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Update on Relapse Prevention Medications for Addiction

Marc Fishman MD Johns Hopkins University

Mountain Manor Treatment Center Tuerk Conference 5/10/11

Outline •  Conceptual framework for anti-addiction

medications •  Some biology and potential mechanisms •  The present: What we already have •  A partial catalog of the future: New

developments and the pipeline •  Delivery, logistics, barriers, implementation •  Discussion

Treatment Misadventures A partial catalog of the future

New uses for existing meds

•  Vigabatrin for cocaine •  XR-Naltrexone for

opioids •  XR-Naltrexone for

stimulants •  Pregabalin for benzos •  Disulfiram for cocaine •  Buspirone for stimulants

New meds •  Cocaine vaccine •  Implant naltrexone •  Implant buprenorphine •  Cannabinoid

antagonists •  NK-1 antagonists for

stress-induced relapse •  Metabolic enzymes

What we already have

•  Methadone •  Buprenorphine •  Nicotine replacement

What we already have (but don’t use enough)

•  Disulfiram •  Nicotine anti-craving •  Naltrexone for alcohol •  Acamprosate

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What we recently got

•  XR-naltrexone for opioids

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 framework for addiction medications

Conceptual Issues

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

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Rationale for medication

•  Reduce craving •  Impact the physiology of dependence •  Protect against lapses, which should be

expected •  Reduce high rates of relapse •  Improve treatment retention •  Improve outcomes of current psychosocial

treatments

Anti-addiction medications - potential effects

•  Block the effects of action •  Reduce reward •  Prevent withdrawal •  Act as non-impairing substitute •  Enhance negative consequences •  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 •  Craving - subjective sense of hunger for substance •  Triggers – salience of environmental cues,

associated with behaviors (conscious or unconscious)

•  Reinforcement - response that increases likelihood of behavior

•  Positive reinforcement - positive stimulus (reward craving) that increases likelihood of behavior

•  Negative reinforcement - removal of noxious stimulus (relief craving) that increases likelihood of behavior

•  Punishment - noxious stimulus that decreases likelihood of behavior

Multiple Mechanisms of Action

•  Agonists •  Antagonists •  Modulators of reinforcement pathways •  Aversive agents •  Modulators of metabolism •  Immunization •  Modulators of sustaining or re-instatement

pathways •  Others?

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A partial catalog for the future

New developments and pipeline

Any meds for cocaine?

•  We’ve tried everything •  A few things are fair at best

– Bupropion – Desipramine – Modafenil – Long-acting ADHD stimulants (Adderall-XR)

Can we create synergy by adding contingency management?

•  CM is one of the most potent treatments we have, but many adoption and sustainability barriers

•  Some suggestion that the combination is more than additive – 2 complimentary approaches to the reward

system? –  “jumpstarting” the meds?

Vigabatrin

•  Currently approved for certain types of epilepsy •  Anti-craving properties for cocaine •  Works by enhancing GABA (blocks enzyme

that breaks down GABA) •  Side effects: peripheral vision problems with

ongoing use > 2 years

VTA

Nucleus Accumbens

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

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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 •  Endogenous cannibinoid system: receptors

and ligands (receptor binders) •  Active in pain, hunger, reward, bone growth •  Cannabinoid antagonists decrease animal

self-administration of cocaine, and reinstatement of cocaine seeking after extinction

•  CB-1 gene deletion nearly eliminate cocaine effects and addiction in rats

Cannabinoid antagonists

•  Could cannabinoid antagonists have a role in cocaine or MJ addiction?

•  Various compounds being studied – agonists, antagonists, reuptake inhibiotrs, synthesis inhibitors, etc

•  One (rimonabant) came close to approval, but rejected because of side effects

Implant Naltrexone for Opioid Dependence

Is an implantable extended release naltrexone formulation effective for treatment of opioid dependence?

Arch Gen Psychiatry. 2009;66(10):1108-1115

Implant naltrexone Background

•  The pure opioid antagonist naltrexone has good lab efficacy for opioid dependence but terrible effectiveness in standard community 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

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Implant naltrexone Intervention

•  Implant of slow release naltrexone tablets delivered with abdominal incision as SQ injection of 2.3 g NTX, with previous lab estimates of 5.5 month duration

Implant naltrexone Method

•  Implant of slow release naltrexone tablets delivered with abdominal incision as SQ injection of 2.3 g NTX, with 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 Results

Naltrexone blood levels Men Women

>2ng/mL 56d 43d >1ng/mL 101d 124d

Copyright restrictions may apply."

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

Implant naltrexone Results���

Results

Cocaine vaccine Summary question

•  Can we treat cocaine dependence immunologically with a vaccine?

Arch Gen Psychiatry. 2009;66(10):1116-1123.

Cocaine vaccine Background

•  What about using antibody clearance of active drug through vaccination as a strategy?

•  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% make low antibody levels

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Cocaine vaccine Results

•  38% of vaccine receivers achieved sufficient antibody

•  Of those, 76% required > 3 doses, and 38% required > 4 doses

•  62% of vaccine receivers did not achieve sufficient Ab after 5 doses

•  All Ab levels decline after week 16

Cocaine vaccine Results

•  From weeks 9-16 high Ab group has greater # cocaine free UDS than low Ab group and than placebo

•  No difference weeks 17-20 •  Exclude early dropouts (insufficient vaccine

exposure) and early abstinence achievers (abstinence not related to vaccine) -- rate of achieving no new cocaine use >50% of the time is greater in the high Ab group (53%) than in the low Ab group (23%)

Copyright restrictions may apply."

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

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

Dronabinol for MJ dependence

•  No difference in MJ use •  Looking for boosting effects of other

meds?

Pregabalin for alcohol and benzodiazepines

•  Pregabalin activates the GABA system (which are central to action of alcohol and BZDs)

•  Some promising early research •  Gabapentin also of some interest for

symptom reduction during detox

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Long-acting buperenorphine - probuphine

•  Subcutaneous buprenorphine rods implanted in upper arm

•  6 months duration •  Dosing adjustable by # of rods •  Significant reduction in opioid positive

urines •  Disadvantage: requires removal •  Look for approval this year or next

Lofexidine for opioid detox

•  Cousin of clonidine but better side effect profile, easier to use

•  Available currently in UK •  May be alternative to opioid agonist

detox, especially in transition to naltrexone induction

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

•  Substance P (neurokinin) acts at NK-1 receptor – peripherally mediates pain, centrally mediates emotional stress reactions, negative emotional over-reaction in alcoholics

•  NK-1 antagonist reduces stress-induced alcohol craving, reduces stress hormone response to challenge, reduces response to negative emotional stimuli, increases response to positive emotional stimuli

Buspirone for cocaine

•  Buspirone is a dopamine D3 antagonist •  Very safe, well tolerated •  Modest benefit for anxiety •  Some modest reduction in cocaine

effects •  Little reduction in ongoing use •  More robust reduction of relapse

following abstinence

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Disulfiram (and cousins) for cocaine

•  Disulfiram blocks dopamine beta hydoxylase, enzyme involved in metabolism of dopamine and synthesis of norepinephrine

•  Disulfiram (and more specific cousin nepicastat) block post-dependent reinstatement of drug seeking but not initial self-administration

Metabolic enzyme treatments

•  Human enzyme butyrylcholinesterase involved in normal metabolism of cocaine

•  Creation of new enzyme cocaine hydrolase 1000 times more efficient through recombinant DNA mutations

•  Prevents cocaine toxicity and reinstatement of drug seeking in post-dependent rats

Pharmacogenetics

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There will be a quiz tomorrow

Delivery, Implementation, Logistics

The devils in the practical details

Barriers to effectiveness and adoption

•  Cost •  Knowledge and training •  Prejudice and misunderstanding •  Lack of medical involvement in treatment •  Lack of delivery system models •  Limited potency of medications •  Side effects •  Problems with adherence and compliance

Emerging context for delivery of relapse prevention

medication

An example in youth opioid dependence

treatment

Youth opioid treatment chart review Patient characteristics

Age, mean 18.2 years Gender, male 53% Race, caucasian 94% Duration of opioid use 2.8 years Rate of injection use 61%

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Youth opioid treatment chart review Medication treatment

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

Cumula&ve  reten&on  by  medica&on  

* = p < 0.01 compared to no medication

Opioid-­‐free  weeks  by  medica&on  Combining  urine  and  self  report  

* = p < 0.01 compared to no medication

Youth opioid treatment chart review Opioid free weeks above the median

Opioid free weeks > median (8):

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

Why medication? Can you be in recovery on medicines

•  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 in recovery on medicines

•  If medications eliminate cravings will patients miss opportunity for needed cravings management? –  Academic if they relapse. Postpone until later

when stronger. Open question - maybe need later high intensity counseling.

•  Abuse and diversion –  Real issue, needs to be managed, but not as

problematic as scare stories make it out to be.

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Is everything on the menu?

Why medication? Can you be in recovery on medicines

•  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 in recovery on medicines

•  If medications eliminate cravings will patients miss opportunity for needed cravings management? –  Academic if they relapse. Postpone until later

when stronger. Open question - maybe need later high intensity counseling.

•  Abuse and diversion –  Real issue, needs to be managed, but not as

problematic as scare stories make it out to be.

Pharmacological Treatment

•  Question: – Which is better - medications or

counseling?

•  Answer: – 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

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CASE (2) •  1 yr later presented back to us after stabilized on

methadone 1 month, re-initiated therapy and Rx for depression

•  After 4 months on methadone, switched to bupe •  Erratic course over 4 months with sporadic medication

non-compliance and lapses leading to progressive full relapse

•  Work with family to arrange inpatient treatment and detox with plan for switch back to NTX

•  Surreptitious use of bupe and cheeking of NTX at residential program

•  Precipitated withdrawal

Case (3) •  Course of XR-NTX with company-sponsored sample

program for 6 months •  Half way house and strong engagement in 12 step

fellowship •  Titration of anti-depressant with gradual remission of

depression and anxiety •  Switch to oral naltrexone for 2 months, but “tired of

meds” •  Oral naltrexone back-up as needed •  18 months sober