Abuse Liability of Suboxone Versus Subutex

Study Overview
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Brief Summary
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The study is designed to compare the abuse liabilities of intravenous buprenorphine and buprenorphine/naloxone in individuals who are physically dependent on sublingual buprenorphine. We hypothesize that the abuse liability of buprenorphine/naloxone is lower than that of buprenorphine alone.

Detailed Description
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Drug dependence is a major international public health problem of which opioid dependence, notably involving heroin, is a major component. Opioid dependence affects an estimated 13 million injection drug users (IDUs) worldwide. The high health service costs for the treatment of diseases related to non-medical drug use and the high cost to society of drug-related behavior have prompted researchers to seek new medications and treatment strategies for opioid dependence. Buprenorphine, a mu-opiate receptor partial agonist and kappa-opiate receptor antagonist, is one such new medication that has had a significant role in expanding access to effective opioid dependence treatment. It is available as Subutex (buprenorphine alone) or Suboxone (a combination of buprenorphine and naloxone). Although it is commonly believed that the abuse potential of buprenorphine is low, numerous countries have reported illicit diversion of buprenorphine and a growing population of buprenorphine abusers. Theoretically, Suboxone would have lower abuse potential. When used sublingually, as prescribed, the amount of naloxone absorbed is negligible. However, if a patient crushes the tablet and attempts to inject or sniff the medication, the naloxone will become effective as an opioid antagonist and may precipitate withdrawal signs and symptoms in individuals dependent on full opioid agonists and/or attenuate the euphoric effects of the buprenorphine that is also contained in the medication. To date, few laboratory studies have evaluated the abuse liability of buprenorphine in humans using a drug self-administration protocol. We are proposing to evaluate the abuse potential of intravenous (IV) buprenorphine compared to IV buprenorphine/naloxone in buprenorphine-maintained injection drug users (IDUs), incorporating self-administration procedures with other measures of opioid effects. The proposed study will investigate the conditions that affect the self-administration of IV buprenorphine by buprenorphine abusers. The primary aim of the study is to compare the reinforcing effects of IV buprenorphine and IV buprenorphine/naloxone in IDUs maintained on different doses of sublingual buprenorphine (2, 8, and 24 mg/day). Secondary aims of the study are to compare the subjective, performance and physiological effects of IV buprenorphine and IV buprenorphine/naloxone. IV-administered placebo (saline), naloxone alone, and heroin alone will be tested as neutral, negative, and positive control conditions, respectively. Participants (N=12 completers) will reside on an inpatient unit (the General Clinical Research Unit, GCRU) during a 7 to 8-week study. This research will provide useful information for clinicians treating opioid dependent individuals with buprenorphine, and importantly, will provide information about the abuse potential and effects of buprenorphine on multiple measures of human functioning.

Official Title
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Reinforcing Effects of Intravenous Buprenorphine Versus Buprenorphine/Naloxone in Buprenorphine-maintained Intravenous Drug Users (P05207)

Conditions
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Opioid-related Disorders

Intervention / Treatment
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* Drug: Heroin
* Drug: Naloxone
* Drug: Low Bup Dose
* Drug: High Bup Dose
* Drug: Low Bup/Nal Dose
* Drug: High Bup/Nal Dose
* Drug: Placebo (PCB)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnostic and Statistical Manual (DSM) IV criteria for heroin dependence No major mood, psychotic, or anxiety disorder Physically healthy Able to perform study procedures 21-45 years of age Normal body weight Current use of i.v. opioids in amounts and/or frequencies that meet or exceed those used in the proposed study (1-2 bags of heroin per occasion at least twice per day) Self-administer at least 4 mg i.v. buprenorphine above placebo levels during the dose run up phase Exclusion Criteria: DSM IV criteria for dependence on drugs other than opioids, nicotine or caffeine Participants requesting treatment Participants on parole or probation Pregnancy or lactation Birth, miscarriage or abortion within 6 months Current or recent history of significant violent behavior Current major Axis I psychopathology, other than opioid dependence (e.g., mood disorder with functional impairment or suicide risk, schizophrenia), that might interfere with ability to participate in the study aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal Significant suicide risk Current chronic pain Sensitivity, allergy, or contraindication to opioids Current or recent (past 30 days) physical dependence on or treatment with methadone, buprenorphine, or the buprenorphine/naloxone combination

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Heroin<br>Heroin 25 mg. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: Heroin<br>* Heroin (25 mg)<br>* Other names: Diacetylmorphine;|
| Active Comparator: Naloxone<br>Naloxone (NAL) .4 mg. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: Naloxone<br>* .4 mg<br>* Other names: Naloxone Hydrochloride (HCl);|
| Experimental: Low Bup Dose<br>Combined dosing groups of (4 mg and 8mg of Buprenorphine) for participants who administered a maximum of 8 mg of Bup during the qualification phase. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: Low Bup Dose<br>* 4 and 8 mg<br>* Other names: Subutex;|
| Experimental: Low Bup/Nal Dose<br>Combined dosing groups of (4/1 mg and 8/2mg of Buprenorphine + Naloxone) for participants who administered a maximum of 8 mg of Bup during the qualification phase. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: Low Bup/Nal Dose<br>* Buprenorphine/Naloxone 4/1 mg, 8/2 mg<br>* Other names: Suboxone;|
| Experimental: High Bup Dose<br>Combined dosing groups of (8mg and 16mg of Bup) for participants who administered a maximum of 16 mg of Bup during the qualification phase. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: High Bup Dose<br>* 8mg and 16 mg<br>* Other names: Subutex;|
| Experimental: High Bup/Nal Dose<br>Combined dosing groups of (8/2mg and 16/4mg of Buprenorphine + Naloxone) for participants who administered a maximum of 16 mg of Bup during the qualification phase. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: High Bup/Nal Dose<br>* Buprenorphine/Naloxone 8/2 mg, 16/4 mg<br>* Other names: Suboxone;|
| Placebo Comparator: Placebo<br>Intravenous placebo (PCB) administration. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions. | Drug: Placebo (PCB)<br>* Placebo control administration<br>* Other names: 0 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug's Breakpoint | Measure of a drug's reinforcing effects. The Breakpoint is the point at which the participant stop performing an operant task (clicks on a mouse) in order to received the drug. Therefore, the reported breakpoint is the total amount of work the participant was willing to perform to receive the dose being tested | Single measurement taken following each of the 7 IV experimental doses | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug Liking | Participant's subjective ratings of how much they Like the dose they just received on a scale of 0 -100. | Peak (highest) rating obtained following drug administration throughout the entire 3 hr session |