Transcript Pharmacology and treatment Pharmacology and

What does pharmacology have
to do with treatment of heroin
addiction?
James Bell
May 2007
Outline of presentation
1. Pharmacology of opioids - heroin,
methadone, buprenorphine
2. Rationale for OTP maintenance treatment
3. Differences during induction and treatment
Pharmacology of opioids
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Mu receptor - mediates analgesia,
sedation, respiratory depression, pupil
constriction, and euphoria
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mu receptor is component of “reward”
pathway
Tolerance and withdrawal
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Follows chronic administration
Two different forms of withdrawal
- acute, drug specific withdrawal
- chronic, non-specific (“resetting” of
reward system?)
Acute withdrawal
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Observed 3-6 weeks after regular opioid
exposure
thought to require continual exposure (may
not occur after ultra-short-acting drugs)
Severity is proportional to the rate at which
mu receptor activation declines (milder with
long-acting drugs)
Chronic withdrawal
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Syndrome of low-grade dysphoria, (listless,
difficulty sleeping) and craving
lasts > 6 months
pronounced after use of short-acting drugs
same after alcohol, heroin, stimulants
hypothesized to represent a “resetting” of
the reward pathway
Heroin
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Highly lipophilic, rapid entry to CNS
Active drug is morphine, which has a
short half-life
Rapid onset (“spike” effect from IV use)
withdrawal 8-12 hours after last dose
intensely reinforcing drug
Methadone
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Potent mu agonist
Slow oral absoption, peak actions 1-4
hours post dose
Extensively stored in tissues (blood levels
rise progressively during first 7 days)
long but variable half-life (mostly ~22
hours)
Buprenorphine
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Partial mu agonist (self-limiting)
at low doses, 25-40 X potency morphine
Ceiling effect
Capacity to antagonise full agonists
(precipitated withdrawal)
Slow sublingual absorption, peak actions 2-4
hours post dose
long but variable half-life
Opioid actions in tolerant subjects
Euphoria (intoxication)
While blood levels are rising, euphoria is
experienced – proportional to the rate of rise in
receptor activation
Dysphoria (withdrawal)
While blood levels are falling, dysphoria is
proportional to the rate of decline in mu
activation
(Dyer, 2000)
Opioid actions
During active heroin use, people fluctuate
between intoxication (due to “spikes” in mu
receptor occupancy following bolus IV
injection), and withdrawal as blood and CNS
concentrations of opioid fall
Treatment with slowly absorbed, long acting
opioids reduces the differential between peaks
and troughs
Pharmacological rationale for
OTP
• Stabilization
• Induction of tolerance
Stabilization I
In the first 7 days of treatment with methadone
or buprenorphine, reported withdrawal and
intoxication scores progressively fall
This “stabilization” frees patients to detach
themselves form the cycle of drug seeking and
drug use
Stabilization II
35% of patients in MMT report persisting
low-grade withdrawal symptoms (Dyer,
1999)
These patients tend to have more rapid
methadone metabolism, and worse
outcomes of treatment (Nilsson, 1983)
Induction of tolerance - methadone
40mg/day of methadone is sufficient to stabilize most
people (abolish withdrawal & intoxication)
However, >90% of people need >40mg/day
Methadone attenuates the effect of heroin, in a dosedependent fashion
This helps to extinguish the powerful reinforcement
of heroin use
Buprenorphine
Dose dependent, but NOT time-dependent attenuation of
heroin (Strain, Walsh & Bigelow, 2002)
- effect not primarily due to increased tolerance
Dose-dependent, non-linear blockade of carfentil binding
(PET study, Greenwald et al, 2003)
- 2mg
41% inhibition
- 16mg
80% inhibition
- 32mg
84% inhibition
Implications of different mechanisms
of action
Lower risk of fatal overdose with buprenorphine
Once stabilized in treatment, both drugs protect
against overdose
However, period of induction onto methadone is one
of increased risk (Caplehorn, 1999; Buster, 2002)
Safety during induction - MMT
Safety policy with methadone:
INFORM PATIENTS OF RISK
START LOW, GO SLOW
• Dose<40mg at day 7
MONITOR RESPONSE
• If intoxicated, go lower, and slower
Buprenorphine induction
NOT methadone template
Less risk of toxicity (?agent of choice)
Expect more withdrawal symptoms in first 24
hours (Petitjiean et al,2002)
Probably, optimal advice is –
ANYTHING GOES
What about heroin maintenance?
Heroin not clearly either more or less effective
than methadone as maintenance drug
• inconsistent results
• data difficult to interpret (selection of patients,
lack of blinding, use of concurrent methadone)
Hypothesis (B Freddy et al, 2007)
Patients like heroin > methadone
Some patients do well on heroin, others don’t
Would anyone fund
A clinial trial commencing all patients on IV
heroin as initial treatment
Transfer to methadone those not doing well
(predicted to be a majority)
?
(answer - it would cost too much)
Components of treatment
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Information
Structure
Therapeutic relationship
Symptom relief
Maintenance treatment
~ 50% of subjects require:
• An adequate dose
• Administered daily
• Regular monitoring
To achieve good outcomes
The remaining 50% require more:
• Attention to comorbidity
• Containment
• ?Contingency management