DI: Cimetidine inhibits CYP450 1A2, 2C19, 2D6 e.g. warfarin, phenytoin, GERD: 150mg po BID $17‐22 Ranitidine ZANTAC, g P L theophylline, etc. Ranitidine minor effect on CYP450; midazolam. OTC
PUD: 150mg po BID or 300mg HS, DU x 4‐8 weeks, GU x 8 weeks 150, 300mg tablet; 75, 150mg tablet Nizatidine/famotidine little or no effect on CYP450. Space antacid see Step‐down: 150mg po BID use lowest effective dose, schedule or PRN; taper $110 soln 15mg/mL oral solution; 50mg (25mg/mL) injectable page 136 administration 30‐60 minutes apart from H2RAs. 50mg IV q8h ($3/dose) or 150mg oral solution BID ↓dosage for renal dysfunction or elderly; hepatic dysfxn ↓ cimetidine ≥1 month:USA 5‐10mg/kg/day GERD & PUD * immediate peak & ~4hrs later ; R‐isomer of lansoprazole OTC
2⁰=secondary =Exception Drug Status SK =non‐formulary SK =prior approval required for NIHB =not covered by NIHB =covered by NIHB =On‐line Extras =reduce dose in kidney dysfunction =reduce dose in liver dysfunction ac=before meals AE=adverse events ASA=acetylsalicyclic acid BID=twice daily CA=cancer Ca++=calcium CAD=coronary artery disease C.difficile=Clostridum difficile COXIB=selective cyclooxygenase 2 inhibitor CV=cardiovascular enzymes DAPT=dual antiplatelet therapy DI=drug interaction DU=duodenal ulcer dysfxn=dysfunction ENRD=endoscopy negative reflux disease Fe++=iron ++
+
g=generic GERD=gastroesophageal reflux disease GI=gastrointestinal GU=gastric ulcer H2RA=H2‐receptor antagonist H.pylori=Helicobacter pylori LFT=liver function tests Mg =magnesium IV=intravenous min=minute mos=month Na =sodium NG=nasogastric OR=odds ratio PPI=proton pump inhibitor 64
PUD=peptic ulcer disease SCr=serum creatinine soln=solution SSRI=selective serotonin reuptake inhibitors sx=symptom tx=treatment UBT=urea breath test UGIB=upper gastrointestinal bleed VBAD=vomiting, bleeding, abdominal mass, dysphagia ZES=Zollinger‐Ellison Syndrome RxFiles: Acid Suppression Chart On‐Line Extras Complete List of Abbreviations 2⁰=secondary =Exception Drug Status SK =non‐formulary SK =prior approval required for NIHB =not covered by NIHB =covered by NIHB =On‐line Extras =reduce dose in kidney dysfunction ++
=reduce dose in liver dysfunction ac=before meals AE=adverse events ASA=acetylsalicyclic acid BID=twice daily CA=cancer Ca =calcium CAD=coronary artery disease C.difficile=Clostridum difficile COXIB=selective ++
cyclooxygenase 2 inhibitor CV=cardiovascular CYP=cytochrome P450 enzymes DAPT=dual antiplatelet therapy DI=drug interaction DU=duodenal ulcer dysfxn=dysfunction ENRD=endoscopy negative reflux disease Fe =iron ++
g=generic GERD=gastroesophageal reflux disease GI=gastrointestinal GU=gastric ulcer H2RA=H2‐receptor antagonist H.pylori=Helicobacter pylori HS=bedtime hx=history IV=intravenous LFT=liver function tests Mg =magnesium +
min=minute mos=month Na =sodium NG=nasogastric NSAID=non‐steroidal anti‐inflammatory drugs NNT=number needed to treat pt=patient(s) OD=daily OR=odds ratio OTC=over the counter PRN=as needed PPI=proton pump inhibitor po=oral PUD=peptic ulcer disease QID=four times daily SCr=serum creatinine soln=solution SSRI=selective serotonin reuptake inhibitors sx=symptom(s) tx=treatment UBT=urea breath test UGIB=upper gastrointestinal bleed VBAD=vomiting, bleeding, abdominal mass, dysphagia wks=week(s) yrs=years ZES=Zollinger‐Ellison Syndrome Alternative PPI Formulations & Routes of Administration Dexlansoprazole DEXILANT 30mg, 60mg dual release* capsule Esomeprazole NEXIUM, g NEXIUM is MUPS (multiple unit pellet formulation), & some g will disperse in water – e.g. Mylan will, Apotex will not Lansoprazole PREVACID, g 20, 40mg delayed release tablet
10mg granules (sachet) for oral soln 15, 30mg delayed release capsule 15, 30mg oral disintegrating tab PREVACID FASTAB Omeprazole LOSEC, g
10mg, 20mg delayed release tablet 20mg delayed release capsule Pantoprazole PANTOLOC, g TECTA +
Pantoprazole Na PANTOLOC, g 20mg, 40mg enteric coated tablet 40mg/10mL injectable (IV po) Rabeprazole PARIET, g
++
Pantoprazole Mg TECTA 40mg enteric coated tablet 10, 20mg enteric coated tablet Route of Administration: Oral Open capsule, sprinkle intact granules onto 1 tablespoon of cold, soft food (e.g. applesauce, yogurt, jam). Swallow immediately. Granules should not be chewed. Suspension from solid dosage form for po or NG tube: Open capsule. Mix intact granules with 20mL of water. Swirl. Administer via po or via NG tube. Refill syringe with 10mL of water to flush and administer po or via NG tube; repeat with another 10mL. Route of Administration: Oral Disperse tablet in half a glass of non‐carbonated water. Stir until the tablet disintegrates & drink the liquid with the pellets within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed. Route of Administration: Gastric tube (8‐20 French) Prepare & give immediately. Pre‐flush tube with 20mL sterile water (SW). Place tablet in a 60mL catheter tip syringe. Draw up 50mL of SW for 8‐13 French, use 25mL if ≥14 French. Shake to disperse tablet. Hold syringe tip up & check tip for clogging. Attach syringe keeping tip up. Point tip down & give 5‐10mL. Remove, shake again & give remaining suspension. Refill syringe with 25mL SW, shake to suspend any remaining sediment & give. Post‐flush with 40mL SW for ND, NJ, PGJ and PG tubes and 20‐30mL for all other tube types. Route of Administration: Oral Dissolve granules in 15mL of water. Stir & leave to thicken for a few minutes. Stir again, and drink within 30 minutes. If need be, rinse container by adding more water, stir & drink immediately. Route of Administration: NG tube Dissolve granules in 15mL of water. Shake syringe & leave to thicken for a few minutes. Shake the syringe & administer via NG tube within 30 minutes. Refill the syringe with another 15mL, shake & flush the line. Route of Administration: Oral Open capsule, sprinkle intact granules onto 1 tablespoon of cold, soft food (e.g. applesauce, yogurt, jam). Swallow immediately. Granules should not be chewed. Route of Administration: NG tube (≥16 French) Open capsule. Mix intact granules into 40mL of apple juice of water. Administer via NG tube. Flush tube with additional apple juice or water. Route of Administration: Oral Dissolve FasTab on tongue with or without water until particles can be swallowed (dissolves in less than 1 minute). Do not chew granules. Route of Administration: Oral Syringe (≥8 French) Dissolve 15mg FasTab (4mL) or 30mg FasTab (10mL) in an oral syringe. Shake. Drink within 15 minutes. Add another 2‐5mL to the syringe, shake & drink any remaining contents. Route of Administration: NG tube Dissolve 15mg FasTab (4mL) or 30mg FasTab (10mL) in a syringe. Shake. Administer via NG tube within 15 minutes. Add another 5mL of water to the syringe, shake & flush the tube. Oral suspension: compound from tablets Route of Administration: Oral Open capsule, sprinkle intact granules onto 1 tablespoon of cold, soft food (e.g. applesauce, yogurt, jam). Swallow immediately. Granules should not be chewed. Route of Administration: NG tube Open capsule. Mix intact granules with 10‐20mL of 8.4% sodium bicarbonate in a 20mL syringe. Shake & administer via NG tube within 30 minutes. Flush the line with 10mL of water. Suspension from solid dosage form for po or NG tube: oral suspension available in the U.S. or compounded from tablets Route of Administration: Intravenous (only PPI available as an injectable) ‐ References 1.
2.
3.
4.
AHFS 2014; Micromedix 2014 Armstrong D, Marshall JK, Chiba N, et al.; Canadian Association of Gastroenterology GER Consensus Group. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults ‐ update 2004. Can J Gastroenterol. 2005 Jan;19(1):15‐35. Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community‐acquired pneumonia and use of gastric acid‐suppressive drugs. JAMA. 2004 Oct 27;292(16):1955‐60. (Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid‐suppressive agents and the risk of community‐acquired Clostridium difficile‐associated disease. JAMA. 2005 Dec 21;294(23):2989‐95. Dial S, Delaney JA, Schneider V, Suissa S. Proton pump inhibitor use and risk of community‐acquired Clostridium difficile‐associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006 Sep 26;175(7):745‐8. ) (Lowe DO, Mamdani MM, Kopp A, Low DE, Juurlink DN. Proton pump inhibitors and hospitalization for Clostridium difficile‐associated disease: a population‐based study. Clin Infect Dis. 2006 Nov 15;43(10):1272‐6. Epub 2006 Oct 13. Among community‐dwelling older patients, PPI use is not a risk factor for hospitalization with CDAD.) [CAG Clinical Affairs Committee. Community‐acquired pneumonia and acid‐suppressive drugs: position statement. Can J Gastroenterol. 2006 Feb;20(2):119‐21, 123‐5.] (Gulmez SE, Holm A, Frederiksen H, et al. Use of proton pump inhibitors and the risk of community‐acquired pneumonia: a population‐based case‐control study. Arch Intern Med. 2007 May 14;167(9):950‐5. The use of PPIs, especially when recently begun, is associated with an increased risk of community‐acquired pneumonia.) Pham C, Sadowski‐Hayes L, Regal R. Prevalent Prescribing of Proton Pump Inhibitors: Prudent or Pernicious. P&T 2006;31(3):159‐165. Yang YX, Lewis JD, Epstein S, Metz DC. Long‐term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006 Dec 27;296(24):2947‐53. Long‐term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture. InfoPOEMs: Long‐term use (greater than one year) of proton pump inhibitors (PPIs) is associated with an increased risk of hip fracture in adults over age 50 years. Risk is also higher among individuals taking higher doses of PPIs and increases with duration of use. Appropriate use, dose, and duration of therapy should be carefully assessed on an individual basis. (LOE = 3b) Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int. 2006 Aug;79(2):76‐83. Epub 2006 Aug 15.] Targownik, L. E., Lix, L. M., Metge, C. J. et al. Use of proton pump inhibitors and risk of osteoporosis‐related fractures. Can Med Assoc J 2008 179: p. 319‐326. Sarkar M, Hennessy S, Yang YX. Proton‐pump inhibitor use and the risk for community‐acquired pneumonia. Ann Intern Med. 2008 Sep 16;149(6):391‐8. Proton‐pump inhibitor therapy started within the past 30 days was associated with an increased risk for CAP, whereas longer‐term current use was not. Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for clostridium difficile‐associated diarrhea in hospitalized patients. Am J Gastroenterol. 2008 Sep;103(9):2308‐13. Epub 2008 Aug 12. This study showed elevated risk of developing CDAD in hospitalized patients with acid suppressive therapy, especially when PPIs were used. Sultan N, Nazareno J, Gregor J. Association between proton pump inhibitors and respiratory infections: A systematic review and meta‐analysis of clinical trials. Can J Gastroenterol. 2008 Sep;22(9):761‐6. Herzig Shoshana J.; Howell Michael D.; Ngo Long H.; et al. Acid‐Suppressive Medication Use and the Risk for Hospital‐Acquired Pneumonia. JAMA. 2009;301(20):2120‐2128. Herzig SJ, Vaughn BP, Howell MD, Ngo LH, Marcantonio ER. Acid‐suppressive medication use and the risk for nosocomial gastrointestinal tract bleeding. Arch Intern Med. 2011 Jun 13;171(11):991‐7. Laine L. Proton pump inhibitors and bone fractures? Am J Gastroenterol 2009;104:S21‐S26. Miano TA, Reichert MG, Houle TT, et al. Nosocomial pneumonia risk and stress ulcer prophylaxis: a comparison of pantoprazole vs ranitidine in cardiothoracic surgery patients. Chest. 2009 Aug;136(2):440‐7. Targownik LE, Lix LM, Leung S, Leslie WD. Proton Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss. Gastroenterology. 2009 Nov 18. Eurich DT, Sadowski CA, Simpson SH, et al. Recurrent community‐acquired pneumonia in patients starting acid‐suppressing drugs. Am J Med. 2010 Jan;123(1):47‐53. Linsky Amy; Gupta Kalpana; Lawler Elizabeth V.; et al. Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection. Arch Intern Med. 2010;170(9):772‐778. Proton pump inhibitor use during incident CDI treatment was associated with a 42% increased risk of recurrence. Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI. Gray Shelly L.; LaCroix Andrea Z.; Larson Joseph; et al. Proton Pump Inhibitor Use, Hip Fracture, and Change in Bone Mineral Density in Postmenopausal Women: Results From the Women's Health Initiative. Arch Intern Med. 2010;170(9):765‐771. Use of PPIs was not associated with hip fractures but wasmodestly associated with clinical spine, forearm or wrist, and total fractures. Howell Michael D.; Novack Victor; Grgurich Philip; et al. Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile Infection. Arch Intern Med. 2010;170(9):784‐790. Increasing levels of pharmacologic acid suppression are associated with increased risks of nosocomial C difficile infection. This evidence of a dose‐response effect provides further support for the potentially causal nature of iatrogenic acid suppression in the development of nosocomial C difficile infection. FDA May/10: Proton‐Pump Inhibitors Might Increase Risk for Wrist, Hip, and Spine Fractures http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213321.htm Redelmeier D, McAlister FA, Kandel CE, Lu H, Daneman N. Postoperative pneumonia in elderly patients receiving acid suppressants: retrospective cohort analysis. BMJ 2010;340:c2608. Eom CS, Jeon CY, Lim JW, et al. Use of acid‐suppressive drugs and risk of pneumonia: a systematic review and meta‐analysis. CMAJ. 2011 Feb 22;183(3):310‐9. Herzig Shoshana J.; Vaughn Byron P.; Howell Michael D.; et al. Acid‐Suppressive Medication Use and the Risk for Nosocomial Gastrointestinal Tract Bleeding. Arch Intern Med. 2011;0(2011):archinternmed.2011.14. Abrahamsen Bo; Eiken Pia; Eastell Richard. Proton Pump Inhibitor Use and the Antifracture Efficacy of Alendronate. Arch Intern Med. 2011 Jun 13;171(11):998‐1004. Furlanetto Tania Weber; Faulhaber Gustavo Adolpho Moreira. Hypomagnesemia and Proton Pump Inhibitors: Below the Tip of the Iceberg. Arch Intern Med. 2011;0(2011):archinternmed.2011.199. Eom CS, Park SM, Myung SK, et al. Use of Acid‐Suppressive Drugs and Risk of Fracture: A Meta‐analysis of Observational Studies. Ann Fam Med. 2011 May‐Jun;9(3):257‐67. Langan RC, Zawistoski KJ. Update on Vitamin B12 Deficiency. Am Fam Physician. 2011 Jun 15;83(12):1425‐1430. Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ. 2012 Jan 30;344:e372. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile Infection With Acid Suppressing Drugs and Antibiotics: Meta‐Analysis. Am J Gastroenterol. 2012 Apr 24. de Jager CP, Wever PC, Gemen EF, et al. Proton pump inhibitor therapy predisposes to community‐acquired Streptococcus pneumoniae pneumonia. Aliment Pharmacol Ther. 2012 Nov;36(10):941‐9. Janarthanan S et al. Clostridium difficile‐associated diarrhea and proton pump inhibitor therapy: A meta‐analysis. Am J Gastroenterol 2012 Jul; 107:1001. Bajaj JS, Ratliff SM, Heuman DM, Lapane KL. Proton pump inhibitors are associated with a high rate of serious infections in veterans with decompensated cirrhosis. Aliment Pharmacol Ther. 2012 Sep 11. Chitnis AS, Holzbauer SM, Belflower RM, et al. Epidemiology of Community‐Associated Clostridium difficile Infection, 2009 Through 2011. JAMA Intern Med. 2013 Jul 22;173(14):1359‐67. Bateman BT, Bykov K, Choudhry NK, et al. Type of stress ulcer prophylaxis (PPIs vs H2) and risk of nosocomial pneumonia in cardiac surgical patients: cohort study. BMJ. 2013 Sep 19;347:f5416. Lam JR, Schneider JL, Zhao W, et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013 Dec 11;310(22):2435‐42. Nylund CM, Eide M, Gorman GH. Association of Clostridium difficile Infections with Acid Suppression Medications in Children. J Pediatr. 2014 Aug 8. Herzig SJ, Doughty C, Lahoti S, et al. Acid‐Suppressive Medication Use in Acute Stroke and Hospital‐Acquired Pneumonia. Ann Neurol. 2014 Aug 28. McDonald EG, Milligan J, Frenette C, et al. Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. JAMA Intern Med. 2015 Mar 2. COXIB/NSAID Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002 Dec 26;347(26):2104‐10. Among patients with a recent history of ulcer bleeding, treatment with celecoxib was as effective as treatment with diclofenac plus omeprazole, with respect to the prevention of recurrent bleeding. (Agrawal NM, Campbell DR, Safdi MA, et al. Superiority of lansoprazole vs ranitidine in healing nonsteroidal anti‐inflammatory drug‐associated gastric ulcers: results of a double‐blind, randomized, multicenter study. NSAID‐Associated Gastric Ulcer Study Group. Arch Intern Med. 2000 May 22;160(10):1455‐61. In patients who require continuous treatment with NSAIDs, lansoprazole is superior to ranitidine for healing of NSAID associated gastric ulcers. Healing is not delayed by the presence of H pylori infection.)(Yeomans ND, Tulassay Z, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID‐associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998 Mar 12;338(11):719‐26. In patients with regular use of NSAIDs, omeprazole healed & prevented ulcers more effectively than did ranitidine.) (Goldstein JL, Johanson JF, et al. Healing of gastric ulcers with esomeprazole versus ranitidine in patients who continued to receive NSAID therapy: a randomized trial. Am J Gastroenterol. 2005 Dec;100(12):2650‐7.) (Hawkey CJ, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID‐induced Ulcer Management (OMNIUM) Study Group. N Engl J Med. 1998 Mar 12;338(11):727‐34. The overall rates of successful treatment of ulcers, erosions, and symptoms associated with NSAIDs were similar for the two doses of omeprazole and misoprostol. Maintenance therapy with omeprazole was associated with a lower rate of relapse than misoprostol. Omeprazole was better tolerated than misoprostol.) (Chan FK, Wong VW, Suen BY, et al. Combination of a cyclo‐
oxygenase‐2 inhibitor (celecoxib 200mg bid) and a proton‐pump inhibitor (esomeprazole 20mg bid) for prevention of recurrent ulcer bleeding in patients at very high risk: a double‐blind, randomised trial. Lancet. 2007 May 12;369(9573):1621‐6. The 13‐month cumulative incidence of the primary endpoint was 0% in the combined‐treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). n=441 12months. Patients at very high risk for recurrent ulcer bleeding who need anti‐inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding. Chan FK, Hung LC, Suen BY, Wong et al. Celecoxib versus diclofenac plus omeprazole in high‐risk arthritis patients: results of a randomized double‐blind trial. Gastroenterology. 2004 Oct;127(4):1038‐43. Among patients with previous ulcer bleeding, neither celecoxib nor diclofenac plus omeprazole adequately prevents ulcer recurrence. Treatment‐induced significant dyspepsia is an indication for endoscopic evaluation.. PEPTI C ULCER BLEEDING Leontiadis GI, Sharma VK, et al. Systematic review & meta‐analysis of proton pump inhibitor therapy in peptic ulcer bleeding. BMJ. 2005 Jan 31; [Epub ahead of print] (InfoPOEMs: Neither oral nor intravenous use of proton pump inhibitors decreases the risk of dying as the result of peptic ulcer bleeding. The likelihood of rebleeding or the need for surgery is reduced, with 1 episode of rebleeding avoided in every 10 pts treated & 1 surgery avoided for every 25 patients who received treatment. (LOE = 1a) ) Leontiadis GI, Sharma VK, Howden CW. WITHDRAWN: Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2010 May 12;(5):CD002094. Sung JJ, Suen BY, Wu JC, et al. Effects of Intravenous and Oral Esomeprazole in the Prevention of Recurrent Bleeding from Peptic Ulcers after Endoscopic Therapy. Am J Gastroenterol. 2014 Apr 29. Sachar H, Vaidya K, Laine L. Intermittent vs Continuous Proton Pump Inhibitor Therapy for High‐Risk Bleeding Ulcers: A Systematic Review and Meta‐analysis. JAMA Intern Med. 2014 Sep 8. Additional References:
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Among patients with H. pylori infection and a history of upper gastrointestinal bleeding who are taking low-dose aspirin, the eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole is superior to the eradication of H.
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Chang
CONCLUSION: Use of a proton pump inhibitor to treat cough associated with GORD has some effect in some adults. The effect, however, is less universal than suggested in consensus guidelines on chronic cough and its magnitude of effect is uncertain. (InfoPOEMs: Treatment for gastroesophageal reflux disease
(GERD) in patients with chronic cough may be effective in some patients, but the effect is not universal or consistent. It might be worth a try, but don't expect many patients to improve. (LOE = 1a))
AB, Lasserson TJ, Gaffney J, et al. Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst Rev. 2011 Jan 19;1:CD004823. PPI is not efficacious for cough
associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for
cough associated with GORD.
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Cremonini F, Wise J, Moayyedi P, Talley N. Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest pain. Am J Gastroenterol 205; 100:1226-32. (InfoPOEMs: The use of a proton pump inhibitor (PPI) is useful in
the diagnosis of gastroesophageal reflux disease (GERD) and an effective treatment for patients with noncardiac chest pain. Because some smaller studies with negative results may not have been published, the estimate of the degree of benefit of PPIs in this study may
be on the high side. (LOE = 1a) )
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de Jager CP, Wever PC, Gemen EF, et al. Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia. Aliment Pharmacol Ther. 2012 Nov;36(10):941-9.
Delaney B, Ford A, Forman D, Moayyedi P, Qume M, Delaney B. Initial management strategies for dyspepsia. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001961& ACP Journal Club. AUTHORS' CONCLUSIONS: Proton
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early investigation by endoscopy or H. pylori testing may benefit some patients with dyspepsia but is not cost effective as part of an overall management strategy.
Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras CA, Katzka DA. ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis
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gastroesophageal reflux disease. Endoscopy is recommended only for patients with alarm symptoms, poor response to therapy, or severe or long-term symptoms. H2 blockers or PPIs are effective in most patient, and many can be tapered to low doses or off treatment all together. (LOE = ))
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Dickman R, Schiff E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther. 2007 Oct 30;26(10):1333-1344. Epub 2007 Sep 17.
Adding acupuncture is more effective than doubling the proton pump inhibitor dose in controlling gastro-oesophageal reflux disease-related symptoms in patients who failed standard-dose proton pump inhibitors. (InfoPOEMs: In this small, short-term study, adding twice
weekly acupuncture to standard-dose proton pump inhibitor (PPI) treatment was more effective in controlling symptoms than doubling the PPI dose. Acupuncture may be useful for some patients, but the long-term benefits, if any, have not been established. (LOE = 1b))
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FDA Mar/11 Proton Pump Inhibitor drugs (PPIs): Drug Safety Communication - Low Magnesium Levels Can Be Associated With Long-Term Use.
FDA Apr/11: Teva’s lansoprazole delayed-release orally disintegrating tablet has clogged and blocked oral syringes and feeding tubes, including both gastric and jejunostomy types, when administered as a suspension.
FDA Feb/12 notified the public that the use of stomach acid drugs known as proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile–associated diarrhea (CDAD).
FDA Mar/12 LINX Reflux Management System is a surgically-placed string of magnetic titanium beads that is placed at the lower esophageal sphincter. When a person swallows, the device expands to accommodate the
liquid or food. Once the food passes, the device keeps a weak lower esophageal sphincter closed, thus preventing material from flowing back into the esophagus.
Fernando HC, Murthy SC, Hofstetter W, et al. Society of Thoracic Surgeons. The Society of Thoracic Surgeons practice guideline series: guidelines for the management of Barrett's esophagus with high-grade dysplasia.
Ann Thorac Surg 2009 Jun;87(6):1993-2002.
Filion KB, Chateau D, et al. CNODES Investigators. Proton pump inhibitors & the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut. 2013 Jul 15.
Fiocca R, Mastracci L, Engström C, et al. Long-Term Outcome of Microscopic Esophagitis in Chronic GERD Patients Treated With Esomeprazole or Laparoscopic Antireflux Surgery in the LOTUS Trial. Am J
Gastroenterol. 2009 Nov 10.
Fitzgerald RC, di Pietro M, Ragunath K, et al. British Society of Gastroenterology. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. Gut. 2014 Jan;63(1):7-42.
Fletcher J, Derakhshan MH, Jones GR, et al. BMI is superior to symptoms in predicting response to proton pump inhibitor: randomised trial in patients with upper gastrointestinal symptoms and normal endoscopy. Gut.
2011 Apr;60(4):442-8.
Flook NW, Moayyedi P, Dent J, et al. Acid-suppressive therapy with esomeprazole for relief of unexplained chest pain in primary care: a randomized, double-blind, placebo-controlled trial.
Am J Gastroenterol. 2013 Jan;108(1):56-64.
Flory J, Haynes K, Leonard CE, et al. Proton Pump Inhibitors Do Not Impair the Effectiveness of Metformin in Diabetic Patients. Br J Clin Pharmacol. 2014 Sep 9.
Fock KM, Teo EK, Ang TL, et al. Rabeprazole vs esomeprazole in non-erosive gastro-esophageal reflux disease: a randomized, double-blind study in urban Asia. World J Gastroenterol. 2005 May 28;11(20):3091-8.
Focks JJ, Brouwer MA, van Oijen MG, et al. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart. 2013 Apr;99(8):520-7.
Ford AC, Qume M, Moayyedi P, et al. Helicobacter pylori "test & treat" or endoscopy for managing dyspepsia: an individual patient data meta-analysis. Gastroenterology. 2005 Jun;128(7):1838-44 & ACP Journal Club.
Freedberg DE, Salmasian H, Abrams JA, Green RA. Orders for Intravenous Proton Pump Inhibitors After Implementation of an Electronic Alert. JAMA Intern Med. 2015 Jan 19.
Frelinger AL 3rd, Lee RD, Mulford DJ, et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics
and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012 Apr 3;59(14):1304-11.
Furlanetto Tania Weber; Faulhaber Gustavo Adolpho Moreira. Hypomagnesemia and Proton Pump Inhibitors: Below the Tip of the Iceberg. Arch Intern Med. 2011;0(2011):archinternmed.2011.199.
Gaddam S, Singh M, et al. Persistence of nondysplastic Barrett’s esophagus identifies patients at lower risk for esophageal adenocarcinoma: results from a large multicenter cohort. Gastroenterology 2013;145:548–553.
Galmiche JP, Hatlebakk J, Attwood S, Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: LOTUS randomized clinical trial. JAMA. 2011 May 18;305(19):1969-77.
Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device for gastroesophageal reflux disease. N Engl J Med. 2013 Feb 21;368(8):719-27.
Garbis H, et al. Pregnancy outcome after exposure to ranitidine and other H2-blockers A collaborative study of the European Network of Teratology Information Services. Reprod Toxicol. 2005 Mar-Apr;19(4):453-8.
Garcia Rodriguez LA, Lagergren J, Lindblad M. Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK. Gut. 2006 Nov;55(11):1538-44. Epub 2006 Jun 19.
Gasparini R, Lai PL, Casabona F, et al. Do the omeprazole family compounds exert a protective effect against influenza-like illness? BMC Infect Dis. 2014 Jun 2;14(1):297.
Gatta L, Vaira D, Sorrenti G, et al. Meta-analysis: the efficacy of proton pump inhibitors for laryngeal symptoms attributed to gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2007 Feb 15;25(4):385-92.
Therapy with a high-dose proton pump inhibitor is no more effective than placebo in producing symptomatic improvement or resolution of laryngo-pharyngeal symptoms. Further studies are necessary to identify the characteristics of patients that may respond to proton pump inhibitor therapy.
Gawron AJ, Pandolfino JE, Miskevics S, Lavela SL. Proton Pump Inhibitor Prescriptions and Subsequent Use in US Veterans Diagnosed with Gastroesophageal Reflux Disease. J Gen Intern Med. 2013 Feb 12.
Gee DW, Andreoli MT, Rattner DW. Measuring the effectiveness of laparoscopic antireflux surgery: long-term results. Arch Surg. 2008 May;143(5):482-7. Contrary to the medical literature, our results demonstrate that patients undergoing primary
LF by an experienced surgical team have near-normal GERD-HRQL scores at long-term follow-up and low reoperation rates and are satisfied with their decision to undergo surgery. Results following redo LF are not as good, highlighting the importance of proper patient selection and surgical technique when
performing primary LF.
Ghebremariam YT, Lependu P, Lee JC, et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013 Aug 20;128(8):845-53.
Giannini EG, Zentilin P, Dulbecco P, Vigneri S, Scarlata P, Savarino V. Management strategy for patients with gastroesophageal reflux disease: a comparison between empirical treatment with esomeprazole and
endoscopy-oriented treatment. Am J Gastroenterol. 2008 Feb;103(2):267-75. Early endoscopy for patients with gastroesophageal reflux disease (GERD) without alarm symptoms does not improve symptoms or quality of life, but increases costs. (LOE = 1b)
Gieruszczak-Bialek D, Konarska Z, Skorka A, et al. No Effect of Proton Pump Inhibitors on Crying and Irritability in Infants: Systematic Review of Randomized Controlled Trials. J Pediatr. 2014 Dec 30.
Gill SK, O`Brien L, Einarson TR, et al. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol. 2009 Jun;104(6):1541-5; quiz 1540, 1546. Epub 2009 Apr 28. On the basis of these
results, PPIs are not associated with an increased risk for major congenital birth defects, spontaneous abortions, or preterm delivery. The narrow range of 95% CIs is further reassuring, suggesting that PPIs can be
safely used in pregnancy.
Gillessen A, Beil W, Modlin IM, Gatz G, Hole U. 40 mg pantoprazole and 40 mg esomeprazole are equivalent in the healing of esophageal lesions & relief from gastroesophageal reflux disease-related symptoms. J Clin
Gastroenterol. 2004 Apr;38(4):332-40. (n=227) In patients with gastroesophageal reflux disease, 40 mg pantoprazole daily and 40 mg esomeprazole daily are equally effective for healing of esophageal lesions and relieving gastroesophageal reflux disease-related symptoms.
Gisbert JP, Calvet X, Cosme A, et al. H. pylori Study Group of the Asociación Española de Gastroenterología (Spanish Gastroenterology Association). Long-term follow-up of 1,000 patients
cured of Helicobacter pylori infection following an episode of peptic ulcer bleeding. Am J Gastroenterol. 2012 Aug;107(8):1197-204.
Goldman RD. Bismuth salicylate for diarrhea in children. Can Fam Physician. 2013 Aug;59(8):843-4.
Gomollon F, Calvet X. Optimising acid inhibition treatment. Drugs. 2005;65 Suppl 1:25-33.
Goodman SG, Clare R, Pieper KS, et al. Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor: Insights From the Platelet Inhibition and Patient Outcomes Trial.
(PLATO) Circulation. 2012 Feb 28;125(8):978-986.
Graham DY, Agrawal NM, Campbell DR, et al. NSAID-Associated Gastric Ulcer Prevention Study Group. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind,
randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med. 2002 Jan 28;162(2):169-75.
Gralnek IM, Barkun AN, Bardou M. Management of acute bleeding from a peptic ulcer. N Engl J Med. 2008 Aug 28;359(9):928-37.
Grant AM, Wileman SM, Ramsay CR, Mowat NA, Krukowski ZH, Heading RC, Thursz MR, Campbell MK; REFLUX Trial Group. Minimal access surgery compared with medical management for chronic gastrooesophageal reflux disease: UK collaborative randomised trial. BMJ. 2008 Dec 15;337:a2664. doi: 10.1136/bmj.a2664. At least up to 12 months after surgery, laparoscopic fundoplication significantly increased
measures of health status in patients with GORD.
Grant AM, Cotton SC, Boachie C, et al. Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial
(REFLUX). BMJ 2013;346:f1908.
Grant AM, Boachie C, Cotton SC, et al. Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease: 5-year follow-up of multicentre
randomised trial (the REFLUX trial). Health Technol Assess. 2013 Jun;17(22):1-167.
Guillet R, et al.; National Institute of Child Health and Human Development Neonatal Research Network. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight
infants. Pediatrics. 2006 Feb;117(2):e137-42. Epub 2006 Jan 3.
Haastrup P, Paulsen MS, Begtrup LM, et al. Strategies for discontinuation of proton pump inhibitors: a systematic review. Fam Pract. 2014 Sep 5.
Hashimoto R, Matsuda T, Chonan A. Iron-deficiency anemia caused by a proton pump inhibitor. Intern Med. 2014;53(20):2297-9.
Health Canada Aug/07 is advising consumers that it is currently reviewing new preliminary safety information regarding serious cardiac events in patients using Losec (omeprazole) and Nexium (esomeprazole), two
prescription drugs used to treat acid-related stomach disorders. (Feb 27, 2008 Health Canada Completes Safety Review of Losec (omeprazole) and Nexium (esomeprazole) OTTAWA - Further to its
Information Update dated August 9, 2007, Health Canada is informing Canadians of the results of its review of safety information for Losec (omeprazole) and Nexium (esomeprazole), two prescription drugs used to
treat conditions where a reduction of gastric acid secretion is required, such as ulcers and reflux. In Canada, omeprazole is also sold in generic form as Apo-omeprazole, Ratio-omeprazole and Sandoz-omeprazole.
Esomeprazole is only sold under the trade name Nexium. Nexium (esomeprazole) Based on its review of the data available at this time, Health Canada has concluded that there is no evidence supporting an increased
cardiovascular risk associated with the long-term use of esomeprazole. The Department will continue to monitor safety issues related to esomeprazole by conducting further analysis of ongoing long-term studies as
this data becomes available. Losec (omeprazole) After a thorough analysis, based on the data available to us at this time, we are unable to definitively conclude if there is a potential for increased cardiovascular risk
associated with the long-term use of omeprazole. We will continue to evaluate should more conclusive data become available, and will advise Canadians if any further regulatory actions are required.)
Health Canada Aug/09 Plavix & PPI Interaction http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/advisories-avis/prof/2009/plavix_hpc-cps-eng.pdf
Health Canada Feb/12 is informing Canadians of a possible association between the use of prescription stomach antacids known as proton pump inhibitors (PPIs) and an increased risk of Clostridium difficile-associated
diarrhea (CDAD).
Health Canada Oct/12 is informing Canadians that the labelling for methotrexate and Proton Pump Inhibitors is being updated to include information on a potential interaction between these products.
Health Canada Apr/13 is informing Canadians and Canadian health care professionals of the potential risk of bone fractures associated with the use of drugs known as proton pump inhibitors.
Heidelbaugh JJ, Inadomi JM. Magnitude and Economic Impact of Inappropriate Use of Stress Ulcer Prophylaxis in Non-ICU Hospitalized Patients. Am J Gastroenterol. 2006 Oct;101(10):2200-5. Epub 2006 Sep 4.
Heidelbaugh JJ, Goldberg KL, Inadomi JM.Overutilization of proton pump inhibitors: a review of cost-effectiveness and risk in PPI. Am J Gastroenterol 2009;104:S27-S32.
Herzig Shoshana J.; Vaughn Byron P.; Howell Michael D.; et al. Acid-Suppressive Medication Use and the Risk for Nosocomial Gastrointestinal Tract Bleeding. Arch Intern Med. 2011;0(2011):archinternmed.2011.14.
Herzig SJ, Rothberg MB, Feinbloom DB, et al. Risk Factors for Nosocomial Gastrointestinal Bleeding and Use of Acid-Suppressive Medication in Non-Critically Ill Patients. J Gen Intern Med. 2013 Jan 5.
Herzig SJ, Doughty C, Lahoti S, et al. Acid-Suppressive Medication Use in Acute Stroke and Hospital-Acquired Pneumonia. Ann Neurol. 2014 Aug 28.
Hirano I, Richter JE; Practice Parameters Committee of the American College of Gastroenterology. ACG practice guidelines: esophageal reflux testing. Am J Gastroenterol. 2007 Mar;102(3):668-85.
Ho PM et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009 Mar 4; 301:937.
Holtmann G, et al. A placebo-controlled trial of itopride in functional dyspepsia. N Engl J Med. 2006 Feb 23;354(8):832-40. (InfoPOEMs: Itopride was somewhat effective for functional dyspepsia, with a number needed to treat of 6 for global
improvement but only a small 2-point benefit on a 40-point symptom scale (essentially, an improvement from 12 to 8 with placebo and from 12 to 6 with itopride). The drug appears to be safe on the basis of this small, short study. (LOE = 1b) )
Hooper L, Brown TJ, Elliott R, et al. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs:
systematic review. BMJ. 2004 Oct 23;329(7472):948. Epub 2004 Oct 8. CONCLUSIONS: Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers,
and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology. 2011 Mar;140(3):791-8.
Huang J, Cao Y, Liao C, Wu L, Gao F. Effect of histamine-2-receptor antagonists versus sucralfate on stress ulcer prophylaxis in mechanically ventilated patients: a meta-analysis of 10 randomized controlled trials. Crit
Care. 2010;14(5):R194. Epub 2010 Oct 29.
Hudson N, Taha AS, Russell RI, et al. Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration. Gastroenterology. 1997 Jun;112(6):1817-22.
Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor co-administration. A systematic metaanalysis. J Am Coll Cardiol 2010; 56:134-143.
Hunt R, Fallone C, Veldhuyzan van Zanten S, et al. CHSG 2004 participants. Canadian Helicobacter Study Group Consensus Conference: Update on the management of Helicobacter pylori--an evidence-based evaluation
of six topics relevant to clinical outcomes in patients evaluated for H pylori infection. Can J Gastroenterol. 2004 Sep;18(9):547-54.
Hvid-Jensen F, Pedersen L, Drewes AM, et al. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med 2011;365:1375-83. (Risk only 0.12%)
Hawwa AF, Westwood PM, Collier PS, et al. Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study. Br J Clin Pharmacol. 2012 Sep 28
Jacobson BC, Somers SC, Fuchs CS, Kelly CP, Camargo CA Jr. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med. 2006 Jun 1;354(22):2340-8.
Jacobson BC, Moy B, Colditz GA, Fuchs CS. Postmenopausal hormone use & symptoms of gastroesophageal reflux. Arch Intern Med. 2008 Sep 8;168(16):1798-804. Postmenopausal use of estrogens, selective estrogen
receptor modulators, or OTC hormone preparations is associated with a greater likelihood of symptoms of GERD.
Janarthanan S et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: A meta-analysis. Am J Gastroenterol 2012 Jul; 107:1001.
Jankowski J, Barr H, Wang K, Delaney B. Diagnosis and management of Barrett's oesophagus. BMJ. 2010 Sep 10;341:c4551. doi: 10.1136/bmj.c4551.
Jarbol DE, et al. Proton pump inhibitor or testing for Helicobacter pylori as the first step for patients presenting with dyspepsia? A cluster-randomized trial. Am J Gastroenterol. 2006 Jun;101(6):1200-8. (InfoPOEMs:
A test-and-treat strategy is the most cost-effective approach to dyspepsia in the primary care setting. (LOE = 1b) )
Jaspers Focks J, Brouwer MA, van Oijen MG, et al. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart. 2012 Jul 31.
Johansen ME, Huerta TR, Richardson CR. National use of proton pump inhibitors from 2007 to 2011. JAMA Intern Med. 2014 Nov 1;174(11):1856-8.
Jones R, Charlton J, Latinovic R, Gulliford MC. Alarm symptoms and identification of non-cancer diagnoses in primary care: cohort study. BMJ. 2009 Aug 13;339:b3094. doi: 10.1136/bmj.b3094. Clinically relevant diagnoses
are made in a high proportion of patients presenting with alarm symptoms. For every four to seven patients evaluated for haematuria, haemoptysis, dysphagia, or rectal bleeding, relevant diagnoses will be identified in one patient within 90 days.
Juurlink DN, Gomes T, Ko D, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180(7). DOI:10.1503/cmaj.082001.
Kahrilas PJ, Shaheen NJ, Vaezi MF; American Gastroenterological Association Institute; Clinical Practice and Quality Management Committee. AGA Institute technical review on the management of gastroesophageal
reflux disease. Gastroenterology. 2008 Oct;135(4):1392-1413, 1413.e1-5. Epub 2008 Sep 16.http://download.journals.elsevierhealth.com/pdfs/journals/0016-5085/PIIS0016508508016065.pdf
Kahrilas PJ. Clinical practice. Gastroesophageal reflux disease. N Engl J Med. 2008 Oct 16;359(16):1700-7.
Kahrilas PJ, Howden CW, Hughes N. Response of regurgitation to proton pump inhibitor therapy in clinical trials of gastroesophageal reflux disease. Am J Gastroenterol. 2011 Aug;106(8):1419-25.
Kahrilas PJ, Howden CW, Hughes N, et al. Response of chronic cough to acid-suppressive therapy in patients with gastroesophageal reflux disease. Chest. 2013 Mar;143(3):605-12.
Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med. 2006 May 8;166(9):965-71. Neither tobacco nor
alcohol cessation was associated with improvement in esophageal pH profiles or symptoms (evidence B). Head of bed elevation and left lateral decubitus position improved the overall time that the esophageal pH
was less than 4.0 (evidence B). Weight loss improved pH profiles and symptoms (evidence B). Weight loss and head of bed elevation are effective lifestyle interventions for GERD. There is no evidence supporting
an improvement in GERD measures after cessation of tobacco, alcohol, or other dietary interventions. (InfoPOEMs: Decreasing gastroesophageal reflux disease (GERD) symptoms with lifestyle changes requires an
empirical approach; the research literature gives very little guidance regarding nondrug approaches. Neither smoking cessation, alcohol avoidance, nor any food avoidances have been shown to make, on average, a
difference in symptoms, although existing studies are small and of poor quality. Elevating the head of the bed may be effective. Weight loss may also be effective. Of course, if patients find something that works,
encourage them to continue doing it. (LOE = 3a-) )
Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease. BMC Gastroenterol. 2010 Jan 18;10:7.
Kapoor N, Bassi A, Sturgess R, Bodger K. Predictive value of alarm features in a rapid access upper gastrointestinal cancer service. Gut 2005; 54:40-5.
Katz PO, Gerson LB, Vela MF. ACG-Guidelines for the diagnosis and management of gastroesophageal reflux disease (GERD). Am J Gastroenterol. 2012 Mar;108(3):308-28.
Kekilli M, Tanoglu A, Ocal S, et al. Rabeprazole-Induced Tinnitus. Ann Pharmacother. 2014 Jun 10;48(7):943.
Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003244. PPI therapy is the most effective
therapy in oesophagitis but H2RA therapy is also superior to placebo. There is a paucity of evidence on prokinetic therapy but no evidence that it is superior to placebo.
Kiljander TO, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2006 May 15;173(10):1091-7. Epub 2005 Dec 15. (InfoPOEMs: In this study,
esomeprazole (Nexium) was no better than placebo in improving peak expiratory flow, asthma symptoms, or quality of life in patients with stable asthma. Furthermore, esomeprazole was no better than placebo in patients with reflux, either. (LOE = 2b-) )
Kiljander TO, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2006 May 15;173(10):1091-7. Epub 2005 Dec 15. Esomeprazole improved PEF in
subjects with asthma who presented with both GERD and nocturnal respiratory symptoms (NOC). In subjects without both GERD and NOC, no improvement could be detected. N=770 16weeks
Kinoshita Y, Hongo M. Efficacy of Twice-Daily Rabeprazole for Reflux Esophagitis Patients Refractory to Standard Once-Daily Administration of PPI: The Japan-Based TWICE Study. Am J Gastroenterol. 2012Mar20.
Klassen S, Krepinsky JC, Prebtani AP. Pantoprazole-induced acute interstitial nephritis. CMAJ. 2013 Jan 8;185(1):56-9.
Klok RM, Postma MJ, van Hout BA, Brouwers JR. Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use. Aliment Pharmacol Ther. 2003 May 15;17(10):1237-45. (InfoPOEMs: There is no
significant difference between equivalent doses of proton pump inhibitors, including equivalent doses of esomeprazole (Nexium) and omeprazole (Prilosec OTC). The decision to choose one over another should be based first on cost and second
on individual patient response. (LOE = 1a) )
Koek GH, Sifrim D, Lerut T, et al. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut. 2003 Oct;52(10):1397-402.
Krishnan K, et al. Increased Risk for Persistent Intestinal Metaplasia in Patients With Barrett's Esophagus and Uncontrolled Reflux Exposure Before Radiofrequency Ablation. Gastroenterology. 2012 Sep;143(3):576-81.
Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile Infection With Acid Suppressing Drugs and Antibiotics: Meta-Analysis. Am J Gastroenterol. 2012 Apr 24.
Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002 Jun 27;346(26):2033-8.
Lai KC, Chu KM, Hui WM, et al. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J Med. 2005 Nov;118(11):1271-8. CONCLUSIONS: Celecoxib was as effective as
lansoprazole co-therapy in the prevention of recurrences of ulcer complications in subjects with a history of NSAID-related complicated peptic ulcers. However, celecoxib, similar to lansoprazole co-therapy, was still associated with a significant proportion of ulcer
complication recurrences. In addition, more patients receiving celecoxib developed dyspepsia than patients receiving lansoprazole and naproxen.
Laine L, Shah A, Bemanian S. Intragastric pH With Oral vs Intravenous Bolus Plus Infusion Proton Pump Inhibitor Therapy in Patients With Bleeding Ulcers. Gastroenterology. 2008 Mar 10. [Epub ahead of print]
Frequent oral PPI may be able to replace the currently recommended intravenous bolus plus infusion PPI {intravenous lansoprazole (90-mg bolus followed by 9-mg/h infusion) or oral lansoprazole (120-mg bolus followed by 30 mg every 3 hours)}therapy in patients with
bleeding ulcers, although the possibility that intravenous PPIs are superior cannot be definitively excluded given our relatively wide confidence intervals. Intravenous PPI provides more rapid increase in pH, reaching mean pH of 6 approximately 1 hour sooner than oral PPI.
Laine L. Proton pump inhibitors and bone fractures? Am J Gastroenterol 2009;104:S21-S26.
Laine L, Kivitz AJ, et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol. 2012 Mar;107(3):379-86.
Laine L, Yang H, Chang SC, Datto C. Trends for Incidence of Hospitalization and Death Due to GI Complications in the United States From 2001 to 2009. Am J Gastroenterol. 2012 Aug;107(8):1190-5.
Laine L, Jensen DM. Management of patients with ulcer bleeding. (ACG) Am J Gastroenterol 2012 Mar;107(3):345-60.
Laine L.NSAID-associated gastrointestinal bleeding: Assessing the role of concomitant medications. Gastroenterology 2014 Oct; 147:730.
Lam JR, Schneider JL, Zhao W, et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013 Dec 11;310(22):2435-42.
Langtry HD, Wilde MI. Lansoprazole: An update of its pharmacological properties and clinical efficacy in the management of acid-related disorders. Drugs 1997;54(3):473-500.
Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009
Mar;104(3):728-38. Epub 2009 Feb 24.
Lau JY, Sung JJ, Lee KK, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers.N Engl J Med. 2000 Aug 3;343(5):310-6.
Lau JY, Leung WK, Wu JC, et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med. 2007 Apr 19;356(16):1631-40. Infusion of high-dose omeprazole before endoscopy accelerated the resolution of
signs of bleeding in ulcers and reduced the need for endoscopic therapy. (InfoPOEMs: An overnight infusion of omeprazole prior to endoscopy in patients with acute upper GI hemorrhage reduces the need for intervention and speeds discharge from the hospital. (LOE = 1b))
Lau JY, Barkun A, Fan DM, et al. Challenges in the management of acute peptic ulcer bleeding. Lancet. 2013 Jun 8;381(9882):2033-43.
Law R, Maltepe C, Bozzo P, Einarson A. Treatment of heartburn and acid reflux associated with nausea and vomiting during pregnancy. Can Fam Physician. 2010 Feb;56(2):143-4.
Lee SJ, Shin DH, Hwang HJ et al. Bleeding Risk and Major Adverse Events in Patients With Previous Ulcer on Oral Anticoagulation Therapy. Am J Cardiol. 2012 Apr 18.
Lee TJ, Fennerty MB, Howden CW. Systematic review: Is there excessive use of proton pump inhibitors in gastro-oesophageal reflux disease? Aliment Pharmacol Ther. 2004 Dec;20(11-12):1241-51.
Leontiadis GI, Sharma VK, Dr. Howden CW. Proton pump inhibitor for acute peptic ulcer bleeding. The Cochrane Database of Systematic Reviews 2006, Issue 1.
Leung WK, et al. Initial treatment with lansoprazole in young dyspeptic patients with negative urea breath test result: a randomized controlled trial with 12-month follow-up. Am J Gastroenterol. 2007 Jul;102(7):1483-8.
Lansoprazole is not effective in the initial management of young dyspeptic patients without H. pylori infection.
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Am J Gastroenterol 2005; 100:784-91. (InfoPOEMs: A cutoff age of over 35 years old for men and 56 years old for women would detect more upper gastrointestinal cancers among patients with uncomplicated dyspepsia than a
single cutoff of 45 years for both sexes. Presumably the cost of more endoscopies among younger men would be balanced by the need to do fewer among women aged 45 to 56 years. However, whether this sort of differential
sex-based screening is politically possible is another matter. (LOE = 1b))
Martín Merino E, Johansson S, Nagy P, García Rodríguez LA. Effect of Baseline Gastrointestinal Risk and Use of Proton Pump Inhibitors on Frequency of Discontinuation of Aspirin for Secondary Cardiovascular
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There is insufficient evidence for concluding superiority, inferiority or equivalence of high dose PPI treatment over lower doses in peptic ulcer bleeding.
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patients (11%) developed new or increased diarrhea and 27 patients (9%) developed bloating postoperatively. One hundred nineteen patients (41%) were taking some form of antacid medication; 66 (23%) patients were using PPIs and 10 (3%) had undergone reoperation. LARS provides
effective long-term relief of GERD. Younger patients, men, and those without dysphagia are predictors of superior outcomes.
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of 17 studies, we can conclude that on-demand therapy with currently available PPI appears to be effective in the long-term management of patients with NERD or mild and uninvestigated forms of GERD, but not
in patients with (severe) erosive oesophagitis.
Pasternak Björn, Hviid Anders, Use of Proton-Pump Inhibitors in Early Pregnancy and the Risk of Birth Defects. N Engl J Med 2010; 363:2114-2123. In this large cohort, exposure to PPIs during the first trimester of pregnancy was not
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Pharmacist’s Letter Feb 2007. PPI and risk of hip fracture.
Pharmacist’s Letter Mar 2007. Update on PPIs.
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study confirms many other study results (all nicely summarized in Aliment Pharmacol Ther 2003;17:1237-1245) that have found no clinically important differences between proton pump inhibitors. Begin with
omeprazole 20 mg per day and, if necessary, increase to 40 mg per day before switching to a much more expensive nongeneric alternative. (LOE = 1b))
Reid M, Keniston A, Heller JC, Miller M, Medvedev S, Albert RK. Inappropriate prescribing of proton pump inhibitors in hospitalized patients. J Hosp Med. 2012 May-Jun;7(5):421-5.
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This study has confirmed the link between ECL cell hyperplasia and elevated serum gastrin concentrations, but has found no evidence that this progresses to high grades of hyperplasia during 5 years of treatment with rabeprazole or omeprazole.
Rissling O, Glander P, Hambach P, et al. No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study. Br J Clin Pharmacol. 2015 Apr 24.
Rodgers C, van Zanten SV. A meta-analysis of the success rate of Helicobacter pylori therapy in Canada. Can J Gastroenterol. 2007 May;21(5):295-300. Both triple therapies consisting of a proton pump inhibitor (PPI), clarithromycin and either
amoxicillin or metronidazole performed well, achieving a success rate of 84% and 82%, respectively. The cure rate of PPI-amoxicillin + metronidazole was 76%. Quadruple therapy consisting of a PPI, bismuth, metronidazole and tetracycline, given for seven to 10 days, achieved a success
rate of 87%.
Rohss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastrooesophageal reflux symptoms. Eur J Clin Pharmacol. 2004 Oct;60(8):531-9. Epub 2004 Sep 2.
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Rosen R, Hu L, Amirault J, et. al. 16S Community Profiling Identifies Proton Pump Inhibitor Related Differences in Gastric, Lung, and Oropharyngeal Microflora. J Pediatr. 2015 Feb 4. pii: S0022-3476(14)01236-0.
RxFiles Jan/09 PPIs May Reduce Effectiveness Of Clopidogrel
Sachar H, Vaidya K, Laine L. Intermittent vs Continuous Proton Pump Inhibitor Therapy for High-Risk Bleeding Ulcers: A Systematic Review and Meta-analysis. JAMA Intern Med. 2014 Sep 8.
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complications may exist when laparoscopic surgery is used to correct perforated peptic ulcer. However, it is necessary to develop more randomised controlled trials that include a greater number of patients to confirm such an
assumption, guaranteeing a long learning curve for participating surgeons. With the information provided by the available clinical trials it could be said that laparoscopic surgery results are not clinically different from those of open surgery.
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Shaheen N, Ransohoff DF. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: clinical applications. JAMA. 2002 Apr 17;287(15):1982-6.
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Siple JF, Morey JM, Gutman TE, et al. Proton Pump Inhibitor Use and Association with Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites (October). Ann Pharmacother. 2012 Oct 2.
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Song H, Zhu J, Lu D. Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. Cochrane Database Syst Rev. 2014 Dec 2;12:CD010623. There is presently no clear evidence that
the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing
either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain.
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endoscopic therapy during index endoscopy. However, there is no evidence that PPI treatment affects clinically important outcomes, namely mortality, rebleeding or need for surgery.
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Stretta Procedure for GERD. Medical Letter Dec 4/18,2006
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Sung JJ, Barkun A, Kuipers EJ,et al.; for the Peptic Ulcer Bleed Study Group*. Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized Trial. Ann Intern Med. 2009 Feb 16. [Epub
ahead of print] High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical
benefits for up to 30 days.
Sung JJ, Suen BY, Wu JC, et al. Effects of Intravenous and Oral Esomeprazole in the Prevention of Recurrent Bleeding from Peptic Ulcers after Endoscopic Therapy. Am J Gastroenterol. 2014 Apr 29.
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Pantoprazole was associated with significantly higher rates of complete control of GORD symptoms than ranitidine at four weeks (40% v 19%; P < 0.001), eight weeks (55% v 33%; P < 0.001), six months (71% v
56%; P = 0.007) and 12 months (77% v 59%; P = 0.001). CONCLUSIONS: Low-dose pantoprazole is an effective alternative to standard-dose ranitidine for initial and maintenance treatment of patients with
symptomatic GORD.
Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology. 2005 Nov;129(5):1756-80. (Talley NJ; American Gastroenterological
Association. AGA medical position statement: evaluation of dyspepsia. Gastroenterology. 2005 Nov;129(5):1753-5.) Talley NJ, Vakil N; Practice Parameters Committee of
the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterol. 2005 Oct;100(10):2324-37. (InfoPOEMs: Patients with dyspepsia may have gastroesophageal reflux
disease (GERD), peptic ulcer, functional (nonulcer) dyspepsia, or (rarely) malignancy. The authors reviewed the world's literature and based their recommendations on the results of the best available evidence. Patients with the onset of dyspepsia at age 56 or older or those with alarm
symptoms (bleeding, anemia, early satiety, unexplained weight loss, dysphagia or odynophagia, persistent vomiting, family history of gastrointestinal malignancy, previous documented peptic ulcer, abdominal mass, or lymphadenopathy) at any age should undergo immediate upper
endoscopy. Patients with reflux predominant symptoms should be treated as if they have GERD. If the prevalence of Helicobacter pylori (HP) infection in your community is less than 10%, a trial of a proton pump inhibitor (PPI) is recommended. If that fails, a test for HP infection followed by
eradication if positive should be pursued. When HP is more common, the test-and-treat strategy should be pursued first, followed by a trial of a PPI. If these strategies fail, upper endoscopy should be considered according to the clinician's judgment. However, the prevalence of ulcer or
malignancy in HP- negative patients is quite low in this group. )
Tang RS, Chan FK. Therapeutic management of recurrent peptic ulcer disease. Drugs. 2012 Aug 20;72(12):1605-16.
Targownik LE, Leslie WD, Davison KS, et al. CaMos Research Group. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based from the Canadian
Multicentre Osteoporosis Study (CaMos). Am J Gastroenterol. 2012 Sep;107(9):1361-9.
Tasaka CL, Burg C, et al. An interprofessional approach to reducing the overutilization of stress ulcer prophylaxis in adult medical and surgical intensive care units. Ann Pharmacother. 2014 Apr;48(4):462-9.
Terrin G et al. Ranitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal Outcome in Newborns. Pediatrics. 2011 Dec 12.
Thakkar K, Boatright RO, Gilger MA, et al. Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics. 2010 Apr;125(4):e925-30. Epub 2010 Mar 29.
Thjodleifsson B, Rindi G, Fiocca R, et al.; Tofts RPH, Ferrer G, Oliveira E. How should one investigate a chronic cough? Cleveland Clinic Journal of Medicine 2011; 78(2):84-85, 89; doi:10.3949/ccjm.77a.10033.
Thomas T, Abrams KR, De Caestecker JS, Robinson RJ. Meta analysis: cancer risk in Barrett's oesophagus. Aliment Pharmacol Ther 2007;26(11-12):1465-1477. Approximately 7 per 1000 (0.7%) patients with Barrett's esophagus will develop
esophageal cancer per year. The low incidence of Barrett's, followed by this low incidence of esophageal cancer, may make routine evaluation of patients with chronic gastroesophageal reflux less important. (LOE = 1b-)
Tighe M, Afzal NA, Bevan A, et al. Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database Syst Rev. 2014 Nov 24;11:CD008550. Moderate evidence was found to support the use of PPIs, along
with some evidence to support the use of H antagonists in older children with GORD, based on improvement in symptom scores, pH indices and endoscopic/histological appearances. However, lack of independent placebo-controlled and head-to-head trials makes conclusions as to relative
efficacy difficult to determine. Further RCTs are recommended. No robust RCT evidence is available to support the use of domperidone, and further studies on prokinetics are recommended, including assessments of erythromycin. Pharmacological treatment of infants with reflux symptoms is
problematic, as many infants have GOR, and little correlation has been noted between reported symptoms and endoscopic and pH findings. Better evidence has been found to support the use of PPIs in infants with GORD, but heterogeneity in outcomes and in study design impairs
interpretation of placebo-controlled data regarding efficacy. Some evidence is available to support the use of Gaviscon Infant® , but further studies with longer follow-up times are recommended. Studies of omeprazole and lansoprazole in infants with functional GOR have demonstrated
variable benefit, probably because of differences in inclusion criteria. No robust RCT evidence has been found regarding treatment of preterm babies with GOR/GORD or children with neurodisabilities. Initiation of RCTs with common endpoints is recommended, given the frequency of
treatment and the use of multiple antireflux agents in these children.
Tleyjeh IM, Abdulhak AA, Riaz M, et al. The Association between Histamine 2 Receptor Antagonist Use and Clostridium difficile Infection: A Systematic Review and Meta-analysis. PLoS One. 2013;8(3):e56498.
Tolia V, Boyer K. Long-Term Proton Pump Inhibitor Use in Children: A Retrospective Review of Safety.Dig Dis Sci. 2008 Feb;53(2):385-393. Epub 2007 Aug 4. Long-term proton pump inhibitor (PPI) therapy (median
treatment duration = 35.2 months) appears to be safe for children. Serum gastrin levels remained elevated in nearly 75% of children, but there was no evidence of an increased risk of carcinoid tumor, abnormal vitamin B12 absorption, or any other concerning outcome. (LOE = 1b-)
Torpy JM, Lynm C, Golub RM. JAMA patient page. Peptic ulcer disease. JAMA. 2012 Mar 28;307(12):1329.
Treatment Guidelines: Drugs for Peptic Ulcers & GERD. The Medical Letter: February, 2004; 2(18) pp. 9-12. Updated August 2008. Updated Sep 2011. New & Updated Apr 2014.
Trikudanathan G, Israel J, Cappa J, O'Sullivan DM. Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients – a systematic review and meta-analysis. Int J Clin Pract. 2011
Jun;65(6):674-8.
Tsai JJ, Hsu YC, Perng CL, Lin HJ. Oral or intravenous proton pump inhibitor in patients with peptic ulcer bleeding after successful endoscopic epinephrine injection. Br J Clin Pharmacol. 2009 Mar;67(3):326-32. Epub
2008 Dec 10. Oral rabeprazole and i.v. regular-dose omeprazole are equally effective in preventing rebleeding in patients with high-risk bleeding peptic ulcers after successful endoscopic injection with epinephrine.
Tsoi KKF et al. Meta-analysis: Comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther 2013 Aug 5; [e-pub ahead of print].
Vaezi MF, Hagaman DD, Slaughter JC, et al. Proton pump inhibitor therapy improves symptoms in postnasal drainage. Gastroenterology. 2010 Dec;139(6):1887-1893.
Vakil N, Moayyedi P, et al. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. Gastroenterology. 2006 Aug;131(2):390-401; quiz 659-60.
Valle PC, et al. "Test, score and scope": a selection strategy for safe reduction of upper gastrointestinal endoscopies in young dyspeptic patients referred from primary care. Scand J Gastroenterol. 2006 Feb;41(2):161-9.
(InfoPOEMs: For men younger than 45 years, the endoscopic yield is very low for those without Helicobacter pylori infection, nonsteroidal anti-inflammatory drug (NSAID) use, unintended weight loss, or anemia. (LOE = 2b) )
van der Pol, Rachel J., Smits, Marije J., van Wijk, Michiel P., et al. Efficacy of Proton-Pump Inhibitors in Children With Gastroesophageal Reflux Disease: A Systematic Review. Pediatrics 2011 0: peds.2010-2719
van der Pol RJ, Smits MJ, Venmans L, et al. Diagnostic Accuracy of Tests in Pediatric Gastroesophageal Reflux Disease. J Pediatr. 2012 Dec 7.
van der Pol R, Langendam M, Benninga M, et al. Efficacy and Safety of Histamine-2 Receptor Antagonists. JAMA Pediatr. 2014 Aug 18. Evidence to support the efficacy and safety of H2RAs in infants and children
is limited and of poor quality.
van Marrewijk CJ, Mujakovic S, Fransen GA, et al. Effect and cost-effectiveness of step-up versus step-down treatment with antacids, H(2)-receptor antagonists, and proton pump inhibitors in patients with new onset
dyspepsia (DIAMOND study): a primary-care-based randomised controlled trial. Lancet. 2009 Jan 17;373(9659):215-225. Although treatment success with either step-up or step-down treatment is similar, the
step-up strategy is more cost effective at 6 months for initial treatment of patients with new onset dyspeptic symptoms in primary care.
van Pinxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative
reflux disease. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD002095.
Vazquez-Elizondo G, Ngamruengphong S, et al. The outcome of patients with oesophageal eosinophilic infiltration after an eight-week trial of a proton pump inhibitor. Aliment Pharmacol Ther. 2013 Nov;38(10):1312-9.
Veldhuyzen van Zanten SJ, Chiba N, Armstrong D, et al. A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in Helicobacter pylori negative, primary care patients with dyspepsia: The CADET-HN
study. Am J Gastroenterol 2005; 100:1477-88. (InfoPOEMs: Omeprazole (and to a lesser extent, ranitidine) are somewhat effective for patients with Helicobacter pylori (HP) negative dyspepsia, even if patients with a primary complaint of heartburn or reflux
are excluded.
Verhoef TI, Zuurhout MJ, van Schie RM, et al. The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon. Br J Clin Pharmacol. 2012 Apr 12.
Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11-21.
Vita R et al. Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab 2014 Dec; 99:4481.
Wallace JL, Syer S, Denou E, et al. Proton Pump Inhibitors Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis. Gastroenterology. 2011 Jul 13.
Wang KK, Sampliner RE, Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 2008;103:788-97. (Americian College of Gastroenterology)
Wang WH, Huang JQ, Zheng GF, et al. Is proton pump inhibitor testing an effective approach to diagnose gastroesophageal reflux disease in patients with noncardiac chest pain?: a meta-analysis. Arch Intern Med. 2005
Jun 13;165(11):1222-8. CONCLUSION: The use of PPI treatment as a diagnostic test for detecting GERD in patients with NCCP has an acceptable sensitivity and specificity and could be used as an initial approach by primary care
physicians to detect GERD in selected patients with NCCP. (InfoPOEMs: In patients with chest pain known NOT to be cardiac in origin, response to treatment with an stomach-acid reducing proton pump inhibitor will identify most patients with gastroesophageal
reflux (GERD) and can be the first step in explaining the chest pain. (LOE = 1b) )
Wang J, Yang K, Ma B, et al. Intravenous pantoprazole as an adjuvant therapy following successful endoscopic treatment for peptic ulcer bleeding. Can J Gastroenterol. 2009 Apr [cited 2010 May 19];23(4):287-99.
Wang Chih-Hung; Ma Matthew Huei-Ming; Chou Hao-Chang; et al. High-Dose vs Non-High-Dose Proton Pump Inhibitors After Endoscopic Treatment in Patients With Bleeding Peptic Ulcer: A Systematic Review and
Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2010;170(9):751-758. Compared with non–high-dose PPIs, highdose PPIs do not further reduce the rates of rebleeding, surgical intervention, or mortality after
endoscopic treatment in patients with bleeding peptic ulcer.
Warlé-van Herwaarden MF, Koffeman AR, Valkhoff VE, et al. Time-trends in the prescribing of gastroprotective agents to primary care patients initiating low-dose aspirin or non-steroidal anti-inflammatory drugs:
a population based cohort study. Br J Clin Pharmacol. 2015 Mar 16.
Wildschut H, Both MI, Medema S, et al. Medical methods for mid-trimester termination of pregnancy. Cochrane Database Syst Rev. 2011 Jan 19;1:CD005216. (mifepristone and misoprostol)
Wilkerson PM, et al. A poor response to proton pump inhibition is not a contraindication for laparoscopic antireflux surgery for gastro esophageal reflux disease. Surg Endosc. 2005 Sep;19(9):1272-7. Epub 2005 Jul 14.
Wileman SM, McCann S, Grant AM, Krukowski ZH, Bruce J. Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults. Cochrane Database Syst Rev. 2010 Mar 17;3:CD003243.
There is evidence that laparoscopic fundoplication surgery is more effective than medical management for the treatment of GORD at least in the short to medium term. Surgery does carry some risk and whether the benefits of surgery are sustained in the long term
remains uncertain. Treatment decisions for GORD should be based on patient and surgeon preference.
Wilkins T, Khan N, Nabh A et al. Diagnosis and Management of Upper Gastrointestinal Bleeding. Am Fam Physician. 2012 Mar 1;85(5):469-476.
Writing Committee for the American Lung Association Asthma Clinical Research Centers. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA. 2012;307(4):373-381.
PPIs does not improve symptom control in children with asthma.
Yachimski Patrick S.; Farrell Elizabeth A.; Hunt Daniel P.; et al. Proton Pump Inhibitors for Prophylaxis of Nosocomial Upper Gastrointestinal Tract Bleeding: Effect of Standardized Guidelines on Prescribing
Practice. Arch Intern Med. 2010;170(9):779-783.
Yeomans N, Lanas A, Labenz J, van Zanten SV, et al. Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol.
2008 Oct;103(10):2465-73. Epub 2008 Jul 12. Twenty-seven patients (5.4%) in the placebo group developed a gastric or duodenal ulcer during 26 weeks' treatment compared with eight patients (1.6%) in the
esomeprazole group (life-table estimates: 6.2%vs 1.8%; P= 0.0007). Esomeprazole 20 mg once daily reduces the risk of developing gastric and/or duodenal ulcers and symptoms associated with the continuous use
of low-dose aspirin in patients aged > or =60 yr without preexisting gastroduodenal ulcers.
Yu EW, Bauer SR, Bain PA, et al. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011 Jun;124(6):519-26.
Zacny J, Zamakhshary M, Sketris I, et al. Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease
patients. Aliment Pharmacol Ther. 2005 Jun 1;21(11):1299-312. CONCLUSIONS: Intermittent proton pump inhibitor or H2-receptor antagonist therapy is not effective in maintaining control in oesophagitis patients. H2-receptor antagonists are effective
for relief of heartburn episodes. On-demand proton pump inhibitor therapy may work in a proportion of non-erosive gastro-oesophageal reflux disease patients excluded. The benefit did not persist through the next 5 months when patients could use medications as
needed rather than in a scheduled manner. Ranitidine was more cost-effective than omeprazole. It still makes sense to try ranitidine first for these patients, then stepping up to omeprazole if their symptoms are not improved adequately, particularly since this is a benign,
self-limited condition. (LOE = 1b) )
Zimmerman TG. Common questions about barrett esophagus. Am Fam Physician. 2014 Jan 15;89(2):92-8
PPIs & Feeding Tubes:
Detail-Document #241204. PHARMACIST’S LETTER / PRESCRIBER’S LETTER. December 2008 ~ Volume 24 ~ Number 241204.
William NT. Medication administration through enteral feeding tubes. Am J Health-Syst Pharm—Vol 65 Dec 15, 2008; 237-2357.
CSHP – PSN email communication.
Web Sites:
American College of Physicians: ACP Special Report: Understanding and Treating Heartburn http://www.acponline.org/patients_families/pdfs/health/heartburn_report.pdf
National Digestive Diseases Information Clearinghouse: Heartburn, Hiatal Hernia, and GERD http://digestive.niddk.nih.gov/ddiseases/pubs/gerd/index.htm
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Evidence Based Medicine (EBM)………………………………….…………… 1
CARDIOLOGY
5yr CVD Risk Assessment Tool………………………………….…………..… 2
Antihypertensives
ACE Inhibitors & ARBs…...…..……….………...…………..……...… 3
Beta Blockers…...…………………………...………………....……...…4
Calcium Channel Blockers……..…………….……………..…….....…5
Diuretics & Misc. Antihypertensives…...….……………………....…6
Antihypertensives Summary - Guidelines & Trials..………….....…7-10
new Antiplatelets & Antithrombotics: Nomogram for Warfarin & Tips………. 11-12
new
Perioperative Management………….… 13-14
Summary………...….……………..…...…15-16
17-19
Atrial Fibrillation………………...……………………...……...…….……………
new Atrial Fibrillation: Anticoagulation Colour Comparison………………...… 21-22
Heart Failure………………...……………………..……...………….…….…… 23-24
25
Lipid Landmark Trials..……...……………………..……...……….….....………
26
Lipid Lowering Agents.……...……………………….…...………….……………
MI: Post Myocardial Infarction.……....……………………..………..……….. 27
QT Prolongation & Torsades de Pointes..……....……...………………………28
Obesity
Weight Loss: Drugs……………………………………………………… 48
Weight Loss: Herbal Products.……...…...…………………………… 49-50
Thyroid: Hypo & Hyperthyroid Chart……………………………………… 51-52
Women’s: Hirsutism, idiopathic…..……..……...…..…………………………53
GASTROINTESTINAL
new Bowel Preparation for Colonoscopy……...………...…………...…………..…54-55
new Constipation Management with Laxatives……...………...…………...…… 56-59
Crohn’s & Ulcerative Colitis……...………...…………...…………..………... 60-62
GERD & Peptic Ulcer Disease: Evidence & Chart ……..……..……...…… 63-64
H. Pylori ……..……..……...……………….……...…..……..……..……...…… 65
Irritable Bowel Syndrome.……………….……...……….………...……………66
Nausea & Vomiting Management.………...…...……….………...……………67-68
Various OTC (see OTC GI: Dyspepsia, Constipation, Diarrhea)
GENITOURINARY
DERMATOLOGY
Acne Treatment…………..….……..………...…………………………..……… 29-30
Topical Corticosteroids…………..…….……..………...…………………...……31
Various OTC (see OTC Acne, Fungal, Dermatitis, Plantar Warts & Head Lice )
EENT (Eye/Ear/Nose/Throat)
Glaucoma (Topical Treatments).………..………...………….………...……… 32
Intranasal Corticosteroids………..……..….………...………...……………… 33
Various OTC (see OTC Congestion, Cough, Cold & Allergy )
ENDOCRINE & METABOLIC
new
Landmark Outcome Trials: Glycemic Control & Prevention…………… 45
Lipids/ASA/BP…………………………………46
Overview & Approach to Type 2 Diabetes…………………………………… 47
Andropause: Testosterone Replacement…...………...…………...…………34
Diabetes
Anti-hyperglycemic Colour Comparison………………………………35
Anti-hyperglycemic (Hypoglycemics)………………………………… 36-38
39
Glucose: Self-Monitoring Blood Glucose (SMBG) Tips………………
Insulin Pen Delivery Devices……..…………………………………… 40
Insulin Management: Chart & Clinical Tips…………………………41-44
Erectile Dysfunction……...…………….………...……….……...………………69
Sexual Dysfunction……...……………….………...…….……...……………… 70
Urinary Incontinence……….………………….………...………………………71-72
INFECTIOUS DISEASES
Adult Vaccines.……………………………………………….………………….. 73
Antifungals.……………………………..…………………………….……………74-76
Anti-Infectives for Common Infections………………………….…………… 77-78
Anti-Infectives Oral.……………………………………………….…………… 79-80
Hepatitis: B,C.…………………………….………………..………...……………81-84
Human Immunodeficiency Virus (HIV)…….……………..………………… 85-86
Influenza..…….…………………………………………………..……………… 87
Malaria Prophylaxis……..………..…….…………………………………….... 88
Pneumonia: Community Acquired…….......…….………………………..……89
Pneumonia: Fine Severity Risk or CURB-65 or CRB-65….……..…………90
Urinary Tract Infections in Adults...………..……………………………...... 91
Disclaimer/Copyright Statement p.188
MUSCULOSKELETAL & CONNECTIVE TISSUE
Back Pain Treatment Options…………...…….………….………….......…… 92
PSYCHIATRY
Attention Deficit Hyperactivity Disorder.……………….……...………139-140
new Chronic/Acute Pain: Overview of Approach & Tx Considerations............. 93-94
Chronic Non-Cancer Pain (CNCP) .…….…………….…………………………95-96
Gout………………………………………………………….…………………...... 97
NSAIDs & Other Analgesics (see OTC Pain Relief Chart) ………….………98
Opioids ……...……..……………….………………………………….……......... 99
Opioids, Pain Approaches: Acute vs Palliative vs CNCP ……...……..……100-101
new Opioids Tapering & Perioperative Pain Considerations...…………………. 102-103
Osteoporosis ………..……..………………………………………….…….......... 105-106
Pediatric Pain Treatment Considerations………..………………………….…104
Rheumatoid Arthritis: DMARDs .……..……………………..………….……. 107
NEUROLOGY
Alzheimer’s/Dementia ……...……………………..……....………………….… 108-110
111
Anticholinergic Drug List……..……………………..…………….…….…..……
Elderly/Long-Term Care: Pearls for Prescribing.…………….………………112
Essential Tremor & Restless Legs Syndrome…….….………….……………113
Multiple Sclerosis……….………….………………………..…………………… 114
115-116
Migraine: Acute & Prophylaxis……….………….…...……………………….…
new Migraine & Headache: Overview & Management...…….……………......… 117-118
Parkinson’s……….………….………………………..………………………….…119-120
Seizures: Antiepileptics…….………...……………..………………………….…121-122
OBSTETRICS & GYNECOLOGY
new Abnormal Uterine Bleeding………………………………………………… 123-124
Contraception
125-126
Oral Contraceptive …….……....……………..……………………..……
127
Other Hormonal Birth Control ………..…………………..……………
Menopause
Postmenopausal Herbal Therapy………………….……...………….. 128
Postmenopausal Drug Therapy………..………………….……...……129
Peri-Pregnancy Drug Considerations…………….……...………………… 131-132
OVER THE COUNTER (OTC) & HERBAL MEDICATIONS
Cold-fX, Glucosamine & Lakota Herbal Products………….....………………130
OTC Herbal Drug Interactions……...…………………………………………………133-134
Congestion; Cough; Cold; Allergy…………………………………….……...… 135
GI: Dyspepsia, Constipation & Diarrhea; Pain relief……………………...…136
Acne; Fungal; Dermatitis……………………………………………….……...…137
Plantar Warts; Head Lice & Vitamins……………...…………………...…… 138
Disclaimer/Copyright Statement p.188
Anxiety Disorders
Antianxiety Agents..…………….……...………….……………….……141
Benzodiazepines……...……………….……...….……………….……... 142
Bipolar Disorder: Mood Stabilizers………….……...…………………...... 143-144
Depression
Antidepressants……...……………….……...…….……………….…… 145-146
Antidepressant Drug Interactions….…….……………….……...……147
Hypersexuality Treatment Options………….……....……...………............. 148
Schizophrenia: Antipsychotics..……………….…...………………………… 149-150
Sleep Disorders: Sedatives.……………….……...………………….............. 151-152
RESPIRATORY
Asthma & COPD
Pharmacotherapy…..……..……...……………….……...………………153-154
Inhalational Devices.……………….………......…………………….... 155
SMOKING CESSATION
Smoking Cessation Chart…….……………….……...……………………....…156
MISCELLANEOUS
new Approach to Tapering……………………………………....……………….……157-158
Cannabinoids: Overview.……………….……...………….………...…........... 159
Canadian Health Agencies & Regulatory Environment.……...…............. 160
CKD Anemia Landmark Trials…….…….………….……...…………..………….…161-162
Erythropoetin Comparison…….……...……………….……...………………. 163
Iron Replacement…….……...………………………….……...……………..… 164
Phosphate Binder…….……...………………………….……...……………..… 165-166
Palliative Care………….………………..…...…………………..…….............. 167-168
Patient Safety: Medication Issues…...…………………..…......................... 169
RxFiles Program, Academic Detailing Overview……..…......................... 170
Substance Abuse Chart……….………..…...…………………..…................. 171-172
Transplantation Chart…………..…...…………………..…........................... 173-174
INDICES
Newsletters & Q&A's…………..…...…...……………..…............................. 175
Drug, Disease & Trial…………..…...…...……………..…............................ 176-184
Abbreviations & Symbols…………..….....………………..…....................... 185-188
