The role of baseline insomnia in moderating the hypnotic properties of quetiapine.

INTRODUCTION: The primary aim of this study was to investigate the effect of quetiapine on insomnia and alcohol craving (craving) in subjects with co-occurring insomnia and AUD. METHODS: Insomnia was assessed with the Insomnia Severity Index (ISI) and craving with the Penn Alcohol Craving Scale (PACS, primary) and Obsessive-Compulsive Drinking Scale (OCDS, secondary). A multivariable model adjusted for covariates (N = 123) evaluated the relationship between craving (PACS and OCDS total scores) and insomnia (ISI total score). To simultaneously assess the effects of treatment arm allocation and insomnia status, subjects (N = 115) were stratified into 4 groups, quetiapine-insomnia(N = 38), quetiapine-No insomnia(N = 19), placebo-insomnia(N = 38), and placebo-No insomnia(N = 20). Linear mixed-effects regression models adjusted for covariates compared the trajectories of ISI, PACS, and OCDS total scores across 12 weeks of treatment and at post-treatment follow-up at week 24, between the four groups. RESULTS: The ISI total score was positively associated with the PACS (p = 0.006) and OCDS (p = 0.001) total scores in the multivariable models. In the longitudinal analysis, when compared to the three other groups, subjects with insomnia treated with quetiapine showed a marked reduction in their insomnia scores with a return of insomnia after stopping treatment. There was no significant difference between the groups for the PACS and OCDS total score trajectories. DISCUSSION: Although craving is associated with insomnia, treatment with quetiapine may improve insomnia but not craving in patients with co-occurring AUD and insomnia.

A delta-opioid receptor genetic variant is associated with abstinence prior to and during cocaine dependence treatment.

INTRODUCTION: An intronic polymorphism in the delta-opioid receptor gene (OPRD1) was previously associated with cocaine dependence in African-Americans. However, it is not known if the polymorphism (rs678849) is associated with dependence-related phenotypes within the cocaine dependent population. METHODS: Cocaine and alcohol dependent subjects were randomized to either topiramate or placebo. Abstinence from cocaine use was confirmed by urine drug screens for benzoylecgonine three times per week. Cocaine withdrawal and craving were assessed at randomization using the Cocaine Selective Severity Assessment (CSSA) and Minnesota Cocaine Craving Scale (MCCS), respectively. Subjects were also interviewed using the Addiction Severity Index (ASI). Genotype at rs678849 was determined for 105 African-American subjects and compared to cocaine abstinence, as well as scores for CSSA, MCCS, and ASI. RESULTS: African-American patients with the C/T or T/T genotypes (n=40) were more likely to be abstinent at the first urine drug screen and more likely to be abstinent for the week prior to randomization compared to patients with the C/C genotype (n=65). Subjects carrying the T allele were also more likely to have abstinent weeks over the course of the trial compared to those with the C/C genotype (RR=1.88, 95% CI=1.59-2.22, p=0.0035). No effects of rs678849 genotype on withdrawal, craving, or addiction severity were observed. CONCLUSIONS: A polymorphism in OPRD1 appears to be associated with both cocaine dependence and cocaine use during treatment in African-Americans. Follow-up studies to confirm the effect on cocaine use are warranted.

Case-control association analysis of polymorphisms in the δ-opioid receptor, OPRD1, with cocaine and opioid addicted populations.

BACKGROUND: Addiction susceptibility and treatment responsiveness are greatly influenced by genetic factors. Sequence variation in genes involved in the mechanisms of drug action have the potential to influence addiction risk and treatment outcome. The opioid receptor system is involved in mediating the rewarding effects of cocaine and opioids. The µ-opioid receptor (MOR) has traditionally been considered the primary target for opioid addiction. The MOR, however, interacts with and is regulated by many known MOR interacting proteins (MORIPs), including the δ-opioid receptor (DOR). METHODS: The present study evaluated the contribution of OPRD1, the gene encoding the DOR, to the risk of addiction to opioids and cocaine. The association of OPRD1 polymorphisms with both opioid addiction (OA) and cocaine addiction (CA) was analyzed in African American (OA n=336, CA n=503) and European American (OA n=1007, CA n=336) populations. RESULTS: The primary finding of this study is an association of rs678849 with cocaine addiction in African Americans (allelic p=0.0086). For replication purposes, this SNP was analyzed in a larger independent population of cocaine addicted African Americans and controls and the association was confirmed (allelic p=4.53 × 10(-5); n=993). By performing a meta-analysis on the expanded populations, the statistical evidence for an association was substantially increased (allelic p=8.5 × 10(-7)) (p-values non-FDR corrected). CONCLUSION: The present study suggests that polymorphisms in OPRD1 are relevant for cocaine addiction in the African American population and provides additional support for a broad role for OPRD1 variants in drug dependence.

Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction.

Genetic factors are believed to account for 30-50% of the risk for cocaine and heroin addiction. Dynorphin peptides, derived from the prodynorphin (PDYN) precursor, bind to opioid receptors, preferentially the kappa-opioid receptor, and may mediate the aversive effects of drugs of abuse. Dynorphin peptides produce place aversion in animals and produce dysphoria in humans. Cocaine and heroin have both been shown to increase expression of PDYN in brain regions relevant for drug reward and use. Polymorphisms in PDYN are therefore hypothesized to increase risk for addiction to drugs of abuse. In this study, 3 polymorphisms in PDYN (rs1022563, rs910080 and rs1997794) were genotyped in opioid-addicted [248 African Americans (AAs) and 1040 European Americans (EAs)], cocaine-addicted (1248 AAs and 336 EAs) and control individuals (674 AAs and 656 EAs). Sex-specific analyses were also performed as a previous study identified PDYN polymorphisms to be more significantly associated with female opioid addicts. We found rs1022563 to be significantly associated with opioid addiction in EAs [P = 0.03, odds ratio (OR) = 1.31; false discovery rate (FDR) corrected q-value]; however, when we performed female-specific association analyses, the OR increased from 1.31 to 1.51. Increased ORs were observed for rs910080 and rs199774 in female opioid addicts also in EAs. No statistically significant associations were observed with cocaine or opioid addiction in AAs. These data show that polymorphisms in PDYN are associated with opioid addiction in EAs and provide further evidence that these risk variants may be more relevant in females.

Tolerance and sensitization to the effects of cocaine use in humans: a retrospective study of long-term cocaine users in Philadelphia.

In the effort to develop medications to combat addiction, researchers have developed models that attempt to describe the neurobiological process of cocaine dependence. It has not, however, yet been determined which of these models, if any, best fits the behaviors and experiences of patients. This project retrospectively evaluated changes in patients' experiences with cocaine over time in order to clarify the model that best fits clinical observations. In 2005 and 2007, 100 treatment-seeking, long-term cocaine users were recruited from an urban university-based treatment center in Philadelphia, PA, United States. Each participant was administered the "Cocaine History Questionnaire" which asked them to describe the initiation and escalation of their cocaine usage, changing reward perceptions, and effects of intoxication at certain points in their drug use careers. This data was then analyzed using repeated measures, examining the within subject differences in reported information over the time points. We found evidence that while the amount of drug used increases, self-reported euphoria decreases while negative symptoms associated with cocaine use also increase. The data provide preliminary evidence for the hedonic dysregulation model of addiction. Limitations and implications of the study are discussed in the conclusion.

Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity.

Propranolol may reduce symptoms of autonomic arousal associated with early cocaine abstinence and improve treatment outcome. This trial was an 8-week, double-blind, placebo-controlled trial of propranolol in 108 cocaine dependent subjects. The primary outcome measure was quantitative urinary benzoylecgonine levels. Secondary outcome measures included treatment retention, addiction severity index results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms, and adverse events. Propranolol treated subjects had lower cocaine withdrawal symptom severity but otherwise did not differ from placebo treated subjects in any outcome measure. However, in a secondary, exploratory analysis, subjects with more severe cocaine withdrawal symptoms responded better to propranolol in comparison to placebo. In these subjects, propranolol treatment was associated with better treatment retention and lower urinary benzoylecgonine levels as compared with the placebo treatment. Propranolol may be useful only for the treatment of cocaine dependent patients with severe cocaine withdrawal symptoms.

Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment.

This study evaluated the ability of cocaine withdrawal symptoms, measured by the Cocaine Selective Severity Assessment (CSSA) and initial urine toxicology results, to predict treatment attrition among 128 cocaine dependent veterans participating in a 4-week day hospital treatment program. The CSSA was administered and a urine toxicology screen was obtained at intake and at the start of the day hospital (about 1 week later). The combination of a positive urine toxicology screen and a high CSSA score at intake predicted failure to complete treatment. Urine toxicology results at the start of the day hospital, but not at intake, predicted failure to complete treatment. Among participants without other psychiatric illness, high CSSA scores at intake predicted failure to complete treatment. The presence of cocaine withdrawal symptoms and a positive urine toxicology screen are clinically useful predictors of treatment attrition.

Amantadine in the treatment of cocaine-dependent patients with severe withdrawal symptoms.

OBJECTIVE: The study examined the effectiveness of amantadine in reducing cocaine withdrawal symptoms and improving treatment outcome among cocaine-dependent patients in outpatient treatment. METHOD: Sixty-one cocaine-dependent subjects participated in a double-blind, placebo-controlled trial of amantadine. RESULTS: Among subjects with severe cocaine withdrawal symptoms at the start of treatment, those who received amantadine used significantly less cocaine during the trial than did subjects who received placebo. Compared to subjects who received placebo, subjects who received amantadine submitted significantly more benzoylecgonine-negative urine samples and used cocaine on significantly fewer days during the trial. CONCLUSIONS: Amantadine may be an effective treatment for cocaine-dependent patients with severe cocaine withdrawal symptoms.

Open trials as a method of prioritizing medications for inclusion in controlled trials for cocaine dependence.

This paper describes a rapid and systematic method of using open trials to identify medications that may be useful for the treatment of cocaine dependence. Results of these open trials can be used to prioritize medications for inclusion in subsequent double-blind, placebo-controlled trials. Preliminary results are presented from the evaluation of propranolol, nefazodone, and the combination of phentermine and fenfluramine (phen/fen). Each medication was evaluated in an open trial, and results were compared to results obtained from a group that received a multivitamin. Outcome measures included treatment retention, urine toxicology screens, self-reported cocaine use, and changes on the Addiction Severity Index (ASI). Treatment retention was significantly better in the propranolol group than in the multivitamin group. Concurrent alcohol abuse was associated with increased rates of attrition in the multivitamin group, and the phen/fen group, but not in the propranolol group. Neither the nefazodone nor the phen/fen groups showed any outcome advantages over the multivitamin group. We conclude that propranolol may enhance retention among cocaine-dependent patients, especially among those who also abuse alcohol. These results encourage a double-blind, placebo-controlled trial of propranolol.

The effects of naltrexone on alcohol and cocaine use in dually addicted patients.

Concurrent dependence on cocaine and alcohol is common among patients seeking addiction treatment. This study was undertaken to explore the effectiveness of naltrexone (150 mg) as a potential treatment for patients who are alcohol and cocaine dependent. Of 15 subjects enrolled in the 12-week, open medication trial, 7 subjects did not complete the study. Relapse to clinically significant drinking occurred in 7 subjects (47%). There was a reduction in the average daily amount of alcohol consumed from pretreatment to treatment (p < .001) and the percentage of days engaged in drinking behavior (p < .001). Similarly, there was a reduction in the average weekly amount spent on cocaine from pretreatment to treatment (p = .001) and the percentage of days using cocaine (p < .001). This preliminary study suggests that naltrexone (150 mg) may be tolerable in patients dependent upon alcohol and cocaine and may be effective in reducing both cocaine and alcohol use. The results of this study provide a rationale for a double-blind placebo-controlled study of the efficacy of naltrexone in this difficult to treat but prevalent population.

Reliability and validity of the Cocaine Selective Severity Assessment.

This article assesses the reliability and validity of the Cocaine Selective Severity Assessment (CSSA), a measure of cocaine abstinence signs and symptoms. Interrater reliability and scale internal consistency were high. Initial CSSA scores were significantly higher in cocaine-dependent subjects than in alcohol-dependent subjects. Initial CSSA scores were highly correlated with recent cocaine use and with severity measures from the Addiction Severity Index (ASI) including the interviewer severity rating and composite score in the drug section. Among cocaine-dependent subjects, initial CSSA scores were higher for those who failed to achieve abstinence or who subsequently dropped out of treatment. Further, CSSA scores showed consistent and marked declines over time for subjects who continued in treatment and remained abstinent. The CSSA appears to be a reliable and valid measure of cocaine abstinence symptoms and a useful predictor of negative outcomes in cocaine dependence treatment.