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Director's Report to the National Advisory Council on Drug Abuse - September, 2004

Research Findings - Research on Pharmacotherapies for Drug Abuse

Benzodiazepine Attenuates the Behavioral Effects of d-Amphetamine in Humans

The results of preclinical studies suggest that gamma-aminobutyric acidA (GABAA) receptor agonists attenuate the behavioral effects of stimulants. In this study, the investigators from College of Medicine, University of Kentucky trained 6 humans to discriminate 15-mg oral d-amphetamine. After acquiring the discrimination, the effects of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and following pretreatment with alprazolam (0 and 0.5 mg), were assessed. d-Amphetamine alone produced stimulant-like self-reported drug effects in a dose-dependent fashion. Alprazolam alone did not occasion d-amphetamine-like discriminative effects, nor did it increase ratings of sedation or impair performance, but Alprazolam pretreatment significantly attenuated the discriminative stimulus effects of d-amphetamine and some of the self-reported drug effects. This study conforms that GABA-A agonists reduce some subjective effects of psychostimulants in humans. Rush, C.R., Stoops, W.W., Wagner, F.P., Hays, L.R. and Glaser, P.E. Alprazolam Attenuates the Behavioral Effects of d-Amphetamine in Humans. Journal of Clinical Psychopharmacology, 24(4), pp. 410-420, 2004.

GABA Agonist Decreases Subjective Effects of Cocaine

Animal research indicates that GABA agonists decrease cocaine self-administration, but their effectiveness to do so in humans has not been investigated in the laboratory. The investigators from the College of Physicians and Surgeons of Columbia University evaluated the effects of gabapentin, a GABA agonist, on cocaine-related behaviors in humans under laboratory conditions. During a 48-day double-blind, crossover design study, the effects of gabapentin maintenance on response to cocaine were investigated in seven cocaine abusers. Cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings, blood pressure and heart rate. Gabapentin did not reduce cocaine choice or cardiovascular measures, but it decreased some subjective effects of cocaine (e.g., "Good Drug Effect" and "Anxious"). The data suggest a potential of gabapentin in treating cocaine dependence. Hart, C.L., Ward, A.S., Collins, E.D., Haney, M. and Foltin, R.W. Gabapentin Maintenance Decreases Smoked Cocaine-related Subjective Effects, but not Self-administration by Humans. Drug and Alcohol Dependence, 73(3), pp. 279-287, 2004.

Intranasal Cocaine Produces Acute Tolerance in Humans

Although recent research has focused on "crack" cocaine, the majority of the cocaine users in the United States snort cocaine rather than smoke it. Acute tolerance to smoked or intravenous cocaine is known to develop, but it was not known whether this is also the case with cocaine snorting. The investigators from the Department of Psychiatry, College of Physicians and Surgeons of Columbia University examined the dose-dependent effects of repeated intranasal cocaine in humans. Ten male cocaine users were admitted to the hospital on two separate occasions for four days each, with a minimal two-week interval between admissions. During each admission, an intranasal cocaine dose-response curve was determined during four laboratory sessions: Two administrations of the same cocaine dose occurred each session at 40-min intervals. Intranasal cocaine produced dose-related increases in ratings of "positive" drug effects, heart rate, and blood pressure. Plasma cocaine levels peaked following the second cocaine snorting of each session, while metabolite levels increased during each session. Although the plasma cocaine level approximately doubled following the second cocaine administration, the ratings of positive drug effects, heart rate, and blood pressure did not increase. The data demonstrate that, as observed with smoked and intravenous cocaine, acute tolerance develops also during repeated intranasal cocaine administration. Foltin, R.W. and Haney, M. Intranasal Cocaine in Humans: Acute Tolerance, Cardiovascular and Subjective Effects. Pharmacology Biochemistry and Behavior, 78(1), pp. 93-101, 2004.

Lack of a Relationship Between D2 Receptor Availability and Cocaine-Taking Behavior

Some brain imaging and animal studies suggested that low availability of striate dopamine D2 receptors may promote cocaine addiction. The investigators from the Department of Psychiatry, College of Physicians and Surgeons of Columbia University assessed D2 receptor availability with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensory-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. The relationship between D2 receptor availability and behavioral measures obtained during cocaine self-administration sessions was also examined in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects, but no relationship was found between D2 availability and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine. This study confirmed a decrease in striatal D2 receptor availability in CCD subjects, but failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Martinez, D., Broft, A., Foltin, R,W., Slifstein, M., Hwang, D.R., Huang, Y., Perez, A., Frankel, W.G., Cooper, T., Kleber, H.D., Fischman, M.W. and Laruelle, M. Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior. Neuropsychopharmacology, 29(6), pp. 1190-1202, 2004.

Predictors of Treatment Contact Among Individuals with Cannabis Dependence

Epidemiological studies have repeatedly shown that cannabis is the most commonly used illegal drug in the United States. Furthermore, individuals with cannabis dependence have high rates of comorbid substance use disorders and depression. A significant proportion of individuals with addictive disorders develop withdrawal symptoms, cannot control their drug use despite substantial adverse psychosocial consequences, and frequently have a coexisting psychiatric disorder. Nevertheless, only a minority of persons with cannabis dependence ever seek treatment. The main findings of this study were that persons with cannabis dependence were more likely to contact a professional during the past year if they previously sought treatment and had alcohol dependence with major depression. Agosti, V. and Levin, F.R. Predictors of Treatment Contact Among Individuals with Cannabis Dependence. Am. J. Drug Alcohol Abuse, 30, pp. 121-127, 2004.

Nicotine Withdrawal and Depressive Symptomatology During Short-term Smoking Abstinence: A Comparison of Postmenopausal Women Using and Not Using Hormone Replacement Therapy

This study investigated whether taking medications for transdermal hormone replacement therapy (HRT) influenced smoking-cessation variables in postmenopausal women undergoing short-term abstinence from cigarettes. Women were recruited into two groups according to their pre-enrollment medication status--those currently on HRT (n = 17) or those not on HRT (n = 13). The HRT group had their previous medication replaced with a standard 0.1 mg estradiol transdermal system and 2.5 mg of Cycrin daily. After 2 weeks of medication adjustment, participants continued smoking as usual for 1 week, at which time baseline measurements were taken. Participants were then instructed to quit smoking for the remaining 2 weeks. They were provided with smoking-cessation counseling and monitored for abstinence. Data were collected during five clinic visits on all dependent measures: Minnesota Nicotine Withdrawal Scale, Beck Depression Inventory (BDI) scale, Profile of Mood States, Motor Speed Tasks, and Reaction Time Test. Contrary to our hypothesis, the exogenous hormone use did not have a differential effect on most of the dependent variables during the first 2 weeks of smoking abstinence. One exception was depressive symptomatology: the BDI change scores (week 2 - baseline) differed significantly for the HRT and non-HRT groups (p = .045), with women in the HRT group experiencing an increase in depressive symptomatology. This finding, though preliminary, may have clinical implications for postmenopausal women who attempt to quit smoking while on HRT, particularly since depressed mood following abstinence is associated with a relapse to smoking. Allen, S.S., Hatsukami, D.K. and Christianson, D. Nicotine Withdrawal and Depressive Symptomatology During Short-term Smoking Abstinence: A Comparison of Postmenopausal Women Using and Not Using Hormone Replacement Therapy. Nicotine. Tob. Res., 5, pp. 49-59, 2003.

The Evidence-based Pharmacological Treatment of Social Anxiety Disorder

Social anxiety disorder (SAD) is a highly prevalent and often disabling disorder. This paper reviews the pharmacological treatment of SAD based on published placebo-controlled studies and published meta-analyses. It addresses three specific questions: What is the first-line treatment of SAD? How long should treatment last? What should be the management of treatment-resistant cases? Based on their efficacy for SAD and common comorbid disorders, tolerability, and safety, SSRIs should be considered as the first-line treatment for most patients. Less information is available regarding the optimal length of treatment, although individuals who discontinue treatment after 12-20 wk appear more likely to relapse than those who continue on medication. Even less empirical evidence is available to support strategies for treatment-resistant cases. Clinical experience suggests that SSRI non-responders may benefit from augmentation with benzodiazepines or gabapentin, or from switching to MAOIs, RIMAs, benzodiazepines or gabapentin. Cognitive-behavioral therapy may also be a helpful adjunct or alternative. Blanco, C., Raza, M.S., Schneier, F.R. and Liebowitz, M.R. The Evidence-based Pharmacological Treatment of Social Anxiety Disorder. Int. J. Neuropsychopharmacol., 6, p. 427-442, 2003.

Pharmacological Treatment of Social Anxiety Disorder: A Meta-Analysis

Placebo-controlled trials have evaluated the efficacy of several medications in the treatment of social anxiety disorder but information regarding their relative efficacy is lacking. We compared the efficacy of medications systematically studied for the treatment of social anxiety disorder using meta-analytic techniques. The methodology included a database search of articles published between January 1980 and June 2001 and manual searches of bibliographies in published manuscripts. Trials were included if they reported outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical measure of responder status. Data were extracted independently by two authors. The Q statistic was used to assess homogeneity across trials. All analyses were conducted using intent-to-treat data. There was substantial heterogeneity across trials. The medications with largest effect sizes were phenelzine [effect size, 1.02; 95% Confidence Interval (CI), 0.52-1.52], clonazepam (effect size, 0.97; 95% CI, 0.49-1.45), gabapentin (effect size, 0.78; 95% CI, 0.29-1.27), brofaromine (effect size, 0.66; 95% CI, 0.38-0.94), and the selective serotonin reuptake inhibitors (SSRIs; effect size, 0.65; 95% CI, 0.50-0.81). There were no statistically significant differences between medications or medication groups. However, formal methods of interim monitoring adapted for meta-analyses suggested strongest evidence of efficacy for SSRIs and brofaromine. Several medications are efficacious for the treatment of social anxiety disorder. The stability of the SSRI effect size estimate in conjunction with other evidence for safety and tolerability and their ability to treat comorbid conditions supports the use of SSRIs as the first-line treatment. Direct comparisons of SSRIs vs. other promising medications deserve consideration. Blanco, C., Schneier, F.R., Schmidt, A., Blanco-Jerez, C.R., Marshall, R.D., Sanchez-Lacay, A. et al. Pharmacological Treatment of Social Anxiety Disorder: A Meta-Analysis. Depress. Anxiety,18, pp. 29-40, 2003.

Tobacco Specific Nitrosamines and Potential Reduced Exposure Products for Smokers: A Preliminary Evaluation of Advance(TM)

The purpose of this study was to develop a method for evaluating the carcinogen delivery of potential reduced exposure products (PREPs) like Advance(TM), a PREP marketed to reduce smokers' exposure to one tobacco specific nitrosamine (TSN), NNK, a potent lung carcinogen. Design, setting, and participants: Latin square ordered, three condition, outpatient, crossover design with 12 smokers of light or ultra-light cigarettes (15 or more cigarettes/day). In each five-day condition, participants either smoked own brand, Advance(TM), or no cigarettes. Also, on the first and last day of each condition, participants smoked one cigarette in the laboratory. Past experience with PREPs that failed to reduce smoking's harm demonstrates the need for clinical methods in PREP evaluation. This study shows how assessing PREP induced changes in withdrawal and exposure to carbon monoxide, nicotine, and carcinogens may help predict PREP harm reduction potential. Adequate withdrawal suppression, slightly lower concentrations of carbon monoxide, and reduction of one TSN biomarker were observed for Advance(TM). In the future, clinical methods like those described here may be valuable for evaluating PREPs before they are marketed publicly. Breland, A.B., Acosta, M.C. and Eissenberg, T. Tobacco Specific Nitrosamines and Potential Reduced Exposure Products for Smokers: A Preliminary Evaluation of Advance(TM). Tob. Control, 12, pp. 317-321, 2003.

Modafinil and Cocaine: A Double-blind, Placebo-controlled Drug Interaction Study

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. Cocaine withdrawal symptoms are associated with poor clinical outcome and are likely to be reversed by modafinil. In addition, the neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. Our results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Furthermore, pretreatment with modafinil did not intensify cocaine euphoria or cocaine-induced craving. In fact, cocaine euphoria was significantly blunted (P=0.02) in one of our subjective measures. Dackis, C.A., Lynch, K.G., Yu, E., Samaha, F.F., Kampman, K.M., Cornish, J.W. et al. Modafinil and Cocaine: A Double-blind, Placebo-controlled Drug Interaction Study. Drug Alcohol Depend., 70, pp. 29-37, 2003.

Response to Alcohol in Females with a Paternal History of Alcoholism

Several studies have demonstrated that males with a family history of alcoholism (FHP) show less of a response to alcohol (e.g. lower ratings of intoxication) than males without a family history of alcoholism (FHN). The purpose of this pilot study was to determine if FHP females also showed a reduced sensitivity to alcohol compared to FHN females. The effects of placebo and alcohol (0.25, 0.50, 0.75 g/kg, based on total body water) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect and subjective ratings of drug effect. There were no differences in breath alcohol levels between FHN and FHP women. FHP women were less impaired by alcohol than FHN women, as shown by DSST scores and observer-ratings. However, FHP women were more impaired on the Digit Recall task after alcohol than FHN women and they tended to have higher ratings of "Good Drug Effect," "Drug Liking" and "Willingness to Take Again." Of note, FHP women reported more dysphoric mood than FHN women in the absence of alcohol administration. The results of the study suggest that FHP women may have a reduced response to alcohol on some measures, but FHP women report greater positive effects on other measures. Overall, the differences between FHP and FHN women are subtle compared to the previous studies demonstrating a reduced response to alcohol in FHP men. Evans, S.M. and Levin, F.R. Response to Alcohol in Females with a Paternal History of Alcoholism. Psychopharmacology (Berl), 169, pp. 10-20, 2003.

Differential Response to Alcohol in Light and Moderate Female Social Drinkers

Individuals who are moderate drinkers are at increased risk to abuse alcohol. Moreover, women are more vulnerable than men to the adverse consequences of alcohol consumption and recent data indicate that the drinking pattern in women is becoming more similar to that of men. However, few studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of alcohol, compared to female light drinkers (LD). Fifteen female MD who consumed an average of 34.7 drinks/month were compared to 15 female LD who consumed an average of 6.7 drinks/month. None of the participants had a first-degree family history of alcoholism or substance abuse. The acute effects of alcohol (0, 0.25, 0.50, 0.75 mg/kg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using a full range of performance measures, subjective-effects questionnaires and observer ratings. Alcohol impaired performance in a dose-related manner on all performance tasks for both groups of females. However, MD was less impaired than LD on balance and Digit Symbol Substitution Test (DSST). This reduced response was also evident from the observer ratings, with MD being viewed as less impaired by alcohol than LD. While ratings of Drug Liking increased in both groups of women on the ascending limb of the breath alcohol curve, alcohol was disliked by LD on the descending limb and LD reported increased ratings of Bad Drug Effects following the high dose of alcohol. The reduced performance impairment, coupled with the positive subjective effects and relative absence of adverse subjective effects, suggestive of behavioral tolerance, could result in a progression towards increased alcohol consumption among moderate female social drinkers. Evans, S.M. and Levin, F.R. Differential Response to Alcohol in Light and Moderate Female Social Drinkers. Behav. Pharmacol., 15, pp. 167-181, 2004.

The Problem of the Placebo Response in Clinical Trials for Psychiatric Disorders: Culprits, Possible Remedies, and a Novel Study Design Approach

The placebo response is a major issue in clinical trials for psychiatric disorders. Possible contributing factors to this problem include diagnostic misclassification, issues concerning inclusion/exclusion criteria, outcome measures' lack of sensitivity to change, measurement errors, poor quality of data entry and verification, waxing and waning of the natural course of illness, regression toward the mean phenomenon, patient and clinician expectations about the trial, study design issues, non-specific therapeutic effects, and high attrition. Over the past few decades, researchers have attempted to reduce the placebo effect in a variety of ways. Unfortunately, approaches with very little or no benefit have included restricting enrollment to selected populations, rater training, requirement of same rater, and placebo lead-in phases. Some benefits, although often marginal, have been derived from standardizing diagnostic procedures, managing clinicians' overestimation of change, simplification of study visits and assessments, minimizing non-specific, therapeutic effects, extending trial duration, reducing number of sites, increasing the sensitivity of outcome measures, and reducing the number of treatment arms. Thus far, there has been no attempt to develop new study designs aimed at reducing the placebo effect. We are proposing a novel study design, called 'Sequential Parallel Comparison Design', suitable for double-blind, placebo-controlled trials in psychiatric disorders. This design is aimed at reducing both the overall placebo response rate and the sample size required for such trials. Its usefulness in clinical research needs to be tested empirically. If this study design were to be found to meet its stated goals, this could markedly facilitate the process of clinical development of new compounds for the treatment of psychiatric disorders. Fava, M., Evins, A.E., Dorer, D.J. and Schoenfeld, D.A. The Problem of the Placebo Response in Clinical Trials for Psychiatric Disorders: Culprits, Possible Remedies, and a Novel Study Design Approach. Psychother. Psychosom., 72, pp. 115-127, 2003.

Selection of a Substance Use Disorder Diagnostic Instrument by the National Drug Abuse Treatment Clinical Trials Network

Several instruments for diagnosing substance use disorders (SUD) have been developed, but to date none has emerged as the standard for community-based clinical studies. To select the most suitable SUD diagnostic instrument for its clinical trials, the National Drug Abuse Treatment Clinical Trials Network (CTN) implemented a procedure in which 36 university-based addiction researchers and 62 community-based addiction treatment providers evaluated and ranked five widely recognized diagnostic instruments: (1) the SUD section of the Structured Clinical Interview for DSM-IV (SCID); (2) the SUD section of the Composite International Diagnostic Interview, 2nd ed. (CIDI-2); (3) the SUD section of the Diagnostic Interview Schedule for DSM-IV Diagnosis (DIS-IV); (4) the Diagnostic Statistical Manual-IV Checklist (DSM-IV Checklist); and (5) the Substance Dependence Severity Scale (SDSS). To assist the evaluation and ranking process, key characteristics of each instrument were presented in tabular and narrative formats. Participants ranked each instrument from 1 (most preferred) to 5 (least preferred). The SCID received the best overall mean score (2.24) followed by the CIDI-2 (2.59), DIS (2.94), DSM Checklist (3.40) and the SDSS (3.83). After discussing the pragmatic and scientific advantages and disadvantages of each instrument, the CTN Steering Committee selected the CIDI-2. The selection of the CIDI-2 standardizes the collection of diagnostic data and provides a common diagnostic tool for practitioners and clinical researchers in the CTN. Implications for practice/research collaboration and initiatives are explored. Forman, R.F., Svikis, D., Montoya, I.D. and Blaine, J. Selection of a Substance Use Disorder Diagnostic Instrument by the National Drug Abuse Treatment Clinical Trials Network. J. Subst. Abuse Treat., 27, pp. 1-8, 2004.

Comorbid Major Depressive Disorder as a Prognostic Factor in Cocaine-Abusing Buprenorphine-Maintained Patients Treated with Desipramine and Contingency Management

Depression is common among patients who abuse both opiates and cocaine, and its treatment has had mixed success. This study compares buprenorphine-maintained patients with lifetime major depressive disorder (MDD, N = 53) with those never depressed (ND, N = 96) on cocaine and opiate-free urines during a 12-week outpatient double-blind, placebo-controlled, randomized clinical trial. The 149 subjects were assigned to four groups: 1) desipramine (DMI) + contingency management (CM); 2) DMI + noncontingency management (NCM); 3) placebo + CM; and 4) placebo + NCM. Depression assessments included Hamilton Depression Rating Scale, Center for Epidemiological Studies Depression Inventory, and Structured Clinical Interview for DSM-IV interview for diagnosis of lifetime MDD. Urine toxicologies were performed thrice weekly and the CES-D was performed monthly. The MDD group had a larger proportion of females (45% vs. 21%, P = 0.02) and was more likely to be married (13.2% vs. 7.3%, P = 0.02) than the ND group. Treatment retention did not vary by depression status. Hierarchical Linear Modeling found that depressive symptoms decreased comparably across the four treatment groups. Although participation in CM improved drug-free urines more for patients with MDD than for the ND group (Z = 2.44, P = 0.01), treatment with DMI was significantly more efficacious for the ND group than for the MDD group (Z = -2.89, P = 0.003). These results suggest that patients with MDD may respond better to behavioral treatments such as CM than to desipramine plus buprenorphine. The ND cocaine-abusing, opiate-dependent patients may be more responsive to the anti-craving effects of DMI. Gonzalez, G., Feingold, A., Oliveto, A., Gonsai, K. and Kosten, T.R. Comorbid Major Depressive Disorder as a Prognostic Factor in Cocaine-abusing Buprenorphine-maintained Patients Treated with Desipramine and Contingency Management. Am. J. Drug Alcohol Abuse, 29, pp. 497-514, 2003.

Tiagabine Increases Cocaine-free Urines in Cocaine-dependent Methadone-treated Patients: Results of a Randomized Pilot Study

The investigators sought to evaluate the safety and efficacy of the GABAergic agent tiagabine in reducing cocaine use among methadone-treated patients. The participants were 45 cocaine-dependent methadone-treated patients who were predominately Caucasian (75.6%), male (77.8%) and never married (53%) with an average age of 38 years (SD = 6.5). Comparison groups received tiagabine 12 mg/day (n = 15), tiagabine 24 mg/day (n = 15) or placebo (n = 15). Treatment retention was over 80% for all treatment groups. The sample mean (+/- SE) of cocaine-free urines for the first week after study entry and before tiagabine was started was 1.16 (0.19) urines/week. During weeks 9 and 10 cocaine-free urines increased significantly from baseline by 33% with high-dose tiagabine (24 mg/day), by 14% with low-dose tiagabine (12 mg/day) and decreased by 10% with placebo (hierarchical linear model, Z= 2.03; P < 0.05). Self-reported cocaine use also decreased significantly more with active medications than with placebo. Tiagabine at 24 mg/day was well tolerated among these methadone-treated patients with only one reporting headache. Tiagabine appears to be a promising GABAergic medication that moderately improves cocaine-free urines. Gonzalez, G., Sevarino, K., Sofuoglu, M., Poling, J., Oliveto, A., Gonsai, K. et al. Tiagabine Increases Cocaine-free Urines in Cocaine-dependent Methadone-treated Patients: Results of a Randomized Pilot Study. Addiction, 98, pp. 1625-1632, 2003.

Paroxetine Treatment of Pathological Gambling: A Multi-center Randomized Controlled Trial

Previous studies have suggested the efficacy of serotonergic agents in the treatment of pathological gambling. The aim of the present study was to determine whether treatment with paroxetine in a large sample of subjects with pathological gambling would effectively diminish the severity of gambling symptoms. A 16-week, double-blind, placebo-controlled trial was conducted at five outpatient academic research centers in two countries (USA and Spain). Seventy-six outpatients (mean age 45.4+/-10.6 years; 30 women, 46 men) with pathological gambling were randomized to acute treatment with paroxetine in flexible daily dosages of 10-60 mg/day (n=36) or placebo (n=40). The primary outcome measure was the Clinical Global Impressions scale. Both the paroxetine- and the placebo-treated groups demonstrated comparable improvement at 16 weeks (59% response rate in the paroxetine group, 49% rate in the placebo group; chi squared=0.737; d.f.=1; P=0.390). Paroxetine consistently resulted in a greater percentage of responders at each study visit compared to placebo but failed to demonstrate statistical superiority to placebo on scores on the Clinical Global Impressions scale, the Yale-Brown Obsessive-Compulsive Scale Modified for Pathological Gambling, or the Gambling Symptom Assessment Scale. High rates of symptom improvement were observed in pathological gamblers receiving either paroxetine or placebo after 16 weeks. Paroxetine consistently demonstrated an advantage over placebo on the Clinical Global Impressions scale; however, a larger sample size may have registered significant differences. Grant, J.E., Kim, S.W., Potenza, M.N., Blanco, C., Ibanez, A., Stevens, L. et al. Paroxetine Treatment of Pathological Gambling: A Multi-center Randomized Controlled Trial. Int. Clin. Psychopharmacol., 18, pp. 243-249, 2003.

Effects of Buprenorphine Maintenance Dose on Mu-opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-dependent Volunteers

The clinical effectiveness of opioid maintenance for heroin dependence is believed to result from a medication's ability to decrease mu-opioid receptor (muOR) availability thereby replacing agonist effects, alleviating withdrawal symptoms and attenuating heroin effects. Authors empirically tested this hypothesis in five heroin-dependent volunteers who were successively maintained on 32, 16, 2, and 0 mg daily buprenorphine (BUP) tablet doses. Authors predicted and confirmed that higher BUP doses would decrease in vivo muOR availability (measured with PET and [(11)C]carfentanil), increase plasma levels of BUP and its metabolite nor-BUP, and decrease withdrawal symptoms and hydromorphone (HYD) responses. Relative to placebo, BUP significantly decreased mean (+/-SEM) whole-brain muOR availability 41+/-8, 80+/-2, and 84+/-2% at 2, 16, and 32 mg, respectively. Regions of interest (ROIs) (prefrontal cortex, anterior cingulate, thalamus, amygdala, nucleus accumbens, caudate) showed similar dose-dependent effects. Changes in muOR availability varied across ROIs (prefrontal cortex, 47% vs. amygdala, 27%) at BUP 2 mg, but were more homogeneous across ROIs at BUP 32 mg (94-98%; except thalamus, 88%). Relative to placebo (0 ng/ml), peak plasma levels of BUP and nor-BUP were comparable and dose-dependent (0.5-1, 5-6, and 13-14 ng/ml at 2, 16, and 32 mg, respectively). muOR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms and attenuation of HYD symptoms. These findings suggest that high-dose BUP maintenance produces near-maximal muOR occupation, muOR availability correlates well with plasma levels, and BUP-related opioid symptoms and antagonist blockade exhibit concentration-effect relationships. Greenwald, M.K., Johanson, C.E., Moody, D.E., Woods, J.H., Kilbourn, M.R., Koeppe, R.A. et al. Effects of Buprenorphine Maintenance Dose on Mu-opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-dependent Volunteers. Neuropsychopharmacology, 28, pp. 2000-2009, 2003.

Transferring Methadone-maintained Outpatients to the Buprenorphine Sublingual Tablet: A Preliminary Study

There is no accepted algorithm to transfer opioid-dependent patients from methadone (METH) to its new alternative, buprenorphine (BUP). Five outpatients transferred (double blind, double dummy) from METH 60 mg/day (with one day at 45 mg) to BUP 8 mg s.l. tablet. Relative to METH maintenance, BUP decreased opioid agonist symptoms (transfer day 1) and increased withdrawal symptoms (days 1 and 2) and blood pressure (day 2). Self-reported heroin use did not increase from METH maintenance levels. It may be feasible to transfer outpatients on METH 60 mg/day to BUP 8 mg/day s.l. tablet, although this pilot protocol needs refinements to improve tolerability and clinical efficacy. Greenwald, M.K., Schuh, K.J. and Stine, S.M. Transferring Methadone-maintained Outpatients to the Buprenorphine Sublingual Tablet: A Preliminary Study. Am. J. Addict., 12, pp. 365-374, 2003.

Treatment of Adolescent Smokers with the Nicotine Patch

This study examined the effects of the nicotine patch on craving and withdrawal symptoms, safety, and compliance among adolescents. The secondary goal was to conduct a preliminary investigation of the effectiveness of the nicotine patch in helping adolescents quit smoking. The study design was a double-blind, placebo-controlled, randomized trial of the nicotine patch. The intervention also provided intensive cognitive-behavioral therapy and a contingency-management procedure. Participants (n=100) attended 10 treatment visits over 13 weeks. Compared with the placebo patch group, the active nicotine patch group experienced a significantly lower craving score and overall withdrawal symptom score (p=.011 and p=.025, respectively), as well as a time trend toward lower scores (p<.001) in craving only. Moreover, the nicotine patch appeared safe for adolescents to use. No differences by treatment group were found in experiencing adverse events, except that the participants in the placebo patch group reported more headaches than those in the active nicotine patch group. As another measure of safety, the overall mean salivary cotinine levels were significantly lower at 1, 6, 8, and 10 weeks post quit (all p<.05) compared with baseline levels, although these results were confounded by dropouts. Additionally, a significant number of participants were compliant with using the nicotine patch daily. Finally, point prevalence (7-day and 30-day abstinence rates) and survival analysis of participant abstinence indicated no significant differences between treatment groups. The results of this study suggest that the nicotine patch is a promising medication and a larger clinical trial of the nicotine patch among adolescents is warranted. Hanson, K., Allen, S., Jensen, S. and Hatsukami, D. Treatment of Adolescent Smokers with the Nicotine Patch. Nicotine. Tob. Res., 5, pp. 515-526, 2003.

Genetics of Pathological Gambling

Pathological gambling (PG) is an impulse control disorder and a model 'behavioral' addiction. Familial factors have been observed in clinical studies of pathological gamblers, and twin studies have demonstrated a genetic influence contributing to the development of PG. Serotonergic, noradrenergic, and dopaminergic dysfunction have been reported as biological factors contributing to the pathophysiology of PG. Molecular genetic techniques have been used to investigate the role of genetic factors in PG. Molecular genetic research has identified specific allele variants of candidate genes corresponding to these neurotransmitter systems to be associated with PG. Associations have been reported between pathological gamblers and allele variants of polymorphisms at dopamine receptor genes, the serotonin transporter gene, and the monoamine-oxidase A gene. Although preliminary data suggest that some of these differences are gender-specific, more research needs to be performed to substantiate gender-specific genetic contributions to the development of pathological gambling. The review of the current findings on genetics of PG suggests that liability to PG is in part mediated by genetic factors. Additional studies are needed to replicate and extend these findings, as well as to better understand the influence of specific allelic variants to differences in biological and behavioral functioning. Ibanez, A., Blanco, C., de Castro, I.P., Fernandez-Piqueras, J. and Saiz-Ruiz, J. Genetics of Pathological Gambling. J. Gambl. Stud., 19, pp. 11-22, 2003.

Gender Differences in Pathological Gambling

Sixty-nine consecutive individuals with DSM-IV pathological gambling (47 men and 22 women) applying to a specialized outpatient treatment program were evaluated with structured interviews, self-report questionnaires, and psychological scales. Sixty-seven percent of men (N = 26) versus 25% of women (N = 5) had been exposed to gambling in adolescence. Women had a later age at first bet and a faster evolution of the disorder. Female pathological gamblers were more likely to play bingo, whereas men tended to prefer slot machines. Male and female pathological gamblers had similar gambling severity and overall rates of psychiatric comorbidity. However, male pathological gamblers had higher rates of alcohol abuse/dependence and antisocial personality disorder, whereas women had higher rates of affective disorders and history of physical abuse. There are substantial gender differences in the clinical presentation and comorbidity of pathological gambling. These gender differences should be incorporated in the selection and planning of treatment for pathological gamblers. Ibanez, A., Blanco, C., Moreryra, P. and Saiz-Ruiz, J. Gender Differences in Pathological Gambling. J. Clin. Psychiatry, 64, pp. 295-301, 2003.

Desipramine and Contingency Management for Cocaine and Opiate Dependence in Buprenorphine Maintained Patients

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, authors recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications authors designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self-reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement. Kosten, T., Oliveto, A., Feingold, A., Poling, J., Sevarino, K., McCance-Katz, E. et al. Desipramine and Contingency Management for Cocaine and Opiate Dependence in Buprenorphine Maintained Patients. Drug Alcohol Depend., 70, pp. 315-325, 2003.

Pharmacotherapy for Marijuana Dependence: A Double-blind, Placebo-con trolled Pilot Study of Divalproex Sodium

There is a noticeable lack of targeted treatment options for marijuana dependence, in particular pharmacologic approaches. This is the first study evaluating a targeted pharmacologic approach for marijuana dependence. The goals of the study were to determine if such patients would seek pharmacologic treatment, whether these patients could be retained in treatment using a design previously developed for cocaine-dependent patients, and especially whether divalproex sodium showed promise as a treatment agent for marijuana dependence. We found that marijuana-dependent patients will seek treatment, and such patients can be adequately maintained in a pharmacologic trial. Regardless of treatment group, patients reported a significant reduction in their frequency and amount of marijuana use as well as a reduction in irritability. Given the lack of proven effective treatments for marijuana dependence, pharmacotherapies should be sought. The design of a preliminary clinical trial should include a psychosocial/behavioral intervention emphasizing motivation and medication compliance and a placebo control group. Levin, F.R., McDowell, D., Evans, S.M., Nunes, E., Akerele, E., Donovan, S. et al. Pharmacotherapy for Marijuana Dependence: A Double-blind, Placebo-controlled Pilot Study of Divalproex Sodium. Am. J. Addict., 13, pp. 21-32, 2004.

Gender and Smoking Status-based Analysis of Views Regarding Water Pipe and Cigarette Smoking in Aleppo, Syria

Narghile (water pipe) smoking is increasing across the Eastern Mediterranean region (EMR), though little is known about the social attitudes and perceptions related to this method of tobacco use, and how those attitudes and perceptions are influenced by gender. Data from two cross-sectional surveys conducted in 2003 in Aleppo, Syria, were used to examine these issues. Overall, 855 participants were included (439 men, 416 women; mean age, 24.4+/-7.1 years; response rate, 97%). The current analysis focuses on responses to four similar nine-item questions tapping perceptions related to narghile smoking by women or men, and cigarette smoking by women or men. Scores on the nine items were summed to yield a total score to gauge participants' perceptions about narghile and cigarette. Generally, participants were less positive about women smoking relative to men smoking, and cigarette smoking relative to narghile smoking. Cigarette smoking by women was the behavior least associated with positive perceptions. Individuals who resided in the city, were economically better off, and were Christian, had higher perception scores (i.e., more positive attitudes) toward all forms of smoking, whereas older and married participants had higher perception scores for narghile only. Smoking status of participants, especially narghile smoking, was also associated with more positive perceptions toward smoking in general. We conclude that preliminary analysis shows that views on different forms of smoking in Syria differ by gender and smoking status. Maziak, W., Rastam, S., Eissenberg, T., Asfar, T., Hammal, F., Bachir, M.E. et al. Gender and Smoking Status-based Analysis of Views Regarding Water Pipe and Cigarette Smoking in Aleppo, Syria. Prev. Med., 38, pp. 479-484, 2004.

Randomized Trial of Buprenorphine for Treatment of Concurrent Opiate and Cocaine Dependence

This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence. Two hundred outpatients currently dependent on both cocaine and opiates were randomly assigned to double-blind groups receiving a sublingual solution of buprenorphine (2, 8, or 16 mg daily, or 16 mg on alternate days, or placebo), plus weekly individual drug abuse counseling, for 13 weeks. The chief outcome measures were urine concentrations of opiate and cocaine metabolites (quantitative) and proportion of urine samples positive for opiates or cocaine (qualitative). Group differences were assessed by use of mixed regression modeling. The target dose of buprenorphine was achieved in 179 subjects. Subjects receiving 8 or 16 mg buprenorphine daily showed statistically significant decreases in urine morphine levels (P =.0135 for 8 mg and P <.001 for 16 mg) or benzoylecgonine concentrations (P =.0277 for 8 mg and P =.006 for 16 mg) during the maintenance phase of the study. For the 16-mg group, mean benzoylecgonine concentrations fell from 3715 ng/mL during baseline to 186 ng/mL during the withdrawal phase; mean morphine concentrations fell from 3311 ng/mL during baseline to 263 ng/mL during withdrawal. For the 8-mg group, mean benzoylecgonine concentrations fell from 6761 ng/mL during baseline to 676 ng/mL during withdrawal; mean morphine concentrations fell from 3890 ng/mL during baseline to 661 ng/mL during withdrawal. Qualitative urinalysis showed a similar pattern of results. Subjects receiving the highest dose showed concomitant decreases in both urine morphine and benzoylecgonine concentrations. There were no significant group differences in treatment retention or adverse events. The results suggest that a sublingual buprenorphine solution at 16 mg daily is well tolerated and effective in reducing concomitant opiate and cocaine use. The therapeutic effect on cocaine use appears independent of that on opiate use. Montoya, I.D., Gorelick, D.A., Preston, K.L., Schroeder, J.R., Umbricht, A., Cheskin, L.J. et al. Randomized Trial of Buprenorphine for Treatment of Concurrent Opiate and Cocaine Dependence. Clin. Pharmacol. Ther., 75, pp. 34-48, 2004.

Treatment of Depression in Patients with Alcohol or Other Drug Dependence: A Meta-Analysis

Depression and substance abuse are common and costly disorders that frequently co-occur, but controversy about effective treatment for patients with both disorders persists. The purpose of this study was to conduct a systematic review and meta-analysis to quantify the efficacy of antidepressant medications for treatment of combined depression and substance use disorders. Data was obtained from PubMed, MEDLINE, and Cochrane database search (1970-2003), using the keywords antidepressant treatment or treatment depressed in conjunction with each of the following alcohol dependence, benzodiazepine dependence, opiate dependence, cocaine dependence, marijuana dependence, and methadone; a search of bibliographies; and consultation with experts in the field. Among inclusion criteria used for study selection were prospective, parallel group, double-blind, controlled clinical trials with random assignment to an antidepressant medication or placebo for which trial patients met standard diagnostic criteria for current alcohol or other drug use and a current unipolar depressive disorder. Of the more than 300 citations extracted, 44 were placebo-controlled clinical trials, 14 of which were selected for this analysis and included 848 patients: 5 studies of tricyclic antidepressants, 7 of selective serotonin re-uptake inhibitors, and 2 from other classes. The investigators independently screened the titles and abstracts of each citation, identified placebo-controlled trials of patients with both substance dependence and depression, applied the inclusion criteria, and reached consensus. Data on study methods, sample characteristics, and depression and substance use outcomes were extracted. The principal measure of effect size was the standardized difference between means on the Hamilton Depression Scale (HDS). For the HDS score, the pooled effect size from the random-effects model was 0.38 (95% confidence interval, 0.18-0.58). Heterogeneity of effect on HDS across studies was significant (P <.02), and studies with low placebo response showed larger effects. Moderator analysis suggested that diagnostic methods and concurrent psychosocial interventions influenced outcome. Studies with larger depression effect sizes (>0.5) demonstrated favorable effects of medication on measures of quantity of substance use, but rates of sustained abstinence were low. The results suggest that antidepressant medication exerts a modest beneficial effect for patients with combined depressive- and substance-use disorders. It is not a stand-alone treatment, and concurrent therapy directly targeting the addiction is also indicated. More research is needed to understand variations in the strength of the effect, but the data suggest that care be exercised in the diagnosis of depression-either by observing depression to persist during at least a brief period of abstinence or through efforts by clinical history to screen out substance-related depressive symptoms. Nunes, E.V. and Levin, F.R. Treatment of Depression in Patients with Alcohol or Other Drug Dependence: A Meta-Analysis. JAMA, 291, pp. 1887-1896, 2004.

A Randomized Controlled Trial of Pemoline for Attention-Deficit/Hyperactivity Disorder in Substance-Abusing Adolescents

In adolescents with substance use disorder (SUD), comorbid attention-deficit/hyperactivity disorder (ADHD) is associated with greater severity of substance abuse, conduct problems, and worse treatment outcomes. Although many controlled trials have established the efficacy of psychostimulants, including pemoline, for ADHD in children and adolescents, none have been conducted in adolescents with SUD. This randomized, placebo-controlled trial, conducted between 1996 and 2000, evaluated the safety and efficacy of pemoline on substance abuse and conduct problems. Sixty-nine adolescents (aged 13-19) with conduct disorder (CD), SUD, and ADHD were recruited from the community and randomly assigned to a 12-week clinical trial of pemoline (n = 35) or placebo (n = 34), titrated over 4 weeks to a single morning dose of 75 to 112.5 mg as tolerated. Results showed that pemoline had greater efficacy than placebo for ADHD as determined by significantly more Clinician's Global Impression-Improvement (CGI-I) ratings of 1 (very much improved) or 2 (much improved) at the study endpoint (n = 69; p <.05). There was also greater reduction in ADHD severity on the parent-rated Conners Hyperactivity-Impulsivity scale in pemoline-treated study completers compared to placebo-treated completers (pemoline, n = 17; placebo, n = 16; p <.01), but no difference between groups in the intent-to-treat analysis (n = 68; p <.13). Substance use did not decline in either group, and there was no difference between groups in baseline to study endpoint change in substance use or CD symptoms. Overall, pemoline was well tolerated, demonstrating a good safety profile and no elevation in liver enzyme levels. The results suggest that pemoline was efficacious for ADHD but did not have an impact on CD or substance abuse in the absence of specific treatment for SUD. Riggs, P.D., Hall, S.K., Mikulich-Gilbertson, S.K., Lohman, M., and Kayser, A. A Randomized Controlled Trial of Pemoline for Attention-Deficit/Hyperactivity Disorder in Substance-abusing Adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 43, pp. 420-429, 2004.

Prediction of Treatment Outcome by Baseline Urine Cocaine Results and Self-reported Cocaine Use for Cocaine and Opioid Dependence

This study examined the usefulness of baseline cocaine urine toxicology results and self-reported days of cocaine use in predicting treatment response in cocaine- and opioid-dependent subjects. Ninety-nine male and 52 female subjects, maintained on buprenorphine, participated in a 24-week, randomized, double-blind, four-cell trial that evaluated desipramine (150 mg/d) or placebo plus contingency management or a non-contingent voucher control. Out of 151, 102 (67%) subjects had cocaine-positive and 49 (32%) cocaine-negative urines at the beginning of treatment. For the previous 30 days before study participation, 91 (60%) subjects reported using cocaine 15 or less days (low baseline cocaine use) and 60 (40%) subjects reported more than 15 days (high baseline cocaine use). By using the treatment effectiveness score (TES) as the outcome measure, a negative urine for cocaine at baseline predicted a better outcome during a 24-week trial for cocaine and opioid use. There also was a significant interaction between baseline cocaine urine results and desipramine response with the urine cocaine-negative group showing greater desipramine response than placebo for opioid and cocaine use. Self-reported cocaine use at baseline did not show significant predictive power for TES scores during the clinical trial. These results suggest that baseline cocaine urine results should be considered as stratifying variables in clinical trials for cocaine dependence. Sofuoglu, M., Gonzalez, G., Poling, J. and Kosten, T.R. Prediction of Treatment Outcome by Baseline Urine Cocaine Results and Self-reported Cocaine Use for Cocaine and Opioid Dependence. Am. J. Drug Alcohol Abuse, 29, pp. 713-727, 2003.

Serious Mental Illness and Tobacco Addiction: A Model Program to Address this Common but Neglected Issue

Tobacco addiction among persons with serious mental illness (SMI) has been largely ignored. About 75 to 85% of persons with schizophrenia, bipolar disorder, and other SMI use tobacco; most will either die and/or have reduced quality of life because of tobacco-caused medical diseases. Tobacco addiction is the most common co-occurring disorder for the SMI population. A dramatic reduction in tobacco use in the general population has occurred during the past 40 years; however, there has been almost no reduction for smokers with SMI. Clinical and research evidence supports motivation-based treatment, blending mental health and addiction treatment approaches, and integrating tobacco dependence treatment within mental health settings. The unique barriers and clinical issues for this population are described. Ziedonis, D., Williams, J.M. and Smelson, D. Serious Mental Illness and Tobacco Addiction: A Model Program to Address this Common but Neglected Issue. Am. J. Med. Sci., 326, pp. 223-230, 2003.


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