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CORK Bibliography: Pharmacotherapies for Drug Use Problems

93 citations. January 2011 to present

Prepared: September 2011

Abraham AJ; Rieckmann T; McNulty T; Kovas AE; Roman PM. Counselor attitudes toward the use of naltrexone in substance abuse treatment: A multi-level modeling approach. Addictive Behaviors 36(6, special issue): 576- 583, 2011. (43 refs.)

Alcohol use disorders (AUDs) continue to be one of the most pervasive and costly of the substance use disorders (SUDs). Despite evidence of clinical effectiveness, adoption of medications for the treatment of AUDs is suboptimal. Low rates of AUD medication adoption have been explained by characteristics of both treatment organizations and individual counselor's attitudes and behaviors. However, few studies have simultaneously examined the impact of organizational-level and counselor-level characteristics on counselor perceptions of EBPs. To address this gap in the literature, we use data from a national sample of 1178 counselors employed in 209 privately funded treatment organizations to examine the effects of organizational and individual counselor characteristics on counselor attitudes toward tablet and injectable naltrexone. Results of hierarchical linear modeling (HLM) show that organizational characteristics (use of tablet/injectable naltrexone in the program. 12-step orientation) were associated with counselor perceptions of naltrexone. Net of organizational characteristics, several counselor level characteristics were associated with attitudes toward tablet and injectable naltrexone including gender, tenure in the field, recovery status, percentage of AUD patients, and receipt of medication-specific training. These findings reveal that counselor receptiveness toward naltrexone is shaped in part by the organizational context in which counselors are embedded.

Alguacil LF; Salas E; Gonzalez-Martin C. Identification of new drug targets and biomarkers related to obesity and eating disorders: An approach based on reward deficit and addiction. (review). Current Pharmaceutical Design 17(5): 462- 470, 2011. (99 refs.)

Current pharmacological treatments for eating disorders and obesity are of limited value and thus the identification of novel targets is highly needed to enhance the development of more effective drugs. Among the bottlenecks limiting the introduction of new medicines is the reported heterogeneity of these diseases, which makes it difficult to find drugs with broad activity and the lack of animal models with translational validity, especially in the case of anorexia nervosa. Some kinds of obesity and eating disorders can be classified within the pathologies affecting the brain reward system together with drug addiction and others, and therefore specific treatments in these cases can be directed to restore normal function in brain reward pathways. Target identification in this field can greatly benefit from the combined application of genomic/proteomic techniques and robust animal models of reward deficits.

Ambermoon P; Carter A; Hall WD; Dissanayaka NNW; O'Sullivan JD. Impulse control disorders in patients with Parkinson's disease receiving dopamine replacement therapy: Evidence and implications for the addictions field. (review). Addiction 106(2): 283-293, 2011. (62 refs.)

Aims: To describe the prevalence, phenomenology and correlates of 'impulse control disorders' (ICDs) in patients with Parkinson's disease (PD) treated with dopamine replacement therapy (DRT); to assess the strength of the evidence that DRT plays a contributory causal role in these disorders; and to highlight the implications of these disorders for research in the addiction field. Methods: PubMed and Web of Science databases were searched and the reference lists of papers examined. Results: The prevalence of ICDs in Parkinson's patients using DRT varied between 3.5% and 13.6%, depending on the severity and range of disorders assessed. PD patients with ICDs were: generally younger; had an earlier onset of PD; had a personal or family history of substance abuse or an ICD; and were more likely to be treated with dopamine receptor agonists (DA agonists) than levodopa (l-dopa). There is reasonable evidence that dopaminergic medications play a causal role in ICDs in that they occur at a higher rate in an otherwise low-risk population of adults, begin after initiation of DA agonist therapy and cease upon its discontinuation. A causal relationship is biologically plausible, but the role of other factors (such as concurrent mood disorders) remain to be clarified by better-controlled studies. Conclusions: Impulse control disorders among patients with Parkinson's disease receiving dopamine replacement therapy may provide a unique opportunity for addiction researchers to study the neurobiology of impulsive forms of behaviour (such as problem gambling) that appear to be caused, in part, by the therapeutic use of dopamine receptor agonists.

Backstrom P; Etelalahti TJ; Hyytia P. Attenuation of reinforcing and psychomotor stimulant effects of amphetamine by aripiprazole. Addiction Biology 16(1): 55-63, 2011. (50 refs.)

Partial dopamine agonists are potential medications for the treatment of amphetamine addiction. They have been hypothesized to stabilize the dopamine system by acting as antagonists during high dopaminergic tone resulting from amphetamine use and as agonists during withdrawal. Aripiprazole is an atypical antipsychotic that acts as a partial D2 dopamine and a serotonin 5-HT1A agonist and a serotonin 5-HT2A antagonist. The aim of the present study was to examine the effects of aripiprazole on behaviors induced and maintained by d-amphetamine. To this end, intravenous d-amphetamine self-administration [fixed ratio 3 (FR3) schedule, 0.02 mg/infusion] and d-amphetamine-induced (0, 1.5 mg/kg intraperitoneally) locomotor activity, as well as spontaneous locomotor activity and sucrose pellet self-administration (FR3 schedule) were studied in male Wistar rats after aripiprazole (0, 0.3, 1, 3 mg/kg i.p.) administration. Aripiprazole pre-treatment resulted in bidirectional effects on amphetamine self-administration. The 1 mg/kg dose increased, and the highest dose decreased the number of amphetamine infusions. In the locomotor activity experiments, aripiprazole attenuated amphetamine-induced activity dose-dependently and tended to suppress spontaneous activity. The highest aripiprazole doses decreased also sucrose pellet self-administration. The increase in amphetamine self-administration with the intermediate aripiprazole dose, as well as the decrease in amphetamine-induced locomotor activity, suggests that aripiprazole acted as a dopamine antagonist. Suppression of amphetamine and sucrose self-administration by the highest aripiprazole dose was probably caused by non-specific effects. Together, these results indicate that under conditions of dopaminergic stimulation, aripiprazole attenuates the reinforcing and psychomotor stimulant effects of d-amphetamine, but the dose range for this effect is rather limited.

Balmford J; Borland R; Hammond D; Cummings KM. Adherence to and reasons for premature discontinuation from stop-smoking medications: Data from the ITC Four-Country Survey. Nicotine & Tobacco Research 13(2): 94-102, 2011. (25 refs.)

Nicotine replacement therapies (NRTs) have been demonstrated to be effective in clinical trials but may have lower efficacy when purchased over-the-counter (OTC). Premature discontinuation and insufficient dosing have been offered as possible explanations. The aims are to (a) investigate the prevalence of and reasons for premature discontinuation of stop-smoking medications (including prescription only) and (b) how these differ by type, duration of use, and source (prescription or OTC). The sample includes 1,219 smokers or recent quitters who had used medication in the last year (80.5% NRT, 19.5% prescription only). Data were from Waves 5 and 6 of the International Tobacco Control (ITC) Four-Country Survey. Most of the sample (69.1%) discontinued medication use prematurely. This was more common among NRT users (71.4%) than in users of bupropion and varenicline (59.6%). OTC NRT users were particularly likely to discontinue (76.3%). Relapse back to smoking was the most common reason for discontinuation of medication reported by 41.6% of respondents. Side effects (18.3%) and believing that the medication was no longer needed (17.1%) were also commonly reported. Of those who completed treatment, 37.9% achieved 6-month continuous abstinence compared with 15.6% who discontinued prematurely. Notably, 65.6% who discontinued because they believed the medication had worked were abstinent. Premature discontinuation of stop-smoking medications is common but is not a plausible reason for poorer quit outcomes for most people. Encouraging persistence of medication use after relapse or in the face of minor side effects may help increase long-term cessation outcomes.

Bartlett N; Xin DM; Zhang H; Huang BM. A qualitative evaluation of a peer-implemented overdose response pilot project in Gejiu, China. International Journal of Drug Policy 22(4): 301-305, 2011. (30 refs.)

Background: A harm reduction NGO in southern Yunnan operating an emergency overdose response hotline service successfully reversed 76 overdoses through the administration of naloxone in one of the first interventions of its kind in China. Method: To explore local understandings of risk factors related to overdose, assess ongoing barriers to overdose response, and solicit client input on how to further reduce opiate overdose mortality in Gejiu, the authors conducted qualitative interviews with 30 clients, including 15 individuals who received naloxone injections to reverse an overdose and 15 individuals who called the hotline in response to the overdose of a peer. Results: Participants pointed to a number of local structural shifts in heroin use including the ageing of the opiate using population and drug mixing practises that contribute to the city's overdose toll. Concerns over medical professionals' willingness to treat drug users, protection of confidentiality, and financial costs associated with treatment frequently cause drug users to avoid contact with the city's emergency service providers. Participants suggest directly distributing naloxone to clients as one strategy to further reduce overdose mortality. Conclusion: The authors explore possible strategies, including targeted trainings and new partnerships with local hospitals, to further reduce opiate overdose mortality in this resource-poor setting.

Bolliger CT; Issa JS; Posadas-Valay R; Safwat T; Abreu P; Correia EA et al. Effects of varenicline in adult smokers: A multinational, 24-week, randomized, double-blind, placebo-controlled study. Clinical Therapeutics 33(4): 465-477, 2011. (26 refs.)

Background: Prevalence rates of smoking are rising in developing countries. Previous trials evaluating the efficacy and tolerability of the smoking-cessation medication varenicline have used largely participants of Caucasian origin. Objective: This study was conducted to evaluate the efficacy and tolerability of varenicline in populations of participants from Latin America, Africa, and the Middle East to investigate potential differences in the therapeutic response to varenicline. Methods: This multinational, randomized, double-blind, placebo-controlled trial was conducted at 42 centers in 11 countries (Latin America: Brazil, Colombia, Costa Rica, Mexico, and Venezuela; Africa: Egypt and South Africa; Middle East: Jordan, Lebanon, Saudi Arabia, and the United Arab Emirates). Participants were male and female smokers aged 18 to 75 years who were motivated to stop smoking; smoked >= 10 cigarettes/d, with no cumulative period of abstinence >3 months in the previous year; and who had no serious or unstable disease within the previous 6 months. Subjects were randomized in a 2:1 ratio to receive varenicline 1 mg or placebo, BID for 12 weeks, with a 12-week nontreatment follow-up. Brief smoking-cessation counseling was provided. The main outcome measures were carbon monoxide confirmed continuous abstinence rate (CAR) at weeks 9 to 12 and weeks 9 to 24. Adverse events (AEs) were recorded for tolerability assessment. Results: Overall, 588 subjects (varenicline, 390; placebo, 198) were randomized and treated. The mean (SD) ages of subjects in the varenicline and placebo groups were 43.1 (10.8) and 43.9 (10.8) years, respectively; 57.7% and 65.7% were male; and the mean (SD) weights were 75.0 (16.0) and 76.7 (16.3) kg (range, 40.0-130.0 and 45.6-126.0 kg). CAR at weeks 9 to 12 was significantly higher with varenicline than with placebo (53.59% vs 18.69%; odds ratio [OR] = 5.76; 95% CI, 3.74-8.88; P < 0.0001), and this rate was maintained during weeks 9 to 24 (39.74% vs 13.13%; OR = 4.78; 95% CI, 2.97-7.68; P < 0.0001). Nausea, headache, and insomnia were the most commonly reported AEs with varenicline and were reported numerically more frequently in the varenicline group compared with the placebo group. Serious AEs (SAEs) were reported in 2.8% of varenicline recipients compared with 1.0% in the placebo group, with 6 subjects reporting psychiatric SAEs compared with none in the placebo group. Conclusion: Based on these data, varenicline was apparently efficacious and generally well tolerated as a smoking-cessation aid in smokers from selected sites in Latin America, Africa, and the Middle East.

Booth RE; Lehman WEK; Latkin CA; Dvoryak S; Brewster JT; Royer MS et al. Individual and network interventions with injection drug users in 5 Ukraine cities. American Journal of Public Health 101(2): 336-343, 2011. (4 refs.)

Objectives. We evaluated the effects of an individual intervention versus a network intervention on HIV-related injection and sexual risk behaviors among street-recruited opiate injection drug users in 5 Ukraine cities. Methods. Between 2004 and 2006, 722 opiate injection drug users were recruited to participate in interventions that were either individually based or based on a social network model in which peer educators intervened with their network members. Audio computer-assisted self-interview techniques were used to interview participants at baseline and follow-up. Results. Multiple logistic analyses controlling for baseline injection and sexual risks revealed that both peer educators and network members in the network intervention reduced injection-related risk behaviors significantly more than did those in the individually based intervention and that peer educators increased condom use significantly more than did those in the individual intervention. Individual intervention participants, however, showed significantly greater improvements than did network members with respect to reductions in sexual risk behaviors. Conclusions. Social network interventions may be more effective than individually based interventions in changing injection risk behaviors among both peer educators and network members. The effectiveness of network interventions in changing sexual risk behaviors is less clear, probably owing to network composition and inhibitions regarding discussing sexual risk behaviors.

Brady KT; Gray KM; Tolliver BK. Cognitive enhancers in the treatment of substance use disorders: Clinical evidence. (review). Pharmacology, Biochemistry and Behavior 99(2, special issue): 285-294, 2011. (140 refs.)

Attenuation of drug reward has been the major focus of medication development in the addiction area to date. With the growth of research in the area of cognitive neuroscience, the importance of executive function and inhibitory cognitive control in addictive disorders is becoming increasingly apparent. An emerging strategy in the pharmacotherapy of addictions and other psychiatric disorders involves the use of medications that improve cognitive function. In particular, agents that facilitate inhibitory and attentional control, improve abstraction, planning and mental flexibility could be beneficial in the treatment of substance use disorders. Because there are multiple neurotransmitter systems involved in the regulation of cognitive function, agents from a number of drug classes have been tested. In particular, agents acting through the cholinergic, adrenergic and glutamatergic systems have shown potential for improving cognitive function in a number of psychiatric and neurologic disorders, but most of these agents have not been tested in the treatment of individuals with substance use disorders. This manuscript provides a review of clinical data supporting the use of the major classes of cognitive enhancing agents in substance use disorders. Agents that have shown promise in cognitive enhancement in other disorders, and have a theoretical or mechanistic rationale for application to substance use disorders are also highlighted.

Brunette MF; Dawson R; O'Keefe CD; Narasimhan M; Noordsy DL; Wojcik J et al. A randomized trial of clozapine versus other antipsychotics for cannabis use disorder in patients with schizophrenia. Journal of Dual Diagnosis 7(1-2): 50- 63, 2011. (71 refs.)

Objective: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. The authors launched a randomized controlled trial to assess the impact of clozapine compared with treatment as usual on cannabis use in patients with schizophrenia and co-occurring cannabis use disorder. Methods: Thirty-one patients with schizophrenia and co-occurring cannabis use disorder were randomly assigned to switch to clozapine or to stay on their current antipsychotic and were then followed weekly for 12 weeks. Blinded raters assessed participants weekly with the Timeline Followback for substance use and the expanded Brief Psychiatric Rating Scale for symptoms. Longitudinal random effects models were used to investigate the time-varying differences in cannabis use and other outcomes between the treatment as usual and clozapine groups. Results: The two groups differed in average intensity of cannabis use by approximately 4.5 joints/week, with lesser use in the clozapine group (t = -1.77; df = 28.5; p = .086; effect size 0.6). Symptoms and functioning were not different between the two groups. Conclusions: Clozapine may reduce cannabis use among patients with schizophrenia and co-occurring cannabis use disorder. Further controlled trials are warranted.

Cahill K; Stead LF; Lancaster T. Nicotine receptor partial agonists for smoking cessation. (review). Cochrane Database of Systematic Reviews 2: article CD006103, 2011. (161 refs.)

Background: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials have now been published or are currently underway. Objectives: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. Search strategy: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The latest search was in September 2010. Selection criteria: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. Data collection and analysis We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up. The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis to produce a risk ratio, using the Mantel-Haenszel fixed-effect model. Main results: We found 11 trials of varenicline compared with placebo for smoking cessation; three of these included a bupropion experimental arm. We also found one relapse prevention trial, comparing varenicline with placebo, and two open-label trials comparing varenicline with nicotine replacement therapy (NRT). We also include one trial in which all the participants were given varenicline, but received behavioural support either online or by phone calls, or by both methods. This trial is not included in the analyses, but contributes to the data on safety and tolerability. The included studies covered >10,300 participants, 6892 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion. The pooled risk ratio (RR) (10 trials, 4443 people, excluding one trial evaluating long term safety) for continuous abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.31 (95% confidence interval [CI] 2.01 to 2.66). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4 trials, 1272 people). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 1.35; 2 trials, 778 people). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Post-marketing safety data raised questions about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline was amended in 2008, and the manufacturers produced a Medication Guide. Thus far, surveillance reports and secondary analyses of trial data lend little support to a causal relationship. The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08). Authors' conclusions: Varenicline at standard dose increased the chances of successful long-term smoking cessation between two-and threefold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion. Two open-label trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence intervals did not rule out equivalence. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, have been reported but are so far not substantiated. There is a need for further independent community-based trials of varenicline, to test its efficacy and safety in smokers with varying co-morbidities and risk patterns. There is a need for further trials of the efficacy of treatment extended beyond 12 weeks. Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.

Cahill K; Ussher MH. Cannabinoid type I receptor antagonists for smoking cessation. (review). Cochrane Database of Systematic Reviews 3: article CD005353, 2011. (33 refs.)

Background: Selective type 1 cannabinoid (CB1) receptor antagonists may assist with smoking cessation by restoring the balance of the endocannabinoid system, which can be disrupted by prolonged use of nicotine. They also seeks to address many smokers' reluctance to persist with a quit attempt because of concerns about weight gain. Objectives: To determine whether selective CB1 receptor antagonists (currently rimonabant and taranabant) increase the numbers of people stopping smoking To assess their effects on weight change in successful quitters and in those who try to quit but fail. Search strategy: We searched the Cochrane Tobacco Addiction Review Group specialized register for trials, using the terms ('rimonabant' or 'taranabant') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, CINAHL and PsycINFO, using major MESH terms. We acquired electronic or paper copies of posters of preliminary trial results presented at the American Thoracic Society Meeting in 2005, and at the Society for Research on Nicotine and Tobacco European Meeting 2006. We also attempted to contact the authors of ongoing studies of rimonabant, and Sanofi Aventis (manufacturers of rimonabant). The most recent search was in January 2011. Selection criteria Types of studies: Randomized controlled trials Types of participants: Adult smokers Types of interventions/ Types of outcome measures: The primary outcome is smoking status at a minimum of six months after the start of treatment. We preferred sustained cessation rates to point prevalence, and biochemically verified cessation to self-reported quitting. We regarded smokers who drop out or are lost to follow up as continuing smokers. We have noted any adverse effects of treatment. A secondary outcome is weight change associated with the cessation attempt. Data collection and analysis: Two authors checked the abstracts for relevance, and attempted to acquire full trial reports. One author extracted the data, and a second author checked them. Main results: We found three trials which met our inclusion criteria, covering 1567 smokers (cessation: STRATUS-EU and STRATUS-US), and 1661 quitters (relapse prevention: STRATUS-WW). At one year, the pooled risk ratio (RR) for quitting with rimonabant 20 mg was 1.50 (95% confidence interval (CI) 1.10 to 2.05). No significant benefit was demonstrated for rimonabant at 5 mg dosage. Adverse events included nausea and upper respiratory tract infections. In the relapse prevention trial, smokers who had quit on the 20 mg regimen were more likely to remain abstinent on either active regimen than on placebo; the RR for the 20 mg maintenance group was 1.29 (95% CI 1.06 to 1.57), and for the 5 mg maintenance group 1.30 (95% CI 1.06 to 1.59). There appeared to be no significant benefit of maintenance treatment for the 5 mg quitters. One trial of taranabant was not included in our meta-analyses, as it followed participants only until end of treatment; at eight weeks it found no benefit for treatment over placebo, with an OR of 1.2 (90% CI 0.6 to 2.5). For rimonabant, weight gain was reported to be significantly lower among the 20 mg quitters than in the 5 mg or placebo quitters. During treatment, overweight or obese smokers tended to lose weight, while normal weight smokers did not. For taranabant, weight gain was significantly lower for 2-8 mg versus placebo at the end of eight weeks of treatment. In 2008, post-marketing surveillance led the European Medicines Agency (EMEA) to require Sanofi Aventis to withdraw rimonabant, because of links to mental disorders. The development of taranabant was also suspended by Merck & Co because of unacceptable adverse events. Authors' conclusions: From the trial reports available, rimonabant 20 mg may increase the chances of quitting approximately 1 1/2-fold. The evidence for rimonabant in maintaining abstinence is inconclusive. Rimonabant 20 mg may moderate weight gain in the long term. Taranabant 2-8 mg may moderate weight gain, at least in the short term. In 2008, development of both rimonabant and taranabant was discontinued by the manufacturers.

Carlsten C; Halperin A; Crouch J; Burke W. Personalized medicine and tobacco-related health disparities: Is there a role for genetics? (editorial). Annals of Family Medicine 9(4): 366-371, 2011. (69 refs.)

Genetic testing has been proposed as a means to increase smoking cessation rates and thus reduce smoking prevalence. To understand how that might be practically possible, with appreciation of the current social context of tobacco use and dependence, we performed a contextual analysis of smoking-related genetics and smoking cessation. To provide added value, genetics would need to inform and improve existing interventions for smokers (including behavioral and pharmacological treatments). Pharmacogenetics offers the most promising potential, because it may improve the efficacy of medication-based smoking cessations strategies. All proven interventions for treating tobacco dependence, however, including simple cost-effective measures, such as quit lines and physician counseling, are underutilized. As tobacco use occurs disproportionately among disadvantaged populations, efforts to improve smokers' access to health care, and to the tools that are known to help them quit, represent the most promising approaches for reducing smoking prevalence within these groups. Similar considerations apply to other chronic diseases contributing to population-level health disparities. We conclude that although genetics offers increasing opportunities to tailor drug treatment, and may in some cases provide useful risk prediction, other methods of personalizing care are likely to yield greater benefit to populations experiencing health disparities related to tobacco use.

Carter-Pokras OD; Feldman RH; Kanamori M; Rivera I; Chen L; Baezconde-Garbanati L; Nodora J et al. Barriers and facilitators to smoking cessation among Latino adults. Journal of the National Medical Association 103(5): 423-431, 2011. (38 refs.)

Background: Previous studies have found that Latinos who smoke are less likely than non-Latino white smokers to use pharmaceutical aids such as nicotine replacement therapies or to receive physician advice to stop smoking. This qualitative study further explored barriers and facilitators to smoking cessation among Latino adults in Maryland. Methods: Five Spanish-language focus groups were conducted in September 2008 in Maryland with Latino current smoker and ex-smoker men and women (n = 55). Participants were recruited through flyers, information sheets, and site visits at community health clinics and Latino events, and were predominately of Central American origin. Results: Personal health concerns were the main reason to quit smoking; impact on children and family health and role model pressure were frequently mentioned. Barriers to quit smoking included environmental temptation and social factors, emotional pressure, addiction, and habitual behavior. Respondents mostly relied on themselves for cessation, with little use of cessation products or other medications, or awareness of available services. Conclusions: Social influence serves both as a strong motivation for Latinos to quit smoking and as a source of temptation to continue smoking. Favored by both current smokers and ex-smokers, lay health promoters are effective agents to reach Latinos with smoking cessation interventions. In addition, the low use of cessation services could be improved by increasing awareness and availability of Spanish-language cessation services.

Catz SL; Jack LM; McClure JB; Javitz HS; Deprey M; Zbikowski SM et al. Adherence to varenicline in the COMPASS Smoking Cessation Intervention Trial. Nicotine & Tobacco Research 13(5): 361- 368, 2011. (32 refs.)

Introduction: Patient adherence to smoking cessation medications can impact their effectiveness. It is important to understand the extent to which prescribed medications are actually taken by smokers, how this influences smoking cessation outcomes, and what factors may influence adherence. Methods: Smokers recruited from a large health plan were randomized to receive different modes of cessation counseling in combination with varenicline (Swan, G. E., McClure, J. B., Jack, L. M., Zbikowski, S. M., Javitz, H. S., Catz, S. L., et al. 2010.Behavioral counseling and varenicline treatment for smoking cessation. American Journal of Preventive Medicine, 38, 482-490). One thousand one hundred and sixty-one participants were mailed a 28-day varenicline supply when they set a quit date and were able to request up to two refills from the health plan pharmacy at no cost. Pharmacy fill records were obtained and telephone surveys completed at baseline, 21 days, 12 weeks, and 6 months post target quit date. Results: Good adherence to varenicline (>= 80% of days taken) was associated with a twofold increase in 6-month quit rates compared with poor adherence (52% vs. 25%). Smokers were more likely than nonsmokers to stop varenicline early. Purposeful nonadherence was associated with smoking at 12 weeks and was predicted in multivariate analyses by age, gender, adherence self-efficacy, and initial medication side effect severity. Conclusions: Innovative methods for increasing adherence to smoking cessation medications are needed, particularly early in the quit process. Simple metrics of adherence such as number of days cessation medication is taken can and should be routinely incorporated in effectiveness trials and reported to advance future attempts to understand and reduce nonadherence.

Cox LS; Wick JA; Nazir N; Cupertino AP; Mussulman LM; Ahluwalia JS et al. Predictors of early versus late smoking abstinence within a 24-month disease management program. Nicotine & Tobacco Research 13(3): 215-220, 2011. (24 refs.)

Introduction: Standard smoking cessation treatment studies have been limited to 6- to 12-month follow-up, and examination of predictors of abstinence has been restricted to this timeframe. The KanQuit study enrolled 750 rural smokers across all stages of readiness to stop smoking and provided pharmacotherapy management and/or disease management, including motivational interviewing (MI) counseling every 6 months over 2 years. This paper examines differences in predictors of abstinence following initial (6-month) and extended (24-month) intervention. Methods: Baseline variables were analyzed as potential predictors of self-reported smoking abstinence at Month 6 and at Month 24. Chi-square tests, 2-sample t tests, and multiple logistic regression analyses were used to identify predictors of abstinence among 592 participants who completed assessment at baseline and Months 6 and 24. Results: Controlling for treatment group, the final regression models showed that male gender and lower baseline cigarettes per day predicted abstinence at both 6 and 24 months. While remaining significant, the relative advantage of being male decreased over time. Global motivation to stop smoking, controlled motivation, and self-efficacy predicted abstinence at 6 months but did not predict abstinence at Month 24. In contrast, stage of change was strongly predictive of 24-month smoking status. Conclusions: While the importance of some predictors of successful smoking cessation appeared to diminish over time, initial lack of interest in cessation and number of cigarettes per day strongly predicted continued smoking following a 2-year program.

Culbertson CS; Bramen J; Cohen MS; London ED; Olmstead RE; Gan JJ et al. Effect of bupropion treatment on brain activation induced by cigarette-related cues in smokers. Archives of General Psychiatry 68(5): 505- 515, 2011. (92 refs.)

Context: Nicotine-dependent smokers exhibit craving and brain activation in the prefrontal and limbic regions when presented with cigarette-related cues. Bupropion hydrochloride treatment reduces cue-induced craving in cigarette smokers; however, the mechanism by which bupropion exerts this effect has not yet been described. Objective: To assess changes in regional brain activation in response to cigarette-related cues from before to after treatment with bupropion (vs placebo). Design:: Randomized, double-blind, before-after controlled trial. Setting: Academic brain imaging center. Participants: Thirty nicotine-dependent smokers (paid volunteers). Interventions: Participants were randomly assigned to receive 8 weeks of treatment with either bupropion or a matching placebo pill (double-blind). Main Outcome Measures: Subjective cigarette craving ratings and regional brain activations (blood oxygen level-dependent response) in response to viewing cue videos. Results: Bupropion-treated participants reported less craving and exhibited reduced activation in the left ventral striatum, right medial orbitofrontal cortex, and bilateral anterior cingulate cortex from before to after treatment when actively resisting craving compared with placebo-treated participants. When resisting craving, reduction in self-reported craving correlated with reduced regional brain activation in the bilateral medial orbitofrontal and left anterior cingulate cortices in all participants. Conclusions: Treatment with bupropion is associated with improved ability to resist cue-induced craving and a reduction in cue-induced activation of limbic and prefrontal brain regions, while a reduction in craving, regardless of treatment type, is associated with reduced activation in prefrontal brain regions.

Cunningham CO; Giovanniello A; Li X; Kunins HV; Roose RJ; Sohler NL. A comparison of buprenorphine induction strategies: Patient-centered home-based inductions versus standard-of-care office-based inductions. Journal of Substance Abuse Treatment 40(4): 349- 356, 2011. (39 refs.)

Although novel buprenorphine induction strategies are emerging, they have been inadequately studied. To examine our newly developed patient-centered home-based inductions, we conducted a subgroup analysis of 79 opioid-dependent individuals who had buprenorphine inductions at an urban community health center. Participants chose their induction strategy. Standard-of-care office-based inductions were physician driven, with multiple assessments, and observed, and the patient-centered home-based inductions emphasized patient self-management and included a "kit" for induction at home. We conducted interviews and extracted medical records. Using mixed nonlinear models, we examined associations between induction strategy and opioid use and any drug use. Compared with those with standard-of-care office-based inductions, participants with patient-centered home-based inductions had no significant differences in opioid use (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.13-2.97) but greater reductions in any drug use (AOR = 0.05, 95% CI = 0.01-0.37). Taking into account the limitations of our observational cohort study design, we conclude that participants with patient-centered home-based inductions had similar reductions in opioid use and greater reductions in any drug use than those with standard-of-care office-based inductions. It is essential that new induction strategies be based on existing models or theories and be well studied.

David SP; Johnstone EC; Churchman M; Aveyard P; Murphy MFG; Munafo MR. Pharmacogenetics of smoking cessation in general practice: Results from the patch II and patch in practice trials. (review). Nicotine & Tobacco Research 13(3): 157- +, 2011. (103 refs.)

Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that 'one size fits all' smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice. New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach. By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed. The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.

de los Cobos JP; Sinol N; Trujols J; Banuls E; Batlle F; Tejero A. Drug-dependent inpatients reporting continuous absence of spontaneous drug craving for the main substance throughout detoxification treatment. Drug and Alcohol Review 30(4): 403-410, 2011. (43 refs.)

Introduction and Aims. Drug craving is considered to be an essential component of substance dependence. We aimed to characterise drug-dependent inpatients reporting continuous absence of subjective spontaneous drug craving. Design and Methods. This is a 3 year chart-review study designed to compare drug-dependent inpatients who did not report craving everyday (non-cravers) and their counterparts who did (cravers). All participants were recruited consecutively and completed a 14 day detoxification treatment. Craving was defined as a desire to use the main detoxification substance. This substance was chosen by patients, who completed a craving visual analogue scale, the Beck Depression Inventory and the State-Trait Anxiety Inventory daily. The Temperament and Character Inventory and the Addiction Severity Index were also used. Results. Of the 195 patients who completed the detoxification treatment, 45 (23.1%) were non-cravers and 32 (16.4%) were cravers. The main detoxification substances were alcohol, benzodiazepines, cannabis, cocaine, heroin and methadone. Non-cravers named methadone as the main detoxification substance more frequently than cravers, and benzoylecgonine was less frequently present in their urine at treatment entry. A decreased score on the Temperament and Character Inventory dimension of harm avoidance (i.e. trait anxiety) was the only independent predictor of absence of craving (odds ratio = 1.16, 95% confidence interval = 1.03-1.31). During admission, non-cravers had lower Beck Depression Inventory and State-Trait Anxiety Inventory scores than cravers. These differences were not accounted for by pharmacological treatment. Discussion and Conclusions. Drug-dependent inpatients who report absence of craving are characterised by relatively low levels of depression and anxiety throughout detoxification treatment, and relatively low levels of trait anxiety.

Donnelly JR. The need for ibogaine in drug and alcohol addiction treatment. (editorial). Journal of Legal Medicine 32(1): 93-114, 2011. (53 refs.)

Duke AN; Bigelow GE; Lanier RK; Strain EC. Discriminative stimulus effects of tramadol in humans. Journal of Pharmacology and Experimental Therapeutics 338(1): 255-262, 2011. (37 refs.)

Tramadol is an unscheduled atypical analgesic that acts as an agonist at mu-opioid receptors and inhibits monoamine reuptake. Tramadol can suppress opioid withdrawal, and chronic administration can produce opioid physical dependence; however, diversion and abuse of tramadol is low. The present study further characterized tramadol in a three-choice discrimination procedure. Nondependent volunteers with active stimulant and opioid use (n = 8) participated in this residential laboratory study. Subjects were trained to discriminate between placebo, hydromorphone (8 mg), and methylphenidate (60 mg), and tests of acquisition confirmed that all volunteers could discriminate between the training drugs. The following drug conditions were then tested during discrimination test sessions: placebo, hydromorphone (4 and 8 mg), methylphenidate (30 and 60 mg), and tramadol (50, 100, 200, and 400 mg). In addition to discrimination measures, which included discrete choice, point distribution, and operant responding, subjective and physiological effects were measured for each test condition. Both doses of hydromorphone and methylphenidate were identified as hydromorphone- and methylphenidate-like, respectively. Lower doses of tramadol were generally identified as placebo, with higher doses (200 and 400 mg) identified as hydromorphone, or opioid-like. The highest dose of tramadol increased ratings on the stimulant scale, but was not significantly identified as methylphenidate-like. Tramadol did not significantly increase subjective ratings associated with reinforcement. Taken together, these results extend previous work with tramadol as a potential medication for the treatment of opioid dependence and withdrawal, showing acute doses of tramadol exhibit a profile of effects similar to opioid agonists and may have abuse liability in certain populations.

Ebbert J; Montori VM; Erwin PJ; Stead LF. Interventions for smokeless tobacco use cessation. (review). Cochrane Database of Systematic Reviews 2: article CD004306, 2011. (98 refs.)

Background: Use of smokeless tobacco (ST) can lead to nicotine addiction and long-term use can lead to health problems including periodontal disease, cancer, and cerebrovascular and cardiovascular disease. Objectives: To assess the effects of behavioural and pharmacologic interventions for the treatment of ST use. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Web of Science, PsycINFO, Dissertation Abstracts Online, and Scopus. Date of last search: October 2010. Selection criteria: Randomized trials of behavioural or pharmacological interventions to help users of ST to quit with follow up of at least six months. Data collection and analysis: Two authors independently extracted data. We summarised as odds ratios. For subgroups of trials with similar types of intervention and without substantial statistical heterogeneity, we estimated pooled effects using a Mantel-Haenszel fixed-effect method. Main results: Data from one study suggest that varenicline increases ST abstinence rates (Odds Ratio [ OR] 1.6, 95% Confidence Interval (CI) 1.08 to 2.36) among Swedish snus users. Two trials of bupropion SR did not detect a benefit of treatment at six months or longer (OR 0.86, 95% CI 0.47 to 1.57). Nicotine replacement therapy (patch, gum, and lozenge) was not observed to increase tobacco abstinence rates (OR 1.14, 95% CI: 0.91 to 1.42). There was statistical heterogeneity among the 14 trials of behavioural interventions; seven of them reported statistically and clinically significant benefits, four suggested benefit but with wide CIs, whilst two had similar intervention and control quit rates and relatively narrow CIs. Heterogeneity was not explained by the design (individual or cluster randomization), whether participants were selected for interest in quitting, or specific intervention components. Most trials included either telephone counselling, an oral examination and feedback about any ST induced mucosal changes, or both. In a post-hoc subgroup analysis there was some evidence that behavioural interventions which include telephone counselling might increase abstinence rates more than interventions with less contact. In one trial an interactive website increased abstinence more than a static website. Authors' conclusions: Varenicline and behavioural interventions may help ST users to quit. Behavioural interventions incorporating telephone counselling or an oral examination are likely to increase abstinence rates.

Fix BV; Hyland A; Rivard C; McNeill A; Fong GT; Borland R; Hammond D et al. Usage patterns of stop smoking medications in Australia, Canada, the United Kingdom, and the United States: Findings from the 2006-2008 International Tobacco Control (ITC) Four Country Survey. International Journal of Environmental Research and Public Health 8(1): 222-233, 2011. (26 refs.)

Varenicline is a new prescription stop smoking medication (SSM) that has been available in the United States since August 1, 2006, in the United Kingdom and other European Union countries since December 5, 2006, in Canada since April 12, 2007, and in Australia since January 1, 2008. There are few population-based studies that have examined use rates of varenicline and other stop smoking medications. We report data from the ITC Four Country survey conducted with smokers in the US, UK, Canada, and Australia who reported an attempt to quit smoking in past year in the 2006 survey (n = 4,022 participants), 2007 (n = 3,790 participants), and 2008 surveys (n = 2,735 participants) Respondents reported use of various stop smoking medications to quit smoking at each survey wave, along with demographic and smoker characteristics. The self-reported use of any stop smoking medication has increased significantly over the 3 year period in all 4 countries, with the sharpest increase occurring in the United States. Varenicline has become the second most used stop smoking medication, behind NRT, in all 4 countries since being introduced. Between 2006 and 2008, varenicline use rates increased from 0.4% to 21.7% in the US, 0.0% to 14.8% in Canada, 0.0% to 14.5% in Australia, and 0.0% to 4.4% in the UK. In contrast, use of NRT and bupropion remained constant in each country. Males and non-whites were significantly less likely to report using any SSM, while more educated smokers were significantly more likely to use any SSM, including varenicline. Our findings suggest that the introduction of varenicline led to an increase in the number of smokers who used evidence-based treatment during their quit attempts, rather than simply gaining market share at the expense of other medications. From a public health perspective, messages regarding increased success rates among medication users and the relative safety of stop smoking medications should be disseminated widely so as to reach all smokers of all socioeconomic classifications equally.

Florez G; Saiz PA; Garcia-Portilla P; Alvarez S; Nogueiras L; Bobes J. Topiramate for the treatment of alcohol dependence: Comparison with naltrexone. European Addiction Research 17(1): 29-36, 2011. (37 refs.)

Background: A 6-month naturalistic, randomized and open-label, trial of topiramate versus naltrexone was conducted, with assessments at enrollment and after 3 and 6 months of treatment. 182 alcohol-dependent patients who had been drinking heavily during the past month were included. Methods: Outcome was measured using tools that assessed alcohol intake, cravings, disability, and quality of life; changes in biomarkers of alcohol intake were also used. Results: At the 6-month evaluation, patients taking topiramate had significantly lower scores on the OCDS (all subscales), the EuropASI (medical, alcohol, family/social, and psychiatric) and the WHO/DAS (employment/social). More patients taking topiramate remained in the abstinence group and the moderate drinking without problems group. Conclusions: Topiramate at a mean dose of 200 mg/day was better than naltrexone at a mean dose of 50 mg/day at reducing alcohol intake and cravings throughout the study.

Franklin T; Wang Z; Suh JJ; Hazan R; Cruz J; Li Y et al. Effects of varenicline on smoking cue-triggered neural and craving responses. Archives of General Psychiatry 68(5): 516- 526, 2011. (58 refs.)

Context: Varenicline, an effective smoking cessation medication, functions as an alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue-elicited craving. Design:: A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal. Setting: Center for the Study of Addictions, University of Pennsylvania, Philadelphia. Subjects: Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated "this is not a Quit Smoking Study" and "smokers may be contemplating but not currently considering quitting." Results: Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t = 3.77) and elicited subjective reports of craving (P = .006). Craving reports correlated with increased activity in the posterior cingulate (t = 4.11). Administration of varenicline diminished smoking cue-elicited ventral striatum and medial orbitofrontal cortex responses (t values from -3.75 to -5.63) and reduced self-reported smoking cue-elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t = 5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r = -0.74). Conclusions: Varenicline's reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.

Fucito LM; Toll BA; Wu R; Romano DM; Tek E; O'Malley SS. A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology 215(4): 655- 663, 2011. (52 refs.)

Varenicline, an approved smoking cessation pharmacotherapy, also shows promise as a potential treatment for alcohol dependence. However, varenicline has not been tested in heavy drinkers, and it remains to be determined whether varenicline could reduce alcohol craving and consumption in smokers who are trying to quit smoking. We conducted a preliminary study to examine the effect of varenicline on drinking behavior and the effects of extended varenicline pretreatment on smoking. Thirty heavy drinking smokers received smoking cessation counseling and were randomly assigned to receive either an extended 4-week pretreatment with varenicline 2 mg daily or the usual 1-week pretreatment. Those in the extended pretreatment group received active medication for 8 weeks (i.e., 4 weeks of active pre-treatment followed by 4 weeks of active treatment), and participants in the usual pretreatment group received active medication after a placebo lead in (i.e., 3 weeks of placebo followed by active medication for 5 weeks). Participants who received varenicline during the first 3 weeks reported significantly greater reductions in alcohol craving and numerically fewer heavy drinking days compared to those who received placebo, and these differences persisted during the open-label phase. Extended pretreatment was associated with numerically greater reductions in cigarette smoking over the entire study period. There were no differences, however, in smoking abstinence rates following the smoking quit date between the two groups. Findings from this preliminary study suggest that varenicline may be a promising strategy for concurrently reducing heavy drinking and promoting smoking changes in heavy drinkers.

Galloway GP; Buscemi R; Coyle JR; Flower K; Siegrist JD; Fiske LA et al. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clinical Pharmacology & Therapeutics 89(2): 276-282, 2011. (49 refs.)

Sixty treatment-seeking individuals with methamphetamine (MA) dependence entered a randomized, placebo-controlled, double-blind clinical trial of oral dextroamphetamine (d-AMP) as a replacement therapy for MA dependence. The subjects took 60 mg sustained-release d-AMP for 8 weeks, during which time they received eight 50-min sessions of individual psychotherapy. Adverse events and urine toxicology for MA were assessed two times a week. There were no serious adverse events. Urine samples containing < 1,000 ng/ml of MA were classified as negative for MA. The MA-negative scores in the d-AMP group (3.1 +/- SD 4.6) were no higher than those in the placebo group (3.3 +/- SD 5.3; P > 0.05). However, withdrawal and craving scores were significantly lower in the d-AMP group (P < 0.05 for both). Although subjects taking d-AMP did not reduce their use of MA, the significant reductions observed in withdrawal and craving scores in this group support the need for further exploration of d-AMP as a pharmacologic intervention for MA dependence, possibly at higher doses.

Galloway GP; Coyle JR; Guillen JE; Flower K; Mendelson JE. A simple, novel method for assessing medication adherence: Capsule photographs taken with cellular telephones. Journal of Addiction Medicine 5(3): 170-174, 2011. (11 refs.)

Objectives: Medication nonadherence is an important factor in clinical practice and research methodology. Although many methods of measuring adherence have been investigated, there is as yet no "gold standard." We compared the usefulness and accuracy of a novel measure of adherence, photographs taken by cellular telephones with 2 incumbents: capsule count and the Medication Event Monitoring System (MEMS). Method: Twenty subjects participated in a clinical trial of the efficacy of modafinil for the treatment of methamphetamine dependence. Subjects were issued cell phones and medication in MEMS Cap equipped bottles and were instructed to take 1 capsule a day for 8 weeks, recording adherence with both systems. Pill counts were recorded at weekly inpatient visits. Subjects were paid for participation and for each capsule photograph and the returned medication bottle with MEMS Cap. Results: Capsule count-indicated adherence (proportion of prescribed medication taken) was 94.9%. When compared with capsule count, the novel method was found to underestimate adherence, whereas MEMS overestimated adherence. By using the dosing time data collected, we determined that subjects who dosed at a consistent time daily were more likely to adhere to the prescribed regimen. We also detected discrepancies in the timestamps recorded by MEMS. Conclusions: Capsule photographs are a useful measure of adherence, allowing more accurate time measures and more frequent adherence assessment than MEMS or capsule count. Given the ubiquity of cellular telephone use, and the relative ease of this adherence measurement method, we believe it is a useful and cost-effective approach.

Garza D; Murphy M; Tseng LJ; Riordan HJ; Chatterjee A. A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo. Biological Psychiatry 69(11): 1075- 1082, 2011. (37 refs.)

Background: Varenicline is an alpha 4 beta 2 partial nicotinic agonist approved for smoking cessation. There have been spontaneous postmarketing reports of neuropsychiatric adverse events (NPAEs) in smokers without a history of psychiatric illness quitting with varenicline. Methods: One hundred ten smokers without history of psychiatric illness (screened by Structured Clinical Interview for DSM-IV) were randomized to 12 weeks of varenicline 1 mg twice daily (n = 55) or placebo. Adverse events were solicited systematically. Depressive symptoms, anxiety, aggression, and irritability were measured at baseline and weekly using the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Scale (HAM-A), and the Overt Aggression Scale-Modified (OAS-M). The Profile of Mood States (POMS) was administered daily. Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods. Results: Participants' mean baseline characteristics were 33 years of age, 22 cigarettes/day and Fagerstrom Test for Nicotine Dependence score > 7. Reported NPAEs were similar between groups. No suicidal events were reported. There were no significant differences between groups for the MADRS (treatment difference vs. placebo = .03, 95% confidence interval [CI] -.68-.73; NS), HAM-A (treatment difference [TD] = .14, 95% CI -.62-.90; NS), OAS-M Aggression subscale (TD = .5, 95% CI -1.18-2.18; NS), OAS-M Irritability subscale (TD = .08, 95% CI -.17-.34; NS), and the POMS total scores (TD = .5, 95% CI -.52-1.53; NS). Conclusions: There were no significant differences between groups on measures of depressive symptoms, anxiety, or aggression/hostility. Systematically solicited NPAEs were similar between the varenicline and placebo groups.

Ghahremani DG; Tabibnia G; Monterosso J; Hellemann G; Poldrack RA; London ED. Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals. Neuropsychopharmacology 36(5): 950-959, 2011. (76 refs.)

Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function. Therefore, medications that improve cognition in these subjects may improve the success of therapy for their addiction, especially when cognitive behavioral therapies are used. Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers. We therefore conducted a randomized, double-blind, placebo-controlled, cross-over study, using functional magnetic resonance imaging, to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent, MA-dependent, and healthy control participants. Modafinil (200 mg) and placebo were administered orally (one single dose each), in counterbalanced fashion, 2 h before each of two testing sessions. Under placebo conditions, MA-dependent participants showed worse learning performance than control participants. Modafinil boosted learning in MA-dependent participants, bringing them to the same performance level as control subjects; the control group did not show changes in performance with modafinil. After controlling for performance differences, MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants. The findings suggest that modafinil improves learning in MA-dependent participants, possibly by enhancing neural function in regions important for learning and cognitive control. These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence.

Gramage E; Herradon G. Connecting Parkinson's disease and drug addiction: Common players reveal unexpected disease connections and novel therapeutic approaches. (review). Current Pharmaceutical Design 17(5): 449- 461, 2011. (178 refs.)

Parkinson's disease (PD) is generally a sporadic disease, and only a small proportion of cases have a clear genetic component. During the last few years, a possible specific cause triggering death of dopaminergic neurons in the substantia nigra, drug of abuse-induced neurotoxicity, is being considered as a potential mechanism to develop PD, especially in the case of abuse of amphetamine and its derivatives. Recent evidences have shown pleiotrophin, a growth factor with important functions in remodeling and repair of injured neural tissue, as an important factor involved in the pathogenesis of both diseases by preventing neurodegeneration in Parkinson's disease, neurotoxicity induced by drug abuse and by its ability to modulate drugs addictive effects. This review discusses targeting growth factors such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) to treat Parkinson's disease and/or drug addiction and compiles recent evidences to propose the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta signaling pathway as a new therapeutic target to treat Parkinson's disease and to prevent drug of abuse-induced neurotoxicity and addictive effects.

Grassi MC; Enea D; Ferketich AK; Lu B; Pasquariello S; Nencini P. Effectiveness of varenicline for smoking cessation: A 1-year follow-up study. Journal of Substance Abuse Treatment 41(1): 64-70, 2011. (53 refs.)

We examined the rate of smoking cessation associated with 6 weeks of group counseling therapy (GCT) given alone or in combination with 12 weeks of varenicline (VAR) in 112 smokers. Follow-ups were conducted at 12, 26, and 52 weeks post enrollment. Since participants chose the treatment, differences between the two groups were adjusted using propensity matching. Only 33.3% completed VAR treatment, yet at I year, the abstinence rate among participants who were not compliant was not different from subjects who were compliant. VAR resulted in a 23% improvement in the abstinence rates at 26 and 52 weeks (GCT + VAR rates were 62.5% and 56.3%, respectively; GCT-only rates were 39.6% and 33.3%, respectively). Increased carbon monoxide concentration, cigarette consumption, and Beck Depression Inventory score were associated with continued smoking. In conclusion, we found that the combination of counseling and VAR is effective at promoting abstinence at 1 year even when compliance with the medication is not 100%.

Gray KM; Carpenter MJ; Baker NL; Hartwell KJ; Lewis AL; Hiott DW et al. Bupropion SR and contingency management for adolescent smoking cessation. Journal of Substance Abuse Treatment 40(1): 77-86, 2011. (46 refs.)

There is a significant need for evidence-based treatments for adolescent smoking cessation. Prior research, although limited, has suggested potential roles for bupropion sustained-release (SR) and contingency management (CM), but no previous studies have assessed their combined effect. In a double-blind, placebo-controlled design, 134 adolescent smokers were randomized to receive a 6-week course of bupropion SR + CM, bupropion SR + non-CM, placebo + CM, or placebo + non-CM, with final follow-up at 12 weeks. The primary outcome was 7-day cotinine-verified point prevalence abstinence, allowing for a 2-week grace period. Combined bupropion SR + CM treatment yielded significantly superior abstinence rates during active treatment when compared with placebo + non-CM treatment. In addition, combined treatment showed greater efficacy at multiple time points than did either bupropion SR + non-CM or placebo + CM treatment. Combined bupropion SR and CM appears efficacious, at least in the short-term, for adolescent smoking cessation and may be superior to either intervention alone.

Greene WM; Sylvester M; Abraham J. Addiction liability of pharmacotherapeutic interventions in obesity. (review). Current Pharmaceutical Design 17(12): 1188- 1192, 2011. (42 refs.)

Obesity and substance use disorders are rapidly growing problems throughout the world. Of the current mainstay therapies of diet, exercise, behavioral modification, surgery, and medications, drugs have the greatest risk for abuse and dependence. As each of these disorders share similar underpinnings mediated by the dopaminergic brain reward pathways, clinicians must seriously consider the safety of both the patient's physical and mental health when prescribing treatments. Specifically, balance and awareness of the factors involved in the variable abuse potentials of these prescribed medications is paramount. A cursory review of weight loss medications commonly used is performed with attention to FDA status, mechanism of action, and abuse potential. Concurrent strategies to minimize risk such as drug screening, ruling out doctor shopping, temporal considerations, monitoring for signs and symptoms of abuse and/or dependency, and a safety-tiered prescribing approach is also discussed in order to optimize best treatment practice. As the understanding of these disorders progresses along with the evolution of agreed nomenclature and awareness of compulsive behavioral disorders in general, greater safety and more appropriate interventions may be achieved. Further areas of research will help to elucidate nuances of the coocurrance and treatment of these disorders and perhaps guide drug research and development in the area of drug treatments of obesity.

Grief SN. Nicotine dependence: Health consequences, smoking cessation therapies, and pharmacotherapy. Primary Care 38(1): 23+, 2011. (46 refs.)

Nicotine dependence is a significant addiction with many health consequences. Consistent attempts and efforts at addressing this condition, guiding and advising afflicted patients using motivational techniques and the 5-A stepwise strategies, and instituting appropriate therapies will result in better health outcomes and less incidence of diseases. In pharmacotherapy, Nicotine replacement therapy and oral medications can be used alone or in combination with varying degrees of success.

Hays JT; Croghan IT; Schroeder DR; Ebbert JO; Hurt RD. Varenicline for tobacco dependence treatment in recovering alcohol-dependent smokers: An open-label pilot study. Journal of Substance Abuse Treatment 40(1): 102-107, 2011. (32 refs.)

The purpose of this study was to obtain preliminary evidence of the efficacy of a 12-week course of varenicline for 7-day point prevalence smoking abstinence among recovering alcohol-dependent smokers. We enrolled 32 smokers with 6 months or more of recovery from alcohol dependence in an open-label clinical trial. Participants received varenicline 1 mg twice daily and 12 weeks of behavioral counseling. Participants were 69% men, 94% Caucasian, and smoking an average of 20.3 +/- 5.0 cigarettes per day. After 12 weeks of treatment, 31% were biochemically confirmed 7-day point prevalence abstinent from smoking and 28% had prolonged smoking abstinence (2 weeks after target quit date onward). The most common adverse effects were mild to moderate nausea (28%) and sleep disturbance (19%). No serious adverse events were reported. Varenicline may be a useful aid for treating tobacco dependence among smokers who are in stable recovery from alcohol dependence. Further study of this treatment is warranted.

Hesselink JMK; Kopsky DJ. Enhancing acupuncture by low dose naltrexone. Acupuncture in Medicine 29(2): 127- 130, 2011. (35 refs.)

To find appropriate and effective treatment options for chronic pain syndromes is a challenging task. Multimodal treatment approach has been gaining acceptance for chronic pain. However, combining treatments, such as acupuncture, with rational pharmacology is still in its infancy. Acupuncture influences the opioid and cannabinoid system through releasing endogenous receptor ligands. Low dose naltrexone also acts on both these systems, and upregulates the opioid and cannabinoid receptors. The authors hypothesise that low dose naltrexone could enhance the pain-relieving effect of acupuncture.

Hilberink SR; Jacobs JE; Breteler MHM; de Vries H; Grol RPTM. General practice counseling for patients with chronic obstructive pulmonary disease to quit smoking: Impact after 1 year of two complex interventions. Patient Education and Counseling 83(1): 120-124, 2011. (34 refs.)

Objective: To evaluate two counseling programs in general practice to help smokers with chronic obstructive pulmonary disease (COPD) to quit smoking. Methods: Cluster randomized controlled trial including 68 general practices (667 patients) using a randomly assigned intervention program with counseling and advice about nicotine replacement therapy (and additional bupropion-SR in one of the programs) or usual care. Usual care consisted of periodic regular check-ups and COPD information. The main outcome measure was biochemically verified point prevalence at 12 months. Results: The two intervention groups were treated as one in the analysis because they were equally effective. The intervention resulted in a significantly self-reported higher success rate (14.5%) compared to usual care (7.4%); odds ratio = 2.1, 95% confidence interval = 1.1-4.1. Biochemically verified quit rates were 7.5% (intervention) and 3.4% (usual care); odds ratio = 2.3, 95% confidence interval = 0.9-6.0. Conclusion: The program doubled the cessation rates (statistically nonsignificant). Too few participants used the additional bupropion-SR to prove its effectiveness. Practice implications: The protocols can be used for COPD patients in general practice, but expectations should be modest. If quitting is unsuccessful, a stepped care approach should be considered.

Ingersoll KS; Farrell-Carnahan L; Cohen-Filipic J; Heckman CJ; Ceperich SD; Hettema J et al. A pilot randomized clinical trial of two medication adherence and drug use interventions for HIV plus crack cocaine users. Drug and Alcohol Dependence 116(1-3): 177-187, 2011. (60 refs.)

Background: Crack cocaine use undermines adherence to highly active antiretroviral therapy (HAART). This pilot randomized clinical trial tested the feasibility and efficacy of 2 interventions based on the Information-Motivation-Behavioral Skill model to improve HAART adherence and reduce crack cocaine problems. Methods: Participants were 54 adults with crack cocaine use and HIV with <90% HAART adherence. Most participants were African-American (82%) heterosexual (59%), and crack cocaine dependent (92%). Average adherence was 58% in the past 2 weeks. Average viral loads (VL) were detectable (log VL 2.97). The interventions included 6 sessions of Motivational Interviewing plus feedback and skills building (M/+), or Video information plus debriefing (Video+) over 8 weeks. Primary outcomes were adherence by 14day timeline follow-back and Addiction Severity Index (ASI) Drug Composite Scores at 3 and 6 months. Repeated measure ANOVA assessed main effects of the interventions and interactions by condition. Results: Significant increases in adherence and reductions in ASI Drug Composite Scores occurred in both conditions by 3 months and were maintained at 6 months, representing medium effect sizes. No between group differences were observed. No VL changes were observed in either group. Treatment credibility, retention, and satisfaction were high and not different by condition. Conclusions: A counseling and a video intervention both improved adherence and drug problems durably among people with crack cocaine use and poor adherence in this pilot study. The interventions should be tested further among drug users with poor adherence. Video interventions may be feasible and scalable for people with HIV and drug use.

Japuntich SJ; Piper ME; Leventhal AM; Bolt DM; Baker TB. The effect of five smoking cessation pharmacotherapies on smoking cessation milestones. Journal of Consulting and Clinical Psychology 79(1): 34-42, 2011. (28 refs.)

Objective: Most smoking cessation studies have used long-term abstinence as their primary outcome measure. Recent research has suggested that long-term abstinence may be an insensitive index of important smoking cessation mechanisms. The goal of the current study was to examine the effects of 5 smoking cessation pharmacotherapies using Shiffman et al.'s (2006) approach of examining the effect of smoking cessation medications on 3 process markers of cessation or smoking cessation milestones: initial abstinence, lapse, and the lapse relapse transition. Method: The current study (N = 1,504: 58.2% female and 41.8% male; 83.9% Caucasian, 13.6% African American, 2.5% other races) examined the effect of 5 smoking cessation pharmacotherapy treatments versus placebo (bupropion, nicotine lozenge, nicotine patch, bupropion + lozenge, patch + lozenge) on Shiffman et al.'s smoking cessation milestones over 8 weeks following a quit attempt. Results: Results show that all 5 medication conditions decreased rates of failure to achieve initial abstinence and most (with the exception of the nicotine lozenge) decreased lapse risk; however, only the nicotine patch and bupropion + lozenge conditions affected the lapse relapse transition. Conclusions: These findings demonstrate that medications are effective at aiding initial abstinence and decreasing lapse risk but that they generally do not decrease relapse risk following a lapse. The analysis of cessation milestones sheds light on important impediments to long-term smoking abstinence, suggests potential mechanisms of action of smoking cessation pharmacotherapies.

Jones HE. Commentary on Kraft, et al. (2011): Treatment of neonatal abstinence syndrome - morphine, buprenorphine and beyond. (editorial). Addiction 106(3): 581-582, 2011.

Kalechstein AD; Yoon JH; Croft DE; Jaeggi S; Mahoney JJ; De la Garza R. Low dose, short-term rivastigmine administration does not affect neurocognition in methamphetamine dependent individuals. Pharmacology, Biochemistry and Behavior 99(3): 423-427, 2011. (27 refs.)

Neurocognitive impairment is a well-documented consequence of methamphetamine addiction. Not surprising, methamphetamine-associated neurocognitive impairment has been identified as an important target of treatment. Thus, this study sought to determine whether rivastigmine, an acetylcholinesterase inhibitor and cognition enhancing agent, could improve neurocognitive performance in a sample of long-term, high-dose methamphetamine addicts who were not seeking treatment at the time of enrollment in the study. This double-blind, placebo-controlled study evaluated whether a daily dose 0, 3, or 6 mg of rivastigmine, administered over six consecutive days, would enhance performance on measures of attention/information processing speed, episodic memory, and executive/frontal lobe functioning relative to test performance at baseline. The results revealed that rivastigmine did not alter neurocognition in this cohort. There are a number of factors that may have mitigated the effects of rivastigmine in this particular study, including especially the short-term, low-dose treatment regimen utilized. The negative findings notwithstanding, the study serves as a springboard for future investigations that will examine whether other medications can alter neurocognition in methamphetamine dependent study participants.

Kaplan G; Ivanov I. Pharmacotherapy for substance abuse disorders in adolescence. (review). Pediatric Clinics of North America 58(1): 243-+, 2011. (75 refs.)

The public health effects of adolescent substance abuse disorders (SUD) reaches further than the immediate intoxicating effects. Medications play a limited role in the treatment of youth beyond addressing short-term symptoms but may improve longer-term outcomes for some patients. Given the potential devastating consequences of SUD, clinicians should become familiar with all available treatment options. This article reviews the pharmacotherapy for adolescent SUD to inform clinicians considering the use of this modality for selected groups of patients.

Katz DA; Tang FM; Faseru B; Horwitz PA; Jones P; Spertus J. Prevalence and correlates of smoking cessation pharmacotherapy in hospitalized smokers with acute myocardial infarction. American Heart Journal 162(1): 74-80, 2011. (36 refs.)

Background Although current performance measures recommend smoking cessation counseling at the time of acute myocardial infarction (AMI), the American College of Cardiology/American Heart Association guidelines recommend pharmacotherapy as well. The aim of this study was to describe the prevalence and correlates of smoking cessation pharmacotherapy in hospitalized patients with AMI. Methods. In the 24-center TRIUMPH registry, 4,340 AMI patients underwent detailed interviews; and 1,631 reported smoking within 30 days of admission. Prescription of first-line smoking cessation medications at discharge was assessed by medical record review. All patient-related factors associated with smoking cessation treatment, based on literature review, were included in hierarchical modified log Poisson models. Results. Only 14% (222/1,631) of AMI patients who smoked were prescribed smoking cessation medication at discharge. After multivariable adjustment for patient characteristics, there was significant variation across sites (range 0%-28%, median rate ratio 1.41, 95% CI 1.23-2.67). Independent factors associated with smoking cessation pharmacotherapy included older age (rate ratio 0.81 per 10-year increment, 95% CI 0.71-0.93), high school graduation (rate ratio 1.37, 95% CI 1.10-1.66), heavy cigarette usage (>20/d) (rate ratio 3.08, 95% CI 2.20-4.12), in-hospital revascularization (rate ratio 1.41, 95% CI 1.0-1.94), and instructions on smoking cessation (rate ratio 2.37, 95% CI 1.40-4.01). Conclusions. Smokers surviving an AMI are infrequently prescribed guideline-recommended smoking cessation treatments, and there is considerable variation across hospitals. Older, less educated, and lighter smokers are less likely to receive aggressive smoking cessation treatment. Novel strategies to augment current practice are needed.

Kennedy J; Dipzinski A; Roll J; Coyne J; Blodgett E. Medicare prescription drug plan coverage of pharmacotherapies for opioid and alcohol dependence in WA. Drug and Alcohol Dependence 114(2-3): 201- 206, 2011. (43 refs.)

Objectives: Pharmacotherapeutic treatments for drug addiction offer new options, but only if they are affordable for patients. The objective of this study is to assess the current availability and cost of five common antiaddiction medications in the largest federal medication insurance program in the US, Medicare Part D. Methods: In early 2010, we collected coverage and cost data from 41 Medicare Part D prescription drug plans (PDPs) and 45 Medicare Advantage Plans (MAPs) in Washington State. Results: The great majority of Medicare plans (82-100%) covered common pharmacotherapeutic treatments for drug addiction. These Medicare plans typically placed patent protected medications on their highest formulary tiers, leading to relatively high patient co-payments during the initial Part D coverage period. For example, median monthly co-payments for buprenorphine (Suboxone (R)) were about $46 for PDPs, and about $56 for MAPs. Conclusion: While Medicare prescription plans usually cover pharmacotherapeutic treatments for drug addiction, high co-payments can limit access. For example, beneficiaries without supplemental coverage who use Vivitrol (R) would exceed their initial coverage cap in 7-8 months, reaching the "doughnut hole" in their Part D coverage and becoming responsible for the full cost of the medication (over $900 per month). The 2010 Patient Protection and Affordable Care Act will gradually eliminate this coverage gap, and loss of patent protection for other antiaddiction medications (Suboxone and Campral (R)) should also drive down patient costs, improving access and compliance.

Knudsen HK; Abraham AJ; Oser CB. Barriers to the implementation of medication-assisted treatment for substance use disorders: The importance of funding policies and medical infrastructure. Evaluation and Program Planning 34(4): 375-381, 2011. (28 refs.)

Despite growing interest in the use of evidence-based treatment practices, adoption of pharmacotherapies for treating substance use disorders (SUDs) remains modest. Using data from telephone interviews with 250 administrators of publicly funded SUD treatment programs, this study estimated a model of adoption of medication assisted treatment (MAT) for SUDs and examined the relative importance of regulatory, cultural, medical resource, patient-level, and funding barriers to MAT implementation. MAT-adopting programs had significantly greater medical resources, as measured by the employment of physicians and nurses, than non-adopting programs. Administrators of non-adopting programs were asked to rate the importance of 18 barriers to MAT implementation. The most strongly endorsed barriers were regulatory prohibitions due to the program's lack of medical staff, funding barriers to implementing MAT, and lack of access to medical personnel with expertise in delivering MAT. Barriers related to insufficient information about MAT and unsupportive staff attitudes were not widely endorsed. These findings suggest that efforts to promote the implementation of MAT that are inattentive to funding barriers and weaknesses in medical infrastructure may achieve sub-optimal results.

Knudsen HK; Abraham AJ; Roman PM. Adoption and implementation of medications in addiction treatment programs. Journal of Addiction Medicine 5(1): 21-27, 2011. (32 refs.)

Objectives: Little is known about the extent to which medications are being implemented as routine care in addiction treatment programs. This research describes medication adoption and implementation within the privately funded treatment sector. Methods: Face-to-face interviews were conducted with 345 administrators of a nationally representative sample of privately funded substance treatment organizations in the United States. Results: Rates of adoption of addiction treatment medications in private sector programs were lower than the adoption of psychiatric medications. Even when analyses were restricted to programs with access to physicians, adoption of each addiction treatment medication had occurred in less than 50% of programs. Within adopting programs, implementation was highly variable. Although approximately 70% of patients with cooccurring psychiatric diagnoses received psychiatric medications, rates of implementation of medication-assisted treatment for opioid dependence and alcohol use disorders were just 34.4% and 24.0%, respectively. Conclusions: Although previous research has documented higher rates of medication adoption in privately funded treatment programs, this study revealed that both adoption and implementation of pharmacotherapies to treat addiction remains modest. Future research should examine the different types of barriers to implementation, such as physician decision making, patient preferences, and system-level barriers stemming from financing and public policy.

Kraft WK; Dysart K; Greenspan JS; Gibson E; Kaltenbach K; Ehrlich ME. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction 106(3): 574-580, 2011. (27 refs.)

Aims: More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS. Design: Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine. Setting: Large, urban, tertiary care hospital. Participants: Twenty-four term infants requiring pharmacological treatment for NAS. Measurements: Outcomes were neonatal safety, length of treatment and length of hospitalization. Findings: Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine (P = 0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days (P = 0.05). Conclusions: Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine.

Krebs EE; Becker WC; Zerzan J; Bair MJ; McCoy K; Hui S. Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain. Pain 152(8): 1789-1795, 2011. (35 refs.)

Data on comparative safety of opioid analgesics are limited, but some reports suggest disproportionate mortality risk associated with methadone. Our objective was to compare mortality rates among patients who received prescribed methadone or long-acting morphine for pain. This is a retrospective observational cohort drawn from Department of Veterans Affairs (VA) health care databases, January 1, 2000, to December 31, 2007. We included 28,554 patients who received methadone and 79,938 who received long-acting morphine from VA pharmacies. Compared with those who received long-acting morphine, patients who received methadone were younger, less likely to have some medical comorbidities, and more likely to have psychiatric and substance use disorders. Patients were stratified into quintiles according to propensity score; the probability of receiving methadone was conditional on demographic, clinical, and VA service area variables. Overall propensity-adjusted mortality was lower for methadone than for morphine. Hazard ratios varied across propensity score quintiles; the magnitude of the between-drug difference in mortality decreased as the propensity to receive methadone increased. Mortality was significantly lower for methadone in all but the last quintile, in which there was no between-drug difference in mortality (hazard ratio = 0.92, 95% confidence interval = 0.74, 1.16). Multiple sensitivity analyses found either no difference in mortality between methadone and long-acting morphine or lower mortality rates among patients who received methadone. In summary, we found no evidence of excess all-cause mortality among VA patients who received methadone compared with those who received long-acting morphine. Randomized trials and prospective observational research are needed to better understand the relative safety of long-acting opioids.

Krupitsky E; Nunes EV; Ling W; Illeperuma A; Gastfriend DR; Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet 377(9776): 1506- 1513, 2011. (35 refs.)

Background: Opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences. We aimed to assess the efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. Methods We did a double-blind, placebo-controlled, randomised, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX or placebo by an interactive voice response system, stratified by site and gender in a centralised, permuted-block method. Participants also received 12 biweekly counselling sessions. Participants, investigators, staff, and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5-24, assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00678418. Findings Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90.0% (95% CI 69.9-92.4) in the XR-NTX group compared with 35.0% (11.4-63.8) in the placebo group (p=0.0002). Patients in the XR-NTX group self-reported a median of 99.2% (range 89.1-99.4) opioid-free days compared with 60.4% (46.2-94.0) for the placebo group (p=0.0004). The mean change in craving was -10.1 (95% CI -12.3 to -7.8) in the XR-NTX group compared with 0.7 (-3.1 to 4.4) in the placebo group (p<0.0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63-165) in the placebo group (p=0-0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0.0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events. Interpretation: XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients.

Lambers FAE; Stolte IG; van den Berg CHSB; Coutinho RA; Prins M. Harm reduction intensity: Its role in HAART adherence amongst drug users in Amsterdam. International Journal of Drug Policy 22(3): 210-218, 2011. (35 refs.)

Background: Opioid substitution treatment seems to improve adherence to highly active antiretroviral therapy (HAART) in drug users (DU). DU in Amsterdam receive methadone within a harm reduction programme. We hypothesized that not only receiving methadone, but joining this complete comprehensive programme would improve HAART adherence. Methods: Included were 102 HIV-positive DU attending the Amsterdam Cohort Study (ACS), reporting HAART use at multiple visits between 1999 and 2009. Non-adherence was defined as taking less than 95% of medication in the past 6 months (self-reported). Harm reduction intensity (HR) was measured by combining injecting drug use, methadone dosage and needle exchange, in different levels of participation, ranging from no/incomplete HR, complete HR to low or no dependence on HR. We studied the association between non-adherence and harm reduction intensities with logistic regression models adjusted for repeated measurements. Results: Non-adherence was reported in 11.9% of ACS visits. Non-injecting DU with low dependence on HR were less adherent than DU with complete HR (aOR 1.78; CI 95% 1.00-3.16), although there was no overall effect of HR. No difference was demonstrated in adherence between DU with complete HR and incomplete HR. Unsupervised housing (no access to structural support at home) (aOR 2.58; CI 95% 1.40-4.73) and having a steady partner (aOR 0.48; CI 95% 0.24-0.96) were significantly associated with respectively more and less non-adherence. Conclusions: In Amsterdam, still-injecting DU who are exposed to systematic and integrated care, although not practising complete harm reduction, can be just as adherent to HAART as DU who make use of complete harm reduction and non-injecting DU with no dependence on harm reduction. These findings suggest the importance of a systematic and comprehensive support system including supervised housing and social and medical support to increase HAART adherence rates amongst all HIV-infected DU. When such programmes are introduced in settings where injecting drug use is highly prevalent, access to HAART for drug users in these settings can and should be increased.

Levin FR; Mariani JJ; Brooks DJ; Pavlicova M; Cheng W; Nunes EV. Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial. Drug and Alcohol Dependence 116(1-3): 142-150, 2011. (64 refs.)

Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double-blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20 mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline followback method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P = .02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P = .02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.

Licata SC; Penetar DM; Ravichandran C; Rodolico J; Palmer C; Berko J et al. Effects of daily treatment with citicoline: A double-blind, placebo-controlled study in cocaine-dependent volunteers. Journal of Addiction Medicine 5(1): 57-64, 2011. (32 refs.)

Many pharmacotherapies for treating cocaine dependence are aimed at reducing drug effects, alleviating craving, and preventing relapse. We demonstrated previously that citicoline, a compound used to repair neuronal damage in stroke and brain injury, is safe in cocaine-abusing volunteers. Objectives: This study assessed the effectiveness of an 8-week citicoline treatment period and 4-week follow-up in cocaine-dependent individuals. Methods: Twenty-nine healthy nontreatment-seeking, cocaine-dependent male and female volunteers were randomized in this double-blind, placebo-controlled study, 18 of whom completed the treatment period of the study. Participants took citicoline (500 mg twice daily) or matched placebo each day and recorded the measures of craving and drug use. Participants visited the laboratory twice a week for urine screens and to attend weekly group therapy sessions. Results: Citicoline had no effect on cocaine craving or total use. Conclusions: Although the current preliminary results from this small trial suggest that citicoline is not an effective treatment for heavy cocaine users, further investigation on efficacy citicoline as a treatment for substance dependence in other settings may be warranted.

Mannelli P; Peindl K; Patkar AA; Wu LT; Tharwani HM; Gorelick DA. Problem drinking and low-dose naltrexone-assisted opioid detoxification. Journal of Studies on Alcohol and Drugs 72(3): 507- 513, 2011. (42 refs.)

Objective: The influence of alcohol use on opioid dependence is a major problem that warrants a search for more effective treatment strategies. The addition of very-low-dose naltrexone (VLNTX) to methadone taper was recently associated with reduced withdrawal intensity during detoxification. In a secondary analysis of these data, we sought to determine whether problem drinking affects detoxification outcomes and whether symptoms are influenced by VLNTX use. Method: Opioid-dependent patients (N = 174) received naltrexone (0.125 or 0.250 mg/day) or placebo in a double-blind, randomized design during methadone-based, 6-day inpatient detoxification. Alcohol consumption was assessed at admission using the Addiction Severity Index and self-report. Outcome measures were opioid withdrawal intensity, craving, and retention in treatment. Results: Problem drinking opioid dependent patients (n = 79) showed episodic heavy alcohol use and reported increased subjective opioid withdrawal intensity (p = .001), craving (p =.001), and significantly lower rate of retention in treatment (p = .02). Individuals with problem drinking and opioid dependence who were treated with VLNTX (n = 55) showed reduced withdrawal (p = .05) and a lower rate of treatment discontinuation (p = .03), resuming alcohol intake in smaller numbers the day following discharge (p = .03). Treatment effects were more pronounced on anxiety, perspiration, shakiness, nausea, stomach cramps, and craving. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Conclusions: Heavy drinking is associated with worse opioid detoxification outcomes. The addition of VLNTX is safe and is associated with reduced withdrawal symptoms and better completion rate in these patients. Further studies should explore the use of VLNTX in detoxification and long-term treatment of combined alcohol-opioid dependence and alcohol dependence alone.

Mccance-Katz EF. (R)-methadone versus racemic methadone: What is best for patient care? (editorial). Addiction 106(4): 687-688, 2011. (11 refs.)

Minozzi S; Amato L; Vecchi S; Davoli M; Kirchmayer U; Verster A. Oral naltrexone maintenance treatment for opioid dependence. (review). Cochrane Database of Systematic Reviews 2: article CD001333, 2011. (64 refs.)

Background: Research on the clinical application of oral naltrexone agrees on several things. From a pharmacological perspective, naltrexone works. From an applied perspective, however, the medication compliance and the retention rates are very poor. Objectives: To evaluate the effects of naltrexone maintenance treatment versus placebo or other treatments in preventing relapse in opioid addicts after detoxification. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library issue 6 2010), PubMed (1973-June 2010), CINAHL (1982-June 2010). We inspected reference lists of relevant articles and we contacted pharmaceutical producers of naltrexone, authors and other Cochrane review groups. Selection criteria: All randomised and controlled clinical trials which focus on the use of naltrexone maintenance treatment versus placebo, or other treatments to reach sustained abstinence from opiate drugs Data collection and analysis Three reviewers independently assessed studies for inclusion and extracted data. One reviewer carried out the qualitative assessments of the methodology of eligible studies using validated checklists. Main results: Thirteen studies, 1158 participants, met the criteria for inclusion in this review. Comparing naltrexone versus placebo or no pharmacological treatments, no statistically significant difference were noted for all the primary outcomes considered. The only outcome statistically significant in favour of naltrexone is re-incarceration, RR 0.47 (95% CI 0.26-0.84), but results come only from two studies. Comparing naltrexone versus psychotherapy, in the two considered outcomes, no statistically significant difference was found in the single study considered. Naltrexone was not superior to benzodiazepines and to buprenorphine for retention and abstinence and side effects. Results come from single studies. Authors' conclusions: The findings of this review suggest that oral naltrexone did not perform better than treatment with placebo or no pharmacological agent with respect to the number of participants re-incarcerated during the study period. If oral naltrexone is compared with other pharmacological treatments such as benzodiazepine and buprenorphine, no statistically significant difference was found. The percentage of people retained in treatment in the included studies is however low (28%). The conclusion of this review is that the studies conducted have not allowed an adequate evaluation of oral naltrexone treatment in the field of opioid dependence. Consequently, maintenance therapy with naltrexone cannot yet be considered a treatment which has been scientifically proved to be superior to other kinds of treatment.

Mohler H. The rise of a new GABA pharmacology. Neuropharmacology 60(7-8, special issue): 1042- 1049, 2011. (110 refs.)

Key developments in GABA pharmacology over the last 30 years are reviewed with special reference to the advances pioneered by Erminio Costa. His passion for innovative science, and his quest for novel therapies for psychiatric disorders are particularly apparent in his fundamental contributions to the field of GABA research, with a focus on anxiety disorders and schizophrenia. He was a cofounder of the GABAergic mechanism of action of benzodiazepines. He envisaged partial agonists as novel anxiolytics. He identified DBI (diazepam binding inhibitor) as endogenous agonist of neurosteroidogenesis with multiple CNS effects and he pointed to the developmental origin of GABAergic dysfunctions in schizophrenia through his discovery of a reelin deficit, all this in collaboration with Sandro Guidotti. Today, the GABA pharmacology comprises selective hypnotics, non-sedative anxiolytics, memory enhancers and powerful analgesics. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

Nordt SP; Zilberstein J; Gold B. Methadone-induced torsade de pointes. American Journal of Emergency Medicine 29(4): 476.e1, 2011. (5 refs.)

Torsade de pointes is a rare but life-threatening ventricular dysrhythmia that has been associated with numerous medications. We present a case of polymorphic ventricular tachycardia in a 55-year-old man on methadone. The patient's QTc interval normalized after discontinuation of the methadone. Emergency physicians should be aware of this potential adverse effect from methadone.

Ockert DM; Volpicelli JR; Baier AR; Coons EE; Fingesten A. A non-opioid procedure for outpatient opioid detoxification. Journal of Addiction Medicine 5(2): 110- 114, 2011. (21 refs.)

Objectives: (1) To describe a new protocol using nonopioid medications (clonidine, lorazepam, trazodone, and a stimulant) to successfully complete outpatient opioid detoxification, (2) to determine clinical and demographic characteristics of patients who successfully complete an outpatient opioid detoxification, and (3) to determine the safety and clinical utility of the use of this combination of medications in the treatment of opioid withdrawal. Methods: In a posthoc evaluation study in a New York State-licensed outpatient detoxification unit of a substance abuse treatment facility, 223 heroin-dependent adults presenting for treatment were provided outpatient opioid detoxification. In the course of the opioid detoxification protocol of the facility, patients received clonidine, lorazepam, trazodone, and either a stimulant (methylphenidate or modafinil) or no stimulant, in combination on a daily basis. At each daily visit, signs and symptoms were assessed, and medications and dosing instructions were given for the following 24 hours. On completion of the detoxification protocol, patients were induced with oral naltrexone. Results: Overall, 61.0% (136) of the patients in this study successfully completed the outpatient detoxification protocol and were induced with naltrexone. Pretreatment demographic variables that predicted successful treatment included full-time employment, family support, private medical insurance, and referral by an employee assistance program. About 77% of patients with good prognosis successfully completed outpatient detoxification treatment. The addition of a stimulant improved patient retention and reduced the incidence of hypotension. Conclusions: The outpatient detoxification of opioid-dependent patients without the use of opioids has traditionally led to such high drop out rates that most clinical programs do not even consider the option. This makes it difficult to induce patients with opioid antagonists such as oral naltrexone or sustained release naltrexone. We describe a protocol here that leads to excellent rates of successful detoxification. This nonopioid detoxification methodology permits induction of naltrexone without the delay experienced in opioid-based titrations, and it thus facilitates the use of opioid antagonists for sustained abstinence, enhanced aftercare treatment outcomes, and opioid-free recovery.

Oliveto A; Poling J; Mancino MJ; Feldman Z; Cubells JF; Pruzinsky R et al. Randomized, double blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. Drug and Alcohol Dependence 113(2-3): 184-191, 2011. (67 refs.)

This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants. Design: One hundred and sixty-one cocaine- and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites. Methods: Participants were stabilized on methadone during weeks 1-2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3-14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained. Results: Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p<0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04). Conclusions: Disulfiram may be contraindicated for cocaine dependence at doses <250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined.

Pelet A; Favrat B; Cavassini M; Eap CB; Besson J; Monnat M. Usefulness of methadone plasma concentration measurement in patients receiving nevirapine or efavirenz. American Journal of Drug and Alcohol Abuse 37(4): 264-268, 2011. (28 refs.)

Objective: To determine methadone plasma trough and peak concentrations in patients presenting opiate withdrawal symptoms after introduction of nevirapine or efavirenz. To describe the disappearance of these symptoms after methadone titration based on plasma concentrations rather than on the symptoms. Methods: Nine patients undergoing highly active antiretroviral therapy (HAART) and either nevirapine or efavirenz treatment were monitored daily for opiate withdrawal in a specialized drug addiction center. Methadone dose was titrated daily, and plasma concentrations were measured. The data are retrospective (case series). Results: Several patients complained of symptoms such as nausea, vomiting, accelerated intestinal transit, or insomnia. Even after methadone titration based on clinical symptoms, patients and health-care providers trained in infectious disease did not classify these as withdrawal symptoms and considered them as the side effects of HAART or anxiety. Methadone plasma trough concentration showed low levels of (R)- and (R, S)-methadone. Further methadone dose adjustment according to plasma level resulted in the disappearance of these withdrawal symptoms. The daily methadone dose was split when the peak/trough (R)-methadone ratio was more than 2. Conclusions: When introducing efavirenz or nevirapine to patients undergoing methadone treatment, withdrawal symptoms should be monitored, especially those such as insomnia, vomiting, or nausea. Methadone plasma trough and peak measurements can be of value in preventing unnecessary side effects of HAART.

Pennay AE; Lee NK. Putting the call out for more research: The poor evidence base for treating methamphetamine withdrawal. (review). Drug and Alcohol Review 30(2): 216-222, 2011. (57 refs.)

Issues. Treatment seeking for methamphetamine withdrawal is low in Australia. Insufficient knowledge regarding the withdrawal syndrome of methamphetamine and the appropriate management of these symptoms may be a contributing factor to the low treatment attendance. Approach. A systematic review was performed using a range of electronic databases. Key Findings. Common methamphetamine withdrawal symptoms include symptoms relating to depression, agitation, cognitive impairment and fatigue. These symptoms may last anywhere from a few days to a few months. Methamphetamine withdrawal is most commonly undertaken in an outpatient setting, and psychosocial interventions remain the primary treatment approach in Australia. Two withdrawal scales (Amphetamine Withdrawal Questionnaire and Amphetamine Cessation Symptom Assessment) have been validated for the assessment of methamphetamine withdrawal. Only a small number of medications for methamphetamine withdrawal have been investigated, and to date no medications stand out over the others. Implications. Current recommendations for methamphetamine withdrawal tend to be based on clinical opinion and subsequently vary between settings. More research in the area is essential to ensure the development of more targeted, timely and effective withdrawal treatment interventions. Conclusion. The review exposed a lack of well-conducted research targeted towards the management of methamphetamine withdrawal. Further research is essential, and should focus on understanding the nature of methamphetamine withdrawal, its duration, course and effective treatment.

Perez-Mana C; Castells X; Vidal X; Casas M; Capella D. Efficacy of indirect dopamine agonists for psychostimulant dependence: A systematic review and meta-analysis of randomized controlled trials. (review). Journal of Substance Abuse Treatment 40(2): 109-122, 2011. (98 refs.)

Psychostimulant dependence is characterized by dopamine deficit, which could be reversed with indirect dopamine agonists (IDAs). A systematic review and meta-analysis of randomized, parallel-group, placebo-controlled clinical trials assessing the efficacy of IDAs in psychostimulant-dependent individuals were conducted. The study outcomes were psychostimulant abstinence, assessed by means of urinalysis, and retention in treatment. Risk of bias was determined using a Cochrane Collaboration instrument. Twenty-nine studies fulfilled the inclusion criteria, involving 2,467 participants. Compared with placebo, IDAs increased psychostimulant abstinence (standardized mean difference = 0.20; 95% confidence interval, 0.06-0.35; p = .005) but did not increase retention in treatment. Efficacy was larger in comorbid heroin-dependent individuals and was positively related with treatment length. No study was considered fully free of bias. IDAs appear to be efficacious for reducing psychostimulant use but did not improve retention. Efforts should be undertaken to reduce the risk of bias of clinical trials with psychostimulant-dependent individuals.

Perkins KA; Lerman C. Early human screening of medications to treat drug addiction: Novel paradigms and the relevance of pharmacogenetics. Clinical Pharmacology & Therapeutics 89(3): 460-463, 2011. (31 refs.)

Initial screening of medications for efficacy in treating drug dependence may be accomplished more efficiently by using novel approaches that combine the practical advantages of within-subject laboratory studies with the clinical validity provided by clinical trials. A priori selection of functional gene variants associated with the pharmacokinetic or pharmacodynamic effects of a medication may aid this effort by controlling for individual variability as to clinical response or adverse effects; however, there are limitations to this approach, and these should be carefully considered.

Planer D; Lev I; Elitzur Y; Sharon N; Ouzan E; Pugatsch T et al. Bupropion for smoking cessation in patients with acute coronary syndrome. Archives of Internal Medicine 171(12): 1055-1060, 2011. (28 refs.)

Background: Smokers hospitalized with acute coronary syndrome (ACS) are at high risk for subsequent ischemic events. Nevertheless, over two-thirds of patients continue to smoke after an acute myocardial infarction. Bupropion hydrochloride has proven efficacy as a smoking cessation aid, but data regarding its safety and efficacy in ACS patients are limited. Methods: In a double-blind, randomized controlled trial, we compared the safety and efficacy of 8 weeks of treatment with bupropion slow-release (SR) or placebo for smokers hospitalized with ACS as an adjunct to nurseled hospital- and telephone-based support. Primary efficacy outcome was smoking abstinence at 1 year. Primary safety outcome was clinical events at 1 year. Results: A total of 151 patients were enrolled; all but 2 completed follow-up. Abstinence rates at 3 months were 45% and 44% in the bupropion SR and placebo groups, respectively (P=.99); 37% vs 42% (P=.61) at 6 months; and 31% vs 33% (P=.86) at 1 year. On multivariate analysis, an invasive procedure performed during index hospitalization was an independent predictor for smoking abstinence at 1 year (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.22-14.19). Presence of adverse effects attributed to treatment was a negative predictor for smoking cessation (OR, 0.23; 95% CI, 0.07-0.78). Treatment with bupropion SR was not associated with an increase in clinical events or change in blood pressure or body mass index, but dizziness was more common compared with placebo (14% vs 1.4%; P=.005). Conclusion: In hospitalized patients with ACS who received continuous, intensive nurse counseling about smoking cessation, bupropion did not increase the rates of smoking abstinence.

Polosa R; Benowitz NL. Treatment of nicotine addiction: Present therapeutic options and pipeline developments. (review). Trends In Pharmacological Sciences 32(5): 281-289, 2011. (63 refs.)

Tobacco use is a global pandemic that poses a substantial and costly health burden. There are some treatment options are available, but currently marketed smoking-cessation drugs lack high levels of efficacy, particularly in real-life settings. Consequently, there is a compelling need for more effective pharmacotherapies to aid smokers in maintaining long-term abstinence. Advances in the understanding of the mechanisms involved in nicotine dependence have recently been translated into new medications and vaccines that interfere with nicotine signaling, many of which are currently at an advanced stage of development. In the present article we review current and emerging pharmacotherapies for tobacco dependence, focusing on the mechanistic rationale for their potential anti-addiction efficacy, major findings in preclinical and clinical studies, and future research directions.

Potenza MN; Sofuoglu M; Carroll KM; Rounsaville BJ. Neuroscience of behavioral and pharmacological treatments for addictions. (review). Neuron 69(4): 695-712, 2011. (243 refs.)

Although substantial advances have been made in behavioral and pharmacological treatments for addictions, moving treatment development to the next stage may require novel ways of approaching addictions, particularly ways based on new findings regarding the neurobiological underpinnings of addictions that also assimilate and incorporate relevant information from earlier approaches. In this review, we first briefly review theoretical and biological models of addiction and then describe existing behavioral and pharmacologic therapies for the addictions within this framework. We then propose new directions for treatment development and targets that are informed by recent evidence regarding the heterogeneity of addictions and the neurobiological contributions to these disorders.

Roman PM; Abraham AJ; Knudsen HK. Using medication-assisted treatment for substance use disorders: Evidence of barriers and facilitators of implementation. Addictive Behaviors 36(6, special issue): 584- 589, 2011. (27 refs.)

The use of medications to treat substance use disorders (SUDs) has emerged as a potentially central part of the treatment armamentarium. In this paper we present data from several recent US national surveys showing that despite the clinical promise of these medications, there has been limited adoption of pharmacotherapies in the treatment of SUDs. The data reveal variable patterns of use of disulfiram, buprenorphine, tablet naltrexone, acamprosate and injectable naltrexone. After examining the environmental and institutional context for the adoption of pharmacotherapies, the specific organizational facilitators and barriers of medication adoption are considered. The paper concludes with a discussion of the minimal clinical and administrative guidance available to enhance adoption, the lack of client and consumer knowledge of medications that puts a brake on their adoption and availability, and the difficulties that must be surmounted in bringing new medications to market.

Rothrauff TC; Eby LT. Counselors' knowledge of the adoption of tobacco cessation medications in substance abuse treatment programs. American Journal on Addictions 20(1): 56-62, 2011. (37 refs.)

This study assessed counselors' knowledge of the adoption of evidence-based tobacco cessation medications (TCMs)-varenicline, bupropion, and five nicotine replacement therapies (NRTs)-and predictors of adoption in diverse substance abuse treatment settings. We used Managing Effective Relationships in Treatment Services (MERITS I) data from 658 counselors working in 26 programs. Adoption of varenicline was reported by 16% of counselors, bupropion by 11%, and NRTs by 27%. Knowledge of the adoption of all types of TCMs was more likely to be reported by counselors who worked in treatment programs that adhered less to a 12-step orientation and restricted outdoor smoking for employees. Several additional unique predictors of varenicline and NRTs were identified.

Rush CR; Stoops WW; Lile JA; Glaser PEA; Hays LR. Subjective and physiological effects of acute intranasal methamphetamine during d-amphetamine maintenance. Psychopharmacology 214(3): 665-674, 2011. (37 refs.)

Methamphetamine abuse and dependence are significant public-health concerns. Behavioral therapies are effective for reducing methamphetamine use. However, many patients enrolled in behavioral therapies are unable to achieve significant periods of abstinence, suggesting other strategies like pharmacotherapy are needed. This experiment determined the subjective and physiological effects of intranasal methamphetamine during d-amphetamine maintenance in eight non-treatment-seeking stimulant-dependent participants. We predicted d-amphetamine maintenance would attenuate the acute subjective effects of intranasal methamphetamine. We also predicted intranasal methamphetamine would be well tolerated during d-amphetamine maintenance. After at least 7 days of maintenance on sustained-release d-amphetamine (0 and 45 mg/day), participants were administered ascending doses of intranasal methamphetamine (0, 2.5, 5, 10, and 20 mg) across two experimental sessions. Intranasal methamphetamine doses were separated by 90 min. Intranasal methamphetamine produced prototypical subjective and physiological effects (e.g., increased ratings of Like Drug; increased heart rate, blood pressure, and body temperature). The acute effects of intranasal methamphetamine were significantly diminished during d-amphetamine maintenance relative to placebo maintenance. These results are concordant with those of clinical trials and provide further support for the use of agonist replacement therapy to manage methamphetamine dependence. Additional research in humans is needed to determine the effectiveness of d-amphetamine under different experimental conditions that more closely reflect use in the natural environment (e.g., higher methamphetamine doses) and behavioral arrangements that are predictive of pharmacotherapy effectiveness (e.g., drug self-administration).

Ryan KK; Garrett-Mayer E; Alberg AJ; Cartmell KB; Carpenter MJ. Predictors of cessation pharmacotherapy use among Black and Non-Hispanic white smokers. Nicotine & Tobacco Research 13(8): 646-652, 2011. (36 refs.)

Introduction: Use of pharmacotherapy for smoking cessation improves quit rates, but these treatments are underutilized, particularly among Black smokers. Attitudes toward pharmacotherapy may differ between racial/ethnic minorities and Caucasian smokers. It was hypothesized that Black and non-Hispanic White smokers would differ in their attitudes toward pharmacotherapy and that the association between attitudes toward and actual use of pharmacotherapy would differ by race. Methods: The study consisted of a single, cross-sectional telephone-based survey of current smokers (N = 697), which examined the relationship between race, attitudes toward pharmacotherapy, and pharmacotherapy usage in a representative bi-racial sample (39% Black). Results: Black smokers were significantly less likely to report ever use of pharmacotherapy (23%) than Caucasians (39%; odds ratio [OR] = 0.46; 95% CI: 0.33-0.66). Compared with Caucasians, Blacks had significantly less favorable attitudes toward pharmacotherapy, including disbelief about efficacy (p = .03), addiction concerns (p = .03), harmfulness of pharmacotherapy (p = .008), and need for treatment of any kind to quit smoking (p = .004). In a multiple logistic regression, racial group (Caucasian is referent: OR = 0.55, p = .003), addiction concerns (OR = 0.80, p < .01), and need for treatment of any kind to quit smoking (OR = 1.52, p < .001) were predictive of pharmacotherapy use. Conclusions: These findings replicate and build upon previous research demonstrating underutilization of pharmacotherapy and enduring misconceptions about pharmacotherapy, particularly among Black smokers. Regardless of racial group, misconceptions about pharmacotherapy are related to lower rates of use. Efforts to improve understanding about the efficacy and safety of these products are needed to boost utilization and impact cessation rates.

Saber-Tehrani AS; Bruce RD; Altice FL. Pharmacokinetic drug interactions and adverse consequences between psychotropic medications and pharmacotherapy for the treatment of opioid dependence. (review). American Journal of Drug and Alcohol Abuse 37(1): 1-11, 2011. (138 refs.)

Background: Psychiatric comorbidities among opioid-dependent patients are common. Many medications used to treat both conditions are metabolized through complimentary cytochrome P450 isoenzymes. When medication-assisted treatment for opioid dependence is concurrently used with psychotropic medications, problematic pharmacokinetic drug interactions may occur. Methods: We reviewed relevant English language articles identified through the MedLine, Scopus, and Embase databases from 1950 to December 2009 using the specific generic names of medications and keywords such as pharmacokinetics and drug interactions with buprenorphine, methadone, and naltrexone. Selected references from these articles were reviewed. Additionally, a review was conducted of abstracts and conference proceedings from national and international meetings from 1990 to 2009. A total of 60 studies were identified and reviewed. Results: Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between methadone, buprenorphine, or naltrexone and some psychoactive medications. Important pharmacokinetic drug interactions have been demonstrated within each class of medications affecting either methadone and buprenorphine or psychoactive drugs. Few studies, however, have been conducted with naltrexone. Conclusions and Scientific Significance: Several interactions between methadone, buprenorphine, or naltrexone and psychoactive medications are described and may have important clinical consequences. To optimize care, clinicians must be alerted to these interactions.

Sener S; Eken C; Schultz CH; Serinken M; Ozsarac M. Ketamine with and without midazolam for emergency department sedation in adults: A randomized controlled trial. Annals of Emergency Medicine 57(2): 109-114, 2011. (17 refs.)

Study objective: We assess whether midazolam reduces recovery agitation after ketamine administration in adult emergency department (ED) patients and also compared the incidence of adverse events (recovery agitation, respiratory, and nausea/vomiting) by the intravenous (IV) versus intramuscular (IM) route. Methods: This prospective, double-blind, placebo-controlled, 2x2 factorial trial randomized consecutive ED patients aged 18 to 50 years to 4 groups: receiving either 0.03 mg/kg IV midazolam or placebo, and with ketamine administered either 1.5 mg/kg IV or 4 mg/kg IM. Adverse events and sedation characteristics were recorded. Results: Of the 182 subjects, recovery agitation was less common in the midazolam cohorts (8% versus 25%; difference 17%; 95% confidence interval [CI] 6% to 28%; number needed to treat 6). When IV versus IM routes were compared, the incidences of adverse events were similar (recovery agitation 13% versus 17%, difference 4%, 95% CI -8% to 16%; respiratory events 0% versus 0%, difference 0%, 95% CI -2% to 2%; nausea/vomiting 28% versus 34%, difference 6%, 95% CI -8% to 20%). Conclusion: Coadministered midazolam significantly reduces the incidence of recovery agitation after ketamine procedural sedation and analgesia in ED adults (number needed to treat 6). Adverse events occur at similar frequency by the IV or IM routes.

Sevak RJ; Vansickel AR; Stoops WW; Glaser PEA; Hays LR; Rush CR. Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole. Journal of Clinical Psychopharmacology 31(4): 470-480, 2011. (39 refs.)

Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results. from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, >= 80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D-2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with D-amphetamine and the present findings, D-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine.

Sewell RA; Petrakis IL. Does gamma-hydroxybutyrate (GHB) have a role in the treatment of alcoholism? (editorial). Alcohol and Alcoholism 46(1): 1-2, 2011. (7 refs.)

Steinberg MB; Bover MT; Richardson DL; Schmelzer AC; Williams JM; Foulds J. Abstinence and psychological distress in co-morbid smokers using various pharmacotherapies. Drug and Alcohol Dependence 114(1): 77-81, 2011. (24 refs.)

Background: Existing trials of varenicline have typically excluded smokers with concurrent medical and psychiatric illnesses and no data exist comparing effectiveness of varenicline with combination pharmacotherapy. This study evaluated abstinence and psychiatric outcomes of various tobacco dependence medications, including varenicline. Methods: Retrospective cohort of 723 smokers, most with significant medical and psychiatric comorbidity, was evaluated at the UMDNJ-Tobacco Dependence Clinic from 2006 to 2008. Demographics, measures of tobacco dependence and co-morbidities, and a validated instrument measuring psychological distress (Kessler-6) were obtained. Primary outcome was 7-day point abstinence at 6 months after target quit date. Results: Cessation medications used included combination pharmacotherapy (39%), single nicotine replacement therapy (NRT) or bupropion (29%), and varenicline (23%), with 9% using no medications. Overall, 23% of patients were abstinent at 6 months. In an adjusted regression model, smokers using varenicline or combination medications were more likely abstinent at 6 months than those using no medications (adjusted odds ratio = 2.99; 95% confidence interval = 1.20-7.47 and 2.80; 1.15-6.82, respectively), but not statistically higher than those using single medications (AOR = 1.70). Age, gender, education, marital status, cigarettes per day, time to first cigarette, night smoking, and menthol smoking were not significantly related to abstinence. Varenicline or combination medications did not significantly increase serious psychological distress over the treatment period compared to other medication options. Conclusions: Both varenicline and combination pharmacotherapy were effective and did not increase psychological distress for up to 6 months in smokers with co-morbidities treated at a specialty clinic.

Strain EC; Harrison JA; Bigelow GE. Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films. Clinical Pharmacology & Therapeutics 89(3): 443-449, 2011. (22 refs.)

A sublingual soluble-film formulation of buprenorphine/naloxone (B/N) has been approved by the US Food and Drug Administration for the treatment of opioid dependency. This preparation provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid-dependent volunteers. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Subjects were randomized to receive either B (16 mg, n = 18) or B/N (16/4 mg, n = 16) soluble films for 5 days. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score. Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between the groups. The results support the use of B and B/N soluble films as safe and effective delivery methods for opioid induction.

Sugarman DE; Poling J; Sofuoglu M. The safety of modafinil in combination with oral Delta 9-tetrahydrocannabinol in humans. Pharmacology, Biochemistry and Behavior 98(1): 94-100, 2011. (64 refs.)

Marijuana (cannabis) is the most widely used illicit substance globally, and cannabis use is associated with a range of adverse consequences. Currently, no medications have been proven to be effective for the treatment of cannabis addiction. The goals of this study were to examine the safety and efficacy of a potential treatment medication, modafinil, in combination with oral Delta 9-tetrahydrocannabinol (THC). Twelve male and female occasional cannabis users participated in an outpatient double-blind, placebo-controlled, crossover study. Across four sessions, participants were randomly assigned to a sequence of four oral treatments: (1) 400 mg modafinil + placebo, (2) 15 mg THC + placebo, (3) 400 mg modafinil + 15 mg THC, or (4) placebo + placebo. Outcome measures included heart rate, blood pressure, performance on the Rapid Visual Information Processing (RVIP), and the Hopkins Verbal Learning Test (HVLT), and subjective measures. Oral THC increased heart rate, and produced increased subjective ratings of feeling "high" and "sedated," as well as increased ratings of euphoria. Modafinil alone increased the Profiles of Mood States (POMS) subscales of vigor and tension. These findings support the safety of modafinil in combination with THC. The effects of modafinil in combination with a range of doses of THC need to be determined in future studies.

Tanner GR; Bordon N; Conroy S; Best D. Comparing methadone and Suboxone in applied treatment settings: the experiences of maintenance patients in Lanarkshire. Journal of Substance Use 16(3): 171- 178, 2011. (13 refs.)

Background. Although there is evidence that buprenorphine is more effective than placebo in suppressing heroin use, and is a recommended treatment for opioid dependence, methadone remains the dominant maintenance treatment. However, this may have adverse consequences in increased dependence liability and greater withdrawal effects. Rationale. The study assessed the experiences of clients in Lanarkshire who had experienced both substances to report on the strengths and weaknesses of each. Method. Two phases of opportunistic data were collected - open narrative accounts of those successfully detoxifying from Suboxone (a buprenorphinenaloxone combination) and structured interviews with clients comparing Suboxone and methadone. Results. Consistently, clients reported more clarity of thinking while on Suboxone. However, this was not always perceived positively as increased clarity necessitated more psychosocial therapeutic support than was needed on methadone. Suboxone was associated with increased confidence and lower stigma than methadone. Concerns were expressed about the antagonistic effect of Suboxone, with several reports of ""use on top"". Conclusion. Participants made clear distinctions between methadone and Suboxone, with the strongest difference being increased clarity of thinking on Suboxone. Suboxone has significant potential for staged use within a ""recovery journey"" but only if prescribed within an appropriate package of psychosocial care.

Thompson-Evans TP; Glover MP; Walker N. Cytisine's potential to be used as a traditional healing method to help indigenous people stop smoking: A qualitative study with Maori. Nicotine & Tobacco Research 13(5): 353- 360, 2011. (39 refs.)

Introduction: Maori experience a disproportionate amount of smoking-related harm (46% of adult Maori smoke). Effective cessation treatments that are both accessible and attractive to Maori are urgently needed. Cytisine (a plant extract found in Golden Rain [Cytisus laburnum L.] and the New Zealand Kowhai [Sophora tetraptera L.] has a similar molecular makeup to nicotine, has been used successfully as a cessation product in central and eastern Europe and central Asia for many years, and is low priced. Recent reviews have found that cytisine is twice as effective as a placebo for smoking cessation. This study aimed to explore cytisine's potential as a 'rongoa Maori' (traditional Maori remedy) and its attractiveness to Maori smokers compared with other cessation products. Methods: Maori that smoked were interviewed in two focus groups and eight individual semi-structured interviews. Two key informants were interviewed also. Results: Barriers to using cessation products were financial and effort cost, pervasive smoking among family and peers, environments permissive of smoking, and perceived cultural inappropriateness of treatments. Participants were very interested in cytisine, supported the idea that it would be acceptable to package it as a rongoa Maori, and all wanted to use it. Named appropriately, packaged and promoted as a Maori cessation product, participants thought cytisine would contribute to the restoration of Maori identity and traditional beliefs and practices in addition to reducing smoking. Conclusions: Presented as a rongoa Maori, cytisine would likely be more attractive to Maori than currently available cessation products. Confirmation of efficacy and safety will be needed before promotion of the product could occur.

Tonstad S; Holme I; Tonnesen P. Dianicline, a novel alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist, for smoking cessation: A randomized placebo-controlled clinical trial. Nicotine & Tobacco Research 13(1): 8-13, 2011. (11 refs.)

Dianicline is a alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist, a class of drugs that includes varenicline and cytisine. Varenicline is efficacious for smoking cessation, while cytisine has not been studied systematically. The efficacy of dianicline has not been previously tested in an adequately powered study. In a randomized, double-blind, parallel group placebo-controlled trial, 602 generally healthy cigarette smokers were assigned to dianicline (n = 300) or placebo (n = 302) for 7 weeks followed by a 19-week off drug follow-up period. Exhaled carbon monoxide and cotinine-confirmed continuous abstinence rates for Weeks 4-7 were 24.0% for dianicline versus 20.5% for placebo (odds ratio 1.22; 95% CI, 0.83-1.80; p = .307). For Weeks 4-26, the abstinence rates were 16.7% for dianicline versus 13.9% for placebo (odds ratio 1.24; 95% CI, 0.79-1.93; p = .366). Craving for a cigarettes was reduced by dianicline compared with placebo after 7 weeks (p = .0175). Nicotine withdrawal symptoms measured by the Hughes and Hatsukami Minnesota Withdrawal Scale were lower for dianicline compared with placebo in the first 3 weeks of treatment during which time quit rates were also higher in the dianicline-treated group. Dianicline did not increase cigarette smoking abstinence rates beyond the initial phase of treatment. However, self-reported craving and nicotine withdrawal symptoms were reduced.

Ussher M; Aveyard P; Reid F; West R; Evans P; Clow A et al. A randomised placebo-controlled trial of oral hydrocortisone for treating tobacco withdrawal symptoms. Psychopharmacology 216(1): 43-51, 2011. (51 refs.)

Rationale Many smokers experience a decline in cortisol to sub-normal levels during the first days of smoking cessation. A greater decline in cortisol is associated with more intense cigarette withdrawal symptoms, urge to smoke and relapse to smoking. Findings from an uncontrolled study suggest that glucocorticoids could ameliorate cigarette withdrawal. Objectives We investigated whether taking oral hydrocortisone would reduce withdrawal symptoms and the desire to smoke on the first day of temporary smoking abstinence compared with placebo. Methods. Using a double-blind within-subject randomised crossover design, 48 smokers took a single dose of 40 mg hydrocortisone, 20 mg hydrocortisone or placebo following overnight smoking abstinence. Abstinence was maintained through the afternoon, and withdrawal symptoms and the desire to smoke were rated across the morning. Salivary cortisol was assessed in the afternoon prior to abstinence ( baseline) and while abstinent after each treatment. Results. There was a significant dose-response relation between dose of hydrocortisone and reduction in depression and anxiety ratings while abstinent, but there were no other statistically significant associations with dose. Overall, the decline in cortisol following smoking cessation ( placebo only) was not significant. Cortisol level on the afternoon of smoking abstinence was not significantly associated with symptom ratings. Conclusions. Supplements of hydrocortisone do not reduce the desire to smoke but may ameliorate withdrawal-related depression and anxiety, although the clinical benefit is slight.

Vandrey R; Smith MT; McCann UD; Budney AJ; Curran EM. Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal. Drug and Alcohol Dependence 117(1): 38-44, 2011. (52 refs.)

Background: Sleep difficulty is a common symptom of cannabis withdrawal, but little research has objectively measured sleep or explored the effects of hypnotic medication on sleep during cannabis withdrawal. Methods: Twenty daily cannabis users completed a within-subject crossover study. Participants alternated between periods of ad libitum cannabis use and short-term cannabis abstinence (3 days). Placebo was administered at bedtime during one abstinence period (withdrawal test) and extended-release zolpidem, a non-benzodiazepine GABA(A) receptor agonist, was administered during the other. Polysomnographic (PSG) sleep architecture measures, subjective ratings, and cognitive performance effects were assessed each day. Results: During the placebo-abstinence period, participants had decreased sleep efficiency, total sleep time, percent time spent in Stage 1 and Stage 2 sleep, REM latency and subjective sleep quality, as well as increased sleep latency and time spent in REM sleep compared with when they were using cannabis. Zolpidem attenuated the effects of abstinence on sleep architecture and normalized sleep efficiency scores, but had no effect on sleep latency. Zolpidem was not associated with any significant side effects or next-day cognitive performance impairments. Conclusions: These data extend prior research that indicates abrupt abstinence from cannabis can lead to clinically significant sleep disruption in daily users. The findings also indicate that sleep disruption associated with cannabis withdrawal can be attenuated by zolpidem, suggesting that hypnotic medications might be useful adjunct pharmacotherapies in the treatment of cannabis use disorders.

Wampler DA; Molina DK; McManus J; Laws P; Manifold CA. No deaths associated with patient refusal of transport after naloxone-reversed opioid overdose. Prehospital Emergency Care 15(3): 320- 324, 2011. (15 refs.)

Introduction. Naloxone is widely used in the treatment and reversal of opioid overdose. Most emergency medical services (EMS) systems administer naloxone by standing order, and titrate only to reverse respiratory depression without fully reversing sedation. Some EMS systems routinely administer sufficient naloxone to fully reverse the effects of opioid overdose. Frequently patients refuse further medical evaluation or intervention, including transport. Objectives. The purpose of this study was to evaluate the safety of this practice and determine whether increased mortality is associated with full reversal of opioids. As a component of a comprehensive quality assurance initiative, we assessed mortality during the 48 hours after patients received naloxone to reverse opioid overdose followed by patient-initiated refusal of transportation. Methods. The setting was a large urban fire-based EMS system. Investigators provided the Bexar County Medical Examiner's Office (MEO) with a list of patients who were treated by the San Antonio Fire Department with naloxone, and not transported. Inclusion criteria were administration of naloxone and patient-initiated refusal. Patient dispositions also included aid only, referral to the MEO, or referral to law enforcement. The list was then compared with the MEO database. A chart review was completed on all patients treated and subsequently presented to the MEO within two days. A secondary time period of 30 days was also assessed. Results. The list identified 592 patients treated with naloxone and not transported to the emergency department. Five-hundred fifty-two patients received naloxone and refused transport or were not transported. The remaining 40 patients all presented to EMS in cardiac arrest, naloxone was administered during the course of resuscitation, and subsequent efforts were terminated in the field. None of the patients receiving naloxone with a subsequent patient-initiated refusal were examined at the MEO within the two-day end point. The 30-day assessment revealed that nine individuals were treated with naloxone and subsequently died, but the shortest time interval between date of service and date of death was four days. Conclusion. The primary outcome was that no patients who were treated with naloxone for opioid overdose and then refused care were examined by the MEO within a 48-hour time frame.

Weinsier ST. Integrating results from smoking cessation drug research and development into clinical occupational health practice. AAOHN Journal 59(2): 69-76, 2011. (31 refs.)

This article documents evidence-based pharmacologic interventions to promote successful smoking cessation among employees who smoke. The article also highlights supporting evidence for the use of pharmacologic agents to treat tobacco dependence and can guide successful, personalized, pharmacologic smoking cessation interventions in occupational clinical practice. Prescribing clinicians will also find information about the latest research and development of medications to promote smoking cessation, including recently implemented black box warnings by the U. S. Food and Drug Administration.

Williams JM; Steinberg MB; Steinberg ML; Gandhi KK; Ulpe R; Foulds J. Varenicline for tobacco dependence: Panacea or plight? (review). Expert Opinion on Pharmacotherapy 12(11): 1799-1812, 2011. (82 refs.)

Introduction: This review examines the postmarketing experience with varenicline, including case reports, newer clinical trials and secondary analyses of large clinical datasets. Areas covered: Varenicline has been shown to be an effective treatment in a broad range of tobacco users with medical, behavioral and diverse demographic characteristics. Recent studies finding excellent safety and efficacy in groups of smokers with diseases including chronic obstructive pulmonary disease are particularly encouraging and call for increased use of this medication for smoking cessation. Despite case reports of serious neuropsychiatric symptoms in patients taking varenicline, including changes in behavior and mood, causality has not been established. Recent analyses of large datasets from clinical trials have not demonstrated that varenicline is associated with more depression or suicidality than other treatments for smoking cessation. Expert opinion: Now that additional clinical trials in specific populations and observational studies on treatment-seeking smokers outside of clinical trials have been published, we can be confident that varenicline remains the most efficacious monotherapy for smoking cessation and that its side-effect profile remains good. The risk-to-benefit ratio of receiving varenicline to quit smoking must include the increased chances of quitting smoking and avoiding the sizeable risks of smoked-caused disease and death that remain if tobacco addiction is not properly treated.

Winstanley EL; Bigelow GE; Silverman K; Johnson RE; Strain EC. A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients. Journal of Substance Abuse Treatment 40(3): 255-264, 2011. (31 refs.)

Background: Cocaine abuse and dependence continue to be widespread. Currently, there are no pharmacotherapies shown to be effective in the treatment of cocaine dependence. Methods: A 33-week outpatient clinical trial of fluoxetine (60 mg/day, po) for cocaine dependence that incorporated abstinence-contingent voucher incentives was conducted. Participants (N = 145) were both cocaine and opioid dependent and treated with methadone. A stratified randomization procedure assigned subjects to one of four conditions: fluoxetine plus voucher incentives (FV), placebo plus voucher incentives (PV), fluoxetine without vouchers (F), and placebo without vouchers (P). Dosing of fluoxetine/placebo was double blind. Primary outcomes were treatment retention and cocaine use based on thrice-weekly urine testing. Results: The PV group had the longest treatment retention (M = 165 days) and lowest probability of cocaine use. The adjusted predicted probabilities of cocaine use were 65% in the P group, 60% in the F group, 56% in the FV group, and 31% in the PV group. Conclusions: Fluoxetinc was not efficacious in reducing cocaine use in patients dually dependent on cocaine and opioids.

Wittchen HU; Hoch E; Klotsche J; Muehlig S. Smoking cessation in primary care - a randomized controlled trial of bupropione, nicotine replacements, CBT and a minimal intervention. International Journal of Methods in Psychiatric Research 20(1): 28-39, 2011. (38 refs.)

Background/aims: Smoking cessation has been shown to be effective in randomized controlled trials. It is unclear though, whether interventions also work in routine primary care. Methods: In 167 primary care settings we conducted a randomized four-armed smoking cessation trial to examine the efficacy of a minimal intervention (MI; n = 81), cognitive-behavioral therapy (CBT; n = 175), bupropion (BUP; n = 108) and nicotine replacements (NRT; n = 103). Overall, 467 current smokers were enrolled. Abstinence rates at the end of treatment (12 weeks) were 32.8% for MI patients, 34.8% for CBT, 35.3% for NRT, and 46.5% for BUP patients (ITT, intention to treat) (no differential effects). Retention rates were highest in the BUP group (59.3%) and lowest in the NRT group (50.5%). Completer findings were: MI, 56.4%; CBT, 64%; BUP, 79.3%; NRT, 69.2% (LOCF, lost to follow-up). No serious adverse events occurred during or after the medication phase. At 12-month follow-up continuous abstinence rates were: BUP, 29.0%; CBT, 20.9%; NRT, 29.6%; MI, 29.6%. Conclusion: Our findings suggest that established smoking cessation treatments are effective when applied by non-specialist primary care physicians. Our data supports a structured, multimodal treatment structure as core ingredient of successful smoking cessation in primary care.

Wohlrab J; Kreft B; Tamke B. Skin tolerability of transdermal patches. (review). Expert Opinion on Drug Delivery 8(7): 939-948, 2011. (62 refs.)

Introduction: Transdermal patch systems are an effective method of administering active ingredients through the skin, with considerable advantages over other drug delivery routes, for example, maintenance of constant plasma drug levels and avoidance of first-pass metabolism. However, repeated epicutaneous application may be associated with local skin reactions. Areas covered: This review addresses current issues regarding the effective/safe use of transdermal patch systems, and provides a critical analysis of the addition of 'skin-caring' ingredients to patch systems. Effective use of transdermal systems includes choosing an appropriate body area for application, maintaining regular skin care regimens before application and not replacing a patch in the same area (rotation) within 7 days. Another strategy, developed in an attempt to improve the tolerability of transdermal systems, is the addition of assumed 'skin-caring' ingredients (e.g., Aloe Vera) to patch systems. However, at present there is neither proof nor clinical evidence of any benefit. On the contrary, plant-derived ingredients might be associated with allergenic potential. Expert opinion: Transdermal systems are generally well tolerated; physicians must adequately inform patients of the most effective ways to use these formulations for maximum therapeutic benefit, while minimising local adverse events. Skin-caring agents, including Aloe Vera, cannot be recommended until well-controlled clinical trials with standardised extracts are available.

Wolfe D; Carrieri MP; Dasgupta N; Wodak A; Newman R; Bruce RD. Concerns about injectable naltrexone for opioid dependence. (editorial). Lancet 377(9776): 1468- 1470, 2011. (12 refs.)

Yang JL; Hammond D; Driezen P; O'Connor RJ; Li QA; Yong HH et al. The use of cessation assistance among smokers from China: Findings from the ITC China Survey. BMC Public Health 11: e-article 75, 2011. (32 refs.)

Background: Stop smoking medications significantly increase the likelihood of smoking cessation. However, there are no population-based studies of stop-smoking medication use in China, the largest tobacco market in the world. This study examined stop-smoking medication use and its association with quitting behavior among a population-based sample of Chinese smokers. Methods: Face-to-face interviews were conducted with 4,627 smokers from six cities in the ITC China cohort survey. Longitudinal analyses were conducted using Wave 1 (April to August, 2006) and Wave 2 (November 2007 to January 2008). Results: Approximately 26% of smokers had attempted to quit between Waves 1 and 2, and 6% were abstinent at 18-month follow-up. Only 5.8% of those attempting to quit reported NRT use and NRT was associated with lower odds of abstinence at Wave 2 (OR = 0.11; 95% Cl = 0.03-0.46). Visiting a doctor/health professional was associated with greater attempts to quit smoking (OR = 1.60 and 2.78; 95% Cl = 1.22-2.10 and 2.21-3.49 respectively) and being abstinent (OR = 1.77 and 1.85; 95% Cl = 1.18-2.66 and 1.13-3.04 respectively) at 18-month follow-up relative to the smokers who did not visit doctor/health professional. Conclusions: The use of formal help for smoking cessation is low in China. There is an urgent need to explore the use and effectiveness of stop-smoking medications in China and in other non-Western markets.

Zaborowski DE; Dedert EA; Straits-Troster K; Lee S; Wilson SM; Calhoun PS et al. Public health clinical demonstration project for smoking cessation in American veterans who served since September 11, 2001. Journal of Addiction Medicine 5(1): 79-83, 2011. (17 refs.)

Objective: The purpose of this clinical demonstration project was to increase the reach of effective treatments, such as pharmacotherapy and telephone or web-based support, by offering these treatments in a low cost and convenient manner to a population of Veterans. Methods: Six hundred nine veteran smokers who had served in the military since September 11, 2001 were contacted by invitational letters. Veterans indicating interest in further contacts received telephone calls using standardized scripts that offered referral to the National Cancer Institute's Smoking QuitLine, web-based counseling, and local Department of Veteran Affairs pharmacologic treatment for smoking cessation. Results: Seven percent of survey recipients participated in the clinical program. At follow-up, 23% of participants providing follow-up information reported maintaining smoking abstinence. This clinical demonstration project was associated with a reach of 8.6% (number of smokers who accessed the intervention/the number of targeted smokers), an efficacy of 26% (number of abstinent smokers at follow-up/number who accessed the intervention), and a 24-hour abstinence impact rate of 2.2% (number of smokers with 24-hour abstinence/number of targeted smokers). Conclusions: Results suggested that this project enhanced access to care and promoted short-term smoking cessation in Veterans who have served since September 11. 2001.