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CORK Bibliography: Pharmacotherapies

91 citations. October 2006 to present

Prepared: September 2007

Agabio R; Marras P; Addolorato G; Carpiniello B; Gessa GL. Baclofen suppresses alcohol intake and craving for alcohol in a schizophrenic alcohol-dependent patient - A case report. (letter). Journal of Clinical Psychopharmacology 27(3): 319-320, 2007. (17 refs.)

Baros AM; Latham PK; Moak DH; Voronin K; Anton RF. What role does measuring medication compliance play in evaluating the efficacy of naltrexone? Alcoholism: Clinical and Experimental Research 31(4): 596-603, 2007. (33 refs.)

Background: Compliance with medication in pharmacotherapy trials of alcoholism has been shown to be equal to, or more, important than in other areas of medicine. Research has suggested that naltrexone's effectiveness can be greatly influenced by the compliance of participants in clinical trials. Presently, we compare 2 compliance measurement methods [urine riboflavin and medication event monitoring system (MEMS)] used simultaneously to evaluate naltrexone's efficacy and the impact of compliance on the size of observable treatment effects. Methods: One hundred and thirty-seven of 160 randomized alcoholic patients completed 12-weeks (84 days) of naltrexone or placebo and cognitive behavioral therapy (CBT) or motivational enhancement therapy (MET). Urine riboflavin was determined during study weeks 2, 6, and 12. The MEMS provided a detailed computerized record of when a participant opened their medication bottle throughout the trial. Baseline predictors of MEMS (80% openings) and urine riboflavin (>= 1,500 ng/mL by fluorimetry) compliance were examined. The effects of the treatments in the compliant participants defined by one, the other, or both methods were compared and contrasted with a previously reported intent-to-treat analysis where compliance was not taken into account. Results: Age was predictive of compliance. 105 participants were deemed compliant via urine riboflavin criteria, 87 via MEMS, and 77 when both criteria were met, with no significant differences between treatment groups. The most compliant participants showed a significant medication by therapy interaction. Those treated with naltrexone/CBT showed more abstinence days (p < 0.03), less heavy drinking days (p < 0.03) and less total drinks (p < 0.03) than the other groups. The effect size of this interaction increased from about 0.2 in the intent-to-treat analysis, to about 0.4 to 0.5 in the compliant group analyses, with little difference between compliance measurement methods. Conclusions: Compliance measurement does appear to influence the evaluation of the efficacy of naltrexone within the context of CBT. Treatment effect sizes approximately doubled in the most compliant individuals. Measuring compliance by either of 2 distinct methods provides approximately similar results. As compliance with naltrexone within the context of CBT has such a large impact of treatment outcome, methods of enhancing compliance during treatment should be given the utmost attention.

Berg ML; Idrees U; Ding R; Nesbit SA; Liang HK; McCarthy ML. Evaluation of the use of buprenorphine for opioid withdrawal in an emergency department. Drug and Alcohol Dependence 86(2/3): 239-244, 2007. (13 refs.)

Objectives: To examine the use of buprenorphine for the treatment of opioid withdrawal in an emergency department (ED) setting. Methods: The medical records of all adult patients who presented to the study ED during a 10 week period for opioid withdrawal were abstracted. Subjects were categorized as receiving buprenorphine, symptomatic treatment or no pharmacologic treatment for their opioid withdrawal. The three groups were compared by patient and service characteristics, withdrawal symptoms and outcomes. Results: Of the 11,019 patients who presented to the ED during the 10 week study period, 158 (1.4%) were eligible. Subjects were more likely to receive buprenorphine (56%) compared to symptomatic treatment only (26%) or no pharmacologic treatment (18%). Subjects who received buprenorphine were more likely to have a history of suicide ideation (34% versus 12% p < 0.05) compared to subjects who received symptomatic treatment(s) and were less likely to present with a gastrointestinal complaint (9% versus 25% p < 0.05). Subjects who received buprenorphine were less likely to return to the same ED within 30 days for a drug-related visit (8%) compared to those who received symptomatic treatment (17%) (p < 0.05). Conclusions: Buprenorphine was a common treatment for opioid withdrawal in this ED without any documented adverse outcomes. Given that it did not result in an increase in drug-related return ED visits and its proven efficacy in other settings, a prospective evaluation of its potential value to ED patients who present with opioid withdrawal is warranted.

Berrettini WH; Wileyto EP; Epstein L; Restine S; Hawk L; Shields P et al. Catechol-O-Methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence. Biological Psychiatry 61(1): 111-118, 2007. (39 refs.)

Background: Although bupropion is efficacious for smoking cessation, only a minority of smokers are able to quit. Pharmacogenetic research may improve treatment outcomes through discovery of DNA sequences predictive of successful pharmacotherapy for subgroups of smokers. We investigated variants in the catechol-O-methyltransferase (COMT) gene in a smoking cessation trial of bupropion.MethodsA double-blind, placebo-controlled, 10-week trial of bupropion and counseling (with a 6-month follow-up period) was conducted at two university-based smoking cessation research programs. Abstinence was biochemically verified at the end of treatment and at 6 months after the target quit date.ResultsAt the end of the treatment phase, statistically significant interaction effects indicated that COMT haplotypes of two SNPs (rs737865 and rs165599) predicted the efficacy of bupropion compared with placebo. This interaction effect was attenuated at 6-month follow-up. Conclusions: COMT haplotypes at rs737865 and rs165599 may predict a favorable outcome for bupropion treatment for smoking cessation. European-American smokers with a G allele at both SNPs may not benefit from bupropion treatment. Small numbers of some COMT haplotypes limit interpretation of response. If study findings are confirmed in additional large studies, COMT genotyping could be applied to identify likely responders to bupropion treatment for smoking cessation.

Bifulco M; Grimaldi C; Gazzerro P; Pisanti S; Santoro A. Rimonabant: Just an Antiobesity drug? Current evidence on its pleiotropic effects. (review). Molecular Pharmacology 71(6): 1445-1456, 2007. (119 refs.)

The advent of the highly selective cannabinoid receptor (CB1) antagonist, rimonabant (SR141716; Acomplia) can revolutionize the ability of the clinicians to manage obesity. Large- scale clinical trials have demonstrated that rimonabant therapy can reduce obesity. Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer. Here we review recent data from the literature and discuss the full pharmacological potential of this drug.

Boyle RG; Solberg LI; Asche SE; Maciosek MV; Boucher JL; Pronk NP. Proactive recruitment of health plan smokers into telephone counseling. Nicotine & Tobacco Research 9(5): 581-589, 2007. (22 refs.)

We tested whether a 3-month beneficial effect of telephone counseling as an adjunct to the use of medications for smoking cessation was maintained through 12 months. Health plan members filling a prescription for cessation medications were randomized either to a no-contact control group or to proactive recruitment into telephone counseling. An increased point-prevalence quit rate at 3 months (33.1% vs. 27.4%, p<. 05) among smokers randomized to proactive recruitment for telephone counseling was not maintained. Although at 12 months smokers in the proactive recruitment arm were more likely to report a 24-hr quit attempt, compared with control group smokers (86.7% vs. 80.8%, p=.027), we found no differences between the groups in repeated (3-month and 12-month) 7-day point-prevalence quit rates. In an analysis of predictors of quitting, age, marital status, making a lifestyle change, and the presence of household smokers were associated with repeated 3-month and 12-month point-prevalence abstinence. Offering telephone counseling to insured smokers who have filled prescriptions for cessation medications did not increase long-term quit rates. Although other variations of this approach might be tested, we suspect that it might be more useful to test innovative ways to influence the factors we identified as being most strongly predictive of lack of successful quitting.

Brady KT. Medical treatment of opiate dependence: Expanding treatment options. (editorial). American Journal of Psychiatry 164(5): 702-704, 2007. (3 refs.)

Brigham GS; Amass L; Winhusen T; Harrer JM; Pelt A. Using buprenorphine short-term taper to facilitate early treatment engagement. Journal of Substance Abuse Treatment 32(4): 349-356, 2007. (43 refs.)

The U.S. Federal Food and Drug Administration approved buprenorphine for drug abuse treatment in 2002, and it became available for clinical use in early 2003. Maryhaven, a community treatment program, participated in a National Institute on Drug Abuse Clinical Trials Network trial evaluating buprenorphine-naloxone (BNX; Suboxone) short-term taper for medically managed opioid withdrawal and later adopted this treatment. In a retrospective review, the first 64 patients treated with a BNX taper were compared with two groups of patients treated with clonidine before and after the implementation of the BNX program. Significantly more patients (about 80%) receiving BNX continued in further treatment compared to about 30% of those receiving clonidine. Patient outcomes are discussed in the context of the critical need for treatment continuation following detoxification. Common questions of potential adopters of the BNX taper are presented and addressed. Overall, BNX was readily integrated into the existing treatment service.

Budney AJ; Vandrey RG; Hughes JR; Moore BA; Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug and Alcohol Dependence 86(1): 22-29, 2007. (37 refs.)

Background: This study assessed whether oral administration of delta-9-tetrahydrocannbinol (THC) effectively suppressed cannabis withdrawal in an outpatient environment. The primary aims were to establish the pharmacological specificity of the withdrawal syndrome and to obtain information relevant to determining the potential use of THC to assist in the treatment of cannabis dependence. Method: Eight adult, daily cannabis users who were not seeking treatment participated in a 40-day, within-subject ABACAD study. Participants administered daily doses of placebo, 30 mg (10 mg/tid), or 90 mg (30 mg/tid) oral THC during three, 5-day periods of abstinence from cannabis use separated by 7-9 periods of smoking cannabis as usual. Results: Comparison of withdrawal symptoms across conditions indicated that (7) the lower dose of THC reduced withdrawal discomfort, and (2) the higher dose produced additional suppression in withdrawal symptoms such that symptom ratings did not differ from the smoking-as-usual conditions. Minimal adverse effects were associated with either active dose of THC. Conclusions: This demonstration of dose-responsivity replicates and extends prior findings of the pharmacological specificity of the cannabis withdrawal syndrome. The efficacy of these doses for suppressing cannabis withdrawal suggests oral THC might be used as an intervention to aid cannabis cessation attempts.

Camarasa X; Khazaal Y; Besson J; Zullino DF. Naltrexone-assisted rapid methadone discontinuation: A pilot study. European Addiction Research 13(1): 20-24, 2007. (24 refs.)

Slow downtitration as a methadone discontinuation method is time-consuming and associated to high dropout rates. Whereas ultra-rapid opiate detoxification methods have recently gained some popularity, they are expensive and may be associated with particular problems in methadone patients. In the present study, a 3-day detoxification procedure accelerated with a unique dose of naltrexone was used in 10 methadone-substituted patients. Whereas the treatment resulted in a shortened withdrawal syndrome, which was satisfactorily controlled by the drugs used, a two-phase course was observed, some symptoms reappearing between the end of day 2 and the beginning of day 3. The first phase of withdrawal symptoms was attributed to the antagonistic effect of naltrexone, which possibly also improved under the weakening of naltrexone. The second phase of withdrawal symptoms may be related to falling methadone plasma levels.

Ciccocioppo R; Economidou D; Rimondini R; Sommer W; Massi M; Heilig M. Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system. Biological Psychiatry 61(1): 4-12, 2007. (93 refs.)

Background: Activation of the NOP receptor by its endogenous ligand nociceptin/orphanin FQ reduces ethanol intake in genetically selected alcohol preferring Marchigian Sardinian alcohol preferring (msP) rats. Here we evaluated whether buprenorphine, a partial agonist at [mu]-opioid and NOP receptors, would reduce ethanol consumption in msP rats via activation of NOP receptors.MethodsMarchigian Sardinian alcohol preferring rats trained to drink 10% alcohol 2 hours/day were injected with buprenorphine (.03, .3, 3.0, or 6.0 mg/kg intraperitoneally [IP]) 90 min before access to ethanol. Results: Similar to prototypical [mu]-agonists, the two lowest doses of buprenorphine significantly increased ethanol consumption. Conclusions: Buprenorphine has dualistic effects on ethanol drinking; low doses increase alcohol intake via stimulation of classic opioid receptors, whereas higher doses reduce it via activation of NOP receptors. We suggest that NOP agonistic properties of buprenorphine might be useful in the treatment of alcoholism.

Di Matteo V; Pierucci M; Di Giovanni G; Benigno A; Esposito E. The neurobiological bases for the pharmacotherapy of nicotine addiction. (review). Current Pharmaceutical Design 13(12): 1269-1284, 2007. (234 refs.)

Nicotine, the major psychoactive agent present in tobacco, acts as a potent addictive drug both in humans and laboratory animals, whose locomotor activity is also stimulated. A large body of evidence indicates that the locomotor activation and the reinforcing effects of nicotine may be related to its stimulatory effects on the mesolimbic dopaminergic function. Thus, it is now well established that nicotine can increase in vivo DA outflow in the nucleus accumbens and the corpus striatum. The stimulatory effect of nicotine on DA release most probably results from its ability to excite the neuronal firing rate and to increase the bursting activity of DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), and from its stimulatory action on DA terminals in the corpus striatum and the nucleus accumbens. The neurochemical data are consistent with neuroanatomical findings showing the presence of nicotinic acetylcholine receptors (nAChRs) in the SNc, the VTA, and in projection areas of the central dopaminergic system such as the corpus striatum and the nucleus accumbens. Several lines of evidence indicate that the reinforcing properties of drugs of abuse, including nicotine, can be affected by a number of transmitter systems which may act by modulating central dopaminergic function. In this paper, the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies for new pharmacological treatments of nicotine dependence will be examined.

Ehret GB; Desmeules JA; Broers B. Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology. (review). Expert Opinion on Drug Safety 6(3): 289-303, 2007. (129 refs.)

Methadone is used as the pharmacologic mainstay for substitution for illegal opiates and as analgesic for chronic or cancer-related pain. Given the benefits of methadone substitution for illicit opioids, the finding of an association between methadone and prolongation of cardiac depolarization (QT prolongation) and torsades de pointes is of great concern. QT prolongation can occur with many drugs and is a potentially lethal adverse drug reaction, necessitating risk monitoring and therapeutic alternatives in some patients. Recent studies suggest that QT prolongation with methadone is context dependent: occurrence is more frequent with high doses of methadone, concomitant administration of CYP3A4 inhibitors, hypokalemia, hepatic failure, administration of other QT prolonging drugs and pre-existing heart disease. The valued benefit of methadone substitution therapy on the one hand and the increased cardiovascular risk in particular situations on the other illustrate the difficulties in dealing with drug-induced QT prolongation in general.

Elkashef A; Rawson RA; Smith E; Pearce V; Flammino F; Campbell J et al. The NIDA Methamphetamine Clinical Trials Group: A strategy to increase clinical trials research capacity. Addiction 102(Supplement 1): 107-113, 2007. (16 refs.)

Aims: In order to increase the number of investigative teams and sites conducting research on pharmacological treatments for methamphetamine use disorders, the National Institute on Drug Abuse ( NIDA) established an infrastructure of clinical sites in areas where methamphetamine addiction is prevalent. This multi-site infrastructure would serve to run multiple Phases II and III protocols effectively and expeditiously. Methods NIDA collaborated with investigators from the University of California at Los Angeles (UCLA) to set up the Methamphetamine Clinical Trials Group (MCTG). This paper describes the development process, as well as data from a test trial to assess the capability of research-naive sites to recruit research participants and conduct study procedures according to research protocol. Subsequent trials are also described. Results A total of 151 candidates signed consent; 65 individuals were enrolled and 35 (53.8%) completed the 12 weeks' behavioral trial. Self-reported substance use report (SUR) showed comparable use of methamphetamine across sites with the individual site means ranging from 59% (site 5) to 80% (site 3). Drug use as measured by urinalysis was greatly reduced at week 13 compared to the baseline measure; the average rate of methamphetamine-free urine samples across all participants in sites at week 13 was 53%. The highest percentage of methamphetamine-free samples was 85% at site 5; the lowest was at site 1 (40%). Addiction severity index (ASI) composite scores at baseline and protocol completion for all participants demonstrated improvement in all categories over time, except for the medical composite score. The largest composite score reduction in baseline-protocol completion was in the drug domain (0.23 versus 0.15). The changes in the ASI scores from baseline to week 13 were consistent across all five sites. Conclusions: Outcomes of the behavioral trial indicated that the MCTG recruited well; collected study data accurately and reliably; and created a vehicle that can assess promising pharmacotherapies for methamphetamine addiction treatment medications. The MCTG strategy appears to be a feasible approach to increase NIDA's capacity to conduct clinical trials to evaluate potential pharmacotherapies for methamphetamine addiction.

Etter JF; Burri M; Stapleton J. The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: A meta-analysis. Addiction 102(5): 815-822, 2007. (24 refs.)

Aim To assess whether source of funding affected the results of trials of nicotine replacement therapy (NRT) for smoking cessation. Methods We reviewed all randomized controlled trials included in the Cochrane review. There were insufficient non-industry trials of the newer products for these to be included. We included 90 trials of either the nicotine gum (52) or nicotine patch (38). They comprised 18 238 treatment and 16 235 control participants. Forty-nine showed evidence of industry support (18 gum, 31 patch). Results Industry (31 of 49, 63%) compared with non-industry (seven of 41, 17%, P < 0.001) supported a higher proportion of nicotine patch studies and had larger sample sizes (479 versus 268, P = 0.04). Twenty-five (51%) industry trials reported statistically significant (P < 0.05) results, compared with nine (22%) non-industry trials (OR = 3.70, 95% CI = 1.46-9.35). This difference was not explained by trial characteristics. Industry-supported trials had a pooled odds ratio of 1.90 (1.67-2.16), compared with 1.61 (1.43-1.80) for other studies (chi(2) = 3.6, P = 0.058). There was evidence of funnel-plot asymmetry among industry trials (t = 4.35, P < 0.001), but not among other trials, indicating that several small null-effect industry trials may not have reached publication. After imputation adjustment, the odds ratio for industry trials reduced to 1.64 (1.43-1.89) and the overall NRT odds ratio reduced from 1.73 (1.60-1.90) to 1.62 (1.49-1.77). Conclusions: Compared with independent trials, industry-supported trials were more likely to produce statistically significant results and larger odds ratios. These differences persisted after adjustment for basic trial characteristics. Although we had no data on the amount of funding for each trial, it is possible that more resources led to higher treatment compliance and therefore greater efficacy in industry-supported trials. Differences can also possibly be explained by publication bias with several small, null-effect industry studies not having reached publication. After adjustment for this possible bias, results for industry trials were lower and similar to non-industry results. Similarly, the overall estimate of the net effect for these products reduces to about 5% attributable 1-year successes. This remains of considerable public health benefit. Registration of clinical trials has become mandatory in many countries since most of the trials considered here were conducted, and this should reduce the potential for publication bias in future.

Evans SM; Levin FR; Brooks DJ; Garawi F. A pilot double-blind treatment trial of memantine for alcohol dependence. Alcoholism: Clinical and Experimental Research 31(5): 775-782, 2007. (53 refs.)

Background: There is growing evidence that N-methyl-D-aspartate (NMDA) receptor antagonists may have potential for the treatment of alcohol disorders. Memantine is a selective noncompetitive NMDA receptor antagonist that has been shown to decrease alcohol craving in moderate drinkers. This 16-week double-blind outpatient pilot clinical trial determined if memantine was more effective than placebo at reducing alcohol use in actively drinking alcohol-dependent patients. Methods: Forty-four treatment-seeking alcohol-dependent individuals were enrolled, with 34 patients stratified to either the memantine group (n=19; maximum dose of 40 mg/d) or the placebo (PBO; n=15) group. The primary outcome measures were related to alcohol use (average drinks per day, average drinks per drinking day, percentage of heavy drinking days, and percentage of days abstinent) based on the timeline follow-back (TLFB). Secondary outcome measures included the Obsessive Compulsive Drinking Scale, Clinical Global Impression ratings, and gamma-glutamyltransferase (GGT), a biomarker of recent alcohol use. To enhance retention, patients received voucher incentives for clinic attendance. Results: Of those randomized, approximately 80% (27) completed the entire 16-week trial. Longitudinal analysis of drinks per day and drinks per drinking day showed a significant reduction in alcohol use, but no difference between the 2 groups. Further, the percentage of heavy drinking days indicated that both groups showed a significant decrease in drinking behavior, but there was significant treatment effect in favor of the PBO group. Similarly, for the percentage of days abstinent, the PBO group achieved a significantly greater percentage of days abstinent at a faster rate than the memantine group. Lastly, the memantine group reported a greater number of side effects compared with the PBO group, such that 26% of patients had their drug dose decreased or discontinued due to memantine-related side effects. Conclusions: The results of this double-blind placebo-controlled pilot trial do not support the use of memantine for the treatment of actively drinking alcohol-dependent patients. However, voucher incentives did facilitate retention.

Fehr C; Hohmann N; Grunder G; Dielentheis TF; Buchholz HG; Chechko N et al. Tiagabine does not attenuate alcohol-induced activation of the human reward system. Psychopharmacology 191(4): 975-983, 2007. (52 refs.)

Rationale: The rewarding effects of ethanol and other drugs of abuse are mediated by activation of the mesolimbic dopamine system. Recent neuroimaging studies in primates and humans suggest that cocaine-induced dopamine stimulation might be diminished by drugs augmenting gamma-aminobutyric acid A (GABA-A) receptor function such as the GABA transaminase inhibitor vigabatrin. Objectives The objective of this study was to test the property of the selective GABA transporter 1 (GAT1) inhibitor tiagabine to block ethanol-induced activation of the mesolimbic reward system in an i.v. ethanol challenge. Materials and methods Twenty nonaddicted healthy volunteers underwent an i.v. ethanol challenge after 1 week of tiagabine (15 mg/day) administration. Neuronal activation was measured using [F-18]-fluoro-deoxyglucose positron emission tomography (PET). Results Tiagabine did not prevent ethanol-induced stimulation of the mesolimbic reward system but augmented ethanol-induced hypometabolism within areas of the visual system and the cerebellum. Tiagabine alone also decreased neuronal metabolism within parts of the right temporal cortex that are highly enriched with GABA-ergic neurons. Conclusions Our ethanol challenge imaging study does not provide supporting evidence that the GAT1 inhibitor tiagabine diminishes the rewarding effects of ethanol. Further PET imaging studies using established anticraving compounds, such as the mu-opioid receptor antagonist naltrexone and antiepileptic drugs affecting the GABA-ergic system more broadly, will provide additional important insights on the interaction between the GABA-ergic and the brain reward system in vivo and the suitability of GABA-ergic drugs as anticraving compounds.

Foy A. Circuit breakers for addiction. Internal Medicine Journal 37(5): 320-325, 2007. (42 refs.)

The phenomenon of addiction is complex, although its expression clinically is relatively straightforward. There is a series of neurophysiological changes that mediate changes in the mesolimbic and mesocortical systems which in turn lead to disturbances in reward mechanisms. These then act to perpetuate the cycle of intoxication and reinforcement, withdrawal, craving and compulsive use. As our understanding of the pathophysiology of this process has improved, new pharmalogical agents have been developed with the potential to moderate or even reverse it. This article briefly reviews the treatment of addiction with particular reference to emerging pharmaceutical agents.

Funk CK; Zorrilla EP; Lee M-J; Rice KC; Koob GF. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biological Psychiatry 61(1): 78-86, 2007. (98 refs.)

Background: Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF1 receptor antagonists on excessive ethanol self-administration in dependent rats. Methods: Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF1 antagonists) and ethanol self-administration was measured. Results: The nonpeptide, small molecule CRF1 antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists had no effect on ethanol self-administration in nondependent rats. Conclusions: These data demonstrate that CRF1 receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF1 antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.

Gelernter J; Gueorguieva R; Kranzler HR; Zhang HP; Cramer J; Rosenheck R; VA Study Group. Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: Results from the VA cooperative study. Alcoholism: Clinical and Experimental Research 31(4): 555-563, 2007. (39 refs.)

Background: Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX). Methods: We studied polymorphic variants at each of the 3 opioid receptor genes-OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively-including the OPRM1 Asn40Asp variant-as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence." Results: At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p < 0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response. Conclusions: These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.

Gibson AE; Degenhardt LJ; Hall WD. Opioid overdose deaths can occur in patients with naltrexone implants. Medical Journal of Australia 186(3): 152-153, 2007. (14 refs.)

From Australian coronial records, we identified five deaths involving implantable naltrexone between 2000 and 2004. One man died from acute narcotism with a naltrexone implant in place and a blood naltrexone level of 0.3 mg/L. A woman died of combined drug effect (including naltrexone) accompanied by severe pain from a naltrexone implant site. These cases indicate that patients can die from opioid overdose with a naltrexone implant and blood naltrexone levels higher than reported blockade levels.

Gibson A; Shanahan M. Costs and outcomes of treatments for excessive alcohol consumption: Making policy decisions with the available data. Drugs: Education, Prevention and Policy 14(1): 1-17, 2007. (75 refs.)

AIM: To determine which treatments for risky or dependent alcohol consumption provide the best health outcomes for a given expenditure. Methods: Economic evaluation expressing results in cost per unit outcome, from the perspective of the Australian healthcare system. Interventions considered include brief interventions; psychosocial interventions (motivational approaches, cognitive-behavioural approaches and self-guided materials); and pharmacotherapies (acamprosate and naltrexone). Treatment outcomes and standard treatment costs were measured for selected studies, and costs per unit outcome were calculated. Findings: Twenty-nine studies were selected for the analysis. As treatment outcomes were not consistently expressed in a single unit across interventions, two outcomes were used in the analysis: percentage change in alcohol consumption and percentage change in the proportion of abstinent days. Brief interventions provided the best cost per unit outcome, followed by psychosocial interventions, then pharmacotherapies. Conclusions: By using two treatment outcomes instead of one we demonstrated that some treatments for alcohol dependence provide better value for money, but as a result we were unable to complete a formal health economic evaluation. Consistent measurement of alcohol consumption outcomes in research studies would facilitate similar economic evaluations in the future. This work illustrates the difficulties of using research studies with non-comparable outcomes to inform policy on the cost-effectiveness of different treatments.

Gillman MA; Lichtigfeld FJ; Young TN. Psychotropic analgesic nitrous oxide for alcoholic withdrawal states. (review). Cochrane Database of Systemic Reviews 2: CD005190, 2007. (54 refs.)

Background: Alcoholism is a global problem with 5-10% of the world's population demonstrating alcohol-related diseases. One of the most severe consequences of alcohol dependence is the withdrawal syndrome, for which benzodiazepines are the most popular current treatment. An alternative method to benzodiazepine employs psychotropic analgesic nitrous oxide (PAN). Objectives: To assess the effects of PAN for treating alcohol withdrawal states Search strategy We searched the Cochrane Central Register of Controlled Trials (The Cochrane Librarylssue 2, 2005), MEDLINE, EMBASE, CINAHL (all to May 2005). We scanned internet websites, reference lists of relevant articles and abstracts of the international Conferences on Alcoholism. We contacted researchers in the field and industry to identify unpublished trials. No language and publication restrictions. Selection criteria Randomised controlled trials including voluntary participants dependent on alcohol. PAN was compared to oxygen and/or benzodiazepine regimens. Data collection and analysis Two authors independently assessed the methodological quality of the trials and extracted data. Main results Five studies, 212 participants, were included. PAN showed improvement of symptoms (RR 1.35; 95% CI 1.01 to 1.79), of the amount and duration of sedative medication and of psychomotor function (WMD -8-71; 95% CI -13.71 to -3.71). At one hour post intervention, no significant differences were found for depression (WMD -2.40; 95% CI -8.70 to 3.89) and anxiety (WMD -3.70; 95% CI -10.53 to 3.12). None of the included studies reported any significant adverse effects of any treatment. Authors' conclusions: Results indicate that PAN may be an effective treatment of the mild to moderate alcoholic withdrawal state. The rapidity of the therapeutic effect of PAN therapy coupled with the minimal sedative requirements, may enable patients to enter the psychological treatment phase more quickly than those on sedative regimens, accelerating the patients recovery. Our review does not provide strong evidence due to the small sample sizes of the included trials. Neither does the review indicate any causes for concern that PAN is more harmful than the benzodiazepines. Clinicians wishing to use PAN may initially wish to do so within trial settings. Further high quality trials should be done to confirm these findings and to investigate whether the PAN therapy has fewer adverse effects than other treatments for the alcohol withdrawal states. Studies to investigate the possible cost-effectiveness of PAN by reducing costly hospital admissions and decreasing post administration supervision also need to be performed.

Glover ED; Laflin MT; Schuh KJ; Schuh LM; Nides M; Christen AG et al. A randomized, controlled trial to assess the efficacy and safety of a transdermal delivery system of nicotine/mecamylamine in cigarette smokers. Addiction 102(5): 795-802, 2007. (22 refs.)

Aims: To determine the efficacy and safety of nicotine transdermal therapy co-administered with the nicotine antagonist, mecamylamine, compared to a nicotine transdermal patch alone (21 mg nicotine + 6 mg mecamylamine, 21 mg nicotine + 3 mg mecamylamine, and 21 mg nicotine + 0 mg mecamylamine). Design Multi-center (n = 4), double-blind, randomized, parallel group, repeat-dose study. Setting Clinical laboratory. Participants: A total of 540 subjects were enrolled into the study-135 from each of four sites; 180 patients in each of three treatment arms. Intervention: Treatment was administered for the first 6 weeks of the 8-week study. Patients were instructed to continue smoking for the first 2 weeks of treatment. Measurements: The primary efficacy parameter was 4-week continuous abstinence after the quit date, confirmed with an expired carbon monoxide of < 10 parts per million. Findings Analysis of the 4-week continuous abstinence for the intent-to-treat population showed overall rates of 29% (nicotine + 6 mg mecamylamine), 29% (nicotine + 3 mg mecamylamine) and 23% (nicotine only) using the slip definition which allows smoking in the first 2 weeks after the quit date. Statistical analyses revealed no significant treatment differences. Analyses using the strict definition (no smoking after the quit date) yielded similar non-significant group differences (29%, 27%, 26%). Conclusion: If adding mecamylamine to nicotine replacement therapy (NRT) improves the chances of success at stopping smoking, the results of this study suggest that the effect is very small.

Green AI. Pharmacotherapy for schizophrenia and co-occurring substance use disorders. Neurotoxicity Research 11(1): 33-39, 2007. (79 refs.)

Substance use disorder (SUD) occurs commonly in patients with schizophrenia and is associated with a poor outcome. Despite this common comorbid occurrence (and its negative impact on the course of schizophrenia), there have been very few studies assessing pharmacological strategies for optimal treatment of these patients. A number of theories have been advanced to help explain the high rate of substance use disorder in patients with schizophrenia. Our group has suggested that the brain reward circuit dysfunction model, which may incorporate aspects of all of these models, may help direct research aimed at developing new pharmacological treatments for patients with schizophrenia and co-occurring SUD. Although typical antipsychotic medications appear to be of limited value in these patients, emerging, but preliminary, data suggest that the atypical antipsychotics, particularly clozapine, may be particularly helpful. The role of adjunctive medications, such as those medications that have recently been shown to be useful for the treatment of alcoholism, may have a role in the treatment of these patients, although only naltrexone has, thusfar, been carefully tested in these comorbid patients. Further studies are indicated to assess the role of novel pharmacologic treatment strategies for these patients. Ultimately, any medication given to these patients will need to be prescribed within psychosocial treatment programs aimed at assisting these patients in limiting and ultimately ceasing substance use.

Greenwald M; Johanson C-E; Bueller J; Chang Y; Moody DE; Kilbourn M et al. Buprenorphine duration of action: Mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biological Psychiatry 61(1): 101-110, 2007. (64 refs.)

Background: Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of [mu] opioid receptors ([mu]ORs). This study examined the duration of action of BUP at [mu]ORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers. Methods: Availability of [mu]OR (measured with positron emission tomography and [11C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere. Results: Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain [mu]OR availability was 30%, 54%, 67%, and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of [mu]OR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade. Conclusions: Together with our previous findings, it appears that [mu]OR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50%-60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.

Gueorguieva R; Wu R; Pittman B; Cramer J; Rosenheck RA; O'Malley SS et al. New insights into the efficacy of naltrexone based on trajectory-based reanalyses of two negative clinical trials. Biological Psychiatry 61(11): 1290-1295, 2007. (59 refs.)

Background: The heterogeneity of clinical findings in studies evaluating the efficacy of naltrexone in the treatment of alcohol dependence has led to growing efforts to explore novel approaches to data analysis. The objective of this study was to identify distinct trajectories of daily drinking over time in two negative clinical trials and to determine whether naltrexone affected the probability to follow a particular trajectory. Methods: The Veterans Affairs (VA) Cooperative Study #425 and the Women's Naltrexone Study failed to demonstrate efficacy on primary outcome variables. Separately for each study, we analyzed daily indicators of any drinking and heavy drinking using a semiparametric group-based approach. Results: We estimated three distinct trajectories of daily drinking (both any and heavy drinking) which we described as "abstainer," "sporadic drinker," and "consistent drinker." Naltrexone doubled the odds of following the abstainer trajectory instead of the consistent drinker trajectory but did not significantly change the odds of following the abstainer trajectory as contrasted with the sporadic drinker trajectory. Conclusions: Naltrexone may have a clinically meaningful effect for alcohol-dependent patients with a high chance of consistent drinking, even in studies where it failed to show efficacy in planned analyses.

Guzik P; Bankes L; Brown TM. Acamprosate and primitive reflexes. Annals of Pharmacotherapy 41(4): 715-718, 2007. (14 refs.)

OBJECTIVE: To describe 3 cases of patients with alcohol dependence whose primitive reflexes resolved upon initiation of acamprosate 666 mg 3 times daily. CASE SUMMARIES: A 57-year-old man had a long-standing history of alcohol dependence and a prominent snout reflex. The snout reflex resolved within 24 hours of starting treatment with acamprosate. A 45-year-old man with a long history of alcohol dependence had both a snout and a grasp reflex. These reflexes were present throughout 3 admissions for alcohol detoxification and continued until the end of his third admission, when he elected to begin treatment with acamprosate. Within 24 hours of starting treatment, the snout and grasp reflexes were absent. A 55-year-old man who drank heavily for 35 years presented with both a snout and a grasp reflex on admission. These persisted throughout his detoxification until the day after he had begun treatment with acamprosate. His primitive reflexes remained resolved through the next 4 days until discharge. All 3 of these patients remained on acamprosate at discharge. DISCUSSION: Alcohol dependence is a common, debilitating disorder. One of the difficulties in treating alcohol dependence is its adverse effect on the brain, as higher aspects of cortical function necessary to maintain abstinence are eroded by alcohol. Acamprosate is a drug intended to help prevent relapse among patients with alcohol dependence. Unexpectedly, acamprosate may resolve primitive reflexes -- a neurologic finding that suggests cognitive impairment -- among patients with alcohol dependence. CONCLUSIONS: Acamprosate may relieve snout and grasp reflexes among patients with alcohol dependence.

Hall SM; Gorecki JA; Reus VI; Humfleet GL; Munoz RF. Belief about drug assignment and abstinence in treatment of cigarette smoking using nortriptyline. Nicotine & Tobacco Research 9(4): 467-471, 2007. (16 refs.)

This study assessed the relationship between beliefs about drug assignment and abstinence status in two treatment studies using nortriptyline hydrochloride as an adjunct to smoking cessation. Smokers (N=345) drawn from two clinical trials were asked at the final follow-up at 52 or 64 weeks whether they believed they had received active or placebo drug. Responses were obtained from 262 participants, or 76% of the sample. Biochemically verified abstinence was collected at end of treatment final follow-up. In both studies, participants were correct in guessing drug assignment. At FFU, belief about drug assignment was not related to abstinence for either active or placebo participants. Participants who received active drug and who were smoking at end of treatment were more likely to believe they had received placebo than active drug participants who were abstinent at end of treatment. We found no significant relationship between belief about drug and abstinence status for placebo participants at end of treatment . Baseline variables did not significantly predict correctness of drug identification. Participants who experienced drug side-effects not easily attributable to nicotine withdrawal were more likely to identify their drug assignment as nortriptyline. We conclude that experience during the active treatment period, including side-effects and treatment success, may be related to belief about drug assignment, that the field would be well served by at least two assessments of blindness in clinical trials, and that discrepancy between these findings and those regarding nicotine replacement therapy may be related to differences in dependent variables.

Haney M. Opioid antagonism of cannabinoid effects: Differences between marijuana smokers and nonmarijuana smokers. Neuropsychopharmacology 32(6): 1391-1403, 2007. (64 refs.)

In non-human animals, opioid antagonists block the reinforcing and discriminative-stimulus effects of Delta(9)-tetrahydrocannabinol (THC), while in human marijuana smokers, naltrexone (50 mg) enhances the reinforcing and subjective effects of THC. The objective of this study was to test a lower, more opioid-selective dose of naltrexone (12 mg) in combination with THC. The influence of marijuana-use history and sex was also investigated. Naltrexone (0, 12 mg) was administered 30 min before oral THC (0-40 mg) or methadone (0-10 mg) capsules, and subjective effects, task performance, pupillary diameter, and cardiovascular parameters were assessed in marijuana smoking (Study 1; n = 22) and in nonmarijuana smoking (Study 2; n 21) men and women. The results show that in marijuana smokers, low-dose naltrexone blunted the intoxicating effects of a low THC dose (20 mg), while increasing ratings of anxiety at a higher THC dose (40 mg). In nonmarijuana smokers, low-dose naltrexone shifted THC's effects in the opposite direction, enhancing the intoxicating effects of a low THC dose (2.5 mg) and decreasing anxiety ratings following a high dose of THC (10 mg). There were no sex differences in these interactions, although among nonmarijuana smokers, men were more sensitive to the effects of THC alone than women. To conclude, a low, opioid-selective dose of naltrexone blunted THC intoxication in marijuana smokers, while in nonmarijuana smokers, naltrexone enhanced THC intoxication. These data demonstrate that the interaction between opioid antagonists and cannabinoid agonists varies as a function of marijuana use history.

Hart CL; Haney M; Collins ED; Rubin E; Foltin RW. Smoked cocaine self-administration by humans is not reduced by large gabapentin maintenance doses. Drug and Alcohol Dependence 86(2/3): 274-277, 2007. (14 refs.)

Previously, we reported that gabapentin, a X-aminobutyric acid (GABA) agonist, significantly reduced "positive" subjective effects of cocaine without reducing cocaine self-administration. We speculated that the gabapentin doses used in that study were too low to detect subtle shifts in the reinforcing effects of cocaine. Thus, the present study examined the effects of larger gabapentin maintenance doses on cocaine-related effects, including self-administration. During this 48-day double-blind, crossover design study, the effects of gabapentin maintenance (0, 2400, 3200 mg/day) on response to cocaine (0, 12, 25, 50 mg) were investigated in six cocaine-dependent individuals not seeking treatment for their cocaine use. Active cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings (e.g., "Good Drug Effect"), blood pressure, and heart rate. Gabapentin did not decrease cocaine self-administration, cardiovascular measures, or most subjective effects of cocaine. These data agree with findings from a clinical trial examining the effects of similar gabapentin doses on cocaine use by treatment-seeking cocaine-dependent individuals and suggest that gabapentin does not show promise as a treatment medication for cocaine dependence. reserved.

Hyman SM; Fox H; Hong KIA; Doebrick C; Sinha R. Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment. Experimental and Clinical Psychopharmacology 15(2): 134-143, 2007. (56 refs.)

Background: Naltrexone is a nonaddictive medication that blocks the euphoric effects of opioids. However, naltrexone treatment is associated with high rates of noncompliance and opioid relapse, possibly because it does not reduce stress and protracted withdrawal symptoms during early recovery. Prior clinical and preclinical research has indicated that both stress and drug-cue-related arousal response is associated with craving and vulnerability to relapse in a range of drug-using populations. Aims: To examine opioid craving and the subjective and cardiovascular response to stress and drug cues in naltrexone-treated opioid abusers. Method: Eleven men and three women engaged in naltrexone treatment for opioid dependence. They were exposed to personalized stress, drug-cue, and neutral-relaxing imagery in a single laboratory session. Subjective (craving, emotion) and cardiovascular (heart rate, systolic blood pressure, and diastolic blood pressure) measures were assessed. Results: Stress and drug-cue-related imagery significantly increased opioid craving, anxiety, and negative emotions and significantly decreased positive emotions compared to neutral imagery. Selective emotional responses were greater in the stress condition than in the drug-cue condition. Only stress-related imagery was associated with an increased cardiovascular response. Conclusions: Naltrexone-treated opioid abusers demonstrate vulnerability to stress and drug-cue-induced craving and arousal responses that may contribute to the high rates of noncompliance and relapse among opioid-dependent individuals undergoing naltrexone treatment. Pharmacological and behavioral interventions that specifically target the negative affectivity that co-occurs with drug-cue and stress-induced craving could be of benefit in improving naltrexone treatment outcomes in opioid dependence.

Jeffrey GP; MacQuillan G; Chua F; Galhenage S; Bull J; Young E et al. Hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants. Hepatology 45(1): 111-117, 2007. (33 refs.)

The effectiveness of HCV antiviral therapy in patients who have undergone recent drug dependency treatment and continue to inject drugs sporadically is presently not clear. Patients attending a community-based drug rehabilitation and naltrexone implant clinic from October 2002 until March 2005 were screened for HCV infection and if positive offered further assessment and treatment with interferon and ribavirin therapy. The first 50 patients to commence HCV therapy and complete at least 6 months follow-up were prospectively studied. ETR response (HCV PCR negative) was 34/50 (68%) and SVR 6 months post-treatment was 31/50 (62%). Viral eradication was maintained in those 22 patients that have had 12 months or more post-treatment follow-up. Eleven (22%) patients stopped therapy early due to side effects or poor compliance. Only two patients with an ETR likely reinfected due to unsafe injection practices. One was re-treated and achieved an SVR. Of the patients achieving a 6-month SVR, 17 of 31 patients reported no further IDU and 13 of 31 patients occasional IDU during treatment and this was maintained after HCV treatment cessation. 46% of patients received antidepressant and/or antipsychotic medication during treatment. Conclusion: This study of HCV treatment in a community-based subcutaneous naltrexone implant clinic found antiviral therapy resulted in a 62% SVR. This result is comparable to that reported in hospital-based clinics in non-IDU patients. The side effect profile and compliance was also similar. HCV antiviral therapy should be offered to this large and currently under treated group.

Johanson CE; Lundahl LH; Schubiner H. Effects of oral cocaine on intravenous cocaine discrimination in humans. Experimental and Clinical Psychopharmacology 15(3): 219-227, 2007. (46 refs.)

This study was designed to evaluate the drug discrimination paradigm as a model for assessing the ability of potential agonist medications to block the effects of intravenous cocaine. Previous research has demonstrated that oral cocaine attenuated the subjective and physiological effects of intravenous cocaine injections, and in the absence of a known efficacious medication for cocaine use disorders, a proof-of-concept approach was used in which cocaine was acutely administered orally to block intravenous cocaine's discriminative-stimulus effects. During training, 11 cocaine-dependent participants were able to discriminate between intravenous saline and 20 mg/70 kg iv cocaine, and 8 of these participants completed the study. After training, participants ingested capsules containing either placebo or 300 mg/70 kg cocaine 60 min prior to the intravenous injection of different doses of cocaine during test sessions with no contingencies in place. Each cocaine dose was administered twice, once under each oral pretreatment condition. Training sessions were interspersed among the test sessions. Physiological and subjective effects were measured throughout each session. Oral cocaine moderately increased some of the subjective and physiological effects of the lower doses of intravenous cocaine, whereas effects at the higher doses were unaltered. Similar changes were seen for the discrimination results. Thus, although oral cocaine given acutely likely is not a viable treatment medication for cocaine dependence, the usefulness of the drug discrimination model in the evaluation of agonist treatment medications remains unclear.

Kakko J; Gronbladh L; Svanborg KD; von Wachenfeldt J; Ruck C; Rawlings B et al. A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: A randomized controlled trial. American Journal of Psychiatry 164(5): 797-803, 2007. (34 refs.)

Objective: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. Method: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. Results: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. Conclusions: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered.

Kalivas PW. Neurobiology of cocaine addiction: Implications for new pharmacotherapy. American Journal on Addictions 16(2): 71-78, 2007. (55 refs.)

The development of pharmacotherapies for cocaine addiction has been disappointingly slow. However, new neurobiological knowledge of how the brain is changed by chronic pharmacological insult with cocaine is revealing novel targets for drug development. Certain drugs currently being tested in clinical trials tap into the underlying cocaine-induced neuroplasticity, including drugs promoting GABA or inhibiting glutamate transmission. Armed with rationales derived from a neurobiological perspective that cocaine addiction is a pharmacologically induced disease of neuroplasticity in brain circuits mediating normal reward learning, one can expect novel pharmacotherapies to emerge that directly target the biological pathology of addiction.

Karhuvaara S; Simojoki K; Virta A; Rosberg M; Loyttyniemi E; Nurminen T et al. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: A randomized double-blind placebo-controlled multicenter study. Alcoholism: Clinical and Experimental Research 31(7): 1179-1187, 2007. (38 refs.)

Background: Clinical studies with opioid antagonists for treatment of problem drinking have mainly been conducted in specialized alcohol treatment centers, included structured psychosocial treatment, and have focused on maintaining abstinence after a period of abstinence from alcohol. Methods: This multisite, randomized double-blind study investigated targeted nalmefene in reducing heavy drinking. Specialized alcohol treatment centers and private general practices enrolled 403 subjects (328 men, 75 women). Subjects were instructed to take nalmefene 10 to 40 mg (n=242) or placebo (n=161) when they believed drinking to be imminent. After 28 weeks, 57 subjects from the nalmefene group continued into a 24-week randomized withdrawal extension. Concomitant psychosocial intervention was minimal and no treatment goals were imposed. Alcohol consumption was recorded using the time-line follow-back method. Biochemical indicators of alcohol use were also measured. Results: The mean monthly number of heavy drinking days (HDDs) during the 12-week period before inclusion was 15.5 (SD 6.9) in the nalmefene group and 16.2 (SD 6.9) in the placebo group. During treatment, the mean numbers of HDDs were 8.6 to 9.3 in the nalmefene group and 10.6 to 12.0 in the placebo group (p=0.0065). The levels of serum alanine aminotransferase and gamma-glutamyl transferase decreased in the nalmefene group compared with the placebo group (p=0.0088 and 0.0023). During the randomized withdrawal period, subjects randomized to placebo apparently returned to heavier drinking. Subjects receiving nalmefene reported more nausea, insomnia, fatigue, dizziness, and malaise than subjects on placebo. Conclusions: Nalmefene appears to be effective and safe in reducing heavy drinking, even when accompanied by minimal psychosocial support.

Kenna GA; Nielsen DM; Mello P; Schiesl A; Swift RM. Pharmacotherapy of dual substance abuse and dependence. (review). CNS Drugs 21(3): 213-237, 2007. (212 refs.)

The US FDA has approved a limited number of treatments for alcohol, nicotine and opioid dependence; however, no treatments for other abused drugs such as marijuana, cocaine or methamphetamine are approved. This review focuses on research into drug pharmacotherapies, particularly single-drug therapies, for substance abuse and dependence contributing to the most important dual substance use disorders (SUDs). Given the implications of poly-substance abuse, it is essential that clinicians and researchers be aware of potential pharmacotherapies for the treatment of dual SUDs. A substantial number of patients abuse more than one drug concurrently, complicating the treatment of SUD and leaving clinicians with few FDA-approved drug options for their patients. In this era of evidence-based medicine, such patients are typically treated with therapeutically proven medications, but in ways that are outside the scope of a drug's original indication by the FDA. Such 'off-label' prescribing has become an important therapeutic strategy for practitioners seeking treatments for other diseases in subpopulations such as paediatrics and gerontology or for medical conditions such as oncology or mental illness. Similarly, the information that most clinicians use to make their decisions for treating patients abusing multiple drugs stems from trials treating a single SUD, anecdotal experiences from their own practice or that of their colleagues, or single-case studies reported in the literature. The existing evidence suggests there are few treatments for SUDs that confer significant reductions in substance use across a broad patient population. Moreover, even fewer clinical efficacy trials have been conducted that provide evidence of therapeutic benefit for these drugs. Recognising the difficulty in making the proper drug choice for facilitating maximum treatment success, this review highlights the single drugs or drug combinations that show some potential for treating dual SUDs. This review finds strongest support for the use of disulfiram for treatment of alcohol and cocaine dependence (with or without concomitant methadone maintenance), baclofen for alcohol and cocaine dependence (but not opioid-dependent cocaine users), tiagabine for cocaine dependence in methadone-maintained patients, and topiramate for alcohol, nicotine and cocaine dependence. While ondansetron and olanzapine show some efficacy in treating alcohol and cocaine dependence, more research is needed to better delineate the subpopulation in which these drugs may provide their maximum effect.

Knudsen HK; Ducharme LJ; Roman PM. The use of antidepressant medications in substance abuse treatment: The public-private distinction, organizational compatibility, and the environment. Journal of Health and Social Behavior 48(2): 195-210, 2007. (59 refs.)

Many studies of innovation adoption in health care organizations focus either on organizational characteristics or the institutional environment, but not both. Furthermore, these perspectives are rarely employed simultaneously in both public and private health care organizations. This research considers the public-private distinction, organizational compatibility, and interorganizational referral relationships in the use of selective serotonin reuptake inhibitors (SSRIs) by substance abuse treatment organizations. Using data from nationally representative samples of 3 63 publicly funded and 403 privately funded substance abuse treatment centers, a four-category typology of public and private organizations initially predicted variation in SSRI use. However some differences were no longer significant once organizational and environmental characteristics were added to the statistical model. These data support hypotheses about the associations between organizational characteristics and SSRI use as well as hypotheses regarding the external environment. Future research should continue to integrate both internal and external factors in theoretical explanations of innovation adoption.

Koethe D; Juelicher A; Nolden BM; Braunwarth WD; Klosterkotter J; Niklewski GN et al. Oxcarbazepine - Efficacy and tolerability during treatment of alcohol withdrawal: A double-blind, randomized, placebo-controlled multicenter pilot study. Alcoholism: Clinical and Experimental Research 31(7): 1188-1194, 2007. (29 refs.)

Objective: Alcohol withdrawal syndrome (AWS) is a serious complication of alcohol dependence and often requires intensive medical treatment. Antiepileptic drugs (AEDs) have been shown to be as efficacious in the treatment of AWS in several controlled trials as benzodiazepines and superior to placebo in relieving alcohol withdrawal symptoms. Oxcarbazepine (OXC), a newer anticonvulsive drug, has a favorable safety profile over carbamazepine (CBZ) and other older AEDs due to its excellent efficacy and better side-effect profile. Methods: The efficacy and tolerability of OXC versus placebo were investigated in 50 inpatients during a 6-day treatment of alcohol withdrawal in a 4-site, double-blind, randomized, placebo-controlled pilot study. The amount of rescue medication of clomethiazole (CLO) capsules needed was chosen as the primary variable. The data were collected between May 2003 and September 2004. Results: No initial differences were found regarding sociodemographic data and alcohol-related parameters, indicating successful randomization. No differences were found in the need for rescue medication CLO, decrease of withdrawal symptoms, or craving for alcohol between the OXC and the placebo group. Subjectively experienced side effects, normalization of vegetative parameters, craving, or improvement of psychopathological parameters were not different between the groups. Conclusion: Despite the negative finding, which may be attributable to the design of the study, OXC still poses an interesting alternative to CBZ and other drugs because other studies have found it not only as efficient but also as having no addictive potential, while additionally possessing an anti-craving effect. Therefore, well-designed investigations with larger cohorts are required to further elucidate this issue.

Kosten TR. Pharmacotherapy for addictions: Partnering with contingency management. (editorial). American Journal of Drug and Alcohol Abuse 33(3): 341-342, 2007. (0 refs.)

Kotlyar M; Mendoza-Baumgart MI; Li ZZ; Pentel PR; Barnett BC; Feuer RM; Smith EA; Hatsukami DK. Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge. Tobacco Control 16(2): 138-142, 2007. (25 refs.)

Objective: To compare nicotine pharmacokinetics and subjective effects of three new smokeless tobacco potential reduced exposure products (PREPs; Ariva, Revel and Stonewall) with moist snuff (Copenhagen) and medicinal nicotine (Commit lozenge). Methods: 10 subjects completed a randomised, within-subject, crossover study. Subjects used one product for 30 min at each of the five laboratory sessions. Maximal nicotine concentration (C-max) was determined and area under the concentration time curve (AUC) was calculated for a 90-min period (during use and 60 min after use). Nicotine craving, withdrawal symptoms and ratings of product effects and liking were measured during product use. Results: Nicotine AUC and Cmax were higher for Copenhagen than for any other product (p < 0.002) and higher for Commit than for either Ariva or Revel (p < 0.001). C-max for Commit was also higher than for Stonewall (p=0.03). Craving was lowest during use of Copenhagen (p < 0.03). Craving during use of Stonewall, Ariva and Commit was lower than during use of Revel (p < 0.05). Withdrawal symptom score during use of Copenhagen was lower than during use of Revel (p=0.009). Copenhagen scores were higher (p < 0.005) than all other products in several measures of drug effects and liking (feel good effects, satisfaction, liking and desire for product, and strength of product). Conclusion: The new smokeless tobacco PREPs result in lower nicotine concentrations and equivalent or lower reductions in subjective measures compared with medicinal nicotine. Since health effects of PREPs are largely unknown, medicinal nicotine should be preferentially encouraged for smokers or smokeless tobacco users wishing to switch to lower-risk products.

Kovas AE; McFarland BH; McCarty DJ; Boverman JF; Thayer JA. Buprenorphine for acute heroin detoxification: Diffusion of research into practice. Journal of Substance Abuse Treatment 32(2): 199-206, 2007. (48 refs.)

Buprenorphinc has been approved for heroin detoxification, but little is known about its impact on everyday practice. Concerns about buprenorphine include expense, limited knowledge about its use, patient limits, and social and clinical attitudes regarding opioid treatment for heroin dependence. On the other hand, randomized clinical trials suggest that buprenorphine is superior to clonidine with regard to withdrawal symptom relief In June 2004, a community-based residential medical detoxification center switched from clonidine to buprenorphine treatment for all new and returning heroin clients. This study is a retrospective chart review of subject outcomes with clonidine (n = 100) versus buprenorphine (n = 100). Bivariate analysis suggested few cohort differences in pretreatment demographics and client characteristics. In contrast, buprenorphine was significantly associated with increased length of stay and treatment completion. The positive associations between buprenorphine and both treatment completion and length of stay persisted and were slightly enhanced after regression analysis adjusted for potential confounders. Additionally, clinical staff reported better subject engagement in treatment and psychosocial group sessions. This single-site study is an example of successful integration of an evidence-based treatment into community-based practice.

Krupitsky EM; Neznanova O; Masalov D; Burakov AM; Didenko T; Romanova T et al. Effect of memantine on cue-induced alcohol craving in recovering alcohol-dependent patients. American Journal of Psychiatry 164(3): 519-523, 2007. (16 refs.)

Objective: Ethanol blocks N-methyl-D-aspartic acid (NMDA) glutamate receptors. Increased NMDA receptor function may contribute to motivational disturbances that contribute to alcoholism. The authors assessed whether the NMDA receptor antagonist memantine reduces cue-induced alcohol craving and produces ethanol-like subjective effects. Method: Thirty-eight alcohol-dependent inpatients participated in three daylong testing sessions in a randomized order under double-blind conditions. On each test day, subjects received 20 mg of memantine, 40 mg of memantine, or placebo, and subjective responses to treatment were assessed. The level of alcohol craving was assessed before and after exposure to an alcohol cue. Results: Memantine did not stimulate alcohol craving before exposure to an alcohol cue, and it attenuated alcohol cue-induced craving in a dose-related fashion. It produced dose-related ethanol-like effects without adverse cognitive or behavioral effects. Conclusions: These data support further exploration of whether well-tolerated NMDA receptor antagonists might have a role in the treatment of alcoholism.

Krupitsky EM; Rudenko AA; Burakov AM; Slavina TY; Grinenko AA; Pittman B et al. Antiglutamatergic strategies for ethanol detoxification: Comparison with placebo and diazepam. Alcoholism: Clinical and Experimental Research 31(4): 604-611, 2007. (52 refs.)

Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-D-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. Methods: This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately. Results: All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam. Conclusions: This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal.

Kruptisky EM; Burakov AM; Tsoy MV; Egorova VY; Slavina TY; Grinenko AY et al. Overcoming opioid blockade from depot naltrexone (Prodetoxon((R))). Addiction 102(7): 1164-1165, 2007. (0 refs.)

Aim: To describe a situation in which an opioid-dependent patient overcame naltrexone blockade. Design, case report, setting Addiction treatment center in St Petersburg, Russia. Participant Patient with naltrexone implant. Intervention Detoxification. Measurements: Clinical observations. Conclusions: It is possible, but very difficult, to overcome naltrexone blockade by using large doses of heroin.

Lawrence AJ. Therapeutics for alcoholism: What's the future? Drug and Alcohol Review 26(1): 3-8, 2007. (39 refs.)

As with other addictions, human alcoholism is characterised as a chronically relapsing condition. Consequently, the therapeutic goal is the development of clinically effective, safe drugs that promote high adherence rates and prevent relapse. These products can then be used in conjunction with psychosocial approaches. In this review, preclinical studies are highlighted that indicate the mechanism of action of currently used anti-craving medications or demonstrate the potential of novel pharmacological agents for the treatment of alcohol use disorders. While current pharmacological strategies are far from ideal, there are a number of candidate molecules that may ultimately be developed into therapeutic agents. In addition, prescribing clinicians should also consider strategies such as combinations of various drugs to aid in the regulation of aberrant alcohol consumption.

Le Foll B; Goldberg SR; Sokoloff P. Dopamine D-3 receptor ligands for the treatment of tobacco dependence. Expert Opinion on Investigational Drugs 16(1): 45-57, 2007. (116 refs.)

This review considers the potential use of the dopamine D-3 receptor (DRD3) as a novel therapeutic target for the treatment of tobacco dependence. Among the 5 dopamine receptors identified, the DRD3 is located in the nucleus accumbens, ventral tegmental area and amygdala: 3 brain structures that are implicated in the motivational control of drug-seeking behaviour and drug-conditioning processes. Although it has been proposed that modulating dopamine transmission would be effective in the treatment of drug dependence, no validation has been provided in humans so far. Several highly selective DRD3 ligands have recently been evaluated in preclinical models of drug dependence. These ligands act as DRD3 antagonists in vivo and are able to decrease the motivation to take various drugs of abuse and reduce the influence of associated drug-conditioned behaviour. Of note is that these effects have been found with nicotine-seeking behaviour and nicotine relapse in rodents, suggesting a potential use of these ligands for the treatment of tobacco smokers. In contrast to nicotine replacement therapy, varenicline and bupropion (which are currently used for the treatment of smokers), DRD3 antagonists do not seem to produce nicotine-like effects in experimental animals and, therefore, may not substitute for nicotine or alleviate nicotine withdrawal symptoms in human smokers. This behavioural profile, which was also reported recently with cannabinoid CB, receptor antagonists, may result from effects on specific brain pathways that express DRD3 receptors and are involved in relapse and conditioning processes. These preclinical studies suggest that the clinical evaluation of DRD3 ligands should be performed with clinical trials designed specifically to evaluate the relapse phenomena.

Levy S; Vaughan BL; Angulo M; Knight JR. Buprenorphine replacement therapy for adolescents with opioid dependence: Early experience from a children's hospital-based outpatient treatment program. Journal of Adolescent Health 40(5): 477-482, 2007. (20 refs.)

Opioid use by adolescents is on the rise and replacement therapy is an effective treatment. Methadone replacement has been used safely and effectively with adults, but methadone programs are often unattractive to teenagers. Buprenorphine is a new replacement therapy that has been shown to be as effective as high dose methadone and may be better suited for the treatment of younger patients. We describe the experiences of several adolescent patients who received treatment from an outpatient adolescent substance abuse program that operates within a children's hospital, with an emphasis on issues of adolescent development.

LoVecchio F; Pizon A; Riley B; Sami A; D'Incognito C. Onset of symptoms after methadone overdose. American Journal of Emergency Medicine 25(1): 57-59, 2007. (4 refs.)

Background: Methadone ingestion may cause delayed coma and require naloxone infusion. Few studies exist regarding the time development of symptoms following methadone overdose in adults. Methods: After a brief training period, reviewers who were blinded to the purpose of the study completed a standardized data collection sheet. Two consecutive years of poison center patient encounters were reviewed. Age, outcomes, coingestions, vital signs, clinical manifestations, hospital admissions, and mortality were abstracted. Data were analyzed using descriptive statistics. The first reviewer was designated to extract the data. The second reviewer conducted a review of 20% of all the charts for a kappa value to be calculated. Results: In total, 44 cases of isolated methadone overdose in patients older than 18 years were identified. A mean age of 32.5 (18-58) years and a mean presumed ingestion of 106 mg of methadone was calculated. Of the 44 patients, 32 received naloxone for symptoms consistent with opiate toxicity. All symptoms occurred with in 9 hours of methadone ingestion, with a mean symptom onset of 3.2 hours. All patients had resolution of symptoms within 24 hours. No deaths were recorded. The kappa score for interreviewer reliability was 0.69, with a 95% confidence interval of 0.58 to 0.73. Limitations: This was a retrospective study that was limited by patient history. Conclusion: Acute methadone toxicity typically results in symptoms within 9 hours of ingestion.

Makris AP; Rush CR; Frederich RC; Taylor AC; Kelly TH. Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults. Experimental and Clinical Psychopharmacology 15(2): 123-133, 2007. (60 refs.)

Modafinil is indicated for the management of excessive daytime sleepiness; however, recent studies have examined a broad range of potential uses. Given that clinical uses of modafinil may be expanding, this study compared modafinil and d-amphetamine effects on subjective and performance measures. Across 11 sessions, 11 healthy adults were tested after oral doses of placebo (5 sessions), modafinil (1.75 mg/kg, 3.50 mg/kg, or 7.00 mg/kg), and d-amphetamine (0.035 mg/kg, 0.070 mg/kg, 0.140 mg/kg) under double-blind, randomized conditions. Assessments of cognitive performance and subjective effects were completed before drug administration, 30 min after drug administration, and at hourly intervals after drug administration for 5 hr. Modafinil increased ratings on the Amphetamine and Morphine Benzedrine Group scales of the Addiction Research Center Inventory (ARCI) and increased ratings on the Vigor and Total Positive scales of the Profile of Mood States. d-Amphetamine increased visual analog ratings of feeling stimulated and liking the drug and increased ratings on the Morphine Benzedrine Group scale of the ARCI. Both medications significantly reduced visual analog scale ratings of feeling sleepy, and modafinil decreased ratings on the ARCI Pentobarbital-Chlorpromazine-Alcohol Group scale. Both medications sustained performance that deteriorated across time on the Sternberg Number Recognition Test. Modafinil also enhanced performance rate on the Digit-Symbol Substitution Task above baseline levels and increased response rate on the Repeated Acquisition of Response Sequences Task. These results suggest that modafinil engenders alerting effects and increases performance in healthy non-sleep-deprived individuals comparable with that of d-amphetamine.

Mardikian PN; LaRowe SD; Hedden S; Kalivas PW; Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: A pilot study. Progress in Neuro-Psychopharmacology & Biological Psychiatry 31(2): 389-394, 2007. (30 refs.)

Recent preclinical studies implicate N-acetylcysteine (NAC), a cysteine prodrug, as a potential medication for preventing relapse to cocaine use; however, little is known about the safety and tolerability of NAC in cocaine-dependent subjects in an outpatient setting. This pilot study examines the safety and tolerability of 3 doses of NAC for the treatment of cocaine dependence. Twenty three treatment-seeking cocaine-dependent patients participated in a 4-week medication trial and received NAC at doses of 1200 mg/day, 2400 mg/day or 3600 mg/day. Results suggested that the three doses were well tolerated. Overall, the retention rates appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n = 16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine on an outpatient basis.

Markou A. Metabotropic glutamate receptor antagonists: Novel therapeutics for nicotine dependence and depression? Biological Psychiatry 61(1): 17-22, 2007. (26 refs.)

Nicotine dependence is the primary motivational factor perpetuating the tobacco smoking habit that is one of the leading preventable causes of morbidity throughout the world. This Neuroscience Perspectives article summarizes and discusses recent evidence demonstrating the critical role of glutamate transmission in nicotine dependence and emerging data suggesting that compounds acting as antagonists at metabotropic glutamate receptors may be useful therapeutics to assist people in achieving and maintaining abstinence from tobacco smoking. Metabotropic glutamate 5 receptor antagonists may be useful in decreasing the reinforcing effects of nicotine, reducing motivation for nicotine and preventing relapse during protracted abstinence, whereas metabotropic glutamate 2/3 receptor antagonists may alleviate the depression observed during the early nicotine withdrawal phase. Metabotropic glutamate 2/3 receptor antagonists may also be therapeutics for non-drug-induced depressions.

Martinotti G; Di Nicola M; Janiri L. Efficacy and safety of aripiprazole in alcohol dependence. American Journal of Drug and Alcohol Abuse 33(3): 393-401, 2007. (18 refs.)

Dopaminergic agonists and antagonists have both been examined for the treatment of substance abuse with contrasting results. To the best of our knowledge dopamine receptor partial agonists have not been investigated in alcohol use disorders. Thirteen detoxified alcohol-dependent subjects were treated with flexible doses of aripiprazole for 16 weeks. Six patients maintained an alcohol free condition for all the study period. All the subjects experienced a reduction of craving in both OCDS (p < .05) and VAS (p < .05), and a decrease of the SCL-90 General Severity Index (GSI) (p < .05). The data of this pilot clinical study, suggest a possible role for this drug in the treatment of individuals with alcohol problems.

McCambridge J; Gossop M; Beswick T; Best D; Bearn J; Rees S et al. In-patient detoxification procedures, treatment retention, and post-treatment opiate use: Comparison of lofexidine plus naloxone, lofexidine plus placebo, and methadone. Drug and Alcohol Dependence 88(1): 91-95, 2007. (36 refs.)

Objective: In-treatment and post-treatment outcomes were compared for three detoxification procedures (lofexidine+naloxone, lofexidine+placebo naloxone, and methadone). Sample and design: The sample was 137 opiate dependent in-patients. Detoxification treatments were 6-day lofexidine+naloxone (n = 45), lofexidine+placebo naloxone (n = 46), or 10-day methadone reduction (n = 46). A cohort study design was, used with double-blind random allocation to lofexidine+naloxone versus lofexidine+placebo. Patients who did not consent to, or who were excluded from randomisation received methadone. Results: Outcome differences between treatment groups at follow-up were generally associated with length of stay post-detoxification rather than detoxification procedure. Among patients who were not opiate abstinent throughout follow-up (n = 85), those who received lofexidine+naloxone detoxification reported a longer interval to first heroin use, with an interaction between detoxification medication and subsequent retention in treatment also identified. Conclusions: Detoxification medication may influence medium-term opiate use outcomes via its effect upon retention in treatment.

McCarty D; Fuller BE; Arfken C; Miller M; Nunes EV; Edmundson E et al. Direct care workers in the national drug abuse treatment clinical trials network: Characteristics, opinions, and beliefs. Psychiatric Services 58(2): 181-190, 2007. (22 refs.)

Objective: Individuals with direct care responsibilities in 348 drug abuse treatment units were surveyed to obtain a description of the workforce and to assess support for evidence-based therapies. Methods: Surveys were distributed to 112 programs participating in the National Drug Abuse Treatment Clinical Trials Network (CTN). Descriptive analyses characterized the workforce. Analyses of covariance tested the effects of job category on opinions about evidence-based practices and controlled for the effects of education, modality (outpatient or residential), race, and gender. Results: Women made up two-thirds of the CTN workforce. One-third of the workforce had a master's or doctoral degree. Responses from 1,757 counselors, 908 support staff, 522 managers-supervisors, and 511 medical staff (71% of eligible participants) suggested that the variables that most were most consistently associated with responses were job category (19 of 22 items) and education (20 of 22 items). Managers-supervisors were the most supportive of evidence-based therapies, and support staff were the least supportive. Generally, individuals with graduate degrees had more positive opinions about evidence-based therapies. Support for using medications and contingency management was modest across job categories. Conclusions: The relatively traditional beliefs of support staff could inhibit the introduction of evidence-based practices. Programs initiating changes in therapeutic approaches may benefit from including all employees in change efforts.

Meier BR; Patkar AA. Buprenorphine treatment: Factors and first-hand experiences for providers to consider. Journal of Addictive Diseases 26(1): 3-14, 2007. (40 refs.)

The viability of using buprenorphine to treat opiate dependence was well documented prior to federal approval in October 2002. What has been lacking in the literature is "hands-on" experience of providers from a clinical management and practice management perspective. This article adds to the knowledge base by providing information about buprenorphine treatment as well as anecdotes from patients treated by the authors, leading to a detailed list of factors worth considering for the treatment provider contemplating adding an opiate-addicted population to an existing treatment base.

Meinke L; Chitkara R; Krishna G. Advances in the management of chronic obstructive pulmonary disease. (review). Expert Opinion on Pharmacotherapy 8(1): 23-37, 2007. (150 refs.)

Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death, seems to be increasing in worldwide prevalence, and carries with it a significant health and economic burden. Smoking cessation is the only available intervention proven to halt disease progression. The authors discuss the role of the newly approved agent, varenicline, in promotion of smoking cessation. The remainder of presently available therapies treat the symptoms of COPD, but do not impact progression of disease. As the understanding of the pathogenesis of COPD improves, new targets for therapies are emerging. Given the large number of potential targets and the results of recent studies, it seems unlikely that a single new agent will result in a cure. Rather, management of COPD should involve a multi-pronged approach including smoking cessation, bronchodilators, treatment of infection, and eventual targeting of inflammatory pathways and genetic predispositions. In this article, the authors discuss presently available therapies as well as agents under development.

Miller DK; Lever JR; Rodvelt KR; Baskett JA; Will MJ; Kracke GR. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists. Drug and Alcohol Dependence 89(2-3): 282-291, 2007. (41 refs.)

Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced (K-i = 0.74 mu M) the binding of [H-3]DAMGO [(D-Ala(2), N-ME-Phe(4), Gly(5)-ol)-enkephalin]. In a functional assay system comprised of MOR-1 mu opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC50 = 1.1 mu M) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [H-3]overflow from rat striatal slices preloaded with [H-3]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1-0.3 mu M) that did not have intrinsic activity attenuated (similar to 50%) morphine-evoked [H-3]overflow. Overall, the results suggest that lobeline functions as a mu opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction.

Mitrouska I; Bouloukaki I; Siafakas NM. Pharmacological approaches to smoking cessation. (review). Pulmonary Pharmacology & Therapeutics 20(3): 220-232, 2007. (144 refs.)

Smoking, the most prominent nongenetic factor contributing to mortality, remains the major public health problem throughout the world. There are nearly 1.1 billion users of nicotine and tobacco products worldwide while approximately one third to half of them will die from smoking-related disease. The habit of smoking is mainly propelled by nicotine, a strongly addictive substance, to which the vast majority of smokers fall victim. Except for the general and specific support and counseling strategies there are now effective treatments for nicotine addiction. Two types of pharmacological therapies have been approved and are now licensed for smoking cessation. The first therapy consists of nicotine replacement, substituting the nicotine from cigarettes with safer nicotine formulations. The second therapy is bupropion, an antidepressant of the aminoketone class, which has been demonstrated to be effective in smoking cessation. However, although some cigarette smokers are able to quit, many are not, and standard medications to assist smoking cessation are ineffective. Several agents used for other indications (e.g. neurological diseases, depression, alcoholism) might be used to treat this subgroup. In conclusion, new more effective drugs are needed in order to fight the panepidemic of smoking globally.

Moeller FG; Schmitz JM; Steinberg JL; Green CM; Reist C; Lai LY et al. Citalopram combined with behavioral therapy reduces cocaine use: A double-blind, placebo-controlled trial. American Journal of Drug and Alcohol Abuse 33(3): 367-378, 2007. (40 refs.)

Cocaine dependence continues to be a significant problem in the United States, without any approved pharmacotherapy. Promising findings from preclinical research on the effects of cocaine on serotonin lead to examination of selective serotonin reuptake inhibitors (SSRIs) as potential treatments for cocaine dependence with mixed results, possibly due to drug interactions or specifics of concomitant behavioral therapy. The purpose of this study was to examine whether the SSRI citalopram would reduce cocaine positive urines in a 12-week, double-blind placebo-con trotted trial. Seventy-six cocaine dependent patients received either citalopram 20mg per day or placebo along with cognitive behavioral therapy (CBT) and contingency management (CM). Citalopram treated subjects showed a significant reduction in cocaine-positive urines during treatment compared to placebo treated subjects. No differences were noted in retention between the two groups.

Mooney ME; Schmitz JM; Moeller FG; Grabowski J. Safety, tolerability and efficacy of levodopa-carbidopa treatment for cocaine dependence: Two double-blind, randomized, clinical trials. Drug and Alcohol Dependence 88(2-3): 214-223, 2007. (53 refs.)

Rationale: The role of dopamine in cocaine abuse has been long recognized. Cocaine use can profoundly alter dopaminergic functioning through depletion of this monoamine and changes in receptor functioning. Based on these facts, levodopa (L-dopa) pharmacotherapy may be helpful in reducing or abolishing cocaine use. Objective: The current studies sought to evaluate the safety, tolerability and efficacy of L-dopa as a treatment for cocaine dependence. Methods: In Study 1, 67 cocaine-dependent subjects were randomized in a 5-week, double-blind, placebo-controlled safety trial. Subjects received either placebo, or 400 mg L-dopa plus 100 mg of the peripheral decarboxylase inhibitor, carbidopa, in a sustained-release preparation (Sinemet CR (R)). In Study 2, 122 cocaine-dependent subjects were enrolled in a 9-week, randomized, double-blind, placebo-controlled trial to compare placebo to 400/100 mg and 800/200 mg L-dopa/carbidopa treatments. Placebo or L-dopa were administered twice daily in both studies. Results: L-dopa was well tolerated with similar retention and medication adherence rates compared to placebo. Only two side effects occurred more often in L-dopa-treated patients: nausea and dizziness. L-dopa lowered diastolic blood pressure in a dose-dependent fashion. In these trials, L-dopa had no effect on cocaine use, cocaine craving, or mood. Conclusion: These two studies demonstrate the safety and tolerability of L-dopa pharmacotherapy in cocaine-dependent patients. No evidence for greater efficacy of L-dopa compared to placebo was observed. The possibility of enhancing treatment effects by combining L-dopa with other behavioral or pharmacological interventions is discussed.

Moore BA; Fiellin DA; Barry DT; Sullivan LE; Chawarski MC; O'Connor PG et al. Primary care office-based buprenorphine treatment: Comparison of heroin and prescription opioid dependent patients. Journal of General Internal Medicine 22(4): 527-530, 2007. (19 refs.)

BACKGROUND: Prescription opioid dependence is increasing, but treatment outcomes with office-based buprenorphine/naloxone among these patients have not been described. METHODS: We compared demographic, clinical characteristics and treatment outcomes among 200 patients evaluated for entry into a trial of primary care office-based buprenorphine/naloxone treatment stratifying on those who reported exclusive heroin use (n = 124), heroin and prescription opioid use (n = 47), or only prescription opioid use (n = 29). RESULTS: Compared to heroin-only patients, prescription-opioid-only patients were younger, had fewer years of opioid use, and less drug treatment history. They were also more likely to be white, earned more income, and were less likely to have Hepatitis C antibodies. Prescription-opioid-only patients were more likely to complete treatment (59% vs. 30%), remained in treatment longer (21.0 vs. 14.2 weeks), and had a higher percent of opioid-negative urine samples than heroin only patients (56.3% vs. 39.8%), all p values <.05. Patients who used both heroin and prescription opioids had outcomes that were intermediate between heroin only and prescription-opioid-only patients. CONCLUSIONS: Individuals dependent on prescription opioids have an improved treatment response to buprenorphine/naloxone maintenance in an office-based setting compared to those who exclusively or episodically use heroin.

Ngo HTT; Tait RJ; Arnold-Reed DE; Hulse GK. Mental health outcomes following naltrexone implant treatment for heroin-dependence. (review). Progress in Neuro-Psychopharmacology & Biological Psychiatry 31(3): 605-612, 2007. (32 refs.)

Background: Oral naltrexone is an approved treatment for opioid dependence. However, the impact of sustained release naltrexone on the mental health of treated opioid users has not been studied. Aims: To assess if naltrexone via implant treatment was associated with any change in (i) risk, (ii) rate, and (iii) duration for hospital morbidity related to several categories of mental disorders among treated heroin users. Method: A cohort of 359 heroin users treated with sustained release naltrexone via implants in Western Australia was retrospectively followed up for mental health related outcomes via a health record linkage system over an average period of 1.78 years post-treatment. Results: Individual patient's risk for hospital mental diagnoses was not altered after naltrexone implant. On a population cohort level, hospital admission rates related to all mental health problems, except mood disorders, declined significantly post-treatment; however, length of hospital stay did not improve. Overall, young, female patients or those with pre-existing mental illness were more likely than other patients to require hospital care for mental health issues following treatment. Longer period of heroin use was associated with poorer mood outcomes. Conclusions: Naltrexone implants were not associated with an increased risk for hospitalisation due to mental illness, and in most cases, were associated with a decrease in mental related hospital admission rate.

O'Malley SS; Sinha R; Grilo CM; Capone C; Farren CK; Mckee SA et al. Naltrexone and cognitive behavioral coping skills therapy for the treatment of alcohol drinking and eating disorder features in alcohol-dependent women: A randomized controlled trial. Alcoholism: Clinical and Experimental Research 31(4): 625-634, 2007. (64 refs.)

Background: Despite important gender differences in drinking patterns, physiological effects of alcohol, and co-occurring psychiatric conditions, relatively little is known about the efficacy of naltrexone for the treatment of alcohol dependence in women. This study investigated the safety and efficacy of naltrexone in combination with Cognitive Behavioral Coping Skills Therapy (CBCST) in a sample of alcohol-dependent women, some with comorbid eating pathology. Methods: One hundred three women meeting DSM-IV criteria for alcohol dependence (29 with comorbid eating disturbances) were randomized to receive either naltrexone 50 mg or placebo for 12 weeks in addition to weekly group CBCST. Subjects were enrolled between October 1995 and December 2000 at an outpatient research clinic. Results: No significant differences were observed on the primary outcomes of time to first drinking day, time to first day of heavy drinking, or the percentage of participants who continued to meet the criteria for alcohol dependence. Secondary analyses revealed that naltrexone significantly delayed the time to the second (chi(2)=5.37, p=0.02) and third (chi(2)=4.35, p=0.04) drinking days among subjects who did not maintain abstinence from alcohol. Among those with eating disturbances, symptoms of eating pathology improved during treatment, but the effects did not differ according to medication condition. Conclusions: When used in conjunction with CBCST, naltrexone did not significantly improve drinking outcomes in the overall sample of alcohol-dependent women. However, naltrexone may be of benefit to women who are unable to maintain total abstinence from alcohol. For women with concurrent eating pathology, participation in treatment for alcoholism may be associated with improvements in eating pathology.

Ooteman W; Centre MWJ; Verheul R; Schippers GM; van den Brink W. The effect of naltrexone and acamprosate on cue-induced craving, autonomic nervous system and neuroendocrine reactions to alcohol-related cues in alcoholics. European Neuropsychopharmacology 17(8): 558-566, 2007. (49 refs.)

Introduction: Acamprosate and naltrexone have been shown to be effective in relapse prevention of alcoholism. It is hypothesized that naltrexone exerts its effects primarily on cue-induced craving and neuroendocrine cue reactivity, whereas acamprosate exerts its effect primarily on autonomic nervous system reactions to alcohol-related cues. Experimental procedures: In a randomized double-blind experiment, 131 abstinent alcoholics received either acamprosate (n=56), naltrexone (n=52) or placebo (n=23) for three weeks and participated in two cue-exposure sessions: the first the day before and the second at the last day of medication. Results: Consistent with the hypotheses, naltrexone reduced craving more than acamprosate, and acamprosate reduced heart rate more than naltrexone. No medication effect was found on cueinduced cortisot. Discussion: The findings provide some evidence for differential effects of naltrexone and acamprosate: nattrexone may exert its effect, at least partly, by the reduction of cue-induced craving, whereas acamprosate may exert its effect, at least partly, by the reduction of autonomic nervous system reactions to alcohol-related cues.

Piper TM; Rudenstine S; Stancliff S; Sherman S; Nandi V; Clear A et al. Overdose prevention for injection drug users: Lessons learned from naloxone training and distribution programs in New York City. Harm Reduction Journal 4(article 3), 2007. (24 refs.)

Background: Fatal heroin overdose is a significant cause of mortality for injection drug users (IDUs). Many of these deaths are preventable because opiate overdoses can be quickly and safely reversed through the injection of Naloxone [brand name Narcan], a prescription drug used to revive persons who have overdosed on heroin or other opioids. Currently, in several cities in the United States, drug users are being trained in naloxone administration and given naloxone for immediate and successful reversals of opiate overdoses. There has been very little formal description of the challenges faced in the development and implementation of large-scale IDU naloxone administration training and distribution programs and the lessons learned during this process. Methods: During a one year period, over 1,000 participants were trained in SKOOP (Skills and Knowledge on Opiate Prevention) and received a prescription for naloxone by a medical doctor on site at a syringe exchange program (SEP) in New York City. Participants in SKOOP were over the age of 18, current participants of SEPs, and current or former drug users. We present details about program design and lessons learned during the development and implementation of SKOOP. Lessons learned described in the manuscript are collectively articulated by the evaluators and implementers of the project. Results: There were six primary challenges and lessons learned in developing, implementing, and evaluating SKOOP. These include a) political climate surrounding naloxone distribution; b) extant prescription drug laws; c) initial low levels of recruitment into the program; d) development of participant appropriate training methodology; e) challenges in the design of a suitable formal evaluation; and f) evolution of program response to naloxone. Conclusions: Other naloxone distribution programs may anticipate similar challenges to SKOOP and we identify mechanisms to address them. Strategies include being flexible in program planning and implementation, developing evaluation instruments for feasibility and simplicity, and responding to and incorporating feedback from participants.

Polesskaya OO; Smith RF; Fryxell KJ. Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats. Biological Psychiatry 61(1): 56-64, 2007. (100 refs.)

Background: Previous data in humans and animal models has suggested connections between anxiety, depression, smoking behavior, and nicotine dependence. The importance of these connections has been confirmed by clinical studies that led to the recent FDA approval of an anti-depressant (Zyban) for use in human smoking cessation programs. Other anti-depressants (such as rolipram) specifically inhibit PDE4 phosphodiesterases. Methods: We used DNA microarrays to discover gene expression changes in adolescent female rats following chronic nicotine treatments, and real-time PCR assays to confirm and extend those results.ResultsWe found a consistent decrease in the mRNA levels encoded by the Pde4b gene in nucleus accumbens, prefrontal cortex, and hippocampus of adolescent female rats treated with .24 mg/day nicotine, and in prefrontal cortex of adolescent female rats treated with .12 mg/day nicotine. We further show that each of these brain areas produced a different profile of Pde4b isoforms. Conclusions: Chronic nicotine treatments produce a dose-dependent down-regulation of Pde4b, which may have an antidepressant effect. This is the first report of a link between nicotine dependence and phosphodiesterase gene expression. Our results also add to the complex interrelationships between smoking and schizophrenia, because mutations in the PDE4B gene are associated with schizophrenia.

Poling J; Kosten TR; Sofuoglu M. Treatment outcome predictors for cocaine dependence. American Journal of Drug and Alcohol Abuse 33(2): 191-206, 2007. (80/data refs.)

Over the past decade, a large number of potential medications have been examined in clinical trials for cocaine dependence. Unfortunately, no effective pharmacotherapies for cocaine dependence have been found to date. Although effective treatments for cocaine dependence are still being investigated, a few variables have been found to significantly predict cocaine treatment response. These variables include cocaine use variables, such as days of cocaine use in the month before treatment, baseline urine cocaine results, and cocaine withdrawal symptoms. Comorbid depression and alcohol use have also been shown to be risk factors for relapse. Among personality variables, impulsivity and similar personality traits may predict treatment response. Initial promising findings with genetic polymorphism, brain activation, and stress response have also been found and need to be replicated in future studies.

Potts LA; Garwood CL. Varenicline: The newest agent for smoking cessation. American Journal of Health-System Pharmacy 64(13): 1381-1384, 2007. (15 refs.)

Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, and place in therapy of varenicline are reviewed. Summary. Varenicline is the newest therapy approved by the Food and Drug Administration for smoking cessation and the first in its class targeting the neurobiology of nicotine addiction. Varenicline is selective for the alpha 4 beta 2 acetylcholine-receptor subtype as a partial agonist, thus conferring its effect in limiting the reinforcing aspect of the addictive nicotine molecule. Varenicline is completely absorbed orally and not affected by food. Steady state. is reached within four days of administration. Three Phase III clinical trials of varenicline have been published. Two studies compared varenicline with bupropion in patients over age 18 years who smoked more than 10 cigarettes daily. When the data of the two trials were pooled, varenicline use was associated with significant improvements in the four-week carbon-monoxide-confirmed continuous quit rate (44.2% at weeks 9-12 compared with bupropion (29.7%) and placebo (17.7%) (p < 0.0001 for each comparison). The third trial found that continuous quit rates were also significantly higher in patients treated with varenicline versus placebo. Varenicline is generally well tolerated. Varenicline has been administered concurrently with warfarin, digoxin, transdermal nicotine, bupropion, cimetidine, and metformin without any clinically significant drug interactions. Conclusion. Varenicline, a newly approved agent for smoking cessation, offers a new option to patients who cannot tolerate the adverse effects associated with nicotine-replacement therapy and bupropion. It is also an alternative to consider in patients with contraindications to such therapies.

Preti A. New developments in the pharmacotherapy of cocaine abuse. (review). Addiction Biology 12(2): 133-151, 2007. (236 refs.)

Despite huge advances in the neuroscience of substance abuse and dependence in the past 20 years, no approved pharmacological treatment exists for cocaine abuse. The available drugs for the treatment of cocaine abuse are poorly effective, hence the need for new compounds to be screened and tested for efficacy: targeting symptoms might improve the effectiveness of the treatment of cocaine abuse and dependence. On the basis of the known neurochemistry of cocaine, some target compounds have been studied: among others, BP-897, a D3 partial agonist; vanoxerine, a highly selective inhibitor of dopamine uptake; aripiprazole, a partial mixed-action agonist approved for the treatment of schizophrenia. Recently modafinil, approved for the treatment of narcolepsy, proved effective in favouring cocaine abstinence in cocaine-abusing people. Some placebo-controlled studies also reported the effectiveness of topiramate, a licensed antiepileptic drug, and of tiagabine, a gamma-aminobutyric acid (GABA) re-uptake inhibitor also approved as an anticonvulsant; both compounds increased cocaine abstinence with no serious adverse events. Promising results came from two more compounds acting on the GABA circuits, baclofen and valproic acid. Finally disulfiram, prescribed with active psychosocial therapy, was found to favour higher retention rates and longer abstinence periods from both alcohol and cocaine in polydrug-abusing patients. An alternative approach rests on the use of vaccines, to date in the experimental stage still. Psychosocial treatments are a useful companion in the pharmacotherapy of cocaine abuse, with group therapy and contingency management therapies improving motivation and social functioning, particularly in patients abusing alcohol as well.

Reus VI; Obach RS; Coe JW; Faessel H; Rollema H; Watsky E et al. Varenicline: New treatment with efficacy in smoking cessation. Drugs of Today 43(2): 65-75, 2007. (42 refs.)

Smoking is a significant public health problem, and existing treatments have demonstrated only moderate efficacy in assisting smokers to quit. Varenicline, recently approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products as an aid to smoking cessation treatment, has a novel mechanism of action, targeting the specific nicotinic acetylcholine receptor (nAChR) associated with nicotine-induced behaviors (alpha 4 beta 2 nAChR). It has both agonistic and antagonistic properties that together are believed to account for reduction of craving and withdrawal as well as blocking the rewarding effects of smoking. The clinical efficacy and tolerability of varenicline has been demonstrated in phase III clinical trials involving more than 2,000 cigarette smokers. At the end of the treatment period in two 12-week, multicenter, randomized, double-blind, placebo-controlled studies, patients receiving varenicline (1 mg twice daily) experienced an increase in the odds of quitting smoking by nearly fourfold compared with those receiving placebo, and almost twofold compared with the odds for patients receiving 150 mg bupropion SR (sustained release) twice daily. In these two trials where patients were randomized to either varenicline or bupropion, the efficacy of varenicline was consistently superior at 12 weeks; this result sustained significance at 24 weeks in both studies and up to 52 weeks in one study. Nausea, a common adverse event reported in clinical trials, led to few treatment discontinuations. Its targeted mechanism of action, superior efficacy and excellent tolerability make varenicline a welcome and useful addition to the therapeutic options for smoking cessation.

Ribeiro IM; Vale PJ; Tenedorio PA; Rodrigues PA; Bilhoto MA; Pereira HC. Ocular manifestations in fetal alcohol syndrome. European Journal of Ophthalmology 17(1): 104-109, 2007. (10 refs.)

PURPOSE. To report the prevalence of ocular abnormalities in a group of Portuguese children with a complete fetal alcohol syndrome (FAS). METHODS. Complete ophthalmologic examination in a sample of consecutive children with FAS. Ocular fundus photography was carried out on the cooperative FAS children and on 25 reference Children. Ocular fundus anomalies were recorded by the observation of ocular fundus photography. The ratio between the distance of the center of the disc to the fovea and optic disc diameter (DM/DD) was determined. Small optic disc was defined as a DM/DD ratio above mean control group +1 SD. RESULTS. The authors studied 32 children with FAS (mean age: 9 5 years; 72% boys). The mean corrected visual acuity (VA) was 0.8 +/- 0.2. Refraction ranged from -23.00 to +6.50 spherical equivalent. Ocular findings included short horizontal palpebral fissure (81% of children), strabismus (28% of children), epicanthus (27% of eyes), blepharoptosis (16% of eyes), telecanthus (13% of children), nystagmus (1 child), and cataract (1 eye). Ocular fundus photography analysis showed retinal vessel tortuosity in 30% of the eyes and optic disc hypoplasia in 25%. The mean DM/DD for the control and FAS groups was 2.72 +/- 0.20 and 2.89 +/- 0.25 (p=0.001). Forty percent of the eyes of FAS children had small optic discs. CONCLUSIONS. The most common ocular findings were anomalies of retinal fundus and minor changes in the outer region of the eyes. The authors noted better VA and less severity of disease than others, which might be due to a different selection of patients, different Pattern of alcohol consumption, or genetic differences.

Rieckmann T; Daley M; Fuller BE; Thomas CP; McCarty D. Client and counselor attitudes toward the use of medications for treatment of opioid dependence. Journal of Substance Abuse Treatment 32(2): 207-215, 2007. (32 refs.)

Attitudes, perceived social nonns, and intentions were assessed for 376 counselors and 1,083 clients from outpatient, methadone, and residential drug treatment programs regarding four medications used to treat opiate dependence: methadone, louprenorphine, clonidine, and ibogaine. Attitudes, social norms, and intentions to use varied by treatment modality. Methadone clients and counselors had more positive attitudes toward the use of methadone, whereas their counterparts in residential and outpatient settings had neutral or negative assessments. Across modalities, attitudes, perceived social norms, and intentions toward the use of buprenorphine were relatively neutral. Assessments of clonidine and ibogame were negative for clients and counselors in all settings. Social normative influences were dominant across settings and medications in determining counselor and client intentions to use medications, Suggesting that perceptions about beliefs of peers may play a critical role in use of medications to treat opiate dependence.

Rohsenow DJ; Miranda R; McGeary JE; Monti PM. Family history and antisocial traits moderate naltrexone's effects on heavy drinking in alcoholics. Experimental and Clinical Psychopharmacology 15(3): 272-281, 2007. (54 refs.)

Naltrexone's (NAL) effects on alcohol consumption are generally modest, so identifying patients likely to benefit would improve treatment utility. Several studies indicate that potentially significant moderators of naltrexone's effects might include family history of alcohol problems (FH), age of onset of alcohol problems, degree of antisocial traits, and comorbid drug use. Data from 128 alcoholic patients enrolled in a 12-week naltrexone treatment study (50 mg/day) were reanalyzed to determine the role of FH, age of onset, antisocial traits, and comorbid drug use in naltrexone's treatment effects on heavy drinking days. Dichotomized FH, age of onset of alcohol problems, and comorbid cocaine or marijuana use had no interaction effect with medication. Percentage of relatives with problem drinking (family history percentage [FHP]) moderated the effects of naltrexone on drinking such that naltrexone resulted in lower drinking rates only for patients with higher FHP. Antisocial traits also moderated the effects of medication on drinking for patients compliant with >= 70% of medication. Patients with more antisocial traits had less heavy drinking on naltrexone than on placebo, whereas patients low on antisocial traits had no benefit from naltrexone. Covarying antisociality in regressions of drinking outcome on FHP showed that the effects of FHP were not attributable to antisociality. Thus,