Buprenorphine: An Introduction Walter Ling MD Integrated Substance Abuse Programs UCLA Los Angeles, CA April 21 st

Buprenorphine in the Treatment of Opioid Addiction Buprenorphine as a medication –Development: Historical perspective –Pharmacology: Safety and efficacy Buprenorphine as a Treatment –Philosophical, societal and policy implications –The role of the clinicians

Classification of Addicts and Recommended Treatment Types of Addicts Correctional cases Mental defectives (degenerates) Social misfits Otherwise normal Treatment Internment camps Sterilization Vocational guidance Psychoanalysis

Forty years later :Methadone Used as analgesic after WW II Used in detoxification 1950’s Methadone maintenance 1964 Expansion during Vietnam war Most widely used treatment Most regulated “medical treatment”

Forty years later :Methadone Long acting Orally active opiate agonist capable of reducing or eliminating withdrawal signs and symptoms Reducing drug craving Normalizing physiological function

47% 23% 17% 12.5% 6% 0% 10% 20% 30% 40% 50% Not in Tx Currently in Tx In Tx 5 years C&D No needle use since admission to Tx ABCD The Effect of Methadone Treatments on HIV Seropositivity Rates All subjects were male, heterosexual IV drug users in NYC. Treatment provided was methadone maintenance. Novick et al., Presented at CPDD, 1985

Naltrexone

Naltrexone: The Perfect Drug Orally Effective Rapid onset of action Long duration of action Safe Few side effects Completely blocks effects of heroin Non-addicting No tolerance No dependence No withdrawal

One reason not to take naltrexone: Can’t get high!

Naltrexone: The Perfect Drug “victimless cure” It’s like taking nothing.

The Opioid Receptor Family

Potentially lethal dose Positive effect = addictive potential Negative effect Full agonist- morphine/heroin hydromorphone Antagonist - naltrexone dose Antagonist + agonist/partial agonist Agonist + partial agonist Super agonist- fentanyl Partial agonist - buprenorphine Mu efficacy and opiate addiction

Buprenorphine as a Medication: Pharmacological Characteristics Partial Agonist high safety profile/ceiling effect low dependence Tight Receptor Binding long duration of action slow onset mild abstinence

Good Effect

Respiration

Intensity of abstinence Himmelsbach scores Buprenorphine Morphine Days after drug withdrawal

Buprenorphine: Establishing Safety & Efficacy Compared to standard treatment (methadone) –Fixed dose comparison –Variable dose comparison Dose comparison studies Placebo controlled studies

Study # 999A: Buprenorphine’s Effect on Opiate Use Ling et al Addiction 93:475-86, 1998

Buprenorphine Maintenance Treatment of Opiate Dependence: A Multicenter Randomized Clinical Trial

Mean Heroin Craving: 16 week completers

Joint Probability N remaining in treatment X Total N of subjects N giving drug free urines N remaining in treatment

Figure A: A Comparison of Buprenorphine doses from four studies using Joint Probability

A Comparison of Methadone from Four Studies Using Joint Probability

Buprenorphine vs. Methadone

Buprenorphine Made Safer: Addition of Naloxone Reduces Abuse Naloxone will block buprenorphine’s effects by the IV but not the sublingual route Sublingual absorption of 70%; 10% If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict

Buprenorphine made Safer: Buprenorphine/Naloxone Combination 4 part buprenorphine: 1 part naloxone Sublingual:Opiate agonist effect from buprenorphine Intravenous:Opiate antagonist effect from naloxone Discourage IV use Diminish street value Diminish diversion Allow for flexible dosing

Opiate Agonist Measures (2)

Value of a Dose in Dollars Dollars Minutes MS BUP 4:1 8:1 PBO 2:1 Plac 8:14.1 BupMS

Pentazocine: T’s Blues Pentazocine: mixed angonist/antagonist analgesic Pentazocine use and abuse T’s and blues Pentazocine/nx

Study 1008

Buprenorphine as Treatment strategy: The First CTN Protocols Inpatient detoxification: –Buprenorphine/naloxone vs clonidine –(CTN 0001) Outpatient detoxification: –Buprenorphine/naloxone vs clonidine –(CTN 0002)

Study Design Buprenorphine/Naloxone 13 days detoxification Clonidine 13 days detoxification Open Randomized Study Bup/Nx:Clonidine = 2:1

Joint Probability N remaining in treatment X Total N of subjects N giving drug free urines N remaining in treatment

Percent Present and Clean 0001 (Inpatient)

Percent Present and Clean 0002 (Outpatient)

NNT: Number Needed to Treat CTN 0001 (Inpatient) NNT for Bup/Nx 77/59 = 1.31 NNT for Clonidine 36/8 = 4.5 NNT Clonidine : BupNx = 3.44 CTN 0002 (Outpatient) NNT for Bup/Nx: 157/46 = 3.4 NNT for Clonidine: 74/4 = 18.5 NNT Clonidine : Bup/Nx = 5.44 NNT= Number of patients needed to treat to achieve 1 treatment success

Drug Addiction Treatment Act of 2000 An Amendment to the Controlled Substances Act (October, 2000) Subutex and Suboxone approved October 8, 2002 and marketed in January 2003 Qualified physicians can treat up to 30 patients with the Buprenorphine products ( sublingual tablets) Physicians become qualified by training in sessions from designated organizations- APA, ASAM, AAAP, or over the internet; or if otherwise qualified Physicians can treat patients in their usual medical practice setting; able to provide or refer for psychosocial treatment.

Our Treatment Philosophy Addicts are sick; they need help They also sin; don’t treat them too well

Treatment of Opiate Dependence Detoxification Maintenance

Detoxification Detoxification is good for a lot of things; staying off drugs is not one of them.

Pharmacotherapy and Recovery “Medication is not recovery”? Addiction is chemistry went wrong You can change the brain with experience or with medication; they are the same thing

How People Change “You can change the brain with biological treatment or with behavioral treatment” Alan Leshner, Former head NIDA “You can change someone’s life by altering his genes; but you also do that by paying off his credit card” James Watson

Summary: Will Buprenorphine be a Success? Not a new medication but a vehicle for a new treatment philosophy Not just to change patients but to change us New attitude from community leaders like us should lead to new societal attitude towards addiction and change the way we treat and view those afflicted

Thanks to National Institute on Drug Abuse NIDA Clinical Trials Network Staff CTN Publications Committee Participating CTN Nodes and CTPs Reckitt Benckiser Participating Patients You the audience