Treatment Of Cocaine Dependence Research Articles

Buprenorphine+naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study.

To examine the safety and effectiveness of buprenorphine+naloxone sublingual tablets (BUP, as Suboxone(®) ) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol(®) ) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. This multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York and Washington DC, USA to one of three conditions provided with XR-NTX: 4mg/day BUP (BUP4, n=100), 16mg/day BUP (BUP16, n=100, or no buprenorphine (placebo; PLB, n=102). Participants received pharmacotherapy for 8weeks, with three clinic visits per week. Cognitive behavioral therapy was provided weekly. Follow-up assessments occurred at 1 and 3months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention and adverse events. No group differences were found between groups for the primary outcome (BUP4 versus PLB, P=0.262; BUP16 versus PLB, P=0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB [P=0.022, odds ratio (OR)=1.71] but not for BUP4 (P=0.105, OR=1.05). No secondary outcome differences across groups were found for adherence, retention or adverse events. Buprenorphine+naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse.

Efficacy of topiramate in the treatment of crack cocaine dependence: a double-blind, randomized, placebo-controlled trial.

We performed a double-blind, randomized, placebo-controlled trial to assess the efficacy of topiramate in the treatment of crack cocaine dependence. Sixty men who were dependent on cocaine (DSM-IV) (exclusive use of crack cocaine) were selected. The subjects were randomly assigned to either a topiramate group (subjects received 50-200 mg of topiramate per day for 12 weeks) or a control group (subjects received placebo). The initial daily treatment dose was 50 mg, and this dose was increased weekly at increments of 25 to 50 mg, based on the subject's tolerability, to a maximum of 200 mg. All of the subjects also participated in motivational interviews and group therapy. The primary outcome measures were detection of benzoylecgonine in the urine, study retention, frequency of cocaine smoking, amount of cocaine use, and mean amount of money spent on cocaine per week. The study was conducted from February 2013 to February 2014. Twenty-nine subjects in the topiramate group and 29 subjects in the control group completed the study. Longitudinal assessment revealed that retention was not significant (odds ratio [OR] = 1.072, P = .908) between the 2 groups. Negative results from a urine test for benzoylecgonine (a cocaine metabolite), which is a measure of cocaine abstinence, were more frequently obtained from the topiramate group (OR = 8.687, P < .001). Topiramate reduced the quantity of cocaine used (mean reduction = -3.108 g, P < .001), the frequency of cocaine use (mean = -0.784 times per week, P = .005), and the amount of money spent on cocaine (mean [US dollars] = -$25.38, P = .015; this variable did not achieve statistical significance after Bonferroni correction) compared with the placebo during the 12 weeks (or 84 days) of the assessment. However, the differences in reductions between the 2 groups in the quantity of cocaine used, the frequency of cocaine use, and money spent on cocaine over time (time × group interaction) were present only during the first 4 weeks, and none of these variables by 12 weeks. The studied groups did not differ with regard to secondary end points, such as study dropout and the number of subjects who reported side effects. The present findings indicate that topiramate is effective and safe and thus reinforce previous data suggesting that topiramate is a potentially useful treatment for crack cocaine dependence. However, we found that topiramate is only useful as an adjunctive treatment during the first 4 weeks of the treatment. Future studies with larger samples are needed to confirm these results. Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-3vwfjs and UTN: U1111-1131-4443.

Effective drug therapy for cocaine dependence: a milestone.

In The Lancet, Mascha Nuijten and colleagues 1 Nuijten M Blanken P van de Wetering B Nuijen B van den Brink W Hendriks VM Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet. 2016; (published online March 22.)http://dx.doi.org/10.1016/S0140-6736(16)00205-1 Google Scholar present the results of a multicentre, randomised, double-blind, placebo-controlled trial assessing the acceptance, safety, and efficacy of sustained-release dexamfetamine in cocaine-dependent patients on heroin-assisted treatment. The study findings showed that 60 mg/day oral sustained-release dexamfetamine over 12 weeks was well accepted, safe, and superior to placebo in terms of days of cocaine use (mean 44·9 days [SD 29·4] in the sustained-release dexamfetamine group vs 60·6 days [24·3] in the placebo group [95% CI of difference 3·1–28·4]; p=0·031; Cohen's standardised effect size d=0·58) and all self-reported and urine-based cocaine use-related outcomes. Cocaine dependence is prevalent throughout the world and causes major morbidity and mortality. 2 Degenhardt L Hall W Extent of illicit drug use and dependence, and their contribution to the global burden of disease. Lancet. 2012; 379: 55-70 Summary Full Text Full Text PDF PubMed Scopus (868) Google Scholar At present, no effective pharmacotherapy exists. Agonist replacement therapy has been successfully applied to opioid and tobacco dependence, 3 Strain EC Bigelow GE Liebson IA Stitzer ML Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. JAMA. 1999; 281: 1000-1005 Crossref PubMed Scopus (359) Google Scholar , 4 Aubin HJ Luquiens A Berlin I Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice. Br J Clin Pharmacol. 2014; 77: 324-336 Crossref PubMed Scopus (73) Google Scholar but previous studies examining this approach in cocaine dependence failed to find statistically significant benefits in terms of reduced cocaine use, or showed indecisive results. This could be due to limitations in the methods, such as small sample sizes, 5 Shearer J Wodak A van Beek I Mattick RP Lewis J Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction. 2003; 98: 1137-1141 Crossref PubMed Scopus (120) Google Scholar inadequate dosing schemes, 6 Dursteler KM Berger EM Strasser J et al. Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence. Subst Abuse Rehabil. 2015; 6: 61-74 Crossref PubMed Google Scholar or large attrition rates. 7 Grabowski J Rhoades H Stotts A et al. Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology. 2004; 29: 969-981 Crossref PubMed Scopus (168) Google Scholar The study by Nuijten and colleagues 1 Nuijten M Blanken P van de Wetering B Nuijen B van den Brink W Hendriks VM Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet. 2016; (published online March 22.)http://dx.doi.org/10.1016/S0140-6736(16)00205-1 Google Scholar overcomes most of these shortcomings. Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trialSustained-release dexamfetamine is a well accepted, effective, and safe agonist pharmacotherapy for comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment. Future research should aim to replicate these findings in chronic cocaine-dependent and other stimulant-dependent patients in more routine treatment settings, including strategies to optimise treatment adherence like medication management interventions and contingency management. Full-Text PDF

Antipsychotic medications for cocaine dependence.

Cocaine dependence is a public health problem characterised by recidivism and a host of medical and psychosocial complications. Cocaine dependence remains a disorder for which no pharmacological treatment of proven efficacy exists. To evaluate the efficacy and the acceptability of antipsychotic medications for cocaine dependence. This review is an update of a previous Cochrane review published in 2007. We searched up to 15 July 2015 in Cochrane Drugs and Alcohol Group Specialised Register (searched in CRSLive); the Cochrane Library (including the Cochrane Central Register of Controlled Trials (CENTRAL); the Database of Abstracts of Reviews of Effects (DARE)); PubMed; EMBASE; CINAHL and Web of Science. All searches included non-English language literature. All randomised controlled trials and controlled clinical trials with focus on the use of any antipsychotic medication for the treatment of cocaine dependence. We used standard methodological procedures expected by Cochrane. We included 14 studies (719 participants). The antipsychotic drugs studied were risperidone, olanzapine, quetiapine, lamotrigine, aripiprazol, haloperidol and reserpine. Comparing any antipsychotic drugs versus placebo, we found that antipsychotics reduced dropout: eight studies, 397 participants, risk ratio (RR) 0.75 (95% confidence interval (CI) 0.57 to 0.97), moderate quality of evidence. We found no significant differences for any of the other primary outcomes considered: number of participants using cocaine during the treatment, two studies, 91 participants: RR 1.02 (95% CI 0.65 to 1.62); continuous abstinence, three studies, 139 participants: RR 1.30 (95% CI 0.73 to 2.32); side effects, six studies, 291 participants: RR 1.01 (95% CI 0.93 to 1.10); and craving, four studies, 240 participants: RR 0.13 (-1.08 to 1.35). For all of these comparisons we rated the quality of evidence as low.Comparisons of single drug versus placebo or versus another drug are conducted in few trials with small sample sizes, limiting the reliability of the results. Among these comparisons, only quetiapine seemed to outperform placebo in reducing cocaine use, measured by grams per week: mean difference (MD) -0.54 (95% CI -0.92 to -0.16), by US dollars spent per week: MD -53.80 (95% CI -97.85 to -9.75), and by craving: MD -1.23 (95% CI -2.19 to -0.27), but results came from one study with 60 participants.The major limitations of the studies were the high risk of attrition bias (40% of the included studies) and low quality of reporting, mainly for the risk of selection bias, performance and detection bias, that we rated as being at unclear risk for 75% to 80% of the studies. Furthermore, most of the included studies did not report results on important outcomes such as side effects, or use of cocaine during treatment and craving, which prevented the possibility of including them in statistical synthesis. At present, there is no evidence supporting the clinical use of antipsychotic medications in the treatment of cocaine dependence, although results come from only 14 trials, with small sample sizes and moderate to low quality of evidence.

Towards Identifying Biologically Relevant Intermediate Conformational States in Dopamine Transporter

Psychostimulant abuse leads to debilitating disorders, the treatment of which remains an alarming challenge. Cocaine and amphetamine act on the dopamine transporter (DAT), which belongs to the neurotransmitter:sodium symporter family that terminates neurotransmission by reuptake of neurotransmitters from the synaptic cleft. The reuptake process can be described by the Na+-coupled alternating-access mechanism in which the transporter adopts outward-open, occluded and inward-open conformations. Cocaine is known to inhibit DAT function by trapping the protein in an outward-open conformation. Interestingly, several other DAT inhibitors, such as benztropine, modafinil, and some of their derivatives, appear to have low abuse liability. Compared to cocaine, these atypical DAT inhibitors show a preference for the conformation of DAT that can be stabilized by a mutation at the intracellular gate, Y335A, and were deduced to prefer less outward-open conformations than cocaine. Nevertheless their differential inhibiting mechanisms at the atomistic level is not well understood.We carried out comparatively molecular dynamics simulations of both DAT-WT and DAT-Y335A constructs, stabilized by a variety of DAT inhibitors, and used Markov State Models to analyze the resulting trajectories. This analysis identifies an ensemble of conformational states exhibited spontaneously by the molecule at local equilibrium, and has the advantage in its ability to represent both thermodynamic and kinetic characteristics of protein conformational changes. Thus we capture the conformational states and kinetics of transitions between outward-occluded and outward-open states of DAT. Identification and characterization of the intermediate states that are stabilized by the atypical inhibitors and/or Y335A mutation is crucial in understanding the mechanism of action of these inhibitors. This understanding of how these states eventually trigger different downstream cellular effects from cocaine holds new promises to develop targeted treatment of cocaine dependence.

A randomized factorial trial of disulfiram and contingency management to enhance cognitive behavioral therapy for cocaine dependence

BackgroundThis study evaluated the extent to which the addition of disulfiram and contingency management for adherence and abstinence (CM), alone and in combination, might enhance the effects of cognitive behavioral therapy (CBT) for cocaine use disorders. MethodsFactorial randomized double blind (for medication condition) clinical trial where CBT served as the platform and was delivered in weekly individual sessions in a community-based outpatient clinic. 99 outpatients who met DSM-IV criteria for current cocaine dependence were assigned to receive either disulfiram or placebo, and either CM or no CM. Cocaine and other substance use was assessed via a daily calendar with thrice weekly urine sample testing for 12 weeks with a one-year follow-up (80% interviewed at one year). ResultsThe primary hypothesis that CM and disulfiram would produce the best cocaine outcomes was not confirmed, nor was there a main effect for disulfiram. For the primary outcome (percent days of abstinence, self report), there was a significant interaction, with the best cocaine outcomes were seen for the combination of CM and placebo, with the two groups assigned to disulfiram associated with intermediate outcomes, and poorest cocaine outcome among those assigned to placebo and no CM. The secondary outcome (urinalysis) indicated a significant effect favoring CM over no CM but the interaction effect was not significant. One year follow-up data indicated sustained treatment effects across conditions. ConclusionsCM enhances outcomes for CBT treatment of cocaine dependence, but disulfiram provided no added benefit to the combination of CM and CBT.

Modafinil and sleep architecture in an inpatient–outpatient treatment study of cocaine dependence

ObjectiveTo determine whether the increase in slow-wave sleep associated with modafinil treatment in chronic cocaine users mediates improved clinical outcomes. Method57 cocaine dependent participants were randomized to receive modafinil 400mg or placebo daily during a period of inpatient treatment followed by six weeks of outpatient treatment. Participants underwent polysomnographic sleep recording during inpatient treatment prior to and after starting modafinil. Outpatient treatment consisted of weekly cognitive behavioral therapy. Contingency management was used to promote participation in treatment and research demands, including thrice weekly visits during the outpatient phase for urine toxicology screens and other assessments. The primary clinical outcome was the percent of urine toxicology screens that were negative for cocaine. ResultsModafinil treatment was associated with a higher mean percentage (52% vs. 26%) of cocaine-free urine screens (p=0.02) and an increase in N3 sleep time (p=0.002). The change in N3 sleep time mediated the higher rate of cocaine-free urine screens. Modafinil treatment was also associated with more consecutive days abstinent during outpatient treatment, greater survival of abstinence, higher daily rates of abstinence, and less sleep degradation typically associated with abstinence from chronic cocaine use. ConclusionsMorning-dosed modafinil improves slow-wave sleep in abstinent cocaine users in the inpatient setting, and this effect is a statistical mediator of improved clinical outcomes associated with continued modafinil treatment. The high rates of abstinence achieved in this trial suggest that promoting healthy sleep physiology in an inpatient setting may be important in the effective treatment of cocaine dependence.

Nociceptin receptor activation does not alter acquisition, expression, extinction and reinstatement of conditioned cocaine preference in mice

Growing evidence indicates that targeting nociceptin receptor (NOP) signaling may have therapeutic efficacy in treating alcohol and opioid addiction. However, little is known about the therapeutic value of selective NOP agonists for the treatment of cocaine dependence. Recently, we identified a highly selective, brain-penetrant NOP small molecule agonist (SR-8993), and using this compound, we previously showed that nociceptin receptor activation attenuated consolidation of fear-related memories. Here, we sought to determine whether SR-8993 also affects the rewarding properties of cocaine. Using a conditioned place preference (CPP) procedure, we show that SR-8993 (3 or 10mg/kg) failed to disrupt acquisition or expression of cocaine CPP (7.5 or 15mg/kg) in C57BL/6 mice. Additionally, SR-8993 did not affect rate of extinction or reinstatement (yohimbine- and cocaine-induced) of cocaine CPP. These studies indicate that selective activation of NOP may not be sufficient in reducing behavioral responses to cocaine.

Effect of patient choice in an adaptive sequential randomization trial of treatment for alcohol and cocaine dependence.

To evaluate the effect of providing choice of treatment alternatives to patients who fail to engage in or drop out of intensive outpatient programs (IOPs) for substance dependence. Alcohol- and/or cocaine-dependent patients (N = 500) participated in a sequential, multiple-assignment, randomized trial (SMART). Those who failed to engage in an IOP at Week 2 (N = 189) or who dropped out after engagement (N = 84) were randomized for motivational-interviewing (MI) telephone calls that focused on engagement in an IOP (MI-IOP) or provided a choice of IOP type or 3 treatment options (MI-PC, or patient choice). Those not engaged at both 2 and 8 weeks (N = 102) were re-randomized either to MI-PC or no further outreach. Outcomes were treatment attendance and measures of alcohol and cocaine use obtained at 1, 2, 3, and 6 months. MI-PC produced better attendance than comparison conditions in patients who dropped out after initial engagement and in those re-randomized at 8 weeks. However, contrary to study hypotheses, MI-IOP produced significantly better alcohol-use outcomes than MI-PC in alcohol-dependent patients not engaged at Week 2. There were no other significant differences between treatment conditions on other main-effect analyses with alcohol- or cocaine-outcome measures. Providing treatment options via telephone calls to patients who failed to engage in IOP did not produce better substance-use outcomes than outreach calls focused on engagement in IOP. Future researchers should investigate the potential benefits of choice at other points in treatment (e.g., at intake) as well as choice of other combinations of treatments.

Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.

Joint modeling of longitudinal drug using pattern and time to first relapse in cocaine dependence treatment data

An important endpoint variable in a cocaine rehabilitation study is the time to first relapse of a patient after the treatment. We propose a joint modeling approach based on functional data analysis to study the relationship between the baseline longitudinal cocaine-use pattern and the interval censored time to first relapse. For the baseline cocaine-use pattern, we consider both self-reported cocaine-use amount trajectories and dichotomized use trajectories. Variations within the generalized longitudinal trajectories are modeled through a latent Gaussian process, which is characterized by a few leading functional principal components. The association between the baseline longitudinal trajectories and the time to first relapse is built upon the latent principal component scores. The mean and the eigenfunctions of the latent Gaussian process as well as the hazard function of time to first relapse are modeled nonparametrically using penalized splines, and the parameters in the joint model are estimated by a Monte Carlo EM algorithm based on Metropolis-Hastings steps. An Akaike information criterion (AIC) based on effective degrees of freedom is proposed to choose the tuning parameters, and a modified empirical information is proposed to estimate the variance-covariance matrix of the estimators.

A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence

BackgroundModafinil is a medication approved for narcolepsy and shift work sleep disorder. It has both dopaminergic and glutamatergic activity that could be useful for the treatment of cocaine dependence. Modafinil has reduced cocaine subjective effects and cocaine self-administration in human laboratory trials and has reduced cocaine use in cocaine dependent patients in some clinical trials. MethodsThis was an 8-week, double blind, placebo controlled clinical trial involving 94 cocaine dependent subjects. Subjects received 300mg of modafinil or identical placebo daily along with weekly individual therapy. The primary outcome measure was cocaine use measured by self-report, and confirmed by twice weekly urine benzoylecgonine tests (UBT). Additional outcome measures included cocaine craving measured by the Brief Substance Craving Scale and global improvement measured by the Clinical Global Impression Scale (CGI). ResultsThe odds ratio (OR) in favor of abstinence for modafinil vs. placebo was 2.54 (p=. 03) and modafinil-treated subjects were significantly more likely than placebo-treated subjects to be abstinent from cocaine during the last 3 weeks of the trial, 23% vs. 9%, χ2=3.9, p<.05. Modafinil treated subjects were more likely to report very low levels of cocaine craving intensity and duration on the Brief Substance Craving Scale (OR=2.04, p=.03 and OR 1.06, p=.03 respectively). Modafinil-treated subjects were also more likely than placebo-treated subjects to rate themselves as “very much improved” on the CGI (OR=2.69, p=.03). ConclusionModafinil may be an efficacious treatment for cocaine dependence.

Contingency management for substance use disorders in Spain: Implications for research and practice

ObjectiveWe provide a narrative review of published studies evaluating voucher-based contingency management (CM) treatment for cocaine, nicotine and cannabis use disorders in Spain and discuss the concerns and future challenges. MethodPublished studies between 2008 and 2015 that evaluated the impact of incentives for SUD in Spain and included an appropriate control or comparison condition were identified and reviewed. ResultsAdding voucher-based CM to standard treatments obtained better treatment retention and cocaine abstinence than standard care alone. CM also improved psychosocial functioning. Economic status or depressive symptoms did not affect the results of CM treatment for cocaine dependence. The addition of a CM protocol to cognitive behavioral treatment (CBT) also improved treatment effectiveness for smoking cessation. Available data on the effect of CM on cannabis use disorders (CUD) with young people did not allow confirmation of its superiority to date. ConclusionThe research conducted to date in Spain confirms and expands the findings of studies conducted in the US supporting the effectiveness of CM in the context of community settings with cocaine- and nicotine-dependents. However, CM has not yet been readily adopted into general clinical practice in Spain or the rest of Europe. The limited effectiveness of CM for CUD is likely due to the scarcity of data and may change with more studies, taking into account recent research on this topic in the US. Continued efforts are warranted to further develop and disseminate incentive-based treatments for SUD across clinical settings and populations in Spain.

Pilot study of the effects of lisdexamfetamine on cocaine use: A randomized, double-blind, placebo-controlled trial

BackgroundAmphetamine analogs have been demonstrated to have some efficacy in reducing use in cocaine dependent individuals. However, these agents also have potential for abuse. Lisdexamfetamine (LDX), a lysine+dextroamphetamine formulation, has been approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and as a prodrug, has less abuse potential. ObjectiveThis pilot study sought to evaluate the safety, tolerability, and efficacy of LDX as a candidate treatment for cocaine dependence. MethodsA randomized, double-blind, placebo-controlled parallel group study served to evaluate LDX in 43 cocaine-dependent individuals: (1) placebo (PBO; 0mg, n=21), (2) LDX (70mg, n=22). Participants received medication for 14 weeks. Cocaine use was determined based on urine analysis for benzoylecgonine (BE; a cocaine metabolite). ResultsRetention rates were higher though not significantly different in the PBO (71.4%) than the LDX condition (57.1%). Compared to those in the PBO condition, those receiving LDX were more likely to report experiencing (ps<0.05) diarrhea (45.5% vs. 14.3%), headaches (45.5% vs. 9.5%), and anxiety (31.8% vs. 4.8%). No differences in medication conditions were observed for blood pressure, heart rate, or body weight. In the randomized sample, no differences in cocaine use were seen. Those receiving LDX reported significantly less craving for cocaine than participants receiving PBO. ConclusionsLDX did not significantly reduce cocaine use compared to PBO in the randomized sample.

Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence.

BackgroundCocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine.AimTo provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence.MethodsWe searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature.ResultsMPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder.ConclusionClinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research.

Modafinil in the treatment of crack-cocaine dependence in the Netherlands: Results of an open-label randomised controlled feasibility trial

Crack-cocaine dependence is a serious disorder with no approved pharmacological treatment. Modafinil is a promising medication with increased cocaine abstinence and reduced craving in some previous studies. In the present study, we examined the acceptance, safety and potential benefits of modafinil as an add-on treatment to cognitive behavioural therapy (CBT) in crack-cocaine dependent patients. Sixty-five crack-cocaine dependent outpatients participated in an open-label, randomised feasibility trial. Patients were randomised to receive either 12-week individual CBT plus 400 mg/day modafinil or 12-week individual CBT only. The primary outcome measure was CBT treatment retention. Secondary outcomes included modafinil adherence, tolerability and safety, use of cocaine and other substances, cocaine craving, health, social functioning and patient satisfaction. Modafinil adherence was low, with only 10% treatment completers. Intent-to-treat analyses showed that modafinil did not improve CBT treatment retention or any of the secondary cocaine-related outcomes. Both groups showed similar, large reductions in cocaine use during the study treatment. Post hoc exploratory analyses within the CBT plus modafinil group showed significantly larger baseline to week 12 reductions in cocaine use days in high (⩾ 8 weeks) modafinil adherent patients. Acceptance and benefits of modafinil were not demonstrated in the present study. Since reduction in cocaine use was observed in high modafinil adherent patients, further research in the treatment of cocaine dependence, in which modafinil adherence is optimised, is warranted.

Dopamine agonists for the treatment of cocaine dependence.

Cocaine misuse is a disorder for which no pharmacological treatment of proven efficacy exists. Advances in neurobiology could guide future medication development. To investigate the efficacy and acceptability of dopamine agonists alone or in combination with any psychosocial intervention for the treatment of of people who misuse cocaine. We run the search on 12 January 2015. We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE, CINAHL, PsycINFO, ICTRP, clinicaltrials.gov and screened reference lists. Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing dopamine agonists alone or associated with psychosocial intervention with placebo, no treatment or other pharmacological interventions. We used standard Cochrane methodological procedures. Twenty four studies, including 2147 participants, met the inclusion criteria. Comparing any dopamine agonist versus placebo, we found no differences for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). This was also observed when single dopamine agonists were compared against placebo. Comparing amantadine versus antidepressants,we found low quality of evidence that antidepressants performed better for abstinence (RR 0.25, 95% CI 0.12 to 0.53) based on two studies with 44 participants. No differences were found for dropout or adverse events, for both moderate quality of evidence.The major flaws of the included studies concerned selection bias because most studies did not report information about sequence generation (80%) and allocation concealment methods (86%): half of the included studies were judged at unclear risk of performance bias and 62.5% at unclear risk of detection bias for what concerns subjective outcomes. Current evidence from RCTs does not support the use of dopamine agonists for treating cocaine misuse. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Even the potential benefit of combining a dopamine agonist with a more potent psychosocial intervention, which was suggested by the previous Cochrane Review (Soares 2003), is not supported by the results of this Cochrane Review update.

A Randomized, Double-Blind, Placebo-Controlled Trial of Citicoline for Cocaine Dependence in Bipolar I Disorder.

Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use. A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale. In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed. Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.

Anticonvulsants for cocaine dependence.

Cocaine dependence is a major public health problem that is characterised by recidivism and a host of medical and psychosocial complications. Although effective pharmacotherapy is available for alcohol and heroin dependence, none is currently available for cocaine dependence, despite two decades of clinical trials primarily involving antidepressant, anticonvulsivant and dopaminergic medications. Extensive consideration has been given to optimal pharmacological approaches to the treatment of individuals with cocaine dependence, and both dopamine antagonists and agonists have been considered. Anticonvulsants have been candidates for use in the treatment of addiction based on the hypothesis that seizure kindling-like mechanisms contribute to addiction. To evaluate the efficacy and safety of anticonvulsants for individuals with cocaine dependence. We searched the Cochrane Drugs and Alcohol Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1966 to June 2014), EMBASE (1988 to June 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2014), Web of Science (1991 to June 2014) and the reference lists of eligible articles. All randomised controlled trials and controlled clinical trials that focus on the use of anticonvulsant medications to treat individuals with cocaine dependence. We used the standard methodological procedures expected by The Cochrane Collaboration. We included a total of 20 studies with 2068 participants. We studied the anticonvulsant drugs carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate and vigabatrin. All studies compared anticonvulsants versus placebo. Only one study had one arm by which the anticonvulsant was compared with the antidepressant desipramine. Upon comparison of anticonvulsant versus placebo, we found no significant differences for any of the efficacy and safety measures. Dropouts: risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.05, 17 studies, 20 arms, 1695 participants, moderate quality of evidence. Use of cocaine: RR 0.92, 95% CI 0.84 to 1.02, nine studies, 11 arms, 867 participants, moderate quality of evidence; side effects: RR 1.39, 95% CI 1.01 to 1.90, eight studies, 775 participants; craving: standardised mean difference (SMD) -0.25, 95% CI -0.59 to 0.09, seven studies, eight arms, 428 participants, low quality of evidence. Although caution is needed when results from a limited number of small clinical trials are assessed, no current evidence supports the clinical use of anticonvulsant medications in the treatment of patients with cocaine dependence. Although the findings of new trials will improve the quality of study results, especially in relation to specific medications, anticonvulsants as a category cannot be considered first-, second- or third-line treatment for cocaine dependence.

Topiramate impairs cognitive function in methadone-maintained individuals with concurrent cocaine dependence.

Topiramate is being investigated as a potential pharmacotherapy for the treatment of addictive disorders. However, its cognitive side effects raise concerns about its use, especially in populations with cognitive impairment, such as persons with chronic substance use disorders. This study investigated topiramate's cognitive effects in individuals dually dependent on cocaine and opioids as part of a double-blind, randomized, controlled trial of topiramate for cocaine dependence treatment. After 5 weeks of stabilization on daily oral methadone (M = 96 mg), participants were randomized to topiramate (n = 18) or placebo (n = 22). Cognitive testing took place at 2 time points: study weeks 4 through 5 to assess baseline performance and 10 to 13 weeks later to assess performance during stable dosing (300 mg topiramate or placebo). All participants were maintained on methadone at both testing times, and testing occurred 2 hours after the daily methadone plus topiramate/placebo administration. The topiramate and placebo groups did not differ on sex, level of education, premorbid intelligence, methadone dose, or illicit drug use. Topiramate slowed psychomotor and information processing speed, worsened divided attention, reduced n-back working memory accuracy, and increased the false alarm rate in recognition memory. Topiramate had no effects on visual processing, other measures of psychomotor function, risk-taking, self-control, Sternberg working memory, free recall, and metamemory. These findings indicate that topiramate may cause cognitive impairment in this population. This effect may limit its acceptability and use as a treatment in individuals with chronic opioid and cocaine use disorders, among whom preexisting cognitive impairments are common. (PsycINFO Database Record