Abuse Liability of Suboxone Versus Subutex

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00710385
• Collaborator: Schering-Plough (Industry)
• Enrollment: 19
• Location: 1
• Arms: 7
• Duration (Months): 11
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Opioid-related Disorders	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)	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Reinforcing Effects of Intravenous Buprenorphine Versus Buprenorphine/Naloxone in Buprenorphine-maintained Intravenous Drug Users (P05207)
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Heroin Heroin 25 mg. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions.	Drug: Heroin; Heroin (25 mg); Other Names: Diacetylmorphine
Active Comparator: Naloxone Naloxone (NAL) .4 mg. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions.	Drug: Naloxone; .4 mg; Other Names: Naloxone Hydrochloride (HCl)
Experimental: Low Bup Dose 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; 4 and 8 mg; Other Names: Subutex
Experimental: Low Bup/Nal Dose 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; Buprenorphine/Naloxone 4/1 mg, 8/2 mg; Other Names: Suboxone
Experimental: High Bup Dose 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; 8mg and 16 mg; Other Names: Subutex
Experimental: High Bup/Nal Dose 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; Buprenorphine/Naloxone 8/2 mg, 16/4 mg; Other Names: Suboxone
Placebo Comparator: Placebo Intravenous placebo (PCB) administration. Administered intravenously, while participants were under 2, 8 and 24 sublingual (SL) Bup maintenance conditions.	Drug: Placebo (PCB); Placebo control administration; Other Names: 0 mg

Outcome Measures

Primary Outcome Measures

1. Drug's Breakpoint [Single measurement taken following each of the 7 IV experimental doses]

   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

Secondary Outcome Measures

1. Drug "Liking" [Peak (highest) rating obtained following drug administration throughout the entire 3 hr session]

   Participant's subjective ratings of how much they "Like" the dose they just received on a scale of 0 -100.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute/Columbia University	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute
• Schering-Plough

Investigators

• Principal Investigator: Sandra D Comer, PhD, Columbia University/New York State Psychiatric Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT00710385
• Other Study ID Numbers: 5518
• First Posted: Jul 4, 2008
• Last Update Posted: Dec 5, 2016
• Last Verified: Dec 1, 2012

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Opioid-Related Disorders; Buprenorphine, Naloxone Drug Combination; Buprenorphine; Heroin; Naloxone

Study Results

Participant Flow

Recruitment Details	Enrollment dates: September 10, 2007 - August 13, 2008 Location: Medical clinic

Arm/Group Title	Intravenous Challenge Doses
Arm/Group Description	This study employs a within-subjects design, all participants experienced all 7 intravenous challenge doses. The challenge doses were administered under 3 sublingual buprenorphine maintenance conditions. The data presented were collapsed across the 3 sublingual groups.
Period Title: Overall Study
STARTED	17
COMPLETED	12
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Challenge Doses
Arm/Group Description	This study employs a within-subjects design, all participant experience all challenge doses.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.2 (6.2)
Sex: Female, Male (Count of Participants)
Female	4 33.3%
Male	8 66.7%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Drug's Breakpoint
Description	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
Time Frame	Single measurement taken following each of the 7 IV experimental doses

Outcome Measure Data

Analysis Population Description

Heroin users, not seeking treatment

Arm/Group Title	Heroin	Naloxone	Low Bup Dose	High Bup Dose	Lower Bup/Nal Dose	High Bup/Nal Dose	Placebo
Arm/Group Description	Intravenous heroin 25 mg	Intravenous Naloxone HCl	Lower doses of intravenous buprenorphine alone.	Higher doses of intravenous buprenorphine	Lower doses of intravenous buprenorphine + naloxone.	Higher doses of intravenous buprenorphine +naloxone	Control intravenous placebo drug administration.
Measure Participants	12	12	12	12	12	12	12
Mean (Standard Deviation) [number of clicks on a mouse]	1200 (200)	10 (10)	1100 (180)	1200 (190)	300 (100)	750 (175)	0 (0)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heroin	Naloxone	Low Bup Dose	High Bup Dose	Lower Bup/Nal Dose	High Bup/Nal Dose	Placebo
Arm/Group Description	Intravenous heroin 25 mg	Intravenous Naloxone HCl	Lower doses of intravenous buprenorphine alone.	Higher doses of intravenous buprenorphine	Lower doses of intravenous buprenorphine + naloxone.	Higher doses of intravenous buprenorphine +naloxone	Control intravenous placebo drug administration.
Measure Participants	12	12	12	12	12	12	12
Mean (Standard Error) [units on a scale]	41.5 (5)	3 (2.7)	29.8 (4)	42.5 (5)	10.5 (2.4)	27 (4)	1 (.6)

Adverse Events

Time Frame	Adverse events were assessed for daily throughout the study.
Adverse Event Reporting Description	An adverse event (AE) was defined as any symptom, sign, illness or experience that develops or worsens in severity during the course of the study. A serious adverse event is any AE that was: Fatal, Life-threatening, Required or prolonged inpatient stay, Resulted in persistent or significant disability or incapacity.
Arm/Group Title	Combined for All Study Conditions
Arm/Group Description	This study employed a within-subjects design, all participants experienced all study conditions.
All Cause Mortality
	Combined for All Study Conditions
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combined for All Study Conditions
	Affected / at Risk (%)	# Events
Total	0/17 (0%)
Other (Not Including Serious) Adverse Events
	Combined for All Study Conditions
	Affected / at Risk (%)	# Events
Total	4/17 (23.5%)
Gastrointestinal disorders
vomiting	1/17 (5.9%)	1
Injury, poisoning and procedural complications
dizziness	1/17 (5.9%)	1
chest discomfort	1/17 (5.9%)	1
Mild Opioid Withdrawal	3/17 (17.6%)	3
Skin and subcutaneous tissue disorders
urticaria	2/17 (11.8%)	2

Limitations/Caveats

The stringent criteria for enrollment, qualification and retention in this trial were highly selective for a certain subpopulation of opioid-dependent individuals.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.