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

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

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

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

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)

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

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

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)

Buprenorphine 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 dose-dependent 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 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