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Director's Report to the National Advisory Council on Drug Abuse - May, 2006

Research Findings - Research on Pharmacotherapies for Drug Abuse

Pharmacokinetics and Pharmacodynamics of Multiple Sublingual Buprenorphine Tablets in Dose-Escalation Trials

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest. Ciraulo, D.A., Hitzemann, R.J., Somoza, E., Knapp, C.M., Rotrosen, J., Sarid-Segal, O., Ciraulo, A.M., Greenblatt, D.J. and Chiang, C.N. J Clin Pharmacol. 46(2), pp. 179-192, February 2006.

Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans

Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This double-blind, placebo-controlled, randomized study examined gender differences in response to administration of these drugs alone and in combination. Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2)four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min. Responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p =.02). Women consistently reported higher ratings for "Feel Good" a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1). Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women. McCance-Katz, E.F., Hart, C.L., Boyarsky, B., Kosten, T. and Jatlow, P. Subst Use Misuse. 40(4), pp. 511-528, 2005.

Clinical Pharmacodynamics of HIV-1 Protease Inhibitors: Use of Inhibitory Quotients to Optimize Pharmacotherapy

The introduction of HIV-1 protease inhibitors and non-nucleoside reverse transcriptase inhibitors in 1996 began an era described as that of highly active antiretroviral therapy. In addition, the more recent development and availability of HIV-1 genotypic and phenotypic resistance tests and advances in pharmacological assays that support therapeutic drug monitoring (TDM) have created tools that may help clinicians to provide more individualized treatment with HIV-1 protease inhibitors. All current treatment guidelines provide fixed doses of protease inhibitors with vague recommendations for the use of TDM in selected clinical situations. In patients with resistance to protease inhibitors, the combined use of resistance tests with TDM provide a mechanism for individualising the clinical pharmaco-dynamics of protease inhibitors. Current therapeutic approaches seek to include the monitoring of protease-inhibitor concentrations as part of a TDM programme with phenotypic assays to calculate an inhibitory quotient, virtual inhibitory quotient, or normalised inhibitory quotient, whereas genotypic tests are used with TDM to calculate a genotypic inhibitory quotient. Current investigation is focused on examining the predictive value of this approach for clinical monitoring. Morse, G.D., Catanzaro, L.M. and Acosta, E.P. Lancet Infect Dis. 6(4), pp. 215-225, April 2006.

Update on the Pharmacokinetic Aspects of Antiretroviral Agents: Implications in Therapeutic Drug Monitoring

The observed inter-individual variation in antiretroviral pharmacokinetics (PK) that results in a wide range of drug exposures from fixed-dose regimens has led to increasing interest in the clinical use of therapeutic drug monitoring (TDM) to individualize dosing of antiretroviral therapy (ART). The focus of this review is to provide an overview of literature available to support therapeutic drug monitoring among the current classes of antiretrovirals, suggest patient populations that may benefit from TDM and bring forth some of the limitations that may exist for widespread use of TDM in a traditional clinical setting. Slish, J.C., Catanzaro, L.M., Ma, Q., Okusanya, O.O., Demeter, L., Albrecht, M. and Morse, G.D. Curr Pharm Des. 12(9), pp. 1129-1145, 2006.

A Low Dose of Aripiprazole Attenuates the Subject-rated Effects of d-Amphetamine

In a previous published study, 20 mg aripiprazole, an atypical antipsychotic that has partial D2 agonist activity, attenuated many of the behavioral effects of d-amphetamine., but also impaired performance on a computerized version of the DSSTY when administered alone. A study was conducted in six subjects to determine if a lower dose of aripiprazole (10 mg) could acutely attenuate the discriminative and physiological effects of 2.5-15 mg d-amphetamine without impairing performance as measured with a computerized version of the DSST. The results indicated that 10 mg aripiprazole attenuated some abuse-related behavioral effects, and that this dose would be a reasonable starting dose for the treatment of stimulant abuse and dependence. Stoops, W.W., Lile, J.A., Glaser, P.E. and Rush, C.R. Drug Alcohol Depend. (E-publication) 2006.

Memantine Increases Cardiovascular but not Behavioral Effects of Cocaine in Methadone-maintained Humans

Previous work has suggested that maintenance on the noncompetitive N-methyl-d-aspartate (NMDA) antagonist, memantine, increased the subjective effects of smoked cocaine in experienced cocaine users. To determine whether this phenomenon occurs in opioid-dependent individuals, eight (seven male, one female) methadone-maintained cocaine smokers participated in a 47-day inpatient and outpatient study to assess the effects of memantine on smoked cocaine self-administration, subjective effects, and cardiovascular responses. The participants were maintained on memantine (0 mg and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition during inpatient phases, participants smoked a sample dose of cocaine base (0, 12, 25, and 50 mg) once, and were subsequently given five choice opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher (US $5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose were varied systematically. Memantine maintenance did not alter the subjective or reinforcing effects of cocaine. Several cardiovascular responses, however, including peak and initial diastolic pressures following cocaine, were significantly greater during memantine maintenance, although these elevations were not clinically significant. Taken together, these findings corroborate earlier data suggesting that this dose of memantine will not be helpful in the pharmacotherapy of cocaine abuse. Collins, E.D., Vosburg, S.K., Ward, A.S., Haney, M. and Foltin, R.W. Pharmacol.Biochem.Behav., 83, pp. 47-55, 2006.

Injectable, Sustained-release Naltrexone for the Treatment of Opioid Dependence: a Randomized, Placebo-controlled Trial

Oral naltrexone can completely antagonize the effects produced by opioid agonists. However, poor compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence. The purpose of this study was to evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence in a randomized, double-blind, placebo-controlled, 8-week trial conducted at 2 medical centers, in 60 heroin-dependent adults. Participants were stratified by sex and years of heroin use (> or = 5 vs < 5) and then were randomized to receive placebo or 192 or 384 mg of depot naltrexone. Doses were administered at the beginning of weeks 1 and 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit. Retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Time to dropout had a significant main effect of dose, with mean time to dropout of 27, 36, and 48 days for the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively. The percentage of urine samples negative for opioids, methadone, cocaine, benzodiazepines, and amphetamine varied significantly as a function of dose. When the data were recalculated without the assumption that missing urine samples were positive, a main effect of group was not found for any drugs tested except cocaine, where the percentage of cocaine-negative urine samples was lower in the placebo group. Adverse events were minimal and generally mild. This formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention. These data provide new evidence of the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence. Comer, S.D., Sullivan, M.A., Yu, E., Rothenberg, J.L., Kleber, H.D., Kampman, K. et al. Arch.Gen.Psychiatry, 63, pp. 210-218, 2006.

Early Impact of Methadone Induction for Heroin Dependence: Differential Effects of Two Dose Sequences in a Randomized Controlled Study

The pharmacodynamic and pharmacokinetic effects of 2 methadone (METH) induction dose sequences were evaluated in this 15-day outpatient experimental protocol. Heroin-dependent, non-treatment-seeking volunteers were randomly assigned (stratified for gender, race, and route of heroin use) to 2 groups. In 1 sequence, METH doses ascended (28, 56, then 84 mg/day; stepwise, n = 18), whereas in the other sequence doses escalated, then tapered (28-84 mg on Days 1-6 to 56 mg/day; rapid, n = 16). A contingency-management intervention was common to both groups. Drug use and heroin craving and opioid withdrawal symptoms decreased, whereas agonist symptoms and positive mood increased overall across days for both groups. Plasma concentrations and the acute reinforcing effects of METH paralleled each dose sequence. Stepwise relative to rapid METH induction significantly decreased heroin craving and opioid withdrawal symptoms and increased agonist symptoms and positive mood but did not significantly improve drug use or retention. Although these specific dosing procedures would not necessarily be used in clinical settings, they provide a procedural template that might be applied safely and effectively with a broader range of treatment-seeking individuals. Greenwald, M.K. Exp.Clin.Psychopharmacol., 14, pp. 52-67, 2006.

Severity of Dependence and Motivation for Treatment Comparison of Marijuana- and Cocaine-Dependent Treatment Seekers

Most individuals with marijuana dependence do not seek treatment, and there are few data characterizing treatment seeking marijuana dependent patients compared to patients presenting for treatment of other drugs. In this study, 42 marijuana-dependent individuals were compared to 58 cocaine-dependent individuals seeking treatment. Compared to cocaine-dependent individuals, those with marijuana dependence were younger and less likely to be dependent on alcohol or other drugs. Both groups had similar rates of comorbid anxiety and affective disorders. Marijuana-dependent individuals had lower total number of dependence symptoms but a higher percentage of individuals endorsing withdrawal symptoms. Comparison with two different assessment scales suggests that treatment seeking marijuana-dependent individuals have substantial withdrawal dependence symptomatology although it is less clear if they are as motivated to seek out treatment as cocaine-dependent treatment seekers. Levin, F.R., Brooks, D.J., Bisaga, A., Raby, W., Rubin, E., Aharonovich, E., and Nunes, E.V. J. Addict Dis, 25(1), pp. 33-41, 2006.

Effects of Baclofen on Cocaine Self-Administration: Opioid- and Nonopioid-Dependent Volunteers

Preclinical and clinical studies suggest that GABA(B) receptor agonists selectively decrease cocaine use. The behavioral mechanism for the interaction between baclofen and cocaine in humans is not known, nor have its effects been characterized in individuals dependent on both cocaine and methadone. The objective of this study was to determine how maintenance on baclofen influences smoked cocaine's reinforcing and subjective effects, mood and cocaine craving prior to and after the initiation of cocaine use in cocaine-dependent volunteers with and without concurrent opioid dependence. Nontreatment-seeking volunteers (10 nonopioid dependent; seven methadone maintained), residing on an in-patient research unit for 21 days, were maintained on each baclofen dose (0, 30, 60 mg po) for 7 days. A smoked cocaine dose-response curve (0, 12, 25, 50 mg) was determined twice: on days 3-4 and days 6-7 of each baclofen maintenance condition. Cocaine sessions began with a sample trial, when participants smoked the cocaine dose available that session, and five choice trials, when participants chose between smoking the available cocaine dose or receiving one $5 merchandise voucher. The results show that in the nonmethadone group, baclofen (60 mg) decreased self-administration of a low cocaine dose (12 mg). In the methadone group, baclofen decreased craving for cocaine. In both groups, baclofen decreased cocaine's effects on heart rate. Baclofen did not alter cocaine's robust subjective effects (eg 'High,' 'Stimulated') for either group. The results from this laboratory study appear consistent with clinical evidence showing that baclofen decreases cocaine use in nonopioid-dependent patients seeking treatment for cocaine dependence. The distinct pattern of effects in methadone-maintained participants suggests baclofen may not be effective in opioid-dependent cocaine users. Haney, M., Hart, C. L. and Foltin, R.W. Neuropsychopharmacology, January 11, 2006 (e-pub ahead of print).

Effect of Bupropion on Physiological Measures of Stress in Smokers During Nicotine Withdrawal

Studies suggest that among cigarette smokers trying to quit, stress undermines abstinence. Little research has assessed if therapies that increase smoking cessation rates impact physiological measures of stress response. Forty-three subjects completed this repeated-measures study in which a laboratory assessment was completed at baseline and after 17 days of treatment with either placebo (n=15), bupropion sustained release (150mg twice daily) (n=14) or bupropion with stress reduction counseling (n=14). All subjects quit smoking 3 days prior to the second laboratory assessment. At each laboratory assessment physiological measures of stress (i.e. blood pressure, heart rate, plasma epinephrine, norepinephrine and cortisol concentrations) were measured during rest periods and in response to a speech, a math and a cold pressor task. Among subjects taking placebo, physiological measures of stress were generally lower at rest and during the stressors after smoking cessation. In those taking bupropion these measures were equivalent at the two assessments. Additionally, compared to placebo, those on bupropion had a greater diastolic blood pressure response to the speech stressor and greater systolic blood pressure response to the math stressor during the second laboratory session. This study suggests that bupropion may be maintaining physiological measures of stress during the nicotine withdrawal period. Kotlyar, M., Brauer, L.H., al'Absi, M., Adson, D.E., Robiner, W., Thuras, P. et al. Pharmacol. Biochem. Behav., March 6, 2006 (e-pub ahead of print).

Six-month Trial of Bupropion with Contingency Management for Cocaine Dependence in a Methadone-maintained Population

The purpose of this study was to compare the efficacy of bupropion hydrochloride and CM for reducing cocaine use in methadone hydrochloride-maintained individuals. This 25-week, placebo-controlled, double-blind trial randomly assigned participants to 1 of 4 treatment conditions: CM and placebo (CMP), CM and 300 mg/d of bupropion hydrochloride (CMB), voucher control and placebo (VCP), or voucher control and bupropion (VCB). All study participants received methadone hydrochloride (range, 60-120 mg). Participants receiving bupropion hydrochloride were given 300 mg/d beginning at week 3. In the CM conditions, each urine sample negative for both opioids and cocaine resulted in a monetary-based voucher that increased for consecutively drug-free urine samples during weeks 1 to 13. Completion of abstinence-related activities also resulted in a voucher. During weeks 14 to 25, only completion of activities was reinforced in the CM group, regardless of sample results. The voucher control groups received vouchers for submitting urine samples, regardless of results, throughout the study. Groups did not differ in baseline characteristics or retention rates. Opiate use decreased significantly, with all treatment groups attaining equivalent amounts of opiate use at the end of the study. In the CMB group, the proportion of cocaine-positive samples significantly decreased during weeks 3 to 13 (P<.001) relative to week 3 and remained low during weeks 14 to 25. In the CMP group, cocaine use significantly increased during weeks 3 to 13 (P<.001) relative to week 3, but then cocaine use significantly decreased relative to the initial slope during weeks 14 to 25 (P<.001). In contrast, by treatment end, the VCB and VCP groups showed no significant improvement in cocaine use. These findings suggest that combining CM with bupropion for the treatment of cocaine addiction may significantly improve outcomes relative to bupropion alone. Poling, J., Oliveto, A., Petry, N., Sofuoglu, M., Gonsai, K., Gonzalez, G. et al. Arch. Gen. Psychiatry, 63, pp. 219-228, 2006.

Temperament Characteristics, as Assessed by the Tridimensional Personality Questionnaire, Moderate the Response to Sertraline in Depressed Opiate-dependent Methadone Patients

During a randomized, double-blind, placebo controlled study of the effects of sertraline in depressed methadone-maintained patients, 82 completed the tri-dimensional personality questionnaire (TPQ) to assess whether temperament dimensions can affect treatment-related changes in mood and drug use. Mood outcome significantly differed according to scores on the reward dependence scale (RD). Low RD participants displayed a significantly better mood response to sertraline than high RD participants. Participants with high harm avoidance (HA) scores were more likely to be abstinent at the end of the 12 week trial of sertraline than low HA participants. High persistence (P) participants were less likely to be abstinent at the end of the 12-week trial. These results suggest that temperament dimensions may be important for identifying substance dependent patients more likely to benefit from pharmaco-logical interventions for comorbid depressive disorders. Raby, W.N., Carpenter, K.M., Aharonovich, E., Rubin, E., Bisaga, A., Levin, F. et al. Drug Alc Depend. 81, pp. 283-292, 2006.

Emerging Pharmacological Strategies in the Fight Against Cocaine Addiction

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a beta-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials. Sofuoglu, M. and Kosten, T.R. Expert. Opin. Emerg. Drugs, 11, pp. 91-98, 2006.

Effects of Topiramate in Combination with Intravenous Nicotine in Overnight Abstinent Smokers

Topiramate, an anticonvulsant medication, may be effective as a treatment for alcohol and cocaine addiction. While a recent clinical study has demonstrated the potential utility of topiramate for smoking cessation in alcohol-dependent smokers, the effects of topiramate on tobacco addiction have not been systematically examined in humans. The purpose of this study is to determine topiramate's effects on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent smokers. Seven male and five female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. Before each session, participants were treated orally with either a single 25 or 50 mg topiramate dose or with placebo. Starting 2 h following the medication treatment, participants received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. Topiramate treatment at 50 mg, compared to 25 mg or placebo, attenuated heart rate increases induced by nicotine. Topiramate, compared to placebo, enhanced the ratings of subjective effects from nicotine including "drug strength," "good effects," "head rush," and "drug liking." Topiramate treatment did not affect performance on the Stroop test. These results suggest that topiramate may enhance the subjective effects of nicotine and attenuate the heart rate response to nicotine. While the exact mechanisms are unclear, enhancement of the dopaminergic system and attenuation of the noradrenergic system may mediate topiramate's effects on the subjective and cardiovascular responses to nicotine, respectively. The utility of topiramate for smoking cessation needs to be examined further in controlled clinical trials. Sofuoglu, M., Poling, J., Mouratidis, M. and Kosten, T. Psychopharmacology (Berl), 184, pp. 645-651, 2006.


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