Download Opioids and respiratory depression

Structure
•
•
•
•
•
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Epidemiology /Context
Deaths from methadone
Metabolism and risks with other drugs
Respiratory depression with opioids
Hepatitis C
Cardiac problems
Numbers of opiate users /OCU by age
group Cumbria (2011-2012 estimates)
Opiate
OCU
15-24
223
243
25-34
1,183
1,433
35-64
1,271
1,262
Centre for Public Health,
Liverpool John Moores
University (Hay, 2014)
Rate per 1000 estimate of opiate users
by age group (2011-2012 estimates)
15-24
Cumbria
4.00
Manchester
2.63
North West
2.58
ENGLAND
3.60
25-34
16.84
11.58
13.25
13.35
35-64
6.00
17.64
9.91
6.48
In Unity, for those prescribed
Mean =40 SD =8, normal distribution
Rates per 1000 estimate of drug users
15-64 population (2011-2012 estimates)
OCU
Opiate Crack
Cumbria
7.48
7.40
1.35
Manchester 12.97
11.65
9.46
North West
9.99
9.07
5.47
ENGLAND
8.40
7.32
4.76
Injecting
3.59
4.12
2.83
2.49
Cost drug use
UK Focal Point On Drugs Annual Report to the European Monitoring Centre for Drugs and Drug Addiction
Clients (n=4817 ) aged 11–65 years who
sought treatment for drug use (Helsinki)
Primary
Drug
Alive (n=
4321)
Alive %
Dead
(n= 496)
Dead %
Total (n=
4817)
Total %
Dead/
Total %
Alcohol
930
22
74
15
1004
21
7.4
Cannabis
Prescriptio
n medicines
825
19
69
14
894
19
7.7
79
2
17
3
96
2
18
Opiates
1290
30
142
29*
1432
30
9.9**
Stimulants
1146
27
188
38
1334
28
14
51
1
6
1
57
1
11
Others
* For example 142/496 *100 = 29
** For example 142/1432 *100 = 9.9
Onyeka,2014
Deaths for people who sought who
sought treatment for drug use
Causes of death All
All
deaths deaths
(n = 496) %
Disease
Neoplasms
Mental
Circulatory
Deaths
external
Transport
Accidental
poisioning/OD
Suicide
Assault
25–34
25–34
years
years
(n = 189) %
35–44
35–44
years
years
(n = 107) %
≥45 years ≥45 years
(n = 78) %
38
3
9
11
35.5
2.8
8.4
10.3
53
11
4
18
67.9
14.1
5.1
23.1
174
15
49
45
35.1
3
9.9
9.1
53
19
14
28
0.5
10.1
7.4
322
16
64.9
3.2
136
6
72
3.2
69
3
64.5
2.8
25
2
32.1
2.6
165
108
14
33.3
21.8
2.8
66
52
6
34.9
27.5
3.2
42
16
3
39.3
15
2.8
12
8
15.4
10.3
1
Onyeka,2014
Causes of death in people with opioid
dependence in NSW 1985–2006
< 25*
Accidental
opioid-related
Accidental other
drug-related
Suicide
Liver-related
Cardiovascular
Cancer
HIV
Motor vehicle
accidents
Violence
Other
*age of death
<25 %
25-34
25-34
%
35-44
35-44
%
>45
>45 %
209
59.5
699
50.9
542
40.9
124
20.3
14
53
1
2
3
6
4
15.1
0.3
0.6
0.9
1.7
71
211
23
38
17
37
5.2
15.4
1.7
2.8
1.2
2.7
56
167
124
82
90
33
4.2
12.6
9.4
6.2
6.8
2.5
23
53
106
84
80
15
3.8
8.7
17.3
13.7
13.1
2.5
26
11
26
7.4
3.1
0
96
37
144
7
2.7
10.5
42
31
157
3.2
2.3
11.9
16
6
105
2.6
1
17.2
Degenhardt 2013
SMR in people with opioid
dependence in NSW 1985–2006
Causes of death
SMR
Total mortality
6.5
All drug-related
35
Accidental drug-related
39.9
Accidental opioid-related
42.8
Accidental other drug-related 24.1
Unintentional injuries
9.6
Motor vehicle accidents
3.2
Violence
7.6
Suicide
6.2
CI
(6.3–6.7)
(33.4–36.6)
(38.0–41.8)
(40.7–45.0)
(20.6–28.1)
(9.0–10.2)
(2.7–3.7)
(6.1–9.5)
(5.6–6.7)
SMR in people with opioid
dependence in NSW 1985–2006
Causes of death
All liver-related
Chronic liver disease
Viral hepatitis
Cardiovascular
Cancer
HIV AIDS
Alcohol-related
Chronic respiratory disease
Respiratory infections
SMR
11.4
6.5
46.3
2.1
1.7
4.4
5.4
3.9
7.9
CI
(10.1–12.9)
(5.3–8.0)
(38.5–55.2)
(1.9–2.5)
(1.4–1.9)
(3.5–5.3)
(4.4–6.6)
(2.7–5.5)
(5.1–11.8)
Trends in deaths
3500
1000
900
3000
800
700
Drug Related
deaths Methadone
600
2500
2000
400
Drug Related
deaths
Buprenorphine
1500
300
Heroin and
Morphine
1000
500
Drug Related
deaths Methadone
All Drug related
Deaths
200
500
2012
2011
2010
2009
2008
2007
2006
2005
0
2004
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
0
2003
100
ONS 2014
Metabolism review
• Phase 1 metabolism typically subjects the drug to
oxidation or hydrolysis. It involves the
cytochrome P450 (CYP) enzymes
• Phase 2 metabolism conjugates the drug to
hydrophilic substances, such as glucuronic acid,
sulfate, glycine, or glutathione.
• The most important phase 2 reaction is
glucuronidation
• Glucuronidation produces molecules that are
highly hydrophilic and therefore easily excreted.
First Pass Effect
Medcape
First pass effects
• Enzymes for phase 1 metabolism are mainly found in
the GI tract (liver, small intestine, and colon).
• High concentration enzymes in GI epithelium, hence
this is the initial site for first-pass metabolism of drugs.
• The drug via portal circulation goes to the liver,
• Some active drug may miss first-pass metabolism in the
GI tract and liver but subsequent passes through the
liver result in further metabolism of the parent drug
until it is eliminated
• Nasal mucosa and lung also have these enzymes for
first pass. important roles in the first pass metabolism
of airborne pollutants and aerosols.
Goodman
Metabolism
Metabolism of opioids
• The basal rate of metabolism is determined by
genetic makeup, gender, age, as well as
environment including diet, disease state, and
concurrent use of medications.
• Most opioids are metabolized by glucuronidation
or by the P450 (CYP) system.
• Polymorphism in the human OPRM1 gene
(encodes the mu opioid peptide (MOP) receptor)
may relate to variation in opioid sensitivity
– E.g., opioid analgesia, tolerance, and dependence
Smith 2009
Metabolism of opioids
• The CYP2D6 enzyme is entirely responsible for the
metabolism of hydrocodone, codeine, and
dihydrocodeine to their active metabolites which in
turn undergo phase 2 glucuronidation.
• These opioids (and to a lesser extent oxycodone,
tramadol, and methadone) have interaction potential
with an array of other drugs which are substrates,
inducers, or inhibitors of the CYP2D6 enzyme
• Morphine, oxymorphone, and hydromorphone
metabolized by phase 2 glucuronidationand therefore
have little potential for metabolically based drug
interactions.
Smith 2009
Interactions
• http://bioinformatics.charite.de/supercyp/ind
ex.php?site=get_drug_interaction
• Nicotine also important to consider
Methadone
• Methadone plasma concentrations follows a biexponential
1.
rapid phase- transfer of the drug from the central
compartment to the tissue compartment
2. slow phase - corresponds to elimination
• The t1/2 of the first phase of methadone varies
from 1.9 to 4.2 h
• The t1/2 of the second phase (slow) of drug
disappearance from the plasma (-phase, slow,
elimination) varies even more, from 8.5 to 47 h
Ferrari 2004
Methadone
• High lipid solubility, hence rapidly transferred to
tissues, particularly liver, kidneys, lungs and to the
brain
• 1–2% remains in the blood compartment
• 60–90% bound to plasma proteins, mostly to acid 1globulins
• The blood concentrations of acid 1-glycoproteins,
increase in stress conditions and in heroin dependent
users with a decrease of free and active methadone
• Large Volume of distribution of methadone - short
term decreases in blood levels not clinically important
Ferrari 2004
Methadone variability
• Induction of its own metabolism may reduces
methadone concentrations
• Different views about extent of this
1. 30 days treatment of 40 or 80 mg,
1. Decrease plasma level by three to eight-times
2. Excretion of parent drug and metabolites increase from
22.2 to 61.9%.
2. 5–12 months of treatment with 60 or 80 mg
1. Decrease plasma level by 15–25%
•
Body clearance of methadone varies from 0.96 to 6.1
ml/min/kg
Ferrari 2004
Opioid pharmacology
Mu
Delta
Kappa
Mu 1 – Analgesia
Mu 2 – Sedation,
vomiting, respiratory
depression, pruritus,
euphoria, anorexia,
urinary retention,
physical dependence
Analgesia, spinal
analgesia
Analgesia, sedation,
dyspnea,
psychomimetic effects,
miosis, respiratory
depression,
euphoria,dysphoria,
dyspnea
k agonist
Actions of opioids
Drug
Mu
Morphine
Agonist
Codeine
Weak agonist
Fentanyl
Agonist
Methadone
Agonist
Buprenorphine Partial agonist
Delta
Kappa
Weak agonist
Weak agonist
Partial agonist
Opioid induced respiratory depression
case reports
• 34 case reports describing OIRD in 42 adolescent
and adult patients treated for chronic cancer and
non-cancer pain from 1980 to 2012.
• The number of cases is relatively small compared
to OIRD in acute pain patients (120 cases), but
there is a substantial increase in the incidence of
cases post-2000 (pre-2000: 0.8 cases/year versus
post-2000: 2.3 cases/ year).
Dahan 2013
15 cases
1980- 2000
27 cases
2000 - 2013
Indication
cancer pain
67% pre-2000,
41% post- 2000
Dahan 2013
Reason long term opioid used
• The indication for opioid use was cancer pain
in 67% of the cases pre-2000, but dropped to
41% post- 2000
• Post-2000 the indication for opioid
prescriptions for non-cancer pain was 59%,
most commonly for treatment of
musculoskeletal pain (33%) followed by
neuropathic pain and complex regional pain
syndrome (11%)
Age/
Sex
Length
Complication
42 yr. F Methadone
6 years
Sedation/respira Ciprofloxacin Inhibition of
tory
CYP1A2 and 3A4
depression
activity,
responsive to
increasing
naloxone
methadone blood
levels
Methadone
15 days
Respiratory
depression
responsive to
naloxone
60 yr.
M
Drug
Other
Drugs
Cause
Fluconazole
Inhibition of
CYP3A4 and
2Y9, increasing
methadone blood
levels
Dahan 2013
Age/
Sex
Drug
46
Fentanyl TD
yr. M patch
morphine,
oxazepam
Length
Complication
45 days 8 days following
start of fluconazole
patient died during
sleep. Forensic
analysis showed
high plasma conc.
of fentanyl and
fluconazole
34
Buprenorphine 12 h
yr. M TD
patch
Respiratory
depression
upon start of
chemotherapy with
ifosfamide resolved
by removal of the
patch
Other
Drugs
Cause
Fluconazole
Inhibition of
CYP3A4 system,
increasing
fentanyl
blood levels
Ifosfamide,
an
alkylating
agent
Possible
competitive
interaction via
common
metabolic
pathway
(CYP3A4
Age/ Drug
Sex
81 yr Fentanyl TD
M
patch
46 yr Methadone
M
Length
Complication
Longterm
36 h after receiving
the first dose of
clarithromycine he
developed
naloxoneresponsive
respiratory
depression.
4
Smoking cessation
months (after 33 pack years)
initiated naloxoneresponsive
respiratory depression
Other
Cause
Drugs
Clarithrom Inhibition of the
ycin
CYP3A4 system,
increasing
fentanyl’s
plasma levels
Smoking
cessation
Polycyclic
aromatic
hydrocarbons in
tobacco smoke
induce CYP1A2.
Smoking
cessation may
have reduced
methadone’s
metabolism.
Age/
Sex
Drug
70 yr.
M
61 yr F
Length
Complication
Other
Drugs
Cause
Methadone Event 1
week after
long term
opioid use
Respiratory
depression
responsive to
naloxone
Sertraline
Inhibition of
the CYP system,
increasing
methadone blood
levels.
Methadone Long-term
Naloxoneresponsive
respiratory
depression 11
days after
carbamazepine
withdrawal
Carbamaze
pine
Gabapentin
Induction of
CYP3A4 activity.
Its
withdrawal slows
down
methadone’s
metabolism
causing
an increase in
plasma
levels
Hepatitis C
• In England, 160,000 adults are estimated to be
chronically infected with hepatitis C
• This is about 0.4% of the adult population.
• Injecting drug use continues to be the most
important risk factor for HCV infection
• In England, 16% of PWID reported direct
sharing of needles in 2013 (29% in 2003).
PHE 2014
Deaths from ESLD or HCC in those with
HCV mentioned on their death
certificate in England: 1996-2013**
Risk factor information in laboratory
reports* of hepatitis C from
England: 1996-2013
Number of
deaths from
ESLD* or HCC
in those with
HCV
mentioned on
their death
certificate by
PHE Centre
2008-2013**
(per 100,000
population)
Unlinked Anonymous Monitoring
Survey of Hepatitis C* in PWID
80%
70%
*Proportion of
samples antiHCV
positive
60%
50%
40%
England
30%
North West
20%
10%
0%
Factors for QTc
• Methadone prolongs QTc in a dose dependent
manner
• QT prolongation is used as the surrogate marker
for TdP
• If methadone is a risk factor why does not
everyone suffer from QTc elongation on
methadone?
• “Forme fruste” theory
• Certain people at risk for QTc elongation but need
trigger for it to occur
Risk factors of QTc
• Metabolic disorders/ Misc
• hypokalemia,
hypomagnesemia,
hypocalcemia
• Starvation
• Anorexia nervosa
• Hypothyroidism
• HIV infection
• Hypothermia
• Connective tissue disorders
with anti-Ro/SSA antibodies
• Male, age
• Cardiac disease
• Bradyarrhythmias: sinus
node dysfunction, AV blocksecond or third degree
• Advanced cardiac disease
• Myocardial ischemia or
infarction, esp. with
prominent T wave
inversions
Mujtaba, 2013
Drug Causes of QTc
• Antiarrhythmic drugs e.g.: quinidine, procainamide,
sotalol
• Antimicrobial drugs: erythromycin, azithromycin,
levofloxacin
• Antihistamines: terfenadine
• HIV Protease inhibitors: ritonavir, nelfinavir,
atazanavir
• Psychotropic drugs: thioridazine, haloperidol,
olanzapine
• Motility drugs: cisapride, domperidone
http://
www.azcert.org/medical-pros/drug-lists/drug-lists.cfm, www.qtdrugs.org.
Myocardial action potential Phases
K efflux
Na entry
K re-enters
Na exits
Slow Ca entry
K exit cause 2
Gupta 2007
QTc prolongation
• Myocardial repolarization via efflux of potassium
ions.
• Mediated by two subtypes of the delayed
rectifier K+ current, Ikr (rapid) and Iks (slow)
• Drugs prolonging QTc block Ikr thereby delaying
phase 3
• Longer action potential results in QT
prolongation.
– It may also distort T waves or produce prominent U
waves
Gupta 2007
Mechanism of action
• Inhibitor of Ikr
• Increased QT dispersion (marker of
heterogenous cardiac repolarization) has been
observed in association with methadone
• Methadone has bradycardia effect
– Due to anticholinesterase & calcium channel
antagonist properties
– Adds to risks TdP
Mujtaba, 2013
Comparison of opioids effects on Ikr
IC50 for HERG Maximum Plasma
Drug
Blockade (uM) Conc. (Cmax) (uM) Ratio: IC50/Cmax
Methadone
9.8
3.6
2.7
Fentanyl
1.8
0.030
60
Buprenorphine
7.5
0.036
208
Morphine
>1000
2.5
>400
Codeine
>300
0.66
>455
Katchman 2002
Electrical impulse
http://en.wikiversity.org/wiki/User:Bron766/E
CG/Axis
http://courses.kcumb.edu/physio/ecg%20prim
er/ecgaxis.htm
Normal ECG
http://www.ecglibrary.com/ecghome.html
Torsade de pointes
Patients with opioid dependence in
Taiwan
• Taiwan launched MMT in 2006 in response to the
HIV/AIDS surge endemic in eastern Asia
• 33,603 patients registered throughout 2006 to 2008
• Average age = 37.7 years, men (84.8%),
• HIV infection rate was 14.1%
• The average treatment duration was 171.5 days, and
the average follow-up duration 358.4 days.
• Mean (SD) methadone dosage was 46.5 (20.9) mg/day.
• No take-home dosage was permitted throughout the
treatment
Adjusted hazard ratios for all-cause
deaths for MMT patients 2006 -08.
Age
≤30
Adjusteed
hazard rate
CI for
adjusted
hazard rate
P for trend
1
1
30-45
0.96
(0.74-1.25)
0.767
45-60
0.75
(0.56-1.01)
0.057
>60
0.68
(0.50-0.92)
0.016
Adjusted for age, sex, marital status, education, HIV status
Hazard function of low to high
methadone dosage subgroups
Ding-Lieh Liao
2013
Comparison 1 RCT, Outcome 6 Opioid
abstinence at >3-4 weeks (urine
based).
Faggiano 2003
MMT vs No MMT
Morphine positive urine or hair analysis.
Mattick 2009
High-dose buprenorphine versus
placebo, Morphine-positive urines
Treatment opioid dependence
• The needs of all drug misusers should be assessed across
the four domains of drug and alcohol misuse, health, social
functioning and criminal involvement.
• Risks to dependent children should be assessed for all
drug-using parents.
• All drug misusers entering structured treatment should
have a care or treatment plan which is regularly reviewed.
• A named individual should manage and deliver aspects of
the patient’s care or treatment plan
• Drug testing can be a useful tool in assessment and in
monitoring
• Drug misuse treatment involves a range of interventions,
not just prescribing.
DOH 2007
Pharmacological components
• Methadone or buprenorphine are are effective
medicines for maintenance (opioids)
• Dose induction with buprenorphine may be carried
out more rapidly with less risk of overdose
• Care with children
• Supervised consumption should be available
• Methadone, buprenorphine, lofexidine are effective
in detoxification regimens
DoH 2009 Drug misuse and dependence. UK guidelines on clinical management
Opioid substitution treatment (OST)
effectiveness
• The evidence is good that OST
– OST reduces the risk of death among heroin users
participating in treatment
– Suppresses illicit use of heroin
– Prevents people dropping out of treatment
reduces crime – OST reduces involvement in crime
among heroin users participating in treatment
– OST reduces the risk of BBV transmission,
including in prisons
Medications In Recovery Re-orientating Drug Dependence Treatment NTA 2012
Opioid substitution treatment (OST)
effectiveness
• Evidence is less good that OST
– Suppresses other drug use
– Promotes abstinence from all drugs
– Improves physical and mental health –the
evidence suggests rapid and substantial
improvements on treatment entry, which may or
may not be maintained or further improved
– Improves social reintegration of marginalised
heroin users
Medications In Recovery Re-orientating Drug Dependence Treatment NTA 2012