Tara M. Wright

Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence

OBJECTIVE Naltrexone, an efficacious medication for alcohol dependence, does not work for everyone. Symptoms such as insomnia and mood instability that are most evident during early abstinence might respond better to a different pharmacotherapy. Gabapentin may reduce these symptoms and help prevent early relapse. This clinical trial evaluated whether the combination of naltrexone and gabapentin was better than naltrexone alone and/or placebo during the early drinking cessation phase (first 6 weeks), and if so, whether this effect persisted. METHOD A total of 150 alcohol-dependent individuals were randomly assigned to a 16-week course of naltrexone alone (50 mg/day [N=50]), naltrexone (50 mg/day) with gabapentin (up to 1,200 mg/day [N=50]) added for the first 6 weeks, or double placebo (N=50). All participants received medical management. RESULTS During the first 6 weeks, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone-alone group, which had an interval similar to that of the placebo group; had fewer heavy drinking days than the naltrexone-alone group, which in turn had more than the placebo group; and had fewer drinks per drinking day than the naltrexone-alone group and the placebo group. These differences faded over the remaining weeks of the study. Poor sleep was associated with more drinking in the naltrexone-alone group but not in the naltrexone-gabapentin group, while a history of alcohol withdrawal was associated with better response in the naltrexone-gabapentin group. CONCLUSIONS The addition of gabapentin to naltrexone improved drinking outcomes over naltrexone alone during the first 6 weeks after cessation of drinking. This effect did not endure after gabapentin was discontinued.

Efficacy of a combination of flumazenil and gabapentin in the treatment of alcohol dependence: relationship to alcohol withdrawal symptoms.

Improved treatment of alcohol dependence is a high priority, including defining subtypes that might respond differently. We evaluated a medication combination of intravenous flumazenil (FMZ) and oral gabapentin (GBP) in alcoholics who did and did not exhibit pretreatment alcohol withdrawal (AW) symptoms. Sixty alcohol-dependent individuals (44 with low AW and 16 with high AW) were randomized to receive FMZ (2 mg of incremental bolus for 20 minutes for 2 consecutive days) and GBP (up to 1200 mg nightly for 39 days) or their inactive placebos. Alcohol withdrawal was measured for the first 2 days, and drinking, sleep parameters, and adverse events were monitored during weekly evaluations, along with behavioral counseling sessions. Percent days abstinent (PDA) during treatment and time to first heavy drinking (TFHD) day were primary outcome variables. There was an interaction between the pretreatment AW status and the medication group on PDA (P = 0.0006) and TFHD (P = 0.06). Those in the high AW group had more PDA and more TFHD if treated with active medications, whereas those in the low AW group had more PDA and more TFHD if treated with placebo. This interaction remained for those totally abstinent (P = 0.03) and was confirmed by percent carbohydrate-deficient transferrin values. In addition, the pattern of response remained up to 8 weeks after treatment. In addition, in those with high AW, greater improvement in AW symptoms was observed in the active medication group compared with the placebo group. These results suggest a differential response to FMZ/GBP treatment, depending on pretreatment AW status that should be taken into account during future treatment trials.

Risperidone- and Quetiapine-Induced Cholestasis

Objective: To describe a case of a patient who developed drug-induced cholestasis after being on risperidone maintenance therapy for 8 years. Case Summary: A 30-year-old male with schizoaffective disorder, bipolar type, and insulin-dependent diabetes mellitus had been stable on risperidone 6 mg at night for 8 years. His other medications included lithium 900 mg twice daily and enalapril 5 mg daily, as well as regular insulin and NPH insulin as needed. The patient developed cholestasis that resolved once risperidone was discontinued. Over the next 11 months, he tolerated trials of ziprasidone and olanzapine. When quetiapine was initiated, the patient developed signs and symptoms of cholestasis within 3 weeks after starting this medication. The signs and symptoms of cholestasis resolved with removal of quetiapine. The Naranjo probability scale indicated that these atypical antipsychotics (risperidone and quetiapine) were the probable cause of cholestasis in this patient. Discussion: It is well known that atypical antipsychotics can cause isolated asymptomatic increases in aminotransferase levels. Liver injury, both the hepatic and cholestatic type, has been described previously, although the incidence with atypical antipsychotics is rare. Conclusions: To our knowledge, this is the first case of cholestasis that developed after years of treatment and reappeared with another antipsychotic agent. Given that liver failure, of either the hepatic or cholestatic type, is a relatively rare phenomenon with atypical antipsychotics, it seems that the most reasonable approach to manage this risk is through education. By educating patients on early warning signs of hepatotoxicity, this rare but potentially fatal consequence could be detected early to allow appropriate intervention.

Neurocognitive performance, alcohol withdrawal, and effects of a combination of flumazenil and gabapentin in alcohol dependence.

BACKGROUND Among some alcohol-dependent individuals, early alcohol abstinence is marked by alcohol withdrawal (AW), a phenomenon mediated by GABA and glutamate signaling. We previously reported that a combination of 2 medications that affect GABA and glutamate tone, gabapentin and flumazenil, more effectively reduced drinking among individuals with higher pretreatment AW (Anton et al., 2009). This study evaluated whether this finding is related to changes in neurocognitive performance, which is also affected by cortical GABA and glutamate tone. METHODS Neurocognitive performance was assessed at baseline and twice during the first week of treatment among 60 alcohol-dependent participants in the previously published clinical trial. RESULTS AW was associated with poorer baseline performance on 4 of 8 measures, and individuals with higher baseline AW who received the gabapentin and flumazenil combination demonstrated greater improvement on a measure of response inhibition than those with lower AW or those who received a combination of placebos. Improvement in response inhibition during the first week and medication group interacted in their effect on subsequent drinking, such that improvement predicted greater abstinence only among individuals who received gabapentin and flumazenil. Improvement on other neurocognitive measures was neither differentially impacted by medication or baseline AW nor related to subsequent drinking. CONCLUSIONS Taken together, these data suggest that acute AW accounts for a small proportion of variance in neurocognitive performance, that gabapentin and flumazenil slightly improve response inhibition during early abstinence, and that such improvement may somewhat reduce later drinking. However, these medications may not affect other neurocognitive domains.

Impact of lifetime alcohol quit attempts and medicated detoxifications on time to relapse during an index alcohol detoxification.

Previous work has shown that multiple medication-treated alcohol detoxifications are associated with poorer treatment outcomes during subsequent detoxifications. Little is known about the impact of nonmedicated attempts to stop drinking outside the realm of these medically supervised detoxifications on acute detoxification outcomes. This study included 58 subjects enrolled in an outpatient detoxification study. Subjects were asked why and how often they quit alcohol for 3 days or longer during their drinking lifetime using concepts derived from the Cognitive Lifetime Drinking History. The effect of previous attempts at abstinence (both medicated and nonmedicated) on time to relapse during an index detoxification was examined. After the index detoxification, older individuals relapsed later than younger individuals and the number of previous medicated detoxifications rather than total lifetime quit attempts per se was related to quicker relapse. Contrary to expectation, those who reported fewer previous nonmedicated quit attempts tended to relapse sooner than those who reported more past quit attempts. This study supports and extends previous work that suggests that the number of previous medicated detoxifications, rather than the total number of past attempts at abstinence, predicts higher and sooner risk for early relapse drinking during outpatient alcohol detoxification.

Comorbid anxiety and substance use disorders : Diagnostic and treatment considerations

Abstract Substance abuse comorbidity is common in anxiety disorders. This article reviews the co-occurrence and etiopathological significance of comorbid substance abuse in anxiety disorders.

Chapter 7 – Pharmacotherapies for the Treatment of Alcohol Dependence: Current and on the Horizon

Publisher Summary This chapter discusses pharmacotherapies for the treatment of alcohol dependence. The spectrum of alcohol withdrawal symptoms is wide and can range from mild to life threatening. Benzodiazepines have long been considered the standard of care in the treatment of alcohol withdrawal. Once detoxification is successfully completed, the goal of treatment is maintenance of abstinence, including reduction of craving and risk of relapse. It is found that individuals taking naltrexone plus medical management or naltrexone plus medical management and CBI have higher percent days abstinent than those receiving placebo and medical management only. As naltrexone is believed to be effective through blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption, it may be expected to benefit patients whose disease is mostly characterized by reward craving. Acamprosate is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute post-withdrawal period in recently detoxified alcohol dependent individuals. Baclofen has been shown to decrease voluntary alcohol intake and suppress the expected rebound in alcohol intake after alcohol deprivation in rats bred for alcohol preference. The medication compliance and its impact on alcohol pharmacotherapy are elaborated in the chapter.Publisher Summary This chapter discusses pharmacotherapies for the treatment of alcohol dependence. The spectrum of alcohol withdrawal symptoms is wide and can range from mild to life threatening. Benzodiazepines have long been considered the standard of care in the treatment of alcohol withdrawal. Once detoxification is successfully completed, the goal of treatment is maintenance of abstinence, including reduction of craving and risk of relapse. It is found that individuals taking naltrexone plus medical management or naltrexone plus medical management and CBI have higher percent days abstinent than those receiving placebo and medical management only. As naltrexone is believed to be effective through blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption, it may be expected to benefit patients whose disease is mostly characterized by reward craving. Acamprosate is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute post-withdrawal period in recently detoxified alcohol dependent individuals. Baclofen has been shown to decrease voluntary alcohol intake and suppress the expected rebound in alcohol intake after alcohol deprivation in rats bred for alcohol preference. The medication compliance and its impact on alcohol pharmacotherapy are elaborated in the chapter.

Pharmacotherapies for the Treatment of Alcohol Dependence: Current and on the Horizon

Publisher Summary This chapter discusses pharmacotherapies for the treatment of alcohol dependence. The spectrum of alcohol withdrawal symptoms is wide and can range from mild to life threatening. Benzodiazepines have long been considered the standard of care in the treatment of alcohol withdrawal. Once detoxification is successfully completed, the goal of treatment is maintenance of abstinence, including reduction of craving and risk of relapse. It is found that individuals taking naltrexone plus medical management or naltrexone plus medical management and CBI have higher percent days abstinent than those receiving placebo and medical management only. As naltrexone is believed to be effective through blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption, it may be expected to benefit patients whose disease is mostly characterized by reward craving. Acamprosate is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute post-withdrawal period in recently detoxified alcohol dependent individuals. Baclofen has been shown to decrease voluntary alcohol intake and suppress the expected rebound in alcohol intake after alcohol deprivation in rats bred for alcohol preference. The medication compliance and its impact on alcohol pharmacotherapy are elaborated in the chapter.Publisher Summary This chapter discusses pharmacotherapies for the treatment of alcohol dependence. The spectrum of alcohol withdrawal symptoms is wide and can range from mild to life threatening. Benzodiazepines have long been considered the standard of care in the treatment of alcohol withdrawal. Once detoxification is successfully completed, the goal of treatment is maintenance of abstinence, including reduction of craving and risk of relapse. It is found that individuals taking naltrexone plus medical management or naltrexone plus medical management and CBI have higher percent days abstinent than those receiving placebo and medical management only. As naltrexone is believed to be effective through blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption, it may be expected to benefit patients whose disease is mostly characterized by reward craving. Acamprosate is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute post-withdrawal period in recently detoxified alcohol dependent individuals. Baclofen has been shown to decrease voluntary alcohol intake and suppress the expected rebound in alcohol intake after alcohol deprivation in rats bred for alcohol preference. The medication compliance and its impact on alcohol pharmacotherapy are elaborated in the chapter.

Pharmacotherapies for the Treatment of Alcohol Dependence

Publisher Summary This chapter discusses pharmacotherapies for the treatment of alcohol dependence. The spectrum of alcohol withdrawal symptoms is wide and can range from mild to life threatening. Benzodiazepines have long been considered the standard of care in the treatment of alcohol withdrawal. Once detoxification is successfully completed, the goal of treatment is maintenance of abstinence, including reduction of craving and risk of relapse. It is found that individuals taking naltrexone plus medical management or naltrexone plus medical management and CBI have higher percent days abstinent than those receiving placebo and medical management only. As naltrexone is believed to be effective through blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption, it may be expected to benefit patients whose disease is mostly characterized by reward craving. Acamprosate is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute post-withdrawal period in recently detoxified alcohol dependent individuals. Baclofen has been shown to decrease voluntary alcohol intake and suppress the expected rebound in alcohol intake after alcohol deprivation in rats bred for alcohol preference. The medication compliance and its impact on alcohol pharmacotherapy are elaborated in the chapter.Publisher Summary This chapter discusses pharmacotherapies for the treatment of alcohol dependence. The spectrum of alcohol withdrawal symptoms is wide and can range from mild to life threatening. Benzodiazepines have long been considered the standard of care in the treatment of alcohol withdrawal. Once detoxification is successfully completed, the goal of treatment is maintenance of abstinence, including reduction of craving and risk of relapse. It is found that individuals taking naltrexone plus medical management or naltrexone plus medical management and CBI have higher percent days abstinent than those receiving placebo and medical management only. As naltrexone is believed to be effective through blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption, it may be expected to benefit patients whose disease is mostly characterized by reward craving. Acamprosate is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute post-withdrawal period in recently detoxified alcohol dependent individuals. Baclofen has been shown to decrease voluntary alcohol intake and suppress the expected rebound in alcohol intake after alcohol deprivation in rats bred for alcohol preference. The medication compliance and its impact on alcohol pharmacotherapy are elaborated in the chapter.