Pharmacotherapy and other treatments for cocaine abuse and dependence Frank J. Vocci and Ahmed Elkashef

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1 Pharmacotherapy and other treatments for cocaine abuse and dependence Frank J. Vocci and Ahmed Elkashef Purpose of review This review examines progress being made in the treatment of cocaine abuse and dependence, with a particular focus on pharmacotherapies. Medications with apparently very different mechanisms of action have been reported to reduce cocaine use in controlled clinical trials in outpatient settings. This review will summarize the latest findings in this area. Recent findings Of all the medications tested to date, disulfiram has demonstrated the most consistent effect to reduce cocaine use. Several medications have been reported to reduce cocaine use in double-blind, placebo-controlled clinical trials, namely baclofen, modafinil, tiagabine, and topiramate. All pharmacotherapy trials in cocaine-dependent patients include a behavioral therapy that is common to all participants. Consequently, these pharmacotherapy trials can be considered to evaluate whether the medication is adding to the effect of the behavioral therapy. Summary Confirmatory clinical studies are necessary to replicate the initial efficacy findings for baclofen, modafinil, tiagabine, and topiramate. More research is needed in both cocaine and cocaine alcohol dependent populations. Once confirmatory studies have been carried out, testing of rational medication combinations with different behavioral therapies is an obvious next step to increase the ability to manage cocaine dependence. Keywords behavioral therapy, clinical trials, cocaine dependence, pharmacotherapy Curr Opin Psychiatry 18: # 2005 Lippincott Williams & Wilkins. Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA Correspondence to Frank Vocci PhD, Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, 6001 Executive Boulevard, Room 4133, MSC 9551, Bethesda, MD , USA Tel: ; fax: ; fv6k@nih.gov Current Opinion in Psychiatry 2005, 18: Abbreviations CBT cognitive behavioral therapy DBH dopamine-b-hydroxylase IPT interpersonal psychotherapy # 2005 Lippincott Williams & Wilkins Introduction Cocaine use can lead to medical and psychiatric complications, including dependence. Nonetheless, a disconcertingly large number of people try cocaine in any given year. For example, there were an estimated new cocaine users in the US, as gauged by the National Survey on Drug Use and Health 2003 [1]. One percent ( ) of the US population aged 12 or older used cocaine within the 30 days prior to the survey and reported receiving treatment for cocaine dependence in In the US, cocaine users often suffer complications. This is reflected in the fact that almost people in the US sought emergency treatment for medical or psychiatric problems stemming from cocaine use in 2002 [2]. This figure represents about 30% of the emergency department mentions in the US Drug Abuse Warning Network. Cocaine dependence is typically a chronic, relapsing disorder. Behavioral therapies have demonstrated some effectiveness and are currently the standard type of treatment for cocaine dependence in the US [3]. Some individuals respond well to behavioral therapies, while others continue to abuse cocaine, albeit usually at lower levels [4]. A major research effort to develop pharmacotherapies for cocaine dependence has been initiated by the US National Institute on Drug Abuse. The program has concentrated on testing existing psychopharmaceuticals in controlled clinical trials. All trials have utilized some form of behavioral therapy. The present review will concentrate on the effects of the investigational pharmacotherapies. Observations on interactions between pharmacological and behavioral therapies will be made, where appropriate. Prior to any discussion of particular medications, a few contextual comments on clinical trials in cocaine users are necessary. Behavioral therapy is the usual initial approach to help the individual reduce or stop cocaine use. The pharmacotherapy trials mirror this reality and most of the studies can be described as abstinence facilitation studies performed in conjunction with some sort of behavioral therapy platform, for example, 12-step abstinence facilitation. Patients enrolled usually meet DSM-IV criteria for cocaine dependence and often are using cocaine more than times per month. Moderate to high cocaine use is often an inclusion criterion as lesser levels of use could make it difficult to determine a medication effect, i.e. a floor effect may occur. The number of 265

2 266 Addictive disorders nonuse days is the primary variable analyzed in these studies. An alternative type of trial relapse prevention enrolls patients who are not actively using but have histories of relapse. These patients usually score high on cocaine craving measures. Duration to first relapse is the primary outcome in these trials. The type of statistical analysis also varies from trial to trial. In addition, some analyses attempt to account for missing data while others do not. Although not discussed in depth in the cocaine pharmacotherapy literature, the amount of missing data is possibly unique to substance abuse clinical trials. There are two types of missing data occurring intermittently, and due to dropout. Intermittent missing data occur when patients fail to keep appointments during a clinical trial. This often results, for example, in having fewer samples for urinalysis than is called for in the protocol. Many clinical trials do not use strategies to minimize missing data. For example, self-reporting of cocaine use has been employed to compensate for the intermittent type of missing data. Thus, the evaluation of nonuse days is performed on a composite variable, using longitudinal analysis techniques such as General Estimating Equations (GEE) [5]. Several medications have been reported to reduce cocaine use some in early hypothesis testing or proof of concept studies and one in multiple studies in different populations. For this review we will focus on disulfiram and on selected medications (baclofen, topiramate, and tiagabine) that have shown efficacy in proof of concept trials and for which confirmatory clinical trials are under way. Disulfiram Disulfiram has been marketed for over 50 years for the treatment of alcoholism. There are several possible reasons for evaluating disulfiram in a cocaine-abusing population; although these reasons have been known for some time, they warrant repeating here. First, there is evidence of co-abuse and co-dependence seen with cocaine and alcohol. In one study, 88% of cocaine users entering treatment admitted co-use of alcohol [6]. In a case series of treatment-seeking cocaine users, 61% had a history of alcohol dependence [7]. Co-abuse of cocaine and alcohol may result from several factors. Firstly, alcohol may be used to diminish the negative effects of acute cocaine use [8]. Secondly, alcohol use may disinhibit cocaine users and reduce their ability to forego cocaine use. Experimental evidence of this effect has been demonstrated in a clinical pharmacology paradigm in cocaine users [9]. The mechanism associated with this effect may be related to a conditioned cue to increase co-ingestion. Thirdly, cocaethylene, a metabolite of cocaine and ethanol formed during co-ingestion, has pharmacological properties [10] that likely increase the magnitude and duration of the cocaine high [11,12]. Initially, disulfiram was hypothesized to affect cocaine use through indirect mechanisms in cocaine alcohol users; that is, reducing alcohol intake would help to maintain behavioral inhibition, make the immediate after-effects of cocaine more aversive, and inhibit the formation of cocaethylene and its consequent effects. Disulfiram was initially reported (in 1993) to have a potential therapeutic effect in patients co-abusing cocaine and alcohol [13]. A randomized trial of disulfiram was performed with patients with cocaine dependence and concurrent cocaine and alcohol dependence [14]. One hundred and twenty-two patients were randomized into five groups for this 12-week study: cognitive behavioral therapy (CBT) with or without disulfiram, twelvestep facilitation with or without disulfiram, and clinical trial management with disulfiram. All disulfiram patients were started on 250 mg per day and the mean dose was 261 mg. Patients receiving disulfiram fared better than the no-medication groups in terms of retention, reduction of cocaine use, and reduction of alcohol use. Cocaine use and alcohol use were related during the study, more so in the patients receiving disulfiram. Also, the two active psychotherapies were superior to the clinical trial management strategy. Interestingly, a 1-year follow-up study showed that the main effects of disulfiram on alcohol and cocaine use reductions were sustained. In a combined analysis, all groups reported reduced use of cocaine but not alcohol [15]. Clinical pharmacology studies of the interaction of disulfiram and cocaine have contributed additional understanding to the proposed mechanisms of action of disulfiram. Subjective responses to intranasally administered cocaine (2 mg/kg) in disulfiram-treated (250 mg/day) patients included an increase in ratings of high, rush and nervousness. Three of the eight patients became paranoid during the disulfiram cocaine sessions. Cardiovascular responses included an increase in heart rate and systolic blood pressure. Peak plasma cocaine levels were both increased and delayed in the disulfiram sessions [16]. A second study reported the effects of 3 days of dosing with 250 mg of disulfiram and the interaction with 1 and 2 mg/ kg of intranasally administered cocaine. An increase in high with increased nervousness was reported for the subjective responses. Cardiovascular effects of the combination verified that an increase in heart rate occurred at 1 mg/kg and increased systolic pressure was noted at 2 mg/ kg [17]. A third study by this group reported that there were no differences in subjective responses to 1 or 2 mg/kg cocaine given intranasally to patients administered

3 Cocaine abuse and dependence Vocci and Elkashef 267 placebo, or disulfiram 250 or 500 mg/day. Five of the seven patients reported anxiety and two reported restlessness in the cocaine disulfiram condition. Heart rate and systolic pressure increased. Plasma levels of cocaine were three to six times higher in the disulfiram groups than seen under placebo conditions [18]. Thus, disulfiram may increase the aversive qualities of cocaine and increase cardiac output. This safety concern must be taken into account when designing clinical trials or prescribing disulfiram to cocaine-abusing patients. One concern that has been addressed in some disulfiram pharmacotherapy trials for the treatment of cocaine dependence is adherence to therapy. This has been accomplished by enrolling either methadone [19] or buprenorphine-treated [20] opiate-dependent, cocaineabusing patients. The first study enrolled 67 patients in a methadone treatment program who also met criteria for a DSM-IIIR cocaine dependence diagnosis. The majority used cocaine without concurrent alcohol use. Twentythree percent met criteria for alcohol dependence. Disulfiram (250 mg/day) or placebo was administered daily in the methadone liquid for 12 weeks. Patients in the disulfiram group reduced their frequency (P ¼ 0.04) and quantity of cocaine use (P ¼ 0.02) compared with the effects seen in the placebo group. Alcohol use was minimal during the trial. The efficacy of disulfiram was not different in the nondrinking versus drinking subgroups, suggesting a direct effect of disulfiram on cocaine intake. Cocaine craving decreased with time equally across treatment groups. Subjects in the disulfiram-treated group who used cocaine reported no change in the qualitative high, although a medication effect on craving and high might be implied by the greater number of disulfiramtreated patients who achieved complete abstinence. In the second study, 20 buprenorphine-maintained cocaine-dependent patients were randomly assigned to 250 mg of disulfiram or placebo administration for 12 weeks [20]. The medication was dispensed at the same time as the buprenorphine, ensuring adherence. All patients were given weekly group counseling sessions. The primary outcome measures were mean number of weeks of abstinence, number of days to achieving 3 weeks of abstinence, and the number of cocainenegative urines during the 12-week trial. Although the proportion of patients in both groups achieving 3-week abstinence was comparable, the disulfiram-treated patients had a faster time to abstinence and a greater number of abstinent weeks ( versus , P < 0.05). The most recently published disulfiram pharmacotherapy trial employed a sophisticated design [21 ]. One hundred and twenty-one outpatients who met DSM-IV criteria for cocaine dependence were randomized to one of four groups for 12 weeks of treatment: disulfiram plus CBT, placebo plus CBT, disulfiram plus interpersonal psychotherapy (IPT), and placebo plus IPT. Disulfiram (250 mg/day) and identical placebos were prescribed. Riboflavin was used as an adherence marker. A priori hypotheses were that disulfiram would be superior to placebo and CBT would be superior to IPT. The main outcome measures were self-report of cocaine use and urine monitoring of cocaine use. Fifty-two percent of the participants had an alcohol abuse or dependence diagnosis. Twenty-six percent were women. Disulfiram reduced cocaine use in this trial to a greater extent than placebo. CBT was superior to IPT. Patients obtaining the most benefit from CBT and disulfiram were those abstaining from alcohol during the trial, regardless of whether they were nondrinkers or alcohol abstainers during the trial. No effect was seen in the alcohol-using participants, possibly due to poor medication compliance. Adherence varied from 61% in the alcohol-using group assigned to disulfiram to 79% in those assigned to disulfiram who did not drink or abstained from alcohol during the trial. It must be appreciated that patients on disulfiram who chose to drink essentially broke the blind and thereby reduced their compliance either completely or intermittently if they wanted to continue to drink. The results did not support the alcohol mediation hypothesis of disulfiram s efficacy to reduce cocaine use. Rather, the data support the opposite conclusion: disulfiram has a direct effect on reduction of cocaine use. The study results also substantiated the comparative superiority of CBT to IPT as a behavioral therapy. This is noteworthy as comparative psychotherapy trials often fail to show a difference between different therapeutic modalities [22]. A combined analysis of two disulfiram cocaine pharmacotherapy studies [14,19] was performed [23 ] to assess possible (gender treatment) interactions. Thirty-six percent of the enrollees in these trials were women. The primary outcomes were days of abstinence and percentage of drug-free urines. Regression analysis on the combined sample showed a reduction in cocaine use frequency as a whole and a significant medication by time effect. Gender analysis revealed that men treated with disulfiram in these two studies had better outcomes than those assigned to no medication or a placebo treatment. Women receiving disulfiram did not have a better treatment response than women assigned to placebo or no medication, although the overall treatment response seen in women was intermediate compared with that seen in men on disulfiram versus those not on disulfiram. The results held even when baseline level of alcohol use and severity of cocaine use were used as covariates.

4 268 Addictive disorders One explanation advanced to explain a gender difference is the possible stimulatory effect of estrogen on dopamine -b-hydroxylase (DBH). A stimulatory effect of oestradiol in rats on DBH activity has been reported [24]. As disulfiram is an inhibitor of DBH and its mechanism of action may depend on the level of DBH, higher postulated DBH levels in premenopausal women might mitigate against its anticocaine effect. The level of this enzyme is under genetic control. A polymorphism in the DBH gene ( 1021 C!T) accounts for 35 52% of the variance in plasma DBH activity across European American, African-American, and Japanese populations [25]. Homozygosity at the T-allele in European Americans predicts very low DBH activity while heterozygotes are intermediate in activity. This correlation of DBH activity to clinical response to disulfiram is a testable hypothesis and future studies should assess study participants for gender and other possible (age)-related differences in DBH activity. An a priori hypothesis would be that disulfiram treatment responders would have low to intermediate levels of DBH. Interim results of an ongoing randomized, double-blind, placebo-controlled trial of disulfiram in 128 patients dependent on cocaine and opiates maintained on buprenorphine suggest it reduced cocaine use to a greater extent than placebo in those with low DBH activity [26 ]. If confirmed, this would suggest that genotyping patients for DBH activity could predict disulfiram efficacy. It would also suggest that the CC homozygotes might require higher doses of disulfiram to reach an effective level of DBH inhibition. Further research is needed into the mechanism of action of disulfiram and its correlation to the DBH 1021 C!T polymorphism in both genders. The possible modulatory role of estrogen to increase DBH levels should be investigated. The use of genetic markers such as the DBH polymorphism heralds a new approach to the development of medications for addictive disorders. If confirmed, DBH genotyping would likely predict treatment responders to disulfiram, either in an absolute or a dose-related fashion. Moreover, if dose-related effect were found to correlate with DBH activity levels, it could provide a rationale for dosing adjustments in individuals with high DBH activity, e.g. CC homozygotes or premenopausal women. The pharmacogenetics approach would increase the benefit risk calculation by limiting the medication to those who would benefit. Eliminating patients for whom the medication would be ineffective would also reduce the risks associated with disulfiram. GABAergic medications Baclofen is marketed for the treatment of spastic disorders. It is a GABA-B agonist that has shown a robust effect in decreasing cocaine self-administration in animal models [27] and in reducing responses to cue-induced craving in human cocaine users [28]. Baclofen s effect to reduce cocaine use, under double-blind conditions, has recently been reported [29 ]. A post-hoc analysis suggested that baclofen was most effective in the cocainedependent patients who used most often during the study baseline period. If these results are confirmed, baclofen prescribing should be targeted to the more frequent cocaine user entering treatment to facilitate reduction of use or abstinence. Tiagabine is another marketed GABAergic agent [30] that is a GABA reuptake transporter type 1 inhibitor. It has been evaluated for efficacy to reduce cocaine use in a randomized, placebo-controlled study in methadonemaintained cocaine-abusing patients [31 ]. Tiagabine dosage was incrementally increased in the first 6 weeks of the trial to minimize side effects. The high-dose regimen (24 mg/day) significantly decreased cocaine use relative to baseline, primarily during the last 4 weeks of the 10-week trial. Topiramate Another medication with several mechanisms of action is the antiepileptic topiramate. At least six mechanisms are known and have been summarized [32 ]: enhancement of GABA-A-mediated currents at the GABA-A receptor complex; antagonism of a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate ionotropic receptors; inhibition of L-type calcium channels and calcium-dependent second messenger systems; limiting activity-dependent depolarization of and excitability of voltage-dependent sodium channels; activation of potassium conductance; and inhibition of carbonic anhydrase enzymes (II and IV). As expected, the most common side effect is paresthesias. Due to the GABAergic enhancing properties and inhibition of AMPA and kainate receptor systems, it was hypothesized that topiramate would reduce cocaine craving and use. A double-blind, placebo-controlled trial in 40 cocaine-dependent patients was run at the University of Pennsylvania [33 ]. Since there was a concern about topiramate possibly worsening cocaine withdrawal symptoms, the investigator selected patients with low cocaine withdrawal scores [34]. The behavioral treatment, a cognitive behavioral coping therapy, was administered twice weekly to all patients. Following a 1-week baseline in which patients were supposed to remain abstinent from cocaine for at least 3 days, topiramate (or placebo) dosing was started at 25 mg per day and increased by 25 mg per week to a target dose of 200 mg. Patients in the topiramate group achieved higher rates of abstinence compared with placebo when the full dose was administered from week 8 to week 12. Using the variable of 3 weeks of continuous abstinence, 59% of the topiramate group met this criterion compared with 26% of the placebo group

5 Cocaine abuse and dependence Vocci and Elkashef 269 (P ¼ 0.05). Patients who remained clean at baseline were significantly less likely to use cocaine during the trial. The study results are promising but, obviously, need to be repeated. Since only 40 patients (including only one woman) were entered into the trial, more women need to be included in further trials. Furthermore, although topiramate has been reported to reduce alcohol drinking in heavy drinkers [35], those using cocaine with alcohol and those using cocaine alone need to be evaluated. The trial design also suggests that topiramate should be evaluated as a relapse prevention agent. Modafinil Modafinil is marketed for the treatment of daytime sleepiness in narcolepsy. It has effects on glutamate and GABA neurotransmitter systems that may oppose some effects of chronic cocaine administration, as well as an alerting effect that may ameliorate some of the vegetative symptoms of cocaine withdrawal [36 ]. Modafinil has some effect on blunt cocaine euphoria, although the lower dose was more inhibitory than the higher dose [36 ]. Moreover, dose-related effects on prepotent inhibition in normal volunteers suggests a positive effect of modafinil in reducing impulsive responding [37]. This effect was also noted in a follow-up study in patients with attention deficit hyperactivity disorder [38 ]. A doubleblind, placebo-controlled trial in 62 cocaine-dependent men and women was conducted. Patients were randomized to a 400 mg dose of modafinil or placebo [39 ]. All patients received twice weekly CBT as their behavioral therapy. Cocaine abstinence favored modafinil as analyzed by GEE analysis [5] or the proportion of patients achieving 3 weeks of continuous abstinence. Although women comprised approximately 30% of the enrollees, no gender analysis was reported. Naltrexone Naltrexone, 50 mg/day in conjunction with relapse prevention therapy, was reported to prevent relapse to cocaine use in a cocaine-dependent population [40]. A follow-up study in a cocaine alcohol dually dependent population failed to replicate the effect of naltrexone (50 mg/day) [41 ]. This is in contrast to a pilot study that reported 150 mg of naltrexone daily reduced cocaine and alcohol use in a dually dependent population [42]. Further studies are needed to determine whether naltrexone is of value as a relapse prevention agent in cocaine-dependent and cocaine alcohol dually dependent patients. As the effect of naltrexone in preventing relapse to alcohol use is influenced by a m-opioid receptor polymorphism (118 A!G) [43 ], subsequent clinical studies with naltrexone should consider genotyping enrollees and stratifying their randomization sequence on this genetic variable. Conclusion Several medications have shown initial efficacy to reduce cocaine use in well controlled clinical trials in cocainedependent outpatients. Clinical investigators are attempting to replicate these findings and determine potential responders through pretrial genotyping, clinical assessment scales, drug use patterns and severity, single versus dual dependence diagnosis, and ability to abstain from cocaine in the baseline period. Potential gender differences should be assessed. Once a medication is validated in a confirmatory trial, combination trials of medications with different mechanisms should be considered to determine additivity of pharmacological effect. This group of medications will constitute the first generation of medications for management of cocaine dependence. Moreover, an algorithm for assignment to different medications may eventually be made on the basis of cocaine use patterns at treatment intake, presence or absence of a withdrawal syndrome, gender, pharmacogenetics, and single versus dual dependencies. Although it seems rational to believe that less dependent users would benefit from pharmacotherapy since it helps more severely impaired patients, such findings must be confirmed in clinical trials. All clinical trials in cocaine-dependent patients use some form of behavioral therapy. The 2 2 design (drug, placebo CTB, IPT) is capable of validating both behavioral and medication effects. Additionally, it can determine whether there are drug behavioral treatment interactions. The treatment context must be kept in mind when evaluating pharmacotherapies for cocaine dependence. Whether medications will work in less structured forms of treatment and in medical practice without behavioral therapies will need to be determined. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1 Substance Abuse and Mental Health Services Administration. Results from the 2003 National Survey on Drug Use and Health: national findings; September Substance Abuse and Mental Health Services Administration. Emergency department trends from the Drug Abuse Warning Network: final estimates, ; July Crits-Christoph P, Siqueland L, Blaine J, et al. Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Arch Gen Psychiatry 1999; 56: Simpson DD, Joe GW, Broome KM. A national 5-year follow-up of treatment outcomes for cocaine dependence. Arch Gen Psychiatry 2002; 59: Zeger SL, Liang K-Y. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: Wiseman EJ, McMillan DE. Combined use of cocaine with alcohol or cigarettes. Am J Drug Alcohol Use 1996; 22: Heil SH, Badger GJ, Higgins ST. Alcohol dependence among cocainedependent outpatients: demographics, drug use, treatment outcome and other characteristics. J Stud Alcohol 2001; 62:14 22.

6 270 Addictive disorders 8 Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Arch Gen Psychiatry 1986; 43: Higgins ST, Roll JM, Bickel WK. Alcohol pretreatment increases preference for cocaine over monetary reinforcement. Psychopharmacology (Berl) 1996; 123: Jatlow P, Ellsworth JD, Bradberry C, et al. Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine ethanol ingestion. Life Sci 1991; 48: McCance-Katz EF, Price LH, McDougle CJ, et al. Concurrent cocaine ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene. Psychopharmacology 1993; 111: McCance-Katz EF, Price LH, Kosten TR, Jatlow P. Cocaethylene: pharmacology, physiology, and behavioral effects in humans. J Pharmacol Exp Ther 1995; 274: Higgins ST, Budney AJ, Bickel WK, et al. Disulfiram therapy in patients abusing cocaine and alcohol. Am J Psychiatry 1993; 150: Carroll KM, Nich C, Ball SA, et al. 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Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. Biol Psychiatry 2000; 47: Carroll KM, Fenton LR, Ball SA, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients. Arch Gen Psychiatry 2004; 61: This well controlled study confirmed the efficacy of disulfiram to reduce cocaine use when used as an adjunct to a behavioral treatment program. Disulfiram was shown to reduce cocaine use in nonalcoholic cocaine-dependent patients. Two behavioral therapies were compared: CBT was shown to be superior in reducing cocaine use compared with IPT. 22 Luborsky L, Rosenthal R, Diguer L, et al. The dodo bird verdict is alive and well mostly. Clin Psychol Sci Pract 2002; 9: Nich C, McCance-Katz EF, Petrakis IL, et al. Sex differences in cocainedependent individuals response to disulfiram treatment. Addictive Behav 2004; 29: An analysis was conducted of the gender difference in response to disulfiram. Men responded to disulfiram with reduced cocaine use whereas women did not in the two combined trials. This difference should be explored in future clinical studies. 24 Serova L, Rivkin M, Nakashima A, Sabban EL. Oestradiol stimulates gene expression of norepinephrine enzymes in rat locus coeruleus. Neuroendocrinology 2002; 75: Zabetian CP, Anderson GM, Buxbaum SG, et al. A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet 2001; 68: Cubells JF, Chawarski MC, George TP, Schottenfeld RS. DBH genotype in disulfiram treatment for cocaine dependence. Neuropsychopharmacology 2004; 29(Suppl 1):S72. This study evaluated the effect of DBH levels and severity of cocaine use in response to disulfiram in cocaine-dependent patients. If confirmed, it will allow for pretreatment assignment to disulfiram therapy based on DBH levels and severity of cocaine use. The use of genotyping would represent a new approach to treatment of a substance abuse disorder. 27 Roberts DCS, Brebner K. GABA modulation of cocaine self-administration. Ann N Y Acad Sci 2000; 909: Brebner K, Childress AR, Roberts DCS. A potential role for GABA (B) agonists in the treatment of psychostimulant addiction. Alcohol Alcohol 2002; 37: Shoptaw S, Yang X, Rotherman-Fuller EJ, et al. Randomized placebocontrolled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry 2003; 64: Initial report of the efficacy of baclofen in cocaine-dependent outpatients. The results suggest the more impaired patients were helped the most by baclofen. A multi-center confirmatory trial is under way. 30 Schacter SC. Pharmacology and clinical experience with tiagabine. Exp Opin Pharmacother 2001; 2: Gonzalez G, Sevaroni K, Sofuoglu M, et al. Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results from a randomized pilot study. Addiction 2003; 98: This is the initial report of the efficacy of tiagabine. It suggests that increasing GABA levels may be therapeutic. A second study has been completed and is being analyzed. 32 Johnson BA. Topiramate-induced neuromodulation of cortico-mesolimbic dopamine function: a new vista for treatment of comorbid alcohol and nicotine dependence. Addict Behav 2004; 29: This is an outstanding review of the effects of topiramate at the level of receptors and ion channels and cortical circuitry. Johnson lays out the case for treatment of comorbid alcohol and nicotine dependence. 33 Kampman KM, Pettinatti H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 2004; 75: Initial report of the efficacy of topiramate to reduce cocaine use. Patients were admitted to the trial with low scores on the cocaine withdrawal scale to minimize the possibility of topiramate worsening the withdrawal. Patients who were able to refrain from cocaine use for a short time during the baseline period did better on topiramate. 34 Kampman KM, Volpicelli JR, McGinnis DE, et al. Reliability and validity of the Cocaine Severity Assessment. Addict Behav 1998; 23: Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomized controlled study. Lancet 2003; 361: Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend 2003; 70: This report is of a phase I interaction study of modafinil and cocaine. The 200 mg dose of modafinil blunted the cocaine high, suggesting that some of the putative efficacy may be due to interference with the actions of cocaine. 37 Turner DC, Robbins TW, Clark L, et al. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl) 2003; 165: Turner DC, Clark L, Dowson J, et al. Modafinil improves cognition and response inhibition in adult attention deficit/hyperactivity disorder. Biol Psychiatry 2004; 55: This report confirms and expands the response-inhibition effect of modafinil to patients with attention deficit hyperactivity disorder. It also suggests that the response inhibition may be one of the formerly less appreciated effects of modafinil. 39 Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 2005; 30: Initial report of the efficacy of modafinil in cocaine-dependent patients. A single dosage of modafinil (400 mg) was used. Modafinil-treated patients used less cocaine and were more likely to achieve 3 weeks of continuous abstinence during the trial period. Additional studies are under way to confirm the effect. 40 Schmitz JM, Stotts AL, Rhoades HM, Grabowski J. Naltrexone and relapse prevention treatment for cocaine-dependent patients. Addict Behav 2001; 26: Schmitz JM, Stotts AL, Syre SL, et al. Treatment of cocaine alcohol dependence with naltrexone and relapse prevention therapy. Am J Addict 2004; 13: This study failed to replicate the effect of naltrexone to prevent relapse in cocainedependent patients. The reason may be that this patient group also had a coexisting alcohol dependency. It should be noted that 50 mg doses of naltrexone were used. Higher doses should be tested. 42 Oslin DW, Pettinatti HM, Volpicelli JR, et al. The effects of naltrexone on alcohol and cocaine use in dually addicted patients. J Subst Abuse Treat 1999; 16: Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the m-opioid receptor genes is associated with naltrexone response in alcoholdependent patients. Neuropsychopharmacology 2003; 28: This study showed a treatment response to naltrexone that was associated with a single nucleotide polymorphism of the m-opioid receptor. If confirmed, it could predict treatment responsiveness in alcoholic patients. This is the second example of a possible use of genotyping to assess patients for treatment with a substance abuse disorder.