Oxcarbazepine--efficacy and tolerability during treatment of alcohol withdrawal: a double-blind, randomized, placebo-controlled multicenter pilot study. A double-blind comparison of abecarnil and diazepam in the treatment of uncomplicated alcohol withdrawal. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. Divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. [Gamma-hydroxybutyrate for treatment of alcohol withdrawal syndrome in intensive care patients. A comparison between with two symptom-oriented therapeutic concepts]. Carbamazepine versus oxazepam in the treatment of alcohol withdrawal: a double-blind study. Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial. Treatment of acute alcohol withdrawal with gabapentin: results from a controlled two-center trial. Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Oxcarbazepine versus carbamazepine in the treatment of alcohol withdrawal. Gamma-hydroxybutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus benzodiazepine.
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.
                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.
                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.
                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. Treatment of the alcohol withdrawal syndrome is best accomplished using pharmacologic agents that have minimal interaction with alcohol, have limited adverse effects, and are without abuse potential. The partial benzodiazepine receptor agonist beta-carboline compound, abecarnil, has been shown in animal and human studies to possess a number of these characteristics and to be useful in the reduction of alcohol withdrawal convulsions in mice. In this study, 49 alcohol-dependent inpatients who exhibited at least moderate symptoms of uncomplicated alcohol withdrawal were treated over a 5-day detoxification period with abecarnil or diazepam and rated daily for alcohol withdrawal symptoms and adverse events. Both the abecarnil and diazepam treatment groups exhibited a similar marked reduction in withdrawal symptoms over time. In addition, similar rates of successful treatment and improvement were observed after 1 day of treatment and at termination in alcoholics treated with either medication. Overall, rates of adverse events and changes in liver enzymes were similar in both treatment groups and were generally benign. Because of the unique pharmacologic profile of abecarnil in animal and in non-clinical human studies, including anticonvulsant action, low abuse liability, and a favorable side effect profile, further study of compounds of the partial benzodiazepine receptor agonist type in the treatment of alcohol withdrawal syndromes seems warranted. Benzodiazepines are the mainstay of treatment for mild-to-moderate alcohol withdrawal in outpatient settings, but they can interact with alcohol, cause motor incoordination, or be abused. This study compared the therapeutic responses of the benzodiazepine lorazepam and the anticonvulsant carbamazepine for the outpatient treatment of acute alcohol withdrawal in terms of patients' previous detoxification histories, and compared the effects of these 2 medications on drinking behaviors in the immediate postdetoxification period.
                This was a randomized double-blind trial comparing patient responses to carbamazepine and lorazepam across 2 levels of detoxification histories (0-1 or >or=2 previous medicated detoxifications).
                A university medical center substance abuse clinic in Charleston, SC.
                One hundred thirty-six patients in moderate alcohol withdrawal were randomized. Major exclusions were significant hepatic or hematologic abnormalities and use of medications that could alter withdrawal symptoms.
                Patients received 600-800 mg of carbamazepine or 6-8 mg of lorazepam in divided doses on day 1 tapering to 200 mg of carbamazepine or 2 mg of lorazepam.
                The Clinical Institute Withdrawal Assessment for Alcohol-Revised was used to assess alcohol withdrawal symptoms on days 1 through 5 and postmedication at days 7 and 12. Daily drinking was measured by patient report using a daily drinking log and a breath alcohol level with each visit. Side effects were recorded daily.
                Carbamazepine and lorazepam were equally effective at decreasing the symptoms of alcohol withdrawal. In the post-treatment period, 89 patients drank on at least 1 day; on average, carbamazepine patients drank less than 1 drink per drinking day and lorazepam patients drank almost 3 drinks per drinking day (P =.003). Among those with multiple past detoxifications, the carbamazepine group drank less than 1 drink per day on average and the lorazepam group drank about 5 drinks per day on average (P =.033). Lorazepam-treated patients had a significant rebound of alcohol withdrawal symptoms post-treatment (P =.007) and the risk of having a first drink was 3 times greater (P =.04) than for carbamazepine-treated patients. Twenty percent of lorazepam-treated patients had dizziness, motor incoordination, or ataxia and did not recognize their impairment. Twenty percent of carbamazepine-treated patients reported pruritus but no rash.
                Carbamazepine and lorazepam were both effective in decreasing the symptoms of alcohol withdrawal in relatively healthy, middle-aged outpatients. Carbamazepine, however, was superior to lorazepam in preventing rebound withdrawal symptoms and reducing post-treatment drinking, especially for those with a history of multiple treated withdrawals. This pilot study evaluates the safety and efficacy of divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. Sixteen patients in moderate alcohol withdrawal were randomized to receive a standard benzodiazepine detoxification, depakote detoxification, or depakote detox plus maintenance. Symptom reduction occurred more rapidly and consistently in the depakote treated patients than in the benzodiazepine control group, and at six-week follow up a greater percentage of patients in the depakote maintenance group were completely abstinent than either detox-only group. There were no significant differences in sociodemographic or drinking data amongst the three cohort samples at baseline. Our findings suggest that the anticonvulsant divalproex sodium (Depakote) may be a safe and efficacious alternative to benzodiazepines for the treatment of alcohol withdrawal. It may be an advantageous alternative for outpatient detoxification, as it has no abuse potential, pharmacologic synergy with alcohol, or substantial cognitive or psychomotor side effects. Seeing as gamma-hydroxybutyrate (GHB) and benzodiazepines interact with the GABA-transmitter system, we investigated whether GHB can replace the conventional therapy, which uses benzodiazepines in the treatment of alcohol withdrawal syndrome in ICU settings.
                42 chronic alcoholics were included in this prospective and randomized study. Following the development of alcohol withdrawal syndrome, the patients were randomly allocated to the GHB or to the flunitrazepam group. In addition to this, clonidine was administered in order to treat autonomic signs of withdrawal. In cases were hallucinations occurred, haloperidol was administered.
                There was no significant difference in the efficacy of treatment used in the duration of mechanical ventilation and intensive care unit stay between groups. The patients in the GHB-group required significantly higher dosages of haloperidol and significantly lower dosages of clonidine. 14 out of 21 patients from the GHB-group developed hypernatriaemia and 15 out of 21 developed a metabolic alkalosis.
                Symptoms of the autonomic nervous system were more effectively prevented by GHB as evident in the lower dosage requirement of clonidine. However, GHB may not sufficiently block the hyperactivity of the dopaminergic system or may have an hallucinogenic effect itself. This may be evident from the higher dosages of haloperidol which were necessary. Due to the latter fact, the administration of GHB cannot be recommended in all patients suffering from AWS in ICU settings. The use of more than 130 drugs and drug combinations against the alcohol withdrawal syndrome reflects the fact that views on its treatment are far from being unequivocal. Benzodiazepines are the first choice treatment but it should not be disregarded that they have side effects and, above all, a varying risk of dependency themselves. In recent years many trials have focused on carbamazepine in this respect. Its efficacy was proven in various open and double-blind studies, most of them using concomitant sedative drugs, thereby diminishing the reliability of the results. In a double-blind study we compared the efficacy of carbamazepine with that of oxazepam, in 60 in-patients suffering from alcohol withdrawal syndrome. The main rating instrument was the Clinical Institute Withdrawal Scale--Alcohol (CIWA-A). The 7-day trial showed equal efficacy of carbamazepine and oxazepam during the first 5 days and a statistically significant superiority of carbamazepine on days 6 and 7. Four patients in each group had to be dropped from the study due to side effects or after having withdrawn informed consent. There was no decrease in white blood counts under carbamazepine. The experiences with carbamazepine up to now suggest a more widespread use, especially in non-delirious withdrawal states. Divalproex sodium, an anticonvulsant and antikindling agent and gamma-aminobutyric acid enhancer, has been proposed as an alternative to benzodiazepines for treating alcohol withdrawal. This study reports on a randomized, double-blind, placebo-controlled trial of divalproex sodium in acute alcohol withdrawal.
                Thirty-six hospitalized patients experiencing moderate alcohol withdrawal as measured by a score of at least 10 on the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) were randomized to receive either divalproex sodium 500 mg three times per day for 7 days or matched placebo in a double-blind manner. All subjects received a baseline dose of oxazepam and had additional oxazepam available as a rescue medication in accordance with a standard, symptom-triggered detoxification protocol. Mean total milligrams of oxazepam received, progression of withdrawal symptoms, psychological distress as measured by the Symptom Checklist-90, side effects, and adverse outcomes were compared between groups.
                Use of divalproex sodium resulted in less use of oxazepam (p < 0.033). Group differences seemed primarily driven by those subjects who experienced symptoms above threshold level (CIWA-Ar >or=10) after 12 hr. The progression in severity of withdrawal symptoms (increase in CIWA-Ar above baseline) was also significantly greater in the placebo group (p < 0.05).
                This placebo-controlled pilot study suggests that divalproex sodium significantly affects the course of acute alcohol withdrawal and reduces the need for treatment with a benzodiazepine. A more aggressive loading dose strategy may demonstrate a more robust or earlier response. A few case reports and data from animal experiments point to a possible efficacy of gabapentin (GP) in the treatment of alcohol withdrawal syndrome (AWS). Because of ethical considerations, the efficacy of GP in acute AWS was tested in an add-on fashion to clomethiazole (CLO). Given that the symptom-triggered amount of CLO required to limit AWS within the first 24 hours is related to the severity of AWS, we tested this amount of CLO during placebo (P) or GP (400 mg qid) under double blind, randomized conditions. Sixty-one patients (P = 29/GP = 32) suffering from alcohol dependence (ICD-10) and without any other psychiatric condition or psychotropic medication were included. The groups were not significantly different in baseline characteristics (eg, demographic data, severity of AWS). Both ITT and completer analyses revealed no significant differences between the groups considering the primary effectiveness measure: amount of CLO required in the first 24 hours (P = 6.1 +/- 5.4/GP = 6.2 +/- 4.7 capsules). In addition, premature discontinuations (P = 3/GP = 2) and decreases in Mainz Alcohol Withdrawal Scores were not significantly different in the first 48 hours of AWS (secondary effectiveness measures). Tolerability of combined CLO/GP was studied throughout the whole treatment comprising a 5-day lasting reduction part subsequent to the first 48 hours. Throughout the whole 7-day treatment a total of 5 and 2 patients dropped out and 6 and 5 patients reported adverse clinical events in the P and GP groups, respectively. All together, GP (400 mg qid) was no better than P in saving initial consumption of CLO or decreasing initial Mainz Alcohol Withdrawal Scores suggesting that GP was ineffective in the management of acute AWS in this model. The combination of GP and CLO was safe. Of 86 alcoholic men with severe alcohol withdrawal who began a double-blind controlled study comparing carbamazepine, 800 mg/day, to oxazepam, 120 mg/day, 66 (carbamazepine, N = 32; oxazepam, N = 34) completed the 7-day trial. In general, the drugs were found to be equally efficacious in treating the withdrawal syndrome and not significantly different with respect to side effects. The subjects taking oxazepam had an increase in global psychological distress from day 3 to day 7, and those taking carbamazepine exhibited a decline. The study suggests that carbamazepine is as effective and safe as benzodiazepine treatment for alcohol withdrawal. In a single-blinded and randomized pilot study efficacy and tolerability of oxcarbazepine versus carbamazepine were investigated in 29 patients during therapy of alcohol withdrawal. No initial differences were found regarding sociodemographic data and alcohol-related parameters, indicating successful randomization. The oxcarbazepine group showed a significant decrease of withdrawal symptoms and reported significantly less 'craving for alcohol' compared to the carbamazepine group. Subjectively experienced side effects, normalization of vegetative parameters and improvement in the cognitive processing speed did not reveal differences for both groups. Therefore, oxcarbazepine might be an interesting alternative to carbamazepine, and having almost no addictive potential, no clinically relevant interaction with alcohol and no prominent sedatory effect, possibly also to other drugs such as benzodiazepines or clomethiazole, in the treatment of alcohol withdrawal syndrome. Benzodiazepine has been shown to be one of the most effective class of drugs in the management of alcohol withdrawal syndrome (AWS). Gamma-hydroxybutyric acid (GHB) has recently been introduced in the treatment of alcohol problems, including AWS. At present there are no comparative studies between benzodiazepines and GHB in AWS treatment. The aim of the present randomized, controlled, single-blind study was to evaluate the efficacy and safety of GHB compared with diazepam in the treatment of AWS.
                Sixty alcoholics affected by AWS were enrolled in the study. Diazepam (0.5-0.75 mg/kg body weight for 6 days, tapering the dose 25% daily until day 10) was administered orally to 30 patients (25 males, 5 females; mean age 44.3 +/- 10.9 years); GHB (50 mg/kg body weight for 10 days) was administered orally to 30 patients (26 males,4 females; mean age 41.7 +/- 10.4 years). The Clinical Institute Withdrawal Assessment for Alcohol-revised scale (CIWA-Ar) was used to evaluate the AWS physical symptoms. The State Anxiety Inventory test for current anxiety assessment and the Zung self-rating Depression Scale for current depression assessment were performed.
                Eight patients (26.6%) in the diazepam group and 4 patients (13.3%) in the GHB group dropped out. Both treatments were effective in reducing AWS. No significant difference was found between the groups in CIWA-Ar total score at baseline and at the different times of observation. Considering the CIWA-Ar subscore and Zung scale, a significant reduction of anxiety on day 4 (p < 0.02), agitation on day 5 (p < 0.02) and time of recovery of depression on day 5 (p < 0.02) was observed in the GHB group with respect to the diazepam group. Drowsiness and vertigo developed after initial drug administration in the GHB (19.2%) and diazepam (36.4%) groups and quickly resolved in both groups.
                GHB is as effective in the management of AWS as benzodiazepine and it seems to be quicker in reducing anxiety, agitation, and depression. Both drugs are safe and well-tolerated in AWS management.
Results of this review do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS. There are some suggestions that carbamazepine may actually be more effective in treating some aspects of alcohol withdrawal when compared to benzodiazepines, the current first-line regimen for alcohol withdrawal syndrome. Anticonvulsants seem to have limited side effects, although adverse effects are not rigorously reported in the analysed trials.