Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers

Comer, Sandra D.; Walker, Ellen A.; Collins, Eric D.

doi:10.1007/s00213-005-0023-6

Cited by 81 publications

(69 citation statements)

References 38 publications

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“…These data are consistent with the conclusion that naloxone and buprenorphine antagonize the reinforcing effects of heroin. These results are also consistent with the finding that maintenance on the opiate antagonist naltrexone or on buprenorphine decreases heroin versus money choice in detoxified heroin-dependent humans (Mello et al, 1981(Mello et al, , 1982Comer et al, 2005).…”

Section: Discussionsupporting

confidence: 86%

Choice between Heroin and Food in Nondependent and Heroin-Dependent Rhesus Monkeys: Effects of Naloxone, Buprenorphine, and Methadone

Negus

2006

J Pharmacol Exp Ther

117

148

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Several medications are approved for treatment of opiate abuse, but determinants of their clinical effectiveness are not completely understood. States of opiate dependence or withdrawal may constitute one important set of determinants. To test this hypothesis, the effects of naloxone, buprenorphine, and methadone were assessed on choice between heroin and food in nondependent rhesus monkeys and in heroin-dependent monkeys undergoing withdrawal. A choice procedure was used to permit dissociation of medication effects on the relative reinforcing properties of heroin from nonselective effects on response rates. In nondependent monkeys, increasing unit doses of heroin (0 -0.1 mg/kg/injection) maintained dose-dependent increases in heroin choice. Chronic 5-day treatment with naloxone (0.01-0.32 mg/kg/h) or buprenorphine (0.01-0.1 mg/kg/day) produced dose-dependent rightward shifts in heroin choice dose-effect curves, whereas chronic methadone (0.1-0.56 mg/kg/h) had little effect on heroin choice up to doses that suppressed responding. In heroin-dependent monkeys, opiate withdrawal produced overt abstinence signs as well as increases in heroin choice, manifested as leftward shifts in heroin choice dose-effect curves. The withdrawal-associated increases in heroin choice suggest that opiate withdrawal increased the relative reinforcing efficacy of heroin in comparison with food, an effect that may be related to relapse in humans. Methadone prevented withdrawal-associated increases in heroin choice, whereas buprenorphine was less effective. These findings suggest that agonist medications such as methadone may derive their clinical utility from their ability to attenuate withdrawal-associated increases in opiate reinforcement. Moreover, this procedure may be useful for exploring mechanisms underlying withdrawal-associated increases in opiate reinforcement and for testing candidate medications.

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Section: Discussionsupporting

confidence: 86%

Choice between Heroin and Food in Nondependent and Heroin-Dependent Rhesus Monkeys: Effects of Naloxone, Buprenorphine, and Methadone

Negus

2006

J Pharmacol Exp Ther

117

148

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“…than placebo, demonstrating abuse potential by the i.v. route of administration for this group (Comer et al 2002a(Comer et al , 2005(Comer et al , 2008bComer and Collins 2002). These latter findings are generally consistent with the results obtained in self-administration studies with animals and appear to be borne out by international epidemiological evidence of i.v.…”

Section: Human Laboratorysupporting

confidence: 89%

“…A laboratory comparison of a range of buprenorphine/ naloxone doses combinations on intranasal heroin selfadministration (12.5 to 50 mg) by opioid-dependent volunteers demonstrated that 8/2 mg and 32/8 mg buprenorphine/naloxone combinations were well tolerated and decreased heroin's reinforcing and subjective effects compared to a low dose of buprenorphine/naloxone (2/0.5 mg; Comer et al 2005). Thus, the combination appears to be efficacious at sufficient dose levels.…”

Section: Human Laboratorymentioning

confidence: 99%

Controversies in translational research: drug self-administration

2008

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Rationale Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. Objective The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. Results Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. Conclusions The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect.Keywords Cocaine . Opioid . Naloxone . Dopamine receptor . Drug abuse . Model . Monkey . Human . Reinforcement Laboratory testing of potential pharmacotherapies for drug abuse is an essential component of medication development. Although well-designed clinical trials are the standard by which the efficacy of a new medication is assessed, clinical trials test the effects of a potential treatment medication on a broad sample of patients, which is both costly and potentially risky. Before exposing a large number of treatment seekers to a medication, there needs to be both a strong scientific rationale for combining the medication with a drug of abuse as well as a demonstration that the co-administration of the medication and the abused drug is safe and selectively modifies the behavior of interest: drug taking.Models of drug self-administration in rodents, nonhuman primates, and humans have been used to evaluate the effects of candidate medications for the treatment of drug dependence. The self-administration model provides Psychopharmacology (2008) meaningful behavioral data on the safety and efficacy of potentia...

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“…One possible explanation is that the pretreatment dose of d-amphetamine (i.e., 15 mg) was insufficient. It should be noted that previous studies that have demonstrated that the progressive-ratio procedure is sensitive to pharmacological pretreatment agents have been conducted with opioid drugs (e.g., Comer et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans

Stoops¹,

Vansickel²,

Lile³

et al. 2007

Pharmacology Biochemistry and Behavior

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Recent clinical research indicates that d-amphetamine is effective in treating cocaine and methamphetamine dependence. There is concern, however, with the use of d-amphetamine as a pharmacotherapy because acute administration of d-amphetamine decreases inhibition in cocaineusing individuals and may increase drug-taking behavior. The purpose of the present experiment was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine. To this end, 7 human volunteers first sampled doses of oral d-amphetamine (0, 8, and 16 mg). These doses engender moderate drug taking and were selected to avoid a ceiling or floor effect. Volunteers were then allowed to self-administer these sampled doses using a modified-progressive ratio procedure in two sessions in which they received pretreatments with either 0 or 15 mg oral d-amphetamine 2 hours prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects (e.g., increased ratings of stimulated, elevated blood pressure) and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg oral d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressiveratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration.

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Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers

Cited by 81 publications

References 38 publications

Choice between Heroin and Food in Nondependent and Heroin-Dependent Rhesus Monkeys: Effects of Naloxone, Buprenorphine, and Methadone

Choice between Heroin and Food in Nondependent and Heroin-Dependent Rhesus Monkeys: Effects of Naloxone, Buprenorphine, and Methadone

Controversies in translational research: drug self-administration

Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans

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