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METHADONE
MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH
METHADONE
 SYNTHETIC PSEUDOPIPERDINE DEVELOPED
OVER 50 YEARS AGO
 DISTINCTLY DIFFERENT FROM ALKALOID OPIOIDS
(MORPHINE) (CODEINE) AND SYNTHETIC
THEBAINE DERIVATIVES (OXYCODONE)
2
METHADONE
R (L) AND S (D) ENANTIOMER
 R ENANTIOMER BINDS WITH SIMILAR AFFINITY TO
MU RECEPTORS AS MORPHINE (KM 3.5NM AND
1.4NM RESPECTIVELY)
 BOTH R AND S ENANTIOMERS BIND TO NMETHYL-D-ASPARTATE RECEPTORS
 TWICE THE INTRINSIC EFFICACY OF MORPHINE
3
METHADONE
 DELTA OPIOID RECEPTOR AGONIST (R AND S)
 SEROTONIN AND NOREPINEPHRINE REUPTAKE
INHIBITOR (R AND S)
 HIGH DOSES BLOCK POTASSIUM CHANNELS
4
ABSORPTION
 ABSORPTION RAPID AND COMPLETE (47 - 91%)
 DRUG LEVELS CAN BE MEASURED 30 MINUTES
AFTER ORAL DOSING, PEAK CONCENTRATIONS
OCCUR AT 2.5 HOURS
 INTESTINAL CYP3A4 AND P-GLYCOPROTEIN MAY
REDUCE ABSORPTION
 NOT A MAJOR FACTOR IN THE LARGE INTERINDIVIDUAL DIFFERENCES IN KINETICS
5
ABSORPTION
 PKA IS 9.2 (BETTER ABSORBED IN AN ALKALINE
ENVIRONMENT)
 REDUCED ACIDITY (OMEPRAZOLE) INCREASES
ABSORPTION
 NON-SATURABLE KINETICS
 PRESYSTEMIC CLEARANCE (ABSORPTION AND
BIOAVAILABILITY) IS 21%
 UNALTERED BY DIET
6
RECTAL METHADONE
 SIMILAR ABSORPTION AND BIOAVAILABILITY AS
ORAL METHADONE
 MICROENEMAS > HYDROGENATED OIL BASE
SUPPOSITORIES
7
SUBLINGUAL METHADONE
 ABSORPTION IS 34% (51% FENTANYL AND 18%
MORPHINE)
 BUFFERING THE PH TO 8.5 DOUBLES
ABSORPTION (75%)
8
METABOLISM
 BIEXPONENTIAL KINETICS
 EXTRACTION RATIO 0.08 - 0.16
 DEMETHYLATED TO AN INACTIVE METABOLITE
(EDDP) BY CYP3A4
 INDUCTION OF CYP3A4 BY METHADONE WITH
CHRONIC DOSING
9
CYTOCHROME ENZYMES
 CYP3A4 > CYP2D6, CYP1A2, CYP2C9, CYP2C19
 ULTRARAPID METABOLIZERS HAVE HALF THE
METHADONE DRUG LEVELS AS POOR
METABOLIZERS (HOMOZYGOTE CYP2D6
MUTATIONS)
10
METHADONE CLEARANCE
 METHADONE CLEARANCE CAN VARY BETWEEN
INDIVIDUALS 100-FOLD (0.023 - 2.1 LITERS PER
MINUTE) WITH A MEAN OF 0.095 LITERS PER
MINUTE
11
CAUSES OF INTERINDIVIDUAL
DIFFERENCES IN METHADONE
 MU OPIOID RECEPTOR GENETICS
 P-GLYCOPROTEIN ACTIVITY
 CYP3A4 BASAL AND INDUCTION ACTIVITY
 CYP2D6, CYP1A2, CYP2C9, CYP2C19
 GENOTYPE OF ALPHA1 ACID GLYCOPROTEIN
 CO-MEDICATIONS
12
ROUTES
 ORAL
 SUBLINGUAL (1:1)
 RECTAL (1:1)
 SUBCUTANEOUS (2:1)
 INTRAVENOUS (2:1)
13
SAFE COMBINATIONS
 RIFAMBUTIN (FOR RIFAMPICIN)
 FAMOTIDINE (FOR CIMETIDINE)
 MIRTAZAPINE (FOR SSRI)
 HALOPERIDOL OR OLANZAPINE (FOR
RESPERIDONE)
 VALPROIC ACID, GABAPENTIN (FOR
PHENOBARBITOL, PHENYTOIN, CARBAMAZEPINE)
14
METHADONE TOXICITY
 SIMILAR TO OTHER OPIOIDS
 REDUCED CONSTIPATION COMPARED TO
MORPHINE
 TORSADES DE POINTES AND PROLONGED QTC
WITH INCREASED RISK PARTICULAR WITH
PARENTERAL
15
DEATH FROM METHADONE
 MORE COMMON WITH INITIAL THERAPY
 DEATHS AT STEADY STATE ARE RELATED TO:
 INTERFERING CO-MEDICATION
 ILLICIT DRUG TAKING (DIAZEPAM, ALCOHOL, COCAINE,
CANNABIS, OTHER OPIOIDS)
16
METHADONE AND CANCER PAIN
 THE ORIGINAL MANUFACTURER’S
RECOMMENDATION OF 2.5 - 10MG EVERY 3 - 4
HOURS IS EXCESSIVE.
 EQUIANALGESIA TABLES THAT PUT
EQUIVALENTS NEAR UNITY WITH MORPHINE ARE
DANGEROUS.
17
METHADONE AND CANCER PAIN
 METHODS OF OPIOID ROTATION INVOLVE A
“STOP-START” STRATEGY
 A Q 3-HOUR AS NEEDED SCHEDULE
 LINEAR RATIO BASED UPON MORPHINE EQUIVALENTS
EVERY 8 HOURS ATC
18
EQUIVALENTS AND DOSING
 MORPHINE:METHADONE
 4:1 < 90MG MORPHINE DAILY
 8:1 90 - 300MG MORPHINE DAILY
 12:1 300 - 1000MG MORPHINE DAILY
 20:1 > 1000MG MORPHINE DAILY
 DIVIDE DOSE INTO 3 AND GIVE EVERY 8 HOURS
 OPIOID NAÏVE; 3 - 5MG EVERY 8 HOURS OR 7.5MG
EVERY 12 HOURS
19
EQUIVALENTS AND DOSING
 STOP-START
 USE 10% OF TOTAL MORPHINE (OR MORPHINE
EQUIVALENTS) UP TO A SINGLE MAXIMUM DOSE OF 30MG
METHADONE
 DOSE EVERY 3 HOURS AS NEEDED
 STEADY STATE OCCURS AT DAY 4 AND 5
 TOTAL DOSES ON DAY 4 AND 5, DIVIDE BY 4 AND GIVE
EVERY 12 HOURS
20
METHADONE DOSING
 SHOULD BE DONE BY SOMEONE WITH
EXPERIENCE
 DO NOT ADD BENZODIAZEPINES DURING
TITRATION, AVOID ALCOHOL
 USE ACETOMINOPHEN IF PAIN RECURS BEFORE
THREE HOURS
21
EQUIVALENTS WITH OTHER OPIOIDS
 HYDROMORPHONE
 PARENTERAL HYDROMORPHONE TO ORAL METHADONE
1.07 + 0.9
 FENTANYL
 FENTANYL 25µG TO 0.1MG PARENTERAL METHADONE
22
NEUROPATHIC PAIN
 DOSE RATIOS BETWEEN MORPHINE AND
METHADONE ARE NOT DEPENDENT UPON THE
TYPE OF PAIN
GROND S. PAIN 1999
GAGNON B. JPSM 1999
23
CANDIDATES FOR METHADONE
 REFRACTORY PAIN
 PATIENTS ON HIGH DOSE OPIOIDS WITH
BURDENSOME COSTS
 PATIENTS WITH LIMITED FINANCES
 HOSPICES
 NEUROPATHIC PAIN
 CHEAP SUSTAINED RELEASE OPIOID
Ripamonte C. Pain 1997
24
METHADONE
PROS
CONS
1) LACK OF ACTIVE
METABOLITES
1) UNPREDICTABLE AND
LONG HALF-LIFE
2) SAFETY IN ORGAN
FAILURE
2) INTERINDIVIDUAL
VARIABILITY
3) HIGH LIPID SOLUBILITY
3) CHANGING
EQUIANALGESIC
POTENCY WITH DOSE
4) HIGH BIOAVAILABILITY
5) VERSATILITY
6) LOW COST
25
SUMMARY
 METHADONE IS UNIQUE PHARMACOLOGICALLY
 MULITPLE RECEPTOR AGONIST, NMDA
ANTAGONISTS AND MONOAMINE REUPTAKE
INHIBITORS
 RELATIVELY SAFE IN ORGAN FAILURE
 DOSING SCHEMES ARE DIFFERENT THAN WITH
OTHER OPIOIDS
26
27
METHADONE AND CARDIAC
TOXICITY
28
INTRODUCTION
 METHADONE HAS BEEN ASSOCIATED WITH
PROLONGED QTC AND TORSADES DE POINTES
(TDP)
 UNIQUE BLOCK OF IONIC CURRENT THROUGH
SPECIFIC TYPE CARDIAC K+ CHANNELS
 CARDIAC K+ CHANNELS ARE DERIVED FROM
HUMAN ETHER-A-GO-GO-RELATED GENE (HERG)
29
INTRODUCTION
 DELAYED REPOLARIZATION LEADS TO
PROLONGED QTC INTERVALS (>500 MSEC) AND
VENTRICULAR TACHYCARDIA (TDP)
 ALSO INTERLEAD VARIATION BETWEEN QTC
INTERVALS ON SURFACE LEADS
30
31
SUMMARY OF ORAL METHADONE
AND QTc
 METHADONE INCREASES QTC IN 30%
 QTC > 500 MSEC RANGE 0 – 16% (5%)
 POOR CORRELATION WITH DOSE
 MAY BE ASSOCIATION WITH HYPOKALEMIA,
STRUCTURAL HEART DISEASE, LIVER DISEASE
AND DRUGS THAT INHIBIT CYTOCHROMES OR
PROLONG QTC
32
RECOMMENDATIONS
 NO MONITORING FOR LOW RISK INDIVIDUALS
 AT RISK INDIVIDUALS, BASELINE ECG REPEAT IF:
 BASELINE QTC > 430 M SEC
 HIGH DOSE SYMPTOMS (SYNCOPE, PALPITATION, DYSPNEA)
 CO-MEDICATIONS THAT PROLONG QTC
33
MANAGEMENT OF PROLONGED
QTc METHADONE
 DOSE REDUCE, ADD ADJUVANT
 DELETE MEDICATIONS WHICH PROLONG QTC OR
BLOCK CYTOCHROMES
 ROTATE TO MORPHINE OR BUPRENORPHINE OR
FENTANYL
34
IV METHADONE AND QTc
 TOXICITY CAN OCCUR AT LOW DOSES (0.4 MG/H)
 BASELINE ECG AND REPEAT 24 – 72 HOURS
 MONITOR K+
 AVOID DRUGS THAT PROLONG QTC
 OPTIONS IF QTC >500 MSEC




SWITCH TO ORAL METHADONE
DELETE CO-MEDICATIONS THAT PROLONG QTC
DOSE REDUCE/ADD AN ADJUVANT
ROTATE TO MORPHINE, BUPRENORPHINE
35
FDA BLACK BOX WARNING

DEATHS: UNINTENTIONAL OVERDOSE, DRUG
INTERACTIONS, AND CARDIAC TOXICITY (QT
PROLONGATION AND TDP)
 PHYSICIAN’S NEED TO UNDERSTAND TOXICITY
AND UNIQUE METHADONE PROPERTIES
 DOSES SHOULD BE CAREFULLY CHOSEN AND
SLOWLY TITRATED
 CAREFULLY MONITOR WHEN SWITCHING TO
METHADONE AND CHANGING DOSE
36
SUMMARY
 LOW RISK WITH ORAL METHADONE
 AT RISK INDIVIDUALS REQUIRE MONITORING
 RISK GREATER WITH PARENTERAL METHADONE
DUE TO CHLOROBUTANOL
 PARENTERAL METHADONE REQUIRES ROUTINE
ECG MONITORING
 RISK AND BENEFITS OF METHADONE MUST BE
WEIGHED IF NO OTHER TREATMENT OPTIONS
ARE AVAILABLE IN TERMINAL PATIENTS
37
PATIENT CONTROLLED
ANALGESIA (PCA)
MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH
38
BACKGROUND
 CONCEPT
 INTER-INDIVIDUAL VARIABILITY
 OPTIMIZE OPIOID ADMINISTRATION
 IMMEDIATE ACCESS
 ON DEMAND > CONVENTIONAL DOSING
39
PCA MODALITIES
 FIRST PCA PUMP 1976
 MODALITIES
 DEMAND ONLY
 CONTINUOUS INFUSION + DEMAND
 INFUSION RATE BASED ON DEMAND
 VARIABLE RATE
 VARIABLE RATE FEEDBACK
40
PCA SETUP: DRUG CHOICE
 OPIOIDS
 ALL OPIOIDS
 SHORT ACTING ARE SAFER THAN LONG ACTING
 NON-OPIOIDS
 MOST COMPATIBLE WITH OPIOIDS
• ATROPINE, DEXAMETH, DIAZEPAM,
LORAZEPAM, KETEROLAC, HALDOL,
LEVOPROME, METOCHLOPRAMIDE
 PHYENYTOIN IS NOT COMPATIBLE WITH OPIOIDS
41
PCA ROUTES OF DELIVERY
 INTRAVENOUS
 SUBCUTANEOUS
 INTRAMUSCULAR
 ORAL,NASAL,SUBLINGUAL
 SPINAL, VENTRICULAR
 OTHERS...
42
PCA STRATEGY
• LOADING DOSE
•
•
•
•
DEMAND DOSE
LOCKOUT INTERVAL
CONTINUOUS INFUSION
DOSE LIMITS
43
PCA ADVANTAGES
 PATIENT
 REMOVES DELAY DEMAND / DELIVERY
 PATIENT CONTROL / SECURITY
 DETERMINE PAIN THRESHOLDS
 DOSING
 ASSESS ANALGESIC REQUIREMENTS
 INFLUENCES TRADITIONAL DOSING PROTOCOLS
 ADAPTABLE
 INTERINDIVIDUAL REQUIREMENTS
 TEMPORAL PAIN PATTERN
44
PATIENT RISK FACTORS
 AGE
 HEAD INJURY
 SLEEP APNEA
 OBESITY
 RESPIRATORY FAILURE
 BENZODIAZEPINES
 HYPONATREMIA
 RENAL FAILURE
45
COMPLICATIONS
 OPERATOR ERRORS
 PROGRAMMING ERRORS
 ACCIDENTAL BOLUS
 INAPPROPRIATE
DOSE
LOCKOUT
DRUG SELECTION
 SURROGATE ACTIVATION
 PUMP MALFUNCTION
46
PATIENT SELECTION
 AGE = > 5 YRS
 COGNITIVE ABILITY
 UNDERSTAND THE RELATIONSHIPS BETWEEN PAIN,
ACTIVATING THE PUMP, AND GOALS OF PAIN RELIEF
 INTACT MEMORY
 PHYSICAL ABILITY TO ACTIVATE THE BUTTON
 PSYCHOLOGICAL: NEED TO MAINTAIN CONTROL
 EXTREME FEAR OF SIDE EFFECTS
 PRESENCE OF A RELIABLE SURROGATE
47
PCA IN CANCER MAYBE USED IN:
 INCIDENT PAIN
 KIDNEY FAILURE (DEMAND ONLY)
 EXCESSIVE SIDE EFFECTS (N&V, SEDATION)
 INTESTINAL OBSTRUCTION
 IMPAIRED ORAL INTAKE
 CIRCARDIAN VARIATION IN PAIN INTENSITY
 INITIAL TITRATION
48
PCA DOSING (INTRODUCTION)
 LOADING DOSE
 DEMAND DOSING & CONTINUOUS INFUSION(CI)
 A DOSE SHOULD RESULT IN PERCEPTIBLE ANALGESIA
 TITRATION
 LOCKOUT INTERVAL
 PHARMACOKINETICS / DYNAMICS, CNS DWELL TIME
 LONG ENOUGH FOR THE PATIENT TO EXPERIENCE BENEFIT
 LONGER IF CONCOMITTENT CONTINUOUS INFUSION
49
PCA DOSING IN CANCER
 OPIOID NAIVE: 0.5MG/H CI , DEMAND 1MG Q2H
 OPOID TOLERANT: THE HOURLY MORPHINE DOSE
Q2HRS, RARELY Q1HR
 RATIONALE LONG CNS DWELL TIME
 DEMAND DOSE IS TITRATED TO BREAKTHROUGH
PAIN SEVERITY AND DURATION
50
POST-OP DOSING (ON OPIOID)
 MORPHINE LOADING TO EFFECTIVE ANALGESIA:
 2-5MG Q 10 MINUTES
 DEMAND DOSE
 USE 50 -75% OF LOADING DOSE
 CONTINUOUS INFUSION:
 PRE-OPERATIVE DOSE
 >50% PRE-OP DOSE TO AVOID WITHDRAWAL
 HOURLY OPIOID REQUIREMENT:
 75% BY CI
 25% BY DEMAND
51
POST-OP DOSING (OPIOID NAIVE)
PCA OPIOID
DEMAND LOCKOUT
CI
MORPHINE
1-2MG
6-10
0-2MG/H
HYDROMOR
0.2-0.4MG
6-10
0-0.4MG/H
FENTANYL
20-40MCG
5-10
0-60MCG/H
SUFENTANIL
4-6MCG
5-10
0-8MCG/H
TRAMADOL
10-20MG
6-10
0-20MG/H
52
CONCLUSION: PCA IN CANCER
 RARELY STUDIED
 PCA SEEMS USEFUL AND SAFE
 COMPLICATION RATES UNKNOWN
 OPTIMAL DOSING AND LOCKOUT UNKNOWN
53
PERIOPERATIVE
MANAGEMENT OF
CHRONIC PAIN PATIENTS
54
INTRODUCTION

CHRONIC PAIN
 “PAIN WITHOUT APPARENT BIOLOGIC VALUE WHICH
PERSISTS BEYOND NORMAL TISSUE HEALING TIME”
(3 MONTHS)
 PATHOLOGY DOES NOT EXPLAIN PAIN PRESENCE OR
EXTENT
 10-55% IN NORMAL POPULATION
 > 50% IN ADVANCED CANCER
Turk, DC 2001
55
SIGNIFICANCE OF POST-OP PAIN
.
 MODERATE TO SEVERE PAIN IN 20-30%
 CARDIOPULMONARY COMPLICATIONS
 UNEXPECTED ADMISSIONS FROM AMB. SURGERY
 PROLONGED CONVALESCENCE
56
POST-OP PAIN IN OPIOID TOLERANT
 POORER PAIN CONTROL
 INCREASED OPIOID REQUIREMENTS

3X EPIDURAL MORPHINE THAN OPIOID-NAÏVE

4X MORPHINE BY INTERMITTENT BOLUS

POSTOPERATIVE PCA DOSES > REPLACEMENT
57
.
CAUSES OF INCREASED
POSTOPERATIVE PAIN AND OPIOID
REQUIREMENTS IN OPIOIDTOLERANT
.

PROGRESSIVE CANCER

TOLERANCE

OPIOID-INDUCED HYPERALGESIA
 INCREASED PAIN SENSITIVITY
58
DIFFERENCES IN SIDE EFFECTS
BETWEEN OPIOID-NAÏVE AND
TOLERANT INDIVIDUALS
 ↓ NAUSEA & PRURITUS IN OPIOID-TOLERANT
DELEON CASASOLA 1993
RAPP 1995
59
OPTIMIZING PERIOPERATIVE
OPIOIDS USE IN OPIOID-TOLERANT
 MINIMAL EFFECTIVE OPIOID DOSE IS UNKNOWN
 POSTOPERATIVE OPIOID > ANTICIPATED
 ADEQUATE OPIOIDS TO AVOID WITHDRAWAL
 TRANSITION TO PREOPERATIVE OPIOID DOSES
CHALLENGING AND OFTEN DELAYED
60
PLAN PERIOPERATIVE
MANAGEMENT
 EPIDURALS
 REGIONAL BLOCKS
 DISCONTINUE NSAIDS 48 HRS BEFORE EPIDURAL
 OPIOID DOSE MAINTAINED ON DAY OF SURGERY
61
ACUTE POSTOPERATIVE
MANAGEMENT
.
 EXPECT OPIOID REQUIREMENTS 2-4 X NAÏVE
INDIVIDUALS
 START PCA
 ORAL ROUTE: 1.5X PREOPERATIVE ORAL OPIOID
DOSE PLUS DEMAND ONLY FOR RESCUE DOSES
62
ACUTE POSTOPERATIVE
MANAGEMENT
.
 IV ROUTE: CONTINUOUS DOSE TO MATCH
PRE-OP OPIOID REQUIREMENT + DEMAND
 REGIONAL BLOCK: PROVIDE ½ THE PRE-OP
OPIOID DOSE
 ADD ADJUNCT (ACETAMINOPHEN,
KETOROLAC, KETAMINE, GABAPENTIN)
63
MANAGEMENT POSTOPERATIVE
TRANSITION PHASE
 USE OPIOID DOSE DURING FIRST 24-48 HOURS
 DELIVER ½ AS LONG-ACTING OPIOID
 DELIVER ½ AS RESCUE EVERY 3-4 HOURS
 ADD NSAID, ACETAMINOPHEN AND TAPER OPIOID
64
65
PERIOPERATIVE MANAGEMENT OF
ADDICTION: MISCONCEPTIONS
 MAINTENANCE OPIOIDS (BUPRENORPHINE ,
METHADONE) PROVIDES ADEQUATE ANALGESIA
POSTOPERATIVE
 USE OF SHORT ACTING OPIOIDS IN THE
POSTOPERATIVE PERIOD INCREASES RISK OF
ADDICTION RELAPSE
66
PERIOPERATIVE MANAGEMENT OF
ADDICTION: MISCONCEPTIONS
 ADDITIVE EFFECTS OF SHORT ACTING
OPIOIDS WITH MAINTENANCE OPIOIDS
INCREASES RESPIRATORY DEPRESSION
 REPORTING PAIN MAY BE A MANIPULATION
TO OBTAIN OPIOID ANALGESICS OR DRUG
SEEKING
67
ISSUES PARTICULAR TO
ADDICTION
 PSEUDO-ADDICTION:”DRUG SEEKING” DUE TO
INADEQUATELY CONTROLLED PAIN
 THERAPEUTIC DEPENDENCE:”DRUG SEEKING”
OUT OF FEAR OF EMERGENCE OF WITHDRAWAL
 PSEUDO-OPIOID DEPENDENCE:CONTINUED
REPORTS OF PAIN TO PREVENT CURRENTLY
EFFECTIVE DOSES OF OPIOIDS FROM BEING
REDUCED
68
MANAGEMENT
 REASSURANCE THAT ADDICTION DOES NOT
PREVENT PAIN CONTROL
 CONTINUE OPIOID MAINTENANCE IN THE
PERIOPERATIVE PERIOD
 CONFIRM OPIOID TIMING AND DOSE WITH
ADDICTION SPECIALIST
 DISCUSS PAIN MANAGEMENT PLANS W/ PATIENT
69
MANAGEMENT
 SHORT ACTING OPIOIDS TO TREAT PAIN
 REQUIREMENTS MAY BE 3-4 Fold > OPIOID NAÏVE
 MAY REQUIRE SCHEDULED RATHER THAN AS
NEEDED SHORT ACTING OPIOIDS
 DO NOT STOP MAINTENANCE THERAPY
 PCA MAY BE USED BUT SHOULD BE MONITORED
70
MANAGEMENT BUPRENORPHINE
MAINTENANCE
 CONTINUE BUPRENORPHINE AND ADD SHORT
ACTING OPIOIDS
 DIVIDE & GIVE BUPRENORPHINE EVERY 6-8 HRS
 DISCONTINUE BUPRENORPHINE AND USE SHORT
ACTING OPIOIDS VIA CONTINUOUS AND DEMAND
PCA
71
MANAGEMENT BUPRENORPHINE
MAINTENANCE
 CONVERT TO 20-40MG METHADONE DAILY
AND USE SHORT ACTING OPIOIDS FOR PAIN
 CONVERT BACK TO BUPRENORPHINE AT
DISCHARGE
72
REFERENCES

Buvanendran, A. and J. S. Kroin (2007). "Useful adjuvants for postoperative pain management." Best
Pract Res Clin Anaesthesiol 21(1): 31-49.

Carroll, I. R., M. S. Angst, et al. (2004). "Management of perioperative pain in patients chronically
consuming opioids." Reg Anesth Pain Med 29(6): 576-91.

De Leon-Casasola, O. A., D. P. Myers, et al. (1993). "A comparison of postoperative epidural analgesia
between patients with chronic cancer taking high doses of oral opioids versus opioid-naive patients."
Anesth Analg 76(2): 302-7.

Kopf, A., A. Banzhaf, et al. (2005). "Perioperative management of the chronic pain patient." Best Pract
Res Clin Anaesthesiol 19(1): 59-76.

Rapp, S. E., L. B. Ready, et al. (1995). "Acute pain management in patients with prior opioid
consumption: a case-controlled retrospective review." Pain 61(2): 195-201.

Rapp, S. E., L. B. Ready, et al. (1995). "Acute pain management in patients with prior opioid
consumption: a case-controlled retrospective review." Pain 61(2): 195-201.

Tiippana, E. M., K. Hamunen, et al. (2007). "Do surgical patients benefit from perioperative
gabapentin/pregabalin? A systematic review of efficacy and safety." Anesth Analg 104(6): 1545-56.
73
CASE 1
• 48 YEAR OLD FEMALE WITH OVARIAN CANCER
AND TOXICITY AS WELL AS FOR RESPONSE TO
MORPHINE SR 60MG TWICE DAILY FOR
ABDOMINAL PAIN
• PHYSICAL EXAMINATION DEMONSTRATES
WASTING, ASCITES ,PERIUMBILICAL NODES
• MEDICATIONS:SERTRALINE 50MG,
METOPROLOL 25MG TWICE DAILY AND ORAL
STOOL SOFTENERS
74
CASE 1
• ECG QTC 450MSEC
• LABORATORY:CREATININE 1.8, NORMAL
BILIRUBIN
75
CASE 1:TREATMENT
• METHADONE SHOULD NOT BE STARTED DUE TO
THE QTC INTERVAL
• METHADONE SHOULD NOT BE USED DUE TO
INTERACTIONS WITH SERTRALINE
• METHADONE SHOULD NOT BE STARTED DUE TO
THE CREATININE
• “STOP-START” STRATEGY MAY BE USED WITH
STOPPING MORPHINE AND STARTING
METHADONE 10MG EVERY 3 HOURS AS NEEDED
76
CASE 1
• YOU START METHADONE EVERY 3 HOURS AS
NEEDED
• 6 DAYS LATER SHE IS TAKING 20MG PER DAY ON
AVERAGE WITH PAIN CONTROL.
• SHE IS DISCHARGED HOME ON METHADONE
10MG TWICE DAILY AND EVERY 3 HOURS AS
NEEDED
• TWO WEEKS LATER SHE IS ADMITTED WITH
NAUSEA AND VOMITING AND IS UNABLE TO
TAKE HER ORAL MEDICATIONS.
77
CASE 1
• REPEAT ECG QTC 460 MSEC
• IV HYDRATION IS STARTED
78
CASE 1:TREATMENT
• STOP METHADONE AND START FENTANYL OR
BUPRENORPHINE
• START METHADONE IV AT 0.5MG PER HOUR WITH 0.51MG EVERY 3 HOURS, REPEAT ECG IN 2-3 DAYS
• SWITCH TO RECTAL METHADONE 10MG EVERY 12
HOURS AND AS NEEDED
• START HALOPERIDOL FOR NAUSEA AND OBTAIN A
PLAIN X-RAY OF THE ABDOMEN
• START ONDANSETRON FOR NAUSEA AND OBTAIN A
PLAIN X-RAY OF THE ABDOMEN
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CASE 2
• 65 YEAR OLD FEMALE WITH BREAST CANCER
ON 40MG METHADONE TWICE DAILY FOR BONE
PAIN
• SHE SUSTAINS A PATHOLOGIC HIP FRACTURE
REQUIRING SURGERY
• MEDICATIONS: METHADONE , TEMAZEPAM 15MG
AT NIGHT, PRINIVIL 20MG DAILY AND LAXATIVES
• LABORATORY: NORMAL CREATININE AND
BILIRUBIN
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CASE 2 :TREATMENT
• DISCONTINUE METHADONE ON THE DAY OF SURGERY
AND USE AS NEEDED HYDROMORPHONE 2MG
HOURLY AS NEEDED
• USE METHADONE 7.5MG EVERY 3 HOURS AS NEEDED
FOR PAIN FOR POST- OP PAIN
• CONTINUE METHADONE 40MG TWICE DAILY IN THE
POST- OP PERIOD AND USE HYDROMORPHONE 0.81MG EVERY 1-2 HOURS AS NEEDED BY PCA
• START KETOROLAC 15MG IV Q 6 HOURS POST- OP
AND CONTINUE METHADONE 40MG TWICE DAILY
• AVOID COMBINING SHORT ACTING POTENT OPIOIDS
AND METHADONE. USE TRAMADOL100MG EVERY 6
HOURS WITH METHADONE
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