1. What does pharmacology have to do with treatment of heroin addiction?
James Bell
May 2007

2. Outline of presentation
Pharmacology of opioids - heroin, methadone, buprenorphine
Rationale for OTP maintenance treatment
Differences during induction and treatment

3. Pharmacology of opioids
Mu receptor - mediates analgesia, sedation, respiratory depression, pupil constriction, and euphoria
mu receptor is component of “reward” pathway

4. Tolerance and withdrawal
Follows chronic administration
Two different forms of withdrawal
- acute, drug specific withdrawal
- chronic, non-specific (“resetting” of reward system?)

5. Acute withdrawal 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)

6. Chronic withdrawal
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

7. Heroin 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

8. Methadone 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)

9. Buprenorphine Partial mu agonist (self-limiting)
at low doses, 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

10. 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)

11. 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

12. Pharmacological rationale for OTP
Stabilization
Induction of tolerance

13. 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

14. 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)

15. 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 dose-dependent fashion
This helps to extinguish the powerful reinforcement of heroin use

16. 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

17. 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)

18. 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

19. 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

20. 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

21. 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)

22. Components of treatment
Information
Structure
Therapeutic relationship
Symptom relief

23. 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