Thrice-weekly supervised dosing with the combination buprenorphine-naloxone tablet is preferred to daily supervised dosing by opioid-dependent humans.

A sublingual tablet formulation of buprenorphine combining 8 mg of buprenorphine with 2 mg of naloxone is being targeted for use in settings where less than daily dosing strategies and/or prescription-based dispensing will likely be employed. This study determined patient preferences for, and clinical outcomes during, daily and 3-day per week supervised dosing schedules using the combination tablet. Twenty-four opioid-dependent subjects completing a 16-day baseline entered an outpatient triple crossover trial. Twenty-one days of daily dosing were compared to two different 21-day periods of 3-day per week supervised dosing: a 3-day per week clinic schedule and a 3-day per week take-home schedule in which tablets were provided to subjects to take at home on days between clinic visits. Thirteen patients completed the study. Significantly more doses were ingested under the 3-day per week schedules. Illicit drug use did not differ across conditions and 45% of urine samples tested positive for illicit opioids. Subjects 'liked' both 3-day per week schedules more than the daily schedule, and ratings of feeling 'good' were higher for the 3-day take-home as opposed to 3-day clinic condition. Almost all subjects (91%) rated 3-day take-home as the most preferred schedule. Overall, reducing clinic attendance improved medication compliance and increased client satisfaction without impacting illicit drug use.

Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet.

This study evaluated the efficacy of a combination tablet formulation of buprenorphine containing 8 mg of buprenorphine and 2 mg of naloxone for every other day treatment and whether increasing the daily maintenance dose was essential for maintaining an efficacious alternate-day treatment. Twenty-six opioid-dependent outpatients completing a 16-day baseline entered a double-blind, placebo-controlled, triple crossover trial. Twenty-one days of daily combination tablet administration were compared to two different 21-day periods of alternate-day buprenorphine administration where subjects received either 8 or 16 mg of the combination tablet every other day with placebo on the interposed day. Fifty-four percent (14/26) of subjects completed the study, but only two subjects dropped out during the 16-mg alternate-day condition. Rates of medication compliance, illicit opioid use and subject- and observer-rated measures of opioid effects did not distinguish daily from alternate-day treatments in subjects completing the study. However, pupillary diameter was significantly increased during 8-mg alternate-day compared to the 8-mg daily or 16-mg alternate-day treatment. These data replicate earlier findings describing the acceptability of alternate-day buprenorphine treatment using multiples of the daily maintenance dose and extend these findings by establishing the clinical efficacy of daily and alternate-day dosing regimens with the combination buprenorphine naloxone tablet. This study also suggests slightly improved outcomes during alternate-day treatment using multiples of the daily dose.

Secobarbital in humans discriminating triazolam under two-response and novel-response procedures.

Humans were trained to discriminate the benzodiazepine triazolam (0.32 mg/70 kg) from placebo under a two-response (drug vs. placebo) drug discrimination procedure. Dose-effect curves for several drugs were then determined in a crossover design using the two-response procedure and a 'novel-response procedure' that provided a novel-appropriate response for drugs unlike triazolam or placebo. Three subjects were tested with triazolam (0.1-0.32 mg/70 kg), the barbiturate secobarbital (56-177 mg/70 kg), and caffeine (320 and 560 mg/70 kg). Triazolam dose dependently increased triazolam-appropriate responding under both procedures and generally did not occasion novel-appropriate responding under the novel-response procedure. Secobarbital substituted for triazolam in the two-response procedure and dose-dependently increased novel-appropriate responding as well as occasioned some triazolam-appropriate responding in the novel-response procedure. Caffeine generally occasioned placebo-appropriate responding under the two-response procedure and a mix of novel- and placebo-appropriate responding under the novel-response procedure. Triazolam and secobarbital produced qualitatively similar self-reported drug effects. These results suggest that the novel-response procedure for human drug discrimination may enhance the pharmacological selectivity of triazolam- and placebo-appropriate responding.

A bibliography of drug discrimination research, 1992-1994.

The major content of this publication is a comprehensive bibliography of research into the discriminative stimulus effects of drugs in animal and human subjects for the period 1991-1994. The bibliography is accompanied by a detailed cross-index that facilitates access to this literature through keywords based on the drugs studied, how the drugs were used, and numerous other methodological variables such as species of subject and schedule of reinforcement. The article also explains how users may obtain access to the present and earlier versions of the database, which are available as computer disks and over the Internet. The easy access to this literature made possible by the database should increase the working efficiency of the many groups that employ drug discrimination methods and should also support dissemination of the knowledge acquired to a wider scientific community.

Placebo-effects contribute to differences in the acquisition of drug discrimination by humans: a retrospective analysis.

Adult human volunteers (n = 50) were trained to discriminate triazolam (TRZ, 0.32mg/70kg, p.o.) from placebo. Based on a criterion that required greater than 80% capsule-appropriate responding during each of four test sessions, 19 subjects were designated non-discriminators (NDs) and 31 were designated discriminators (Ds). NDs and Ds did not differ significantly in age, weight, gender or previous drug use and generally reported similar effects following TRZ. NDs reported greater effects following placebo than Ds on several measures, including 'good', 'bad', 'high' and sedative drug effects, suggesting that NDs in this study were 'placebo reactors'. These results show that NDs and Ds of TRZ differed in self-reported responses and suggest a close relationship between acquisition of a drug discrimination and self-reported effects of drugs. Moreover, greater placebo effects may hinder acquisition of TRZ discrimination.

Triazolam discrimination by humans under a novel response procedure: effects of buspirone and lorazepam.

Six healthy human volunteers (ages 18 to 24) acquired a triazolam (0.32mg/70kg) vs placebo discrimination under a standard, two-response drug discrimination procedure. Dose-effect curves were then determined for triazolam (0.1-0.56mg/70kg), lorazepam (0.75-3.0mg/70kg) and buspirone (7.5-30mg/70kg) under a novel response procedure that provided a response alternative for drugs unlike triazolam or placebo (i.e. a novel-appropriate response). Triazolam dose-dependently increased triazolam-appropriate responding but did not occasion any novel-appropriate responding. Lorazepam dose-dependently increased triazolam-appropriate responding in four of six subjects, but at least one dose also occasioned novel-appropriate responding in three subjects. Buspirone dose-dependently increased novel-appropriate responding, although three of six subjects also made triazolam-appropriate responses following some dose(s). All three drugs comparably increased self-reported sedation. Self-reported effects did not differentiate triazolam from lorazepam whereas only buspirone increased "bad" self-reports, and did not increase "liking" and "good" self-reports. The results suggest that the novel response procedure enhanced the pharmacological selectivity of human benzodiazepine discrimination and may help interpret partial generalization under two-choice drug discrimination procedures. The results also add to the evidence of a close relationship between the discriminative stimulus and self-reported effects of drugs.

Effects of diazepam and hydromorphone in triazolam-trained humans under a novel-response drug discrimination procedure.

Seven healthy normal male and female volunteers (21-31 years) were trained to discriminate between the benzodiazepine triazolam (0.32 mg/70 kg, PO; e.g., drug A) and placebo (e.g., drug B) under a three-choice, instructed novel response drug discrimination procedure. Once the criterion for discrimination was met (i.e., > 85% correct responding on four consecutive sessions), dose-effect curves were determined for triazolam (0.1-0.56 mg/70 kg), the benzodiazepine diazepam (10-32 mg/70 kg) and the opioid agonist hydromorphone (1-6 mg/70 kg). Subjects met the criterion for discrimination within four to six sessions. Triazolam and diazepam produced dose-related increases in triazolam-appropriate responding and no novel-appropriate responding at any dose tested. In contrast, hydromorphone generally increased novel-appropriate responding in a dose-related manner with placebo-appropriate responding and some triazolam-appropriate responding at intermediate doses occurring also. Triazolam and diazepam produced qualitatively similar increases on several measures of sedative drug effects; hydromorphone increased ratings of "like novel" and sedative-like effects in subjects who discriminated hydromorphone as novel relative to those who did not. These results indicate that the novel response drug discrimination procedure enhances the specificity of the triazolam-placebo discrimination.

The effects of delta(9)-tetrahydrocannabinol on repeated acquisition and performance of response sequences and on self-reports in humans.

This study assessed the acute effects of delta(9)-tetrahydrocannabinol (THC) on learning and performance, using a repeated acquisition and performance paradigm, in eight healthy adult humans. Subjective ratings of drug effects were also collected. In each component of a multiple schedule, subjects completed a different sequence of 10 responses using three keys of a numeric keypad. In the acquisition component, subjects learned a new sequence with each series of 20 trials. In the performance component, the sequence remained constant throughout the study. The multiple schedule and rating scales were presented pre-drug, post-drug and at 30min intervals thereafter for 5h. THC (10-20mg, p.o.) increased the peak percentage of errors during the acquisition component from 7.0% to 9.3% but responding during the performance component was unchanged. THC decreased Digit Symbol Substitution Test performance, increased Profile of Mood State ratings of confusion, depression and general mood disturbance and Visual Analog Scale ratings of strength of drug effect, good and bad effects, but did not alter Addiction Research Center Inventory ratings. In summary, THC in humans caused a slight learning deficit at behaviorally active doses under the repeated acquisition procedure.

Effects of intermittent buprenorphine administration on cocaine self-administration by rhesus monkeys.

In previous studies, daily buprenorphine administration significantly reduced cocaine self-administration by rhesus monkeys over 15 to 120 days (Mello et al., 1990, 1992). This report describes the effects of 60 days of intermittent buprenorphine (0.40 mg/kg) treatment once every 48 hr or 72 hr on cocaine and food self-administration by six rhesus monkeys. Cocaine (0.05 or 0.10 mg/kg/injection) and food (1-g banana pellet) self-administration were maintained on a fixed ratio 4, (variable ratio 16:S) reinforcement schedule. Intermittent buprenorphine treatment reduced cocaine self-administration significantly below saline treatment levels (P < .01). On the first day of buprenorphine treatment, cocaine self-administration averaged 53 and 60% below base line (P < .01-.0001). Cocaine self-administration remained significantly below base line on day 2 (P < .02-.0001) but usually returned to base-line levels by day 3. During buprenorphine treatment once every 48 hr, cocaine self-administration gradually increased over time in four monkeys (P < .001-.0005). These data suggest that intermittent buprenorphine treatment is less effective than daily buprenorphine treatment in reducing cocaine self-administration by rhesus monkeys. Food self-administration decreased by 23.6 and 12.7% from the saline base line during buprenorphine treatment every 48 and 72 hr, respectively. On the day of buprenorphine treatment, food self-administration was usually significantly lower than during the saline base line (P < .05-.0001), but usually returned to or exceeded base line levels by days 2 and 3. There were no significant changes in food self-administration over time with intermittent buprenorphine treatment every 48 hr.

The effects of nalbuphine and butorphanol treatment on cocaine and food self-administration by rhesus monkeys.

This study was designed to determine whether opioid mixed agonist-antagonist analgesics other than buprenorphine also selectively reduce cocaine self-administration by rhesus monkeys. The effects of daily treatment with nalbuphine (0.1 to 3 mg/kg/day) or (0.254 to 7.62 mumol/kg/day), butorphanol (0.01 to 0.3 mg/kg/day) or (0.0209 to 0.628 mumol/kg/day), and saline on cocaine and food self-administration were each studied for 40 sessions over 10 consecutive days. Cocaine (0.05 or 0.10 mg/kg/inj) and food (1-gm banana pellets) self-administration were maintained on a fixed ratio 4 (variable ratio 16:S) schedule of reinforcement. Both nalbuphine and butorphanol reduced cocaine self-administration (p < 0.0001) but this effect was not selective since food self-administration also decreased in a dose-dependent manner (p < 0.0001). Nalbuphine administration (1 to 3 mg/kg/day) decreased cocaine injections to 40% to 60% below baseline (p < 0.01) and food pellets 30% to 68% below baseline (p < 0.01). Lower doses of nalbuphine (0.10 and 0.30 mg/kg) did not change cocaine- or food-maintained responding significantly. All doses of butorphanol (0.01 to 0.3 mg/kg/day) reduced cocaine injections to 16% to 58% below baseline (p < 0.01). Food self-administration decreased to 21% to 70% below baseline (p < 0.01) at butorphanol doses of 0.03 to 0.3 mg/kg/day). These data suggest that these opioid mixed agonist-antagonist analgesics may not be useful as pharmacotherapies for the treatment of cocaine abuse.

A novel-response procedure enhances the selectivity and sensitivity of a triazolam discrimination in humans.

Placebo-appropriate responding in drug discrimination can be difficult to interpret because such responding can indicate either the absence of any drug effect or the absence of a specific drug effect. This study addressed the overinclusiveness of placebo-appropriate responding by providing a response alternative for novel-drug effects (i.e., effects unlike the training stimuli). This "novel-response procedure" used instructions that indicated that only responses on a novel-appropriate manipulandum would be reinforced in the presence of novel drug effects. Four healthy male volunteers (ages 19-32) were trained to discriminate 0.32 mg/70 kg of triazolam from placebo. Then, dose-effect curves were determined for triazolam (0.1-0.32 mg/70 kg) and d-amphetamine (5 and 20 mg/70 kg) with a standard two-response procedure (drug vs. placebo) and the novel-response procedure. Triazolam produced dose-related increases in triazolam-appropriate responding with both procedures. d-Amphetamine produced predominantly placebo-appropriate responding with the two-response procedure and predominantly novel-appropriate responding with the novel-response procedure. Unexpectedly, the triazolam dose-effect curve obtained with the novel-response procedure was shifted to the left relative to the two-response procedure for discrimination measures. A similar effect was evident for both the triazolam and d-amphetamine dose-effect curves for some self-report measures. Because of the increased selectivity of placebo-appropriate responding and the increased potency of the drug stimulus, the novel-response procedure may represent a methodological advance for drug discrimination research.

Drug discrimination by humans compared to nonhumans: current status and future directions.

In drug discrimination (DD) procedures, behavior is differentially reinforced depending on the presence or absence of specific drug stimuli. The DD paradigm has been widely adopted by behavioral pharmacologists because of its specificity of stimulus control, concordance with drug action at cellular levels and its use as a preclinical model of subject-rated effects in humans. With the successful extension of DD to humans, a comparison of human and nonhuman DD will help place each in the context of the other. Twenty-eight studies of DD in humans are reviewed, including studies of amphetamine, opioid, benzodiazepine, caffeine, nicotine, marijuana and ethanol discriminative stimuli. Comparison of procedures between studies in humans and nonhumans reveals a common tradition, except the use of instructions appears to facilitate greatly DD acquisition in humans. Findings were qualitatively similar between humans and nonhumans. Potency relationships were quantitatively similar between humans and most, but not all, other species. Areas of human DD needing additional empirical evaluation include the influence of instructions, the effects of training dose and the effects of antagonists. Additionally, antihistamines, barbiturates, nicotine and marijuana are under-represented in human DD.

The effects of chronic buprenorphine treatment on cocaine and food self-administration by rhesus monkeys.

The goal of this study was to determine if buprenorphine continues to reduce cocaine self-administration over long periods of treatment, or if tolerance develops to this effect. The effects of 30 to 120 days of buprenorphine treatment (0.32 mg/kg/day) on cocaine and food self-administration were examined in six rhesus monkeys. Saline control treatment was studied for 15 days before and after buprenorphine treatment. Intravenous cocaine (0.05 or 0.10 mg/kg) and food (1 g banana pellet) self-administration were maintained on a FR 4 (VR 16:S) schedule of reinforcement. Cocaine self-administration decreased significantly (P less than .0001) and remained 60 to 97% below saline treatment baseline levels (52 +/- 2 injections/day) throughout 120 days of buprenorphine treatment (P less than .01). After substitution of saline for buprenorphine, cocaine self-administration resumed and averaged between 21 (+/- 3.6) and 56 (+/- 6.5) injections per day over 20 days. Buprenorphine plasma levels averaged 18 (+/- 2.84) ng/ml (range 10.9-30 ng/ml) during buprenorphine treatment. Buprenorphine plasma levels usually decreased by 50% or more within 27 hr after the last buprenorphine dose. Low levels of buprenorphine (0.10-0.19 ng/ml) were measured for 30 to 74 days after abrupt termination of daily buprenorphine treatment. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding developed over 30 to 70 days of treatment. Food self-administration returned to and significantly exceeded (P less than .05-.01) saline treatment base-line levels, whereas cocaine self-administration remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of the discriminative-stimulus effects of cocaine by buprenorphine.

Modulation of the discriminative-stimulus effects of cocaine by the mixed-action opioid buprenorsphine was studied in squirrel monkeys trained to discriminate cocaine from saline, using a two-lever drug discrimination procedure. Lever pressing was maintained under a fixed-ratio 10 schedule of food presentation. During test sessions, monkeys received cumulative doses of cocaine after presession treatment with either saline or buprenorphine (0.001-0.01mg/kg). After pretreatment with saline, cocaine engendered dose-related increases in the percentage of cocaine-appropriate responses, reaching a maximum of 99-100 percent at doses of 0.3 or 1.0mg/kg. Pretreatment with buprenorphine shifted the cocaine dose-response function to the left, resulting in 98-100 percent cocaine-appropriate responding at doses of cocaine that previously engendered only saline-appropriate responding. When tested alone, buprenorphine did not occasion cocaine-appropriate responding at any dose. The results show that although buprenorphine does not itself have cocaine-like discriminative-stimulus effects, it can potentiate the discriminative-stimulus effects of cocaine.

N-modified fluorophenyltropane analogs of cocaine with high affinity for cocaine receptors.

The binding properties of three N-modified fluorophenyltropane analogs of cocaine were compared in competition experiments with [3H]cocaine. All three analogs displaced specifically bound [3H]cocaine from caudate-putamen membranes of cynomolgus monkeys with affinities exceeding that of cocaine. The compound with the highest affinity, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-N-allyl-nortropane, (N-allyl-CFNT) was about three times more potent than cocaine. N-Allyl-CFNT also had cocaine-like interoceptive effects and was about three times more potent than cocaine in squirrel monkeys trained to discriminate cocaine from vehicle in an operant drug discrimination procedure. The results suggest that N-modified fluorophenyltropane derivatives may be useful precursors for development of pharmacological probes for cocaine receptors.

Buspirone blocks the discriminative stimulus effects of apomorphine in monkeys.

Three rhesus monkeys were trained to discriminate apomorphine (APO) from saline in a two-lever, food-reinforced drug discrimination procedure. After acquisition of the discrimination, the monkeys were given various doses of APO in combination with saline or buspirone before test sessions in which responses occurring on either lever were reinforced. Combinations of APO (0.01-0.08 mg/kg, IV) and saline resulted in a dose-related increase from 0 to 100% in the percentage of responses that occurred on the APO-appropriate lever. When buspirone (0.04-0.16 mg/kg, IV) was combined with APO, reductions from 100% to 0% APO-appropriate responding were seen following at least one dose combination in all three monkeys. A parallel shift to the right of the APO dose-response curve with buspirone was evident in 2 monkeys, indicating surmountable antagonism. In one case, a further increase in buspirone dose resulted in an insurmountable antagonism, i.e., increasing APO dose still resulted in primarily saline-appropriate responding. These results suggest that buspirone can function as a D2 dopamine (DA) receptor antagonist at behaviorally relevant doses.

Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists.

Effects of the dopamine D(1) antagonist SCH 39166 were compared with those of the D(2) antagonist eticlopride in squirrel monkeys responding under a second-order fixed-interval schedule of i.v. self-administration of cocaine. Dose-response curves were determined for a range of doses of self-administered cocaine (0.01-1.7 mg/kg/injection) alone and after pretreatment with SCH 39166 (0.01-0.1 mg/kg) or eticlopride (0.001-0.006 mg/kg). Cocaine maintained self-administration behavior in a dose-related manner; as the dose of cocaine was increased, rates of responding first increased and then either decreased or leveled off. Optimum doses (0.03-0.3 mg/kg) maintained high rates of responding (0.7-1.7 responses per second) among the different monkeys, and patterns of responding that were characteristic for second-order schedules. Pretreatment with either SCH 39166 or eticlopride altered self-administration behavior in all monkeys. In most cases, dose-response curves for cocaine were shifted to the right, indicative of surmountable antagonism, and a 3 to 6-fold increase in dose of cocaine was necessary to restore optimal performances. In some instances, dose-response curves were shifted either downward or downward and to the right, indicating that the antagonistic effects of SCH 39166 and eticlopride were not always fully surmountable. These results show that self-administration of cocaine can be comparably modified by drugs that selectively block dopamine D(1) or D(2) receptors.