Reinforcing Effects of Intranasal (IN) Buprenorphine Versus Buprenorphine/Naloxone

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01760473
• Collaborator: Indivior Inc. (Industry)
• Enrollment: 27
• Location: 1
• Arms: 9
• Duration (Months): 67
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The study is designed to compare the abuse liabilities of intranasal buprenorphine and buprenorphine/naloxone in individuals who are physically dependent on sublingual buprenorphine. The investigators hypothesize that the abuse liability of buprenorphine/naloxone is lower than that of buprenorphine alone.

Condition or Disease	Intervention/Treatment	Phase
Heroin Dependence	Drug: Intranasal challenge drug	Phase 3

Detailed Description

Although sublingual buprenorphine is an effective treatment for opioid addiction, the medication itself has abuse liability and, in some countries, has largely replaced heroin as the opioid drug of choice. In response to the reports of diversion and abuse of sublingual (SL) buprenorphine, a potentially less abusable formulation of buprenorphine that contains naloxone is being marketed in several countries. However, the relative abuse liability of buprenorphine alone and the buprenorphine/naloxone combination in buprenorphine-dependent individuals is unclear. Preliminary data from a study funded by Schering-Plough Corporation suggest that the buprenorphine/naloxone combination, when given intravenously (IV), does indeed have less abuse liability than IV buprenorphine in buprenorphine-dependent individuals. In addition to IV abuse of buprenorphine, epidemiological data suggest that buprenorphine is widely abused by the intranasal (IN) route. However, no data exist on the abuse liability of either IN buprenorphine alone or the buprenorphine/naloxone combination. Several studies have shown that naloxone is an effective antagonist of opioid agonist effects when given intravenously, but it is not clear whether naloxone given intranasally is as effective as when it is given by other routes of administration. Some studies have suggested that they are equally effective (Loimer et al., 1994), but others have shown that naloxone given intranasally is less effective (i.e., has a slower onset of effects) than when given by other routes of administration (Kelly et al., 2005). How this may impact on the ability of naloxone to reduce the reinforcing effects of IN buprenorphine is unclear. The primary aim of the current study proposal is to compare the reinforcing effects of IN buprenorphine and buprenorphine/naloxone in IN opioid abusers who are maintained on SL buprenorphine using a study design parallel to that used in our recent studies of the abuse liability of IV buprenorphine and buprenorphine/naloxone. Placebo, heroin, and naloxone will be used as neutral, positive, and negative controls, respectively. Secondary aims are to compare the subjective, performance, and physiological effects of IN buprenorphine and buprenorphine/naloxone. Overall, this study will complement our investigations of IV buprenorphine products by allowing for a complete overview within the same laboratory self-administration model of both the intravenous and intranasal abuse liability of buprenorphine versus buprenorphine/naloxone in individuals maintained on buprenorphine. The primary aim of the study is to compare the reinforcing effects of IN buprenorphine and IN buprenorphine/naloxone in opioid abusers maintained on different doses of sublingual buprenorphine. Secondary aims of the study are to compare the subjective, performance and physiological effects of IN buprenorphine and IN buprenorphine/naloxone. IN-administered placebo (lactose powder), 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 (5-South) during a 7 to 8-week study. This research will provide useful information to 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: 27 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: In this study's design, all participants received each of the 9 intranasal test drugs under investigation. This study employed a Latin-square randomization procedure, therefore, the sequence of testing for the 9 intranasal drugs was unique for each participant.In this study's design, all participants received each of the 9 intranasal test drugs under investigation. This study employed a Latin-square randomization procedure, therefore, the sequence of testing for the 9 intranasal drugs was unique for each participant.
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Reinforcing Effects of Intranasal Buprenorphine Versus Buprenorphine/Naloxone in Buprenorphine-maintained Intranasal Drug Users
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bup 8 Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Experimental: Bup 16 Intranasal challenge drug: 16 mg of Buprenorphine administered intranasally.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Experimental: Bup/Nal 8/2 Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 2 mg of Naloxone.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Experimental: Bup/Nal 8/8 Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 8 mg of Naloxone.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Experimental: Bup/Nal 8/16 Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 16 mg of Naloxone.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Experimental: Bup/Nal 16/4 Intranasal challenge drug: 16 mg of Buprenorphine administered intranasally with 4 mg of Naloxone.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Active Comparator: Heroin Intranasal challenge drug: 24 mg of heroin administered intranasally.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Sham Comparator: Placebo Intranasal challenge drug: Intranasal lactose powder.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Active Comparator: Naloxone 4 mg Intranasal challenge drug: Intranasal Naloxone 4mg.	Drug: Intranasal challenge drug; Each of the experimental challenge drugs were administered intranasally to all participants in random order.

Outcome Measures

Primary Outcome Measures

1. Drug Self-administration [Throughout the testing sessions (approximately 9 weeks).]

   The maximum number of responses (clicks on a computer mouse) the participant was willing to perform in order to receive a dose of the intranasal challenge drug under investigation.

Secondary Outcome Measures

1. SOWS [Throughout the testing sessions (approximately 9 weeks).]

   Subjective opioid withdrawal scale (SOWS) measure (0-64). Greater score indicates more severe withdrawal.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 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 opioids in amounts and/or frequencies that meet or exceed those used in the proposed study (e.g., 1-2 bags of heroin per occasion at least twice per day)

• Self-administer IN buprenorphine above placebo levels during the qualification phase (see below)

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

• AST or 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 and Columbia University	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute
• Indivior Inc.

Investigators

• Principal Investigator: Sandra Comer, PHD, 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: NCT01760473
• Other Study ID Numbers: #5879
• First Posted: Jan 4, 2013
• Last Update Posted: Sep 8, 2017
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by New York State Psychiatric Institute: opioid dependence
• Additional relevant MeSH terms: Heroin Dependence

Study Results

Participant Flow

Arm/Group Title	Intranasal Challege Drug
Arm/Group Description	Each of the 9 experimental challenge drugs were administered intranasally to all participants in random order. This study employed a Latin-square randomization procedure, therefore, the testing order of the 9 IN doses was unique for each participant.
Period Title: Overall Study
STARTED	27
COMPLETED	12
NOT COMPLETED	15

Baseline Characteristics

Arm/Group Title	Intranasal Challege Drug
Arm/Group Description	Each of the 9 experimental challenge drugs were administered intranasally to all participants in random order.
Overall Participants	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.3 (7.7)
Sex: Female, Male (Count of Participants)
Female	1 3.7%
Male	26 96.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 37%
White	10 37%
More than one race	3 11.1%
Unknown or Not Reported	3 11.1%
Region of Enrollment (participants) [Number]
United States	27 100%

Outcome Measures

1. Primary Outcome

Title	Drug Self-administration
Description	The maximum number of responses (clicks on a computer mouse) the participant was willing to perform in order to receive a dose of the intranasal challenge drug under investigation.
Time Frame	Throughout the testing sessions (approximately 9 weeks).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bup 8	Bup 16	Bup/Nal 8/2	Bup/Nal 8/8	Bup/Nal 8/16	Bup/Nal 16/4	Heroin	Placebo	Naloxone 4 mg
Arm/Group Description	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 16 mg of Buprenorphine administered intranasally. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 2 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 8 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 16 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 16 mg of Buprenorphine administered intranasally with 4 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 24 mg of heroin administered intranasally. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: Intranasal lactose powder. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: Intranasal Naloxone 4mg. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Measure Participants	12	12	12	12	12	12	12	12	12
Mean (Standard Error) [Clicks on a computer mouse]	350 (135)	255 (121)	223 (113)	113 (83)	2.7 (2.7)	191 (112)	755 (156)	38 (23)	45 (30)

2. Secondary Outcome

Title	SOWS
Description	Subjective opioid withdrawal scale (SOWS) measure (0-64). Greater score indicates more severe withdrawal.
Time Frame	Throughout the testing sessions (approximately 9 weeks).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bup 8	Bup 16	Bup/Nal 8/2	Bup/Nal 8/8	Bup/Nal 8/16	Bup/Nal 16/4	Heroin	Placebo	Naloxone 4 mg
Arm/Group Description	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 16 mg of Buprenorphine administered intranasally. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 2 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 8 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 8 mg of Buprenorphine administered intranasally with 16 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 16 mg of Buprenorphine administered intranasally with 4 mg of Naloxone. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: 24 mg of heroin administered intranasally. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: Intranasal lactose powder. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.	Intranasal challenge drug: Intranasal Naloxone 4mg. Intranasal challenge drug: Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Measure Participants	12	12	12	12	12	12	12	12	12
Mean (Standard Error) [units on a scale]	3 (.5)	3 (.7)	3 (.9)	3 (.8)	5 (1)	3 (.5)	2 (.3)	2 (.53)	7 (1)

Adverse Events

Time Frame	Adverse events were collected from the day of admission until discharge and at 3 month follow-up
Arm/Group Title	Intranasal Challege Drug
Arm/Group Description	Each of the 9 experimental challenge drugs were administered intranasally to all participants in a randomized order. Therefore, the testing sequence for each of the participants was unique. Although we assessed for some averse events on a daily basis, other measures of health (e.g., blood chemistry) were assessed on a weekly basis. As multiple doses were tested during the week, therefore, in some cases we cannot causally connect some AEs to any individual drug/testing condition.
All Cause Mortality
	Intranasal Challege Drug
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Intranasal Challege Drug
	Affected / at Risk (%)	# Events
Total	0/27 (0%)
Other (Not Including Serious) Adverse Events
	Intranasal Challege Drug
	Affected / at Risk (%)	# Events
Total	2/27 (7.4%)
Metabolism and nutrition disorders
Elevated liver function test (AST/ALT)	2/27 (7.4%)	2

Limitations/Caveats

[Not Specified]

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.