Kenzie L. Preston

Clinical pharmacology of buprenorphine: ceiling effects at high doses.

The purpose of this study was to characterize the acute effects of buprenorphine, an opioid partial (μ‐agonist, across a wide range of doses in comparison to methadone.

Abuse potential and pharmacological comparison of tramadol and morphine

The purpose of the study was to assess the abuse potential of the opioid analgesic tramadol. Tramadol (75, 150 and 300 mg), morphine (15 and 30 mg) and placebo were tested intramuscularly in volunteer non-dependent opiate abusers. Subjective, behavioral and miotic changes were assessed prior to dosing and intermittently for 12 h after drug administration. Morphine produced typical subjective effects, opiate identifications and miosis. Tramadol 75 and 150 mg were not different from placebo. Although tramadol 300 mg was identified as an opiate, it produced no other morphine-like effects. These findings suggest that tramadol has a low abuse potential by the parenteral route.

Broad beneficial effects of cocaine abstinence reinforcement among methadone patients.

Escalating reinforcement for sustained abstinence has been effective in treating cocaine abuse. Under this schedule, patients receive vouchers for cocaine-free urine samples; vouchers have monetary values that increase with the number of consecutive cocaine-free urine samples. Cocaine-abusing methadone patients were randomly assigned to receive vouchers for 12 weeks under (a) an escalating schedule (n = 20), (b) an escalating schedule with start-up bonuses (n = 20), or (c) a noncontingent schedule (n = 19). Start-up bonuses were designed to provide added reinforcement for initiating abstinence; however, they did not improve outcomes. Both contingent interventions significantly increased cocaine abstinence. In addition, the contingent interventions increased abstinence from opiates and decreased reports of cocaine craving. These results replicate the efficacy of cocaine abstinence reinforcement and show that it can have broad beneficial effects.

Improvement in naltrexone treatment compliance with contingency management

The efficacy of a voucher-based incentive program for improving adherence to outpatient, thrice weekly naltrexone maintenance was tested in a three group, randomized, 12-week clinical trial. Voucher incentives were given as follows: contingent group (n = 19) for each consecutive naltrexone dose ingested; non-contingent group (n = 19) on unpredictable schedule independently of taking naltrexone; no-voucher group (n = 20) none. Vouchers were exchangeable for goods and services. The contingent group had significantly longer treatment retention and ingested significantly more doses of naltrexone (consecutive and total) than either control group. Voucher incentives can significantly increase adherence to naltrexone maintenance in recently detoxified opioid dependent individuals.

Increasing opiate abstinence through voucher-based reinforcement therapy

Heroin dependence remains a serious and costly public health problem, even in patients receiving methadone maintenance treatment. This study used a within-subject reversal design to assess the effectiveness of voucher-based abstinence reinforcement in reducing opiate use in patients receiving methadone maintenance treatment in an inner-city program. Throughout the study subjects received standard methadone maintenance treatment involving methadone, counseling, and urine monitoring (three times per week). Thirteen patients who continued to use opiates regularly during a 5-week baseline period were exposed to a 12-week program in which they received a voucher for each opiate-free urine sample provided: the vouchers had monetary values that increased as the number of consecutive opiate-free urines increased. Subjects continued receiving standard methadone maintenance for 8 weeks after discontinuation of the voucher program (return-to-baseline). Tukeys posthoc contrasts showed that the percentage of urine specimens that were positive for opiates decreased significantly when the voucher program was instituted. (P < or = 0.01) and then increased significantly when the voucher program was discontinued during the return-to-baseline condition (P < or = 0.01). Rates of opiate positive urines in the return-to-baseline condition remained significantly below the rates observed in the initial baseline period (P < or = 0.01). Overall, the study shows that voucher-based reinforcement contingencies can decrease opiate use in heroin dependent patients receiving methadone maintenance treatment.

Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence

Buprenorphine is a partial μ‐opiate agonist and κ‐opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence.

The reinstatement model and relapse prevention: a clinical perspective

ObjectivesThis commentary assesses the degree to which the reinstatement model is homologous to the human experience of relapse.ResultsA review of the literature suggests that the relationship is less clear than is often assumed, largely due to a lack of prospective data on the precipitants and process of relapse (especially relapse to heroin or cocaine abuse). However, reinstatement does not need to resemble relapse to have immediate clinical value; predictive validity as a medication screen would be sufficient. Whether the model has predictive validity is unknown, because, to date, very few clinical trials have tested medications that are effective in the reinstatement model, and even fewer have used designs comparable to those of reinstatement experiments. A clinical trial comparable to a reinstatement experiment would enroll participants who are already abstinent, and its main outcome measure would be propensity to undergo a specific type of relapse (e.g., relapse induced by stress or cues).ConclusionsUntil clinical and preclinical work are more comparable, criticisms of the reinstatement models presumed shortcomings are premature.

Cognitive-behavioral therapy plus contingency management for cocaine use: findings during treatment and across 12-month follow-up.

Contingency management (CM) rapidly reduces cocaine use, but its effects subside after treatment. Cognitive-behavioral therapy (CBT) produces reductions months after treatment. Combined, the 2 might be complementary. One hundred ninety-three cocaine-using methadone-maintained outpatients were randomly assigned to 12 weeks of group therapy (CBT or a control condition) and voucher availability (CM contingent on cocaine-negative urine or noncontingent). Follow-ups occurred 3, 6, and 12 months posttreatment. Primary outcome was cocaine-negative urine (urinalysis 3 times/week during treatment and once at each follow-up). During treatment, initial effects of CM were dampened by CBT. Posttreatment, there were signs of additive benefits, significant in 3- versus 12-month contrasts. Former CBT participants were also more likely to acknowledge cocaine use and its effects and to report employment.

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 cocaines 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.

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.