Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers

Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence. Received: 9 February 1998/Final version: 8 May 1998     

Effects of buprenorphine/naloxone in opioid-dependent humans

RATIONALE: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. OBJECTIVES: To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers. METHODS: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind. RESULTS: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects. CONCLUSIONS: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).     

Acute and prolonged effects of clocinnamox and methoclocinnamox on nucleus accumbens dopamine overflow

The mu opioid antagonist clocinnamox (CCAM) insurmountably inhibits opioid self-administration. In contrast, CCAM’s prodrug, methoclocinnamox (MCCAM), acts as a weak partial agonist in this paradigm when given acutely and inhibits opioid self-administration for up to 5 days. In vivo microdialysis was employed to determine if these effects are paralleled in basal and opioid-stimulated dopamine (DA) overflow in the rat nucleus accumbens (NAC). When given acutely, CCAM (10 mg/kg SC) was essentially without effect. CCAM also markedly attenuated the overflow of DA induced by heroin (0.5 mg/kg SC; 200% of DA baseline) 24 h later. In contrast, MCCAM (10 mg/kg SC) acutely increased NAC DA overflow to 200–245% baseline within 30 min. NAC DA remained at this elevated level for the whole 3-h period of the experiment. Even after 24 h, NAC DA overflow of MCCAM-pretreated animals remained elevated at 165% of VEH-treated animals. Administration of heroin did not result in any further elevation of NAC DA release under these conditions. Thus, the suggested therapeutic profile of MCCAM, i.e., an acute partial agonistic reinforcing effect followed by antagonism of the reinforcing effects of subsequently abused opioids, was confirmed in NAC DA overflow, a neurochemical correlate of the reinforcing effects of drugs of abuse. The most parsimonious explanation for MCCAM’s effect on NAC DA overflow is that it acted as an essentially irreversible partial agonist. Received: 3 September 1996 / Final version: 7 May 1997     

Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine

RATIONALE: Buprenorphine is an opioid agonist-antagonist used in the treatment of opioid dependence. Naloxone has been combined with buprenorphine to decrease the parenteral abuse potential of buprenorphine. This addition of naloxone may also confer further opioid blockade efficacy. OBJECTIVES: To test the opioid blockade efficacy of sublingual buprenorphine/naloxone versus buprenorphine alone and determine whether: (1) the blockade efficacy of buprenorphine/naloxone varies between the time of expected maximal and minimal effects of naloxone, (2) the blockade efficacy of buprenorphine/naloxone and buprenorphine varies as a function of maintenance dose level, and (3) there are adaptive changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine. METHODS: Residential subjects ( n=6) were maintained on different double-blind dose levels of buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg) and buprenorphine (32 mg) for 6-day periods and challenged with parenteral doses of hydromorphone (12 mg) in laboratory sessions. RESULTS: There was no evidence of additional opioid blockade efficacy conferred by combining naloxone with buprenorphine. Higher doses of buprenorphine/naloxone provided greater blockade of hydromorphone effects. Changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine were minimal. CONCLUSIONS: The addition of naloxone to buprenorphine may deter the parenteral abuse of buprenorphine/naloxone, but it does not enhance the therapeutic efficacy of buprenorphine. The blockade efficacy of buprenorphine/naloxone is dose related; however, doses up to 32/8 mg buprenorphine/naloxone provide only partial blockade when subjects receive a high dose of an opioid agonist.     

Effects associated with double-blind omission of buprenorphine/naloxone over a 98-h period

Rationale Buprenorphine has a long duration of action that allows less than daily dosing for opioid dependence, but pharmacologic characterization of buprenorphine’s duration of effects over multiple days is incomplete.Objectives This study assessed opioid blockade and spontaneous withdrawal effects of buprenorphine/naloxone (B/N) over a 98-h period.Materials and methods Residential opioid-dependent volunteers (n = 8) were maintained, in randomized sequence, on each of three different daily sublingual B/N doses (8/2, 16/4, 32/8 mg). After 2 weeks on each maintenance dose, participants underwent challenge sessions on each weekday for 1 week. Challenges consisted of within-session, ascending dose administration of IM hydromorphone (H: 0, 6, and 12 mg). During that week, active B/N dose was given only on Monday; double-blind placebo was administered on the remaining weekdays. Thus, these sessions assessed the extent of both opioid blockade and spontaneous withdrawal at 2, 26, 50, 74, and 98 h after the last active B/N dose.Results All three maintenance doses provided substantial but incomplete blockade against opioid agonist effects for 98 h. The extent of blockade diminished steadily but modestly over this time and did not differ as a function of B/N maintenance dose. In general, participants did not report marked spontaneous opioid withdrawal, although mild withdrawal effects were observed as time since the last active B/N dose increased. However, withdrawal did not differ as a function of B/N maintenance dose.Conclusions These findings suggest that B/N doses greater than 8/2 mg provide minimal incremental value in terms of opioid blockade and withdrawal suppression.Some of these data were presented at the annual meeting of the College on Problems of Drug Dependence, Bal Harbour, Florida, June of 2003.     

Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers

Rationale: Buprenorphine is an opioid agonist-antagonist under development in the United States as a sublingual medication for treatment of opioid dependence. Buprenorphine may be abused; therefore, tablets combining buprenorphine with naloxone have been developed with the intent of reducing the abuse risk in people physically dependent upon opioids. The characteristics and abuse potential of buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers have not been determined. Non-parenteral abuse of opioids such as buprenorphine may be more likely in people who have less severe substance abuse disorders (e.g., are not physically dependent upon opioids). Objectives: To assess the abuse potential of sublingual buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers. Methods: Subjects (n=7) were tested with sublingual buprenorphine (4, 8, 16 mg), sublingual buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg), as well as intramuscular hydromorphone as an opioid agonist control (2, 4 mg) and placebo in laboratory sessions conducted twice per week. Dosing was double-blind and double-dummy. Results: The higher doses of both buprenorphine and buprenorphine/naloxone produced similar opioid agonist-like effects. The onset of these effects was slowed, consistent with the sublingual route of administration, and the magnitude of effects was moderate. There was no evidence to suggest the addition of naloxone attenuated buprenorphine’s opioid agonist effects in this population when buprenorphine was delivered by the sublingual route. Conclusions: These results suggest that sublingual buprenorphine and buprenorphine/naloxone may both be abused by opioid users who are not physically dependent upon opioids. Received: 15 April 1999 / Final version: 11 September 1999     

Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease

Rationale: One therapeutic benefit of mu opioid agonist or antagonist maintenance is the resultant attenuation of the effects of illicit opioids. It is important to characterize the development and duration of opioid blockade produced by buprenorphine, a novel opioid dependence pharmacotherapy. Objective: This study characterized the ability of buprenorphine to attenuate opioid effects during treatment initiation and discontinuation compared to naltrexone and placebo. Methods: Opioid-experienced volunteers (n = 8) participated in this 10-week, inpatient, double-blind, within-subject, crossover study. Five randomized conditions [buprenorphine (2 and 8 mg, sublingually), naltrexone (25 and 100 mg, PO) and placebo] were each examined during a 2-week period; the test drug was given for 7 days followed by a 7-day placebo wash-out. Cumulative doses of hydromorphone (0, 2 and 4 mg, IM, 45 min apart) were administered thrice-weekly corresponding with treatment and wash-out days 1, 3, and 5; behavioral, physiological and pharmacokinetic measures were collected. Results: Buprenorphine alone produced dose-related prototypic agonist effects during induction (i.e., positive mood, respiratory depression, miosis); tolerance developed only to the subjective effects. Buprenorphine 2 mg partially attenuated the effects of hydromorphone, while nearly complete attenuation was observed with 8 mg that lasted up to 72 h after discontinuation. Both naltrexone doses produced complete hydromorphone blockade after a single dose; blockade of the behavioral, but not physiological, effects persisted for 5 days after discontinuation of 100 mg. Conclusions: These data suggest that 2 mg buprenorphine is a sub-therapeutic maintenance dose, both buprenorphine 8 mg and naltrexone produce immediate and efficacious opioid blockade, and adequate protection against illicit opioids may be achieved with less-than-daily dosing. Received: 2 October 1998/Final version: 4 February 1999     

Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans

RATIONALE: The availability of the highly selective and specific kappa opioid agonist enadoline provides an opportunity to explore the function of kappa receptors in humans and their potential utility as a target for substance abuse pharmacotherapy development. OBJECTIVES: The purpose of this study was to characterize the pharmacodynamic effects of enadoline, a selective kappa agonist, and to compare it with butorphanol, a mixed mu/kappa agonist, and hydromorphone, a mu agonist, in humans. METHODS: Pilot evaluation (n=3) served to establish intramuscular doses of enadoline (20, 40, 80, and 160 microg/70 kg), butorphanol (1.5, 3, 6, and 12 mg/70 kg), and hydromorphone (1.5, 3, and 6 mg/70 kg) of comparable activity. These acute doses were examined under double-blind, placebo-controlled and constrained randomized conditions with a minimum of 72 h between tests in volunteers with polysubstance abuse histories (n=6). Physiological and subject- and observer-rated measures were collected 30 min before and for 4 h after administration. RESULTS: Enadoline significantly increased measures of sedation, confusion and dizziness, produced visual distortions and feelings of depersonalization, and increased urinary output. The highest dose (160 microg/70 kg) was not tolerated and led to psychotomimetic effects. Hydromorphone produced prototypic mu opioid effects including respiratory depression, miosis, and euphoria. Butorphanol was most similar to hydromorphone and shared few effects with enadoline. CONCLUSIONS: These results are discussed with respect to the potential use and safety of kappa agonists for clinical indications.     

Motivational properties of buprenorphine as assessed by place and taste conditioning in rats

Buprenorphine, a mixed agonist-antagonist opioid with considerable analgesic activity, is currently indicated as a therapeutic agent with low abuse potential. Nevertheless, buprenorphine abuse has been recently reported from some countries. Thus the present experiments were performed to characterize further the motivational properties of buprenorphine in rats. Rewarding and aversive effects were assessed by place preference and taste aversion conditioning, respectively. It was found that buprenorphine (0.025, 0.050, 0.100 mg/kg SC) causes a significant increase in the amount of time spent on the conditioned side, but no significant decrease in saccharin consumption. Therefore buprenorphine data are not consistent with the general finding that psychoactive drugs cause rewarding and aversive effects within a similar dose range. Received: 13 March 1996/Final version: 18 October 1996     

Effects of buprenorphine and methadone in methadone-maintained subjects

Buprenorphine, a partial mu opioid agonist, is an experimental medication under development for the treatment of opioid dependence as an alternative to methadone maintenance. The present study examined the relationship between level of opioid physical dependence and response to buprenorphine administration as part of a program to develop procedures for transferring patients from methadone to buprenorphine treatment. This laboratory study characterized the agonist and antagonist effects of acute doses of buprenorphine and methadone in subjects maintained on either 30 (n=7) or 60 (n=6) mg/day oral methadone. Test doses of placebo [sl. and PO), methadone (15, 30, and 60 mg PO) and buprenorphine (2, 4, and 8 mg sl.) were administered to volunteers residing on a closed residential unit. Subjective, physiological, observer-rated, and cognitive/psychomotor measures were collected for 6.5 h after test doses. Test doses of methadone, but not buprenorphine, constricted pupils and produced dose-related increases on subjective report measures reflecting opioid agonist drug effects. Agonist effects of methadone were more prominent in the 30 mg than in the 60 mg methadone maintenance condition. Buprenorphine, but not methadone, precipitated opioid withdrawal signs and symptoms that were more prominent in the 60 mg than in the 30 mg methadone maintenance condition. These findings suggest that abrupt transition from methadone to buprenorphine may produce patient discomfort that is positively related to both methadone maintenance dose and buprenorphine transition dose.     

Buprenorphine alone and in combination with naloxone in non-dependent humans

This study evaluated the effects of concurrent naloxone on the opioid agonist effects of buprenorphine, a mixed agonistantagonist marketed as an analgesic and under development as a treatment for drug abuse. In a residential laboratory seven non-physically-dependent opioid abuser volunteers received intramuscular buprenorphine (0.4 mg or 0.8 mg/70 kg) alone and in combination with naloxone (0.4 mg or 0.8 mg/70 kg) versus placebo. Buprenorphine produced dose-related opioid agonist effects on physiological and subjective measures. Concurrent naloxone attenuated the opioid agonist effects of buprenorphine. Thus, a combination product of buprenorphine and naloxone may have lower abuse liability than buprenorphine alone.     

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.     

Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans

RATIONALE: Buprenorphine can decrease opioid self-administration by humans and animals, but its ability to decrease drug-seeking behavior and craving (i.e. motivational measures) among outpatient volunteers using clinically relevant dosing schedules has not been extensively studied. OBJECTIVES: We investigated whether daily versus alternating-day administration of high versus low buprenorphine doses influenced choice of, and operant responding for, hydromorphone versus money. METHODS: Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet (double blind) dose conditions using a within-subject, randomized crossover design. All participants received, for 2 weeks each, buprenorphine doses of 2 mg daily, 4 mg/placebo on alternating days, 16 mg daily, and 32 mg/placebo on alternating days. In each laboratory test session, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg IM in different sessions) alternatives using an eight-trial non-independent progressive ratio schedule (FR 100, 200,.12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. RESULTS: Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average buprenorphine doses (regardless of daily versus alternate-day schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline heroin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by high-dose buprenorphine. CONCLUSIONS: High-dose buprenorphine attenuated opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alternative reinforcement. These beneficial effects were retained when high-dose buprenorphine was administered on alternate days.     

Modest opioid withdrawal suppression efficacy of oral tramadol in humans

Rationale Tramadol is in an unscheduled atypical analgesic with low rates of diversion and abuse and mixed pharmacologic actions, including modest opioid agonist activity. Objectives The purpose of the current study was to characterize the opioid withdrawal suppression efficacy of oral tramadol. Materials and methods Residential, opioid-dependent adults (n = 10) were maintained on morphine (15 mg subcutaneously, quad in diem) for approximately 6 weeks. Spontaneous opioid withdrawal was produced by substituting placebo for scheduled morphine doses 17.5 h before experimental sessions that occurred twice weekly. The acute effects of placebo, tramadol (50, 100, 200, and 400 mg orally), naloxone (0.1 and 0.2 mg intramuscularly [IM]), and morphine (15 and 30 mg IM) were tested under double-blind, double-dummy, randomized conditions. Outcomes included observer- and subject-rated measures, physiologic indices, and psychomotor/cognitive task performance. Results Naloxone and morphine produced prototypic opioid antagonist and agonist effects, respectively. Tramadol 50 and 100 mg produced effects most similar to placebo. Tramadol 200 and 400 mg initially produced significant dose-related increases in ratings of “bad effects” and “feel sick,” followed by evidence of opioid withdrawal suppression. Tramadol did not produce significant increases on measures of positive drug effects nor any clinically significant physiologic changes. Conclusions Tramadol 200 and 400 mg show evidence of opioid withdrawal suppression without significant observer- and subject-rated opioid agonist effects. The profile of action did not suggest a high risk for tramadol abuse in opioid dependent individuals. Tramadol may be a useful medication for treating opioid withdrawal.     

Cross-tolerance and mu agonist efficacy in pigeons treated with LAAM or buprenorphine

The mechanism responsible for decreased opioid use during opioid substitution therapy is not fully understood. To examine whether l-alpha-acetylmethadol (LAAM) or buprenorphine attenuate behavioral effects of opioids through cross-tolerance, discriminative stimulus effects of high and low efficacy mu agonists were examined following 3- or 7-day treatment with LAAM or buprenorphine in pigeons discriminating between saline and heroin or between saline and buprenorphine, respectively. Heroin, buprenorphine and nalbuphine occasioned high levels of drug-appropriate responding in both groups; kappa opioids and non-opioids occasioned predominantly saline-appropriate responding. Administration of LAAM (3.2 mg/kg) or buprenorphine (3.2 mg/kg) occasioned predominantly heroin- or buprenorphine-appropriate responding, respectively. After discontinuation of LAAM treatment, the potency in occasioning heroin-key responding was markedly decreased for nalbuphine, slightly decreased for buprenorphine, and unchanged for heroin. Following discontinuation of buprenorphine treatment, the potency in occasioning buprenorphine-key responding was decreased for nalbuphine and unchanged for buprenorphine and heroin. Thus, greater cross-tolerance developed from LAAM and buprenorphine to low efficacy mu agonists as compared to a higher efficacy agonist. Failure of LAAM and buprenorphine treatment to modify the effects of heroin, under conditions that attenuate the effects of lower efficacy mu opioids, provides a possible rationale for why heroin abuse persists in some patients receiving large doses of agonists in substitution therapy.     

In vivo apparent affinity and efficacy estimates for μ opiates in a rat tail-withdrawal assay

Experiments in a rat tail-withdrawal assay tested the hypothesis that the magnitude and pattern of antagonism of μ opiate agonists by the insurmountable μ opioid antagonist clocinnamox are inversely related to agonist efficacy. In addition, these experiments examined whether this antagonism could be quantified to yield apparent affinity and efficacy estimates for the pharmacological characterization of five opiate agonists. Etonitazene, etorphine, morphine, buprenorphine, and GPA 1657 produced dose-dependent increases in tail-withdrawal latency until 100% maximum possible effect (%MPE) was obtained. Morphine required a higher dose of clocinnamox for a 50% reduction in maximal antinociceptive effect than did buprenorphine or GPA 1657. In contrast, no dose of clocinnamox tested decreased the%MPE for etonitazene or etorphine. These data suggest a rank order of relative efficacy of etonitazene ≥ etorphine > morphine ≥ GPA 1657 ≥ buprenorphine. Similarly, numerical analysis of these data yielded the following apparent affinity and efficacy estimates: etonitazene (0.38 mg/kg, 128); etorphine (0.68 mg/kg, 125); morphine (50 mg/kg, 38), GPA 1657 (6.6, 39); and buprenorphine (0.042 mg/kg, 2.2). These data illustrate that in vivo affinity and efficacy estimates for a number of agonists are remarkably similar across different methods of analysis and are useful for drug classification. Received: 6 February 1997 / Final version: 16 July 1997     

Acute effects of intramuscular and sublingual buprenorphine and buprenorphine/naloxone in non-dependent opioid abusers

Rationale  

Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid-dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence.     

Discriminative stimulus effects of buprenorphine in the rat

 Buprenorphine, a potent ”low efficacy” or ”partial” morphine-like opioid agonist, has morphine-like discriminative effects in animals and humans discriminating morphine or a related drug. The purpose of the present study was to characterize further the discriminative effects of buprenorphine in subjects trained to discriminate buprenorphine itself. Rats trained to discriminate between SC injections of saline and either 0.03 or 0.1 mg/kg buprenorphine generalized completely to morphine and to other morphine-like agonists. These drugs were approximately 3 times more potent in the rats trained with 0.03 mg/kg buprenorphine than in those trained with 0.1 mg/kg; however, the potency of buprenorphine itself did not differ significantly between groups. Indicative of efficacy differences among mixed-action opioids, rats discriminating 0.03 mg/kg buprenorphine generalized completely to butorphanol and pentazocine and partially to nalbuphine, whereas those discriminating 0.1 mg/kg generalized completely to butorphanol, partially to pentazocine, and little to nalbuphine. Stimulus control of behavior by 0.1 mg/kg buprenorphine was blocked surmountably by low doses of antagonists, stereoselective, and pharmacologically selective. These results are consistent with those of other studies showing that the discriminative effects of buprenorphine are morphine-like and mediated by the mu-opioid receptor, and extend the conditions under which this has been demonstrated to stimulus control maintained by buprenorphine itself. Received: 18 September 1996 / Final version: 6 November 1996     

Buprenorphine and naloxone alone and in combination in opioid-dependent humans

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.Supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse