Update on Relapse Prevention Medications for Addiction Outline

Marc Fishman MD • Conceptual framework for anti-addiction medications Johns Hopkins University Mountain Manor Treatment Center • Some biology and potential mechanisms Tuerk Conference 5/10/11 • The present: What we already have • A partial catalog of the future: New developments and the pipeline • Delivery, logistics, barriers, implementation • Discussion

A partial catalog of the future Treatment Misadventures New uses for existing New meds meds • Cocaine vaccine • Vigabatrin for cocaine • Implant naltrexone • XR-Naltrexone for • Implant buprenorphine opioids • Cannabinoid • XR-Naltrexone for antagonists stimulants • NK-1 antagonists for • Pregabalin for benzos stress-induced relapse • Disulfiram for cocaine • Metabolic enzymes • Buspirone for stimulants

What we already have What we already have (but don’t use enough) • Methadone • Disulfiram • Buprenorphine • Nicotine anti-craving • Nicotine replacement • Naltrexone for alcohol • Acamprosate

1 What we recently got

45% 40% • XR-naltrexone for opioids 35% 30% 25% 20% 15%

% Abstinent 10% 5% 0% weeks 9-12 weeks 9-24 weeks 9-52

Varenicline Bupropion Placebo

Naltrexone • Pure competitive antagonist of opioid receptors • Very effectively prevents and reverses all opioid effects • FDA approved for – Oral NTX for opioid dependence 1984 – Oral NTX for alcohol dependence 1996 – Injectable XR-NTX for alcohol dependence 2004 – Injectable XR-NTX for opioid dependence 2010

Conceptual Issues

• Should medications be used in the Conceptual framework for treatment of addiction? addiction medications – Is this a philosophical question? – Is this a scientific question? – Is this a practical question?

2 Anti-addiction medications - Rationale for medication potential effects • Reduce craving • Block the effects of action • Impact the physiology of dependence • Reduce reward • Protect against lapses, which should be expected • Prevent withdrawal • Reduce high rates of relapse • Act as non-impairing substitute • Improve treatment retention • Enhance negative consequences • Improve outcomes of current psychosocial treatments • Prevent relapse after abstinence

Vocabulary

• Agonist - drug that activates a receptor • Antagonist - drug that blocks a receptor • Partial agonist/antagonist - drug that does some of both

Vocabulary Multiple Mechanisms of Action • Craving - subjective sense of hunger for substance • Triggers – salience of environmental cues, associated with behaviors (conscious or • Agonists unconscious) • Antagonists • Reinforcement - response that increases likelihood • Modulators of reinforcement pathways of behavior • Aversive agents • Positive reinforcement - positive stimulus (reward • Modulators of metabolism craving) that increases likelihood of behavior • Immunization • Negative reinforcement - removal of noxious • Modulators of sustaining or re-instatement stimulus (relief craving) that increases likelihood of pathways behavior • Others? • Punishment - noxious stimulus that decreases likelihood of behavior

3 Any meds for cocaine?

• We’ve tried everything A partial catalog for the future • A few things are fair at best – Bupropion – Desipramine New developments and pipeline – Modafenil – Long-acting ADHD stimulants (Adderall-XR)

Can we create synergy by adding Vigabatrin contingency management? • CM is one of the most potent treatments • Currently approved for certain types of epilepsy we have, but many adoption and • Anti-craving properties for cocaine sustainability barriers • Works by enhancing GABA (blocks enzyme • Some suggestion that the combination that breaks down GABA) is more than additive • Side effects: peripheral vision problems with ongoing use > 2 years – 2 complimentary approaches to the reward system? – “jumpstarting” the meds?

VTA

Nucleus Accumbens For more information or to refer a patient Call Erin Curran 410 233 1400

4 Naltrexone for Amphetamine Relapse Prevention?

• No pharmacotherapy found effective until recent Swedish trial • Significant effect with oral naltrexone in randomized, placebo-controlled trial of 80 patients (Jayaram-Lindstrom et al, 2008)

Cannabinoid antagonists Cannabinoid antagonists

• Endogenous cannibinoid system: receptors • Could cannabinoid antagonists have a and ligands (receptor binders) role in cocaine or MJ addiction? • Active in pain, hunger, reward, bone growth • Various compounds being studied – • Cannabinoid antagonists decrease animal agonists, antagonists, reuptake self-administration of cocaine, and inhibiotrs, synthesis inhibitors, etc reinstatement of cocaine seeking after • One (rimonabant) came close to extinction approval, but rejected because of side • CB-1 gene deletion nearly eliminate effects cocaine effects and addiction in rats

Implant Naltrexone for Opioid Implant naltrexone Dependence Background Is an implantable extended release • The pure opioid antagonist naltrexone has naltrexone formulation effective for good lab efficacy for opioid dependence but terrible effectiveness in standard community treatment of opioid dependence? treatment because of noncompliance • Injectable XR-NTX formulations are a huge advance – the best study to date showed 62% opioid neg urine over 2 months (vs 25% placebo) , but nevertheless 18% did not return for a 2nd dose at 1 month and 32% dropped out by 2 months Arch Gen Psychiatry. 2009;66(10):1108-1115

5 Implant naltrexone Implant naltrexone Intervention Method • Implant of slow release naltrexone tablets delivered with • Implant of slow release naltrexone tablets delivered with abdominal incision as SQ injection of 2.3 g NTX, with abdominal incision as SQ injection of 2.3 g NTX, with previous lab estimates of 5.5 month duration previous lab estimates of 5.5 month duration • Heroin dependent subjects (n=69) randomized to a 6 month trial of single dose of NTX implant + placebo pills vs. placebo implant plus oral NTX 50 mg/d • Follow up monthly for 6 months • Designated helper to supervise oral medication compliance

Implant naltrexone Implant naltrexone Results Results Results Naltrexone blood levels Men Women >2ng/mL 56d 43d >1ng/mL 101d 124d

Hulse, G. K. et al. Arch Gen Psychiatry 2009;66:1108-1115. Copyright restrictions may apply.

Cocaine vaccine Cocaine vaccine Summary question Background • Can we treat cocaine dependence • What about using antibody clearance of active drug through vaccination as a strategy? immunologically with a vaccine? • Cocaine derivative molecule linked to protein subunit of cholera toxin (chosen for immunogenicity and safety) -- Produces cocaine specific IgG • Cocaine produces euphoria at very low levels (0.5µM), so strategy requires high concentrations and effectiveness of antibody (estimate 43µg/mL) • Previous work predicts need for series of 5 vaccinations to produce those levels with peak antibody levels at week 12-16, also predicts 25-30% Arch Gen Psychiatry. 2009;66(10):1116-1123. make low antibody levels

6 Cocaine vaccine Cocaine vaccine Results Results • 38% of vaccine receivers achieved • From weeks 9-16 high Ab group has greater sufficient antibody # cocaine free UDS than low Ab group and than placebo • Of those, 76% required > 3 doses, and • No difference weeks 17-20 38% required > 4 doses • Exclude early dropouts (insufficient vaccine • 62% of vaccine receivers did not exposure) and early abstinence achievers achieve sufficient Ab after 5 doses (abstinence not related to vaccine) -- rate of • All Ab levels decline after week 16 achieving no new cocaine use >50% of the time is greater in the high Ab group (53%) than in the low Ab group (23%)

Cocaine vaccine Results Cocaine vaccine Conclusions • Modest results, hard to get adequate Ab levels, response not sustained, feasibility unclear • However very exciting proof of concept opens up an entire new world of therapeutics (also being pursued with nicotine, angiotensin) • Bottom line: we want it eventually, not yet ready for prime time, keep working out the kinks

Martell, B. A. et al. Arch Gen Psychiatry 2009;66:1116-1123. Copyright restrictions may apply.

Dronabinol for MJ Pregabalin for alcohol and dependence benzodiazepines • No difference in MJ use • Pregabalin activates the GABA system • Looking for boosting effects of other (which are central to action of alcohol meds? and BZDs) • Some promising early research • Gabapentin also of some interest for symptom reduction during detox

7 Long-acting buperenorphine - Lofexidine for opioid detox probuphine • Subcutaneous buprenorphine rods • Cousin of clonidine but better side effect implanted in upper arm profile, easier to use • 6 months duration • Available currently in UK • Dosing adjustable by # of rods • May be alternative to opioid agonist • Significant reduction in opioid positive detox, especially in transition to urines naltrexone induction • Disadvantage: requires removal • Look for approval this year or next

Relapse and stress sensitivity

• Alcoholics are more stress sensitive – Shock and hot plate in rates – Negative emotional stimuli in humans • Stress response is major risk for reinstatement of drinking (relapse) following post-dependent abstinence

NK-1 antagonist for possible anti-stress relapse prevention Buspirone for cocaine • Substance P (neurokinin) acts at NK-1 • Buspirone is a dopamine D3 antagonist receptor – peripherally mediates pain, centrally mediates emotional stress • Very safe, well tolerated reactions, negative emotional over-reaction • Modest benefit for anxiety in alcoholics • Some modest reduction in cocaine • NK-1 antagonist reduces stress-induced effects alcohol craving, reduces stress hormone • Little reduction in ongoing use response to challenge, reduces response • More robust reduction of relapse to negative emotional stimuli, increases following abstinence response to positive emotional stimuli

8 Disulfiram (and cousins) for cocaine Metabolic enzyme treatments

• Disulfiram blocks dopamine beta • Human enzyme butyrylcholinesterase hydoxylase, enzyme involved in involved in normal metabolism of metabolism of dopamine and synthesis cocaine of norepinephrine • Creation of new enzyme cocaine • Disulfiram (and more specific cousin hydrolase 1000 times more efficient nepicastat) block post-dependent through recombinant DNA mutations reinstatement of drug seeking but not • Prevents cocaine toxicity and initial self-administration reinstatement of drug seeking in post- dependent rats

Pharmacogenetics

9 There will be a quiz tomorrow

Barriers to effectiveness and adoption • Cost • Knowledge and training Delivery, Implementation, Logistics • Prejudice and misunderstanding • Lack of medical involvement in treatment The devils in the practical details • Lack of delivery system models • Limited potency of medications • Side effects • Problems with adherence and compliance

Emerging context for delivery Youth opioid treatment chart review of relapse prevention Patient characteristics medication

Age, mean 18.2 years Gender, male 53% An example in youth Race, caucasian 94% opioid dependence Duration of opioid use 2.8 years treatment Rate of injection use 61%

10 Cumulave retenon by medicaon Youth opioid treatment chart review Medication treatment

Treated with: Any medication 61% Buprenorphine 39% Extended release naltrexone 19% Oral naltrexone 3% No medication 39%

* = p < 0.01 compared to no medication

Opioid-free weeks by medicaon Youth opioid treatment chart review Combining urine and self report Opioid free weeks above the median

Opioid free weeks > median (8):

No medication 34% Any medication 60% Buprenorphine 51% Extended release naltrexone 80%

* = p < 0.01 compared to no medication

Why medication? Can you be in Why medication? Can you be recovery on medicines in recovery on medicines • Medicines just a crutch or band-aid • If medications eliminate cravings will patients miss – Maybe. Like meetings or group. opportunity for needed cravings management? • If the patients like it so much, there must be something – Academic if they relapse. Postpone until later wrong. when stronger. Open question - maybe need later – But if they don’t like it, it doesn’t matter how good it is. high intensity counseling. • If medications are an “easy fix” will patients refuse needed • Abuse and diversion psychosocial treatments and supports. – Real issue, needs to be managed, but not as – Actually, they come to psychosocial treatment more. problematic as scare stories make it out to be.

11 Is everything Why medication? Can you be in on the recovery on medicines

menu? • Medicines just a crutch or band-aid – Maybe. Like meetings or group. • If the patients like it so much, there must be something wrong. – But if they don’t like it, it doesn’t matter how good it is. • If medications are an “easy fix” will patients refuse needed psychosocial treatments and supports. – Actually, they come to psychosocial treatment more.

Why medication? Can you be Pharmacological Treatment in recovery on medicines • If medications eliminate cravings will patients miss • Question: opportunity for needed cravings management? – Academic if they relapse. Postpone until later – Which is better - medications or when stronger. Open question - maybe need later counseling? high intensity counseling. • Abuse and diversion – Real issue, needs to be managed, but not as • Answer: problematic as scare stories make it out to be. – Yes

We’ve come a long way Case (1) 16 F injection heroin and depression • Initial tx suboxone, oral NTX, ineffective 2º non- adherence despite close parental monitoring, even went as far as liquid • Received 8 doses XR-NTX, substantial improvement (despite sporadic lapses) • Extreme conflict with mother, moved in with heroin-using boyfriend • Insisted on stopping XR-NTX 2º injection site pain • 5 d oral NTX then immediate relapse and dropout

12 CASE (2) Case (3)

• 1 yr later presented back to us after stabilized on • Course of XR-NTX with company-sponsored sample methadone 1 month, re-initiated therapy and Rx for program for 6 months depression • Half way house and strong engagement in 12 step • After 4 months on methadone, switched to bupe fellowship • Erratic course over 4 months with sporadic medication • Titration of anti-depressant with gradual remission of non-compliance and lapses leading to progressive full depression and anxiety relapse • Switch to oral naltrexone for 2 months, but “tired of • Work with family to arrange inpatient treatment and detox meds” with plan for switch back to NTX • Oral naltrexone back-up as needed • Surreptitious use of bupe and cheeking of NTX at residential program • 18 months sober • Precipitated withdrawal