Buprenorphine for human immunovirus-positive opiate-dependent patients.
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AIDS Serodiagnosis↗
Biomedical subjects
K L Preston
Publications and source records attributed to K L Preston.
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.
Administration, Oral↗
Acute administration of buprenorphine in humans: partial agonist and blockade effects.
Buprenorphine, a mixed opioid agonist-antagonist, is being investigated as a treatment for opioid dependence. This study compared the acute subjective and physiological effects of sublingual buprenorphine to those of p.o. methadone over a wide range of doses and compared the ability of both drugs to alter the effects of an opioid challenge. Male inpatient volunteers (n = 9) with histories of opioid abuse participated in this double-blind, double-dummy study. Sublingual buprenorphine (0, 0.5, 2, 8, 16 and 32 mg) and p.o. methadone (3.75, 15 and 60 mg) were administered once weekly according to a Latin-square design, and subjects were monitored on a variety of physiological and subjective measures. Twenty-four hours later, subjects were tested with ascending doses of i.m. hydromorphone (0, 1 and 4 mg) given 45 min apart. Buprenorphine and methadone produced typical opioid agonist effects of long duration, including pupillary constriction, respiratory depression and elevations on subject-rated and observer-rated indices of euphoria, sedation and opioid-like symptoms. The buprenorphine dose-effect curves were nonlinear and maximal effects for most physiological and subjective measures were observed between 4 and 8 mg, with no greater effects observed at higher doses. The methadone dose-effect curves were linear across the range of doses tested. High doses of buprenorphine and methadone both attenuated the response to hydromorphone challenge 24 hr later. These data indicate that there is a ceiling on the effects of buprenorphine in humans that may reduce its abuse liability and increase its safety, and indicate that opioid blockade occurs after acute administration of buprenorphine or methadone.
Adult↗
Buprenorphine effects in methadone-maintained volunteers: effects at two hours after methadone.
Buprenorphine is an opioid partial agonist being developed for possible use in the treatment of opioid dependence. In a previous study up to 8 mg of buprenorphine administered 20 hr after a daily dose of methadone in methadone-maintained volunteers produced neither agonist-like nor antagonist-like effects. The purpose of this study was to examine the effects of buprenorphine challenges given 2 hr after a daily methadone dose in maintained volunteers. Seven male volunteers maintained on 30 mg of methadone daily underwent pharmacologic challenges two to three times per week. Medication challenges consisted of double-blind i.m. injections of buprenorphine (0.5-8.0 mg), the opioid antagonist naloxone (0.1 and 0.2 mg), the prototypic opioid mu agonist hydromorphone (5 and 10 mg) or saline. Assessments of physiologic measures, volunteers' self-reports and observer ratings of drug effects were collected in a laboratory session for 2 hr after drug administration, and then for 8 additional hr postsession. Results from the laboratory session showed that on subject and observer ratings naloxone produced typical antagonist-like effects, hydromorphone produced mild agonist-like effects and buprenorphine produced antagonist-like effects. Interestingly, buprenorphine's antagonist activity was not directly dose-related; its most prominent antagonist effects occurred at the 1- and 2-mg doses. These results are consistent with buprenorphine's action as a partial mu opioid agonist and demonstrate that antagonist-like effects can occur under some conditions suggesting buprenorphine should have a low abuse liability in methadone-maintained patients.
Adult↗
Discriminative stimulus and subjective effects of theobromine and caffeine in humans.
Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.
Adult↗
Psychopharmacology and abuse potential of transnasal butorphanol.
The effects of butorphanol administered by a nasal spray (transnasal, TN) and by intramuscular (IM) injection were compared to determine the onset of action, relative potency, profile of effects, and relative abuse liability of TN butorphanol. TN/IM placebo and TN and IM butorphanol (1, 2, and 4 mg) were tested in seven male opioid abusers not currently physically dependent on opioids using a double-blind, double-dummy, Latin square design. Measures of subjective, behavioral and physiological response were assessed. The onset and duration of action of butorphanol administered by the IM and TN routes were similar at low doses, but onset of TN butorphanol 4 mg was slower than that of 4 mg IM. IM butorphanol produced miosis, some opiate-like behavioral and subjective effects, and increasing dysphoric sedation and perceptual effects with increasing dose. TN and IM butorphanol 1 and 2 mg produced effects that were qualitatively and quantitatively similar; however, TN butorphanol 4 mg was less potent than 4 mg IM. Pharmacodynamic evidence suggests that the abuse potential of TN butorphanol is not different from that of IM butorphanol.
Administration, Intranasal↗
Clinical pharmacology of buprenorphine: ceiling effects at high doses.
OBJECTIVE: The purpose of this study was to characterize the acute effects of buprenorphine, an opioid partial mu-agonist, across a wide range of doses in comparison to methadone. METHOD: Healthy adult male volunteers, who had experience with but were not physically dependent on opioids, participated while residing on a closed research unit. Four subjects received buprenorphine (0, 1, 2, 4, 8, 16, and 32 mg sublingually and five subjects received methadone (0, 15, 30, 45, and 60 mg orally) in ascending order at 1-week intervals. Physiologic, subjective, and behavioral measures were monitored for 96 hours after drug administration. RESULTS: Both drugs produced typical opioid agonist effects (positive mood, sedation, respiratory depression, and miosis), some of which persisted for 24 to 48 hours. A plateau was observed for the dose effects of buprenorphine on subjective measures and respiratory depression. Pharmacokinetic data revealed that plasma concentrations of buprenorphine were linearly related to dose, indicating no limits on sublingual absorption in this dose range. CONCLUSIONS: This study shows a plateau on buprenorphine effects, consistent with its partial agonist classification, and that single doses of buprenorphine up to 70 times the recommended analgesic dose are well tolerated by nondependent humans.
Administration, Sublingual↗
Buprenorphine reduces cerebral glucose metabolism in polydrug abusers.
Buprenorphine is a mixed opioid agonist-antagonist, which acts as a partial mu agonist and a kappa antagonist. The present study evaluated the acute effects of buprenorphine on cerebral glucose metabolism (CMRglc) in six human substance abusers using a double-blind, placebo-controlled, counterbalanced, crossover design. Each subject participated in two positron emission tomographic (PET) studies, 1 week apart, following the injection of buprenorphine (1 mg, intramuscularly) and placebo. Buprenorphine significantly reduced CMRglc and the regional cerebral metabolic rate for glucose (rCMRglc) by up to 32% in all but three of 22 bilateral and in 4 midline regions (p < .05). No region showed an increase in rCMRglc. Buprenorphine also produced miosis, respiratory depression, and subjective ratings of euphoria and sedation in comparison to placebo (p < .05). These observations extend previous findings of reduced CMRglc following acute treatment with morphine and other nonopioid euphorigenic drugs.
Adult↗
Drug discrimination assessment of agonist-antagonist opioids in humans: a three-choice saline-hydromorphone-butorphanol procedure.
To assess the discriminative stimulus properties of mixed agonist-antagonist opioids in humans, postaddict volunteers were trained in a three-choice drug discrimination procedure to discriminate among the effects of saline (4 ml i.m.), hydromorphone (3 mg i.m.) and butorphanol (6 mg i.m.). Subjects earned monetary reinforcement by correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were concurrently collected. After training, generalization curves for hydromorphone, butorphanol, pentazocine, nalbuphine and buprenorphine were determined. In generalization testing, both hydromorphone and butorphanol produced dose-related increases in hydromorphone-appropriate and butorphanol-appropriate responses, respectively, and other characteristic subjective effect measures. Nalbuphine produced dose-related increases in discrimination as butorphanol and in those subjective effect measures increased by butorphanol. Buprenorphine produced dose-related increases in discrimination as hydromorphone and in those subjective effect measures increased by hydromorphone. Pentazocine was not consistently discriminated as either butorphanol or hydromorphone. These results differ from those of previous discrimination studies using similar methods but different training drugs. Compared to a previous study in which pentazocine served as the kappa-like training drug, the use as a training drug of the more pharmacologically specific kappa-like drug butorphanol permitted greater differentiation among test drugs and yielded discrimination results more consistent with other pharmacological evidence (buprenorphine being mu-like and nalbuphine being kappa-like). There was a close relationship between results of the discrimination measures and the subjective effect measures.
Adult↗
Fluoxetine alters the effects of intravenous cocaine in humans.
Fluoxetine, a selective serotonin reuptake inhibitor, is currently being evaluated as a potential treatment for cocaine abuse. This 4-week inpatient study evaluated the pharmacologic interaction between fluoxetine and cocaine in healthy adult male volunteers (N = 5) with histories of cocaine abuse. Oral capsules were administered daily containing either placebo (weeks 1 and 4) or fluoxetine in a series of ascending doses (10, 20, 30, and 40 mg) where each dose was given for three to four consecutive days. Cocaine challenge sessions were conducted twice weekly, once at each active dose level and twice during both the placebo and washout phases. Subjects received three ascending intravenous doses of cocaine (0, 20, and 40 mg) 1.5 hours apart and were monitored on physiologic and subjective measures. Cocaine alone increased heart rate, blood pressure, and pupillary diameter and increased subjective reports reflecting positive mood effects and drug liking. Fluoxetine (40 mg) significantly decreased subjective ratings of cocaine's positive mood effects on several visual analog measures. Fluoxetine also attenuated the mydriatic effect of cocaine. No adverse physiologic interactions between the two drugs were observed on cardiovascular measures. These data suggest that fluoxetine may be safely used in the presence of cocaine use and should be investigated further as a potential pharmacotherapy for cocaine abuse.
Adult↗
Precipitated withdrawal by pentazocine in methadone-maintained volunteers.
Pentazocine is a partial mu agonist opioid with one-half to one-sixth the parenteral analgesic potency of morphine. The purpose of this study was to characterize the effects of pentazocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu agonist) and saline in methadone-dependent volunteers by using the same experimental methods used previously in the study of the opioid analgesics buprenorphine, butorphanol and nalbuphine. In a residential laboratory, five volunteer male opioid abusers, maintained on 30 mg p.o. of methadone daily, underwent pharmacological challenges 2 to 3 times per week. Pharmacological challenges consisted of a double-blind i.m. injection of: pentazocine (dose range 7.5-120 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg) or saline. Injections were given 20 hr after the last dose of methadone. Measures included physiological indices and self-reports and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively, on subjective, observer and physiological indices. Pentazocine produced primarily antagonist-like effects, with higher doses (> = 60 mg) producing significant elevations of visual analog scale ratings of Drug Effects, Bad Effects and Sick; of observer ratings of piloerection, restlessness and adjective scores of opioid withdrawal; as well as increases in blood pressure, heart rate and pupil diameter and decreases in skin temperature. Similar to the previous study of butorphanol, the specific profile of effects produced by pentazocine differed from that produced by naloxone, suggesting non-mu effects may modulate the mu effects of pentazocine.
Adult↗
Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers.
Naltrexone is more potent in blocking mu receptor activity than kappa receptor activity. This study examined the interactions of naltrexone with the mu agonist, hydromorphone, and with the mixed agonist-antagonist, pentazocine, to assess the apparent receptor mechanisms of their effects. After oral, 2-hr pretreatment with placebo or naltrexone (12.5 or 25 mg), a within-session cumulative dosing procedure (four intramuscular injections at 1-hr intervals) was used to assess the effects of hydromorphone (0, 0.75, 1.5 and 3 mg) and pentazocine (0, 15, 30 and 60 mg) vs. saline placebo. Subjective, physiological and behavioral effects were studied in six substance abusers. Hydromorphone significantly increased ratings on subjective measures typical of mu agonists, increased blood pressure and heart rate and decreased pupil diameter and respiratory rate; pretreatment with naltrexone (12.5 and 25 mg) blocked these effects. Pentazocine produced mu-like subjective effects, miosis and increases in blood pressure and heart rate. Naltrexone (12.5 mg) pretreatment decreased the mu-like subjective effects and miosis produced by pentazocine but increased kappa-like effects such as ratings of bad effects and Addiction Research Center Inventory LSD scale scores. Naltrexone (25 mg) blocked both the mu-like and kappa-like subjective effects of pentazocine. There was incomplete blockade of the cardiovascular effects of pentazocine. Thus, differential blockade of mu-like and kappa-like opioid effects by naltrexone was demonstrated in human subjects. Furthermore, the results suggest that mu agonist activity may suppress kappa-like effects such a dysphoria.
Adult↗
Effects of cocaine alone and in combination with mazindol in human cocaine abusers.
Mazindol is a catecholamine reuptake inhibitor that blocks binding of cocaine at the dopamine reuptake site. This study was conducted to determine whether the acute administration of mazindol modulates the pharmacological effects of intravenous cocaine in humans. In a crossover study, twelve acute drug conditions were tested in randomized order under double-blind, double-dummy conditions in eight cocaine abusers. Cocaine (0, 12.5, 25 and 50 mg, i.v.) was administered in combination with mazindol (0, 1 and 2 mg given orally 2 hr before the cocaine injection). Physiological and subject- and observer-rated responses were measured. Cocaine and mazindol alone both significantly increased heart rate and blood pressure. Cocaine increased ratings on stimulant-like subjective effect measures, including desire for cocaine; mazindol had mild, stimulant-like subjective effects. There were significant interactions between the effects of cocaine and mazindol on heart rate and blood pressure, with combinations producing significantly large and more sustained increases compared with cocaine alone. There was no evidence that mazindol substantially altered the magnitude or profile of the subjective effects of cocaine, including cocaine-induced craving for cocaine. These results do not support the utility of acute administration of mazindol in the treatment of cocaine abusers through a mechanism of modulation of cocaine's subjective effects. Furthermore, mazindol treatment may increase the cardiovascular risks of cocaine.
Adult↗
Supersensitivity to naloxone following acute morphine pretreatment in humans: behavioral, hormonal and physiological effects.
The effects of naloxone (10 mg/70 kg) given 6 h following acute exposure to morphine (4, 8, 16 mg/70 kg) were assessed in 5 opiate-abusing volunteers who were not physically dependent upon entering the study. Naloxone increased cortisol plasma levels more following morphine than placebo pretreatment. Naloxone reversed the effects of morphine on pupil diameter and oral temperature and decreased skin temperature as a function of morphine pretreatment. Subjects' ability to detect the effects of naloxone, their scores on an opiate-withdrawal questionnaire, and their visual-analog ratings of 'bad effects', 'chills', 'confused' and 'restlessness' increased when naloxone followed pretreatment with 8 and 16 mg, but not 4 mg, of morphine. Performance on the Digit Symbol Substitution Test was not discernibly affected under any of the dose conditions. Overall, results from the present study provide further evidence in humans that the administration of naloxone shortly following acute morphine pretreatment increases naloxone sensitivity, produces signs and symptoms typical of opiate withdrawal and that these effects are dependent on the dose of morphine administered.
Adult↗
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 agonist-antagonist 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.
Adult↗
Polaroid photoscreening for amblyogenic factors. An improved methodology.
BACKGROUND: The authors describe a new photoscreening camera designed to detect amblyogenic factors, including strabismus, asymmetric and abnormal refractive errors, and media opacities. The photoscreener uses eccentric photorefraction principles and provides two meridian photographs of the retinal reflex. METHODS: Pass/fail screening data from the photographs of 202 nondilated children as determined by two masked observers were compared with data from complete ophthalmologic examinations. RESULTS: The photoscreener had a sensitivity rate of 87%, a specificity rate of 89%, a positive predictive value of 93%, a negative predictive value of 80%, and an overall agreement rate of 88%. The prescreening probability for amblyogenic factors was 63%. Constant strabismus was detected in all cases. Five intermittent strabismus cases were missed. Two patients with myopia, three patients with hyperopia, and five patients with astigmatism were missed. All media opacities were detected. CONCLUSION: This new two-flash photoscreening camera, which uses high-speed Polaroid film, is an accurate, reliable method of detecting amblyogenic factors in undilated children. The camera offers promise as a useful mass screening tool.
Adolescent↗
Psychoactivity and abuse potential of sumatriptan.
Sumatriptan is a 5-HT1D agonist of therapeutic use in migraine and cluster headaches. To determine the profile of psychoactivity and abuse potential, a double-blind Latin-square crossover study was conducted in 12 male subjects with histories of substance abuse. The effects of subcutaneous placebo, sumatriptan (8 and 16 mg), and morphine (10 and 20 mg) were assessed on measures of subjective, behavioral, and physiologic responses including signs, symptoms, Addiction Research Center Inventory scales, onset of drug effects and miosis. Sumatriptan was psychoactive, was discriminated from placebo, produced a dose-related decrease on euphoria scores, elevated scores on measures of apathetic sedation and disliking, and lacked identification as a prototypic drug of abuse. There were no clinically significant effects on heart rate, pupil size, or blood pressure. In contrast, morphine (the positive control) produced expected dose-response relationships on measures of reinforcing and physiologic effects. The study suggests that sumatriptan has a low abuse potential.
Adult↗
Discrimination of agonist-antagonist opioids in humans trained on a two-choice saline-hydromorphone discrimination.
The stimulus properties of four opioid agonist-antagonists were assessed in postaddict volunteers trained in a two-choice drug discrimination procedure to discriminate between the effects of i.m. saline and hydromorphone (3 mg/70 kg). Behavioral, subjective and physiological measures were concurrently collected. After training, generalization curves were determined for hydromorphone, pentazocine, butorphanol, nalbuphine and buprenorphine. In generalization testing, hydromorphone produced dose-related increases in hydromorphone-appropriate responses and in characteristic opioid agonist-like subjective effects measures. In general, each of the study drugs produced a profile of subjective and physiological effects similar to that reported in other human studies. These subjective indices showed the study drugs to be heterogeneous. However, in this two-choice drug discrimination procedure, they were discriminated as homogeneous (i.e., all were discriminated as hydromorphone-like). The present study also found that all test drugs were subjectively identified as being opiates, and all were subjectively rated as similar to the hydromorphone training condition. A previous three-choice discrimination was sensitive to the heterogeneity among these drugs on both the discrimination measures and subjective ratings of similarity to the hydromorphone training condition. Thus, the specific procedures of drug discrimination studies may have an effect on some subjective indices, although this interaction is not apparent for the majority of subjective effect measures. Also, the characterization of opioids in drug discrimination testing appears to depend upon the specific training subjects receive; this is most clear with discrimination measures, and to a more limited extent, with subjective measures.
Adult↗