Alcohol withdrawal and carbamazepine

The use of pharmacologic intervention in the management of alcohol withdrawal syndrome is briefly presented. The use of carbamazepine, a tricyclic anticonvulsant with clinical efficacy in depressive illness, in alcohol withdrawal treatment is reviewed. A comparative analysis between carbamazepine and major drugs used in alcohol withdrawal syndrome is made. This includes the evaluation of both clinical advantages and disadvantages in addition to identification of drug adverse reaction and interaction with alcohol. The mechanism of action of carbamazepine is also examined. Carbamazepine appears to possess a useful pharmacotherapeutic potential in the management of acute alcohol withdrawal syndrome, and its use in long-term treatment is suggested.     

Carbamazepine and ethanol elicited responses in rodents

The interaction between carbamazepine, and anticonvulsant with clinical efficacy in alcohol withdrawal syndrome, and ethanol was studied in rodents. Voluntary intake of ethanol by the rat was the behavioral performance test used to assess one aspect of such interaction. Carbamazepine, 50 mg/kg, IP, caused aversion to ethanol drinking. The drug was devoid of action on rat hepatic ethanol and acetaldehyde metabolizing enzymes, i.e., alcohol- and aldehyde dehydrogenase, and on testicular aldehyde dehydrogenase. The moderate induction of the latter by prolonged ethanol consumption was antagonized by a single dose of carbamazepine (50 mg/kg). Administration of carbamazepine, 50 mg/kg twice daily for three consecutive days, moderately inhibited mouse liver alcohol dehydrogenase in the male but not in the female mouse. This treatment did not alter endogenous mouse cardiac lactate dehydrogenase isoenzymes or hepatic aldehyde dehydrogenase in either sex. The enzymatic portion of the study suggests species and sex differences in the effects of carbamazepine studied. The reduction of voluntary drinking of ethanol by carbamazepine may have clinical implications, e.g., the extension of its use in alcohol withdrawal phase to alcohol abstinence.     

Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence

We briefly review two double-blind, placebo-controlled surveys conducted in this laboratory with the aim of evaluating the efficacy of gamma-hydroxybutyric acid in the treatment of alcohol withdrawal syndrome as well as alcohol craving and consumption in alcoholics. In the first study, acute administration of 50 mg/kg gamma-hydroxybutyric acid, a nonhypnotic dose in alcoholic patients, resulted in a rapid and significant reduction of the severity score of alcohol withdrawal signs and symptoms that lasted as long as 7 hours. In the second study, treatment with 50 mg/kg/day gamma-hydroxybutyric acid for 3 consecutive months (1) reduced the number of daily drinks by approximately 50%, (2) increased the days of abstinence approximately threefold, and (3) reduced the alcohol craving score by up to 60%. These results feature gamma-hydroxybutyric acid as an effective agent for the treatment of alcohol dependence. Data on the effect of gamma-hydroxybutyric acid on opiate withdrawal syndrome also are reviewed. Administration of 25 mg/kg induced a marked reduction of opiate withdrawal score in both heroin- and methadone-dependent subjects. Finally, we report the cases of adverse reactions to and abuse of gamma-hydroxybutyric acid revealed in a retrospective analysis of patients recruited in this laboratory over a 10-year period.     

Prevention of alcohol withdrawal seizures with carbamazepine and valproic acid

To evaluate the value of the nonsedative anticonvulsants carbamazepine and valproic acid a controlled study including drug monitoring was carried out. Intoxicated alcoholics (n = 138) were admitted for inpatient detoxication and randomly assigned to either carbamazepine (n = 43), sodium valproate (n = 46) or placebo (n = 49) in a double-blind fashion. Drug treatment lasted for four days and the daily doses of both drugs amounted to 1200 mg in the beginning of the study. Sodium valproate induced gastric distress, nausea and vomiting more frequently than placebo. About half of the subjects had to stop carbamazepine because of intolerable side-effects including vertigo, nausea, vomiting, diplopia and rash. Serum carbamazepine levels (18-89 mumol/l) were found to be high (greater than 40 mumol/l) in many but not all of these subjects. Seizures occurred in 3 subjects on placebo, 2 on carbamazepine and 1 on sodium valproate. Delirium tremens developed in 2 on sodium valproate and 1 on placebo. The study demonstrates that drug side-effects may seriously hamper the utility of carbamazepine and sodium valproate as routine treatment for the prevention of alcohol withdrawal symptoms.     

Gamma-hydroxybutyric acid and alcohol-related syndromes

We report on the effectiveness and safety of gamma-hydroxybutyric acid in the therapy of overt alcohol withdrawal syndromes, their prevention, and the prevention of relapses in formerly detoxified alcoholics. We studied 321 patients (236 men, 85 women), divided into two open-study groups for the treatment and prevention of alcohol withdrawal syndromes and one double-blind study group to evaluate the effects of gamma-hydroxybutyric acid versus placebo on alcoholic craving and relapses in detoxified patients. Gamma-hydroxybutyric acid treatment promptly reduced withdrawal symptoms in all patients and prevented alcohol withdrawal syndromes in 55% of cases. The attenuation of craving in detoxified patients was significantly greater in the gamma-hydroxybutyric acid-treated group in comparison with the placebo-treated group. The therapeutic use of gamma-hydroxybutyric acid was not accompanied by serious side effects. Gamma-hydroxybutyric acid diversion was poorly represented: gamma-hydroxybutyric acid-induced abuse was reported in 4 (1.1%) of 345 treated patients, and only 9 cases of gamma-hydroxybutyric acid acute poisoning were reported in the years 1992–1995. Our results suggest that gamma-hydroxybutyric acid, with a favorable risk/benefit ratio, is a clinically useful drug in the treatment of alcohol dependence.     

THE DRUG TREATMENT OF ALCOHOL WITHDRAWAL SYMPTOMS: A SYSTEMATIC REVIEW

A computer-assisted and cross-reference literature search identifiedtrials of therapy for alcohol withdrawal symptoms. Those witha randomized, double-blind placebo-controlled design were systematicallyassessed for quality of methodology. Fourteen studies were identifiedinvestigating 12 different drugs. The quality of methodologicaldesign, even among this highly selected group of published studies,was often poor. Study populations were generally under-defined,most studies excluded severely ill patients, control groupswere poorly matched, and the use of additional medication mayhave confounded results in some studies. Twelve different ratingscales were used to assess severity of symptoms. All 12 compoundsinvestigated were reported to be superior to placebo, but thishas only been replicated for benzodiazepines and chlormethiazole.Further research using better methods is required to allow comparisonof different drugs in the treatment of alcohol withdrawal symptoms.On the evidence available, a long-acting benzodiazepine shouldbe the drug of first choice.     

Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal

The aim of this double-blind, comparative study was to assess the efficacy and safety of gamma-hydroxybutyrate (GHB) in ameliorating the symptoms of alcohol withdrawal. Newly admitted alcohol-dependent patients (n = 98) were randomized to receive either clomethiazole 1000 mg daily (CLO group) (n = 33), or 50 mg GHB/kg body wt (n = 33) or 100 mg GHB/kg body wt (n = 32). This dose was administered for 5 days, halved on day 6, and on days 7 and 8 only placebo was given. As CLO is available as capsules and GHB as syrup, a double-dummy method was used to try to ensure blindness. The groups were matched in terms of baseline demographic and alcohol-related variables. There was no difference between the three treatments in ratings of alcohol withdrawal symptoms nor requests for additional medication. After tapering off the active medication, there was no increase in withdrawal symptoms, indicating that physical tolerance did not develop to either GHB or CLO within the 5-day treatment period. The most frequently reported side-effect of GHB was transient vertigo, particularly after the evening double dose.     

Comparison of cyanamide and placebo in the treatment of alcohol dependence of adolescents

AIMS: About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that cyanamide may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term cyanamide treatment in alcohol dependence of adolescents. METHODS: In this, double-blind, placebo-controlled study, we recruited 26 patients, aged 16-19 years, with chronic (frequent and regular) or episodic (frequent, but irregular) alcohol dependence. Patients were randomly allocated treatment with cyanamide (200 mg daily) or a placebo for 90 days. Patients were assessed on the day the treatment was started, and on days 30 and 90, by interview, self-report, questionnaire and laboratory screening. Patients were classified as abstinent, relapsing or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. RESULTS: The cyanamide (n = 13) and placebo (n = 13) groups were well matched in terms of baseline demographic and alcohol-related variables. Mean cumulative abstinence duration was significantly greater in the cyanamide group than in the placebo group. Apart from occasional diarrhoea, there was no difference in side effects between groups. CONCLUSIONS: Cyanamide seems to be an effective and well tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for the treatment of some adolescent alcohol-dependent patients. Because of reported hepatotoxic, haematological and dermatological side effects, patients should be observed continuously by experienced clinicians. Further studies are necessary to prove the efficacy of cyanamide in adolescents.     

Alcohol withdrawal treatment in intoxicated vs non-intoxicated patients: a controlled open-label study with tiapride/carbamazepine,clomethiazole and diazepam

AIMS AND METHODS: Alcohol withdrawal treatment efficacy of tiapride/carbamazepine (A) vs clomethiazole (B) vs diazepam (C) in non-intoxicated patients and vs tiapride/carbamazepine in intoxicated patients (D; breath alcohol concentration > or = 1 g/l) was tested (n = 127) in a controlled randomized open-label study. RESULTS: Efficacy and safety were not different between groups (total group: delirium, 3.9%; seizure, 0.8%), except for a lack of efficacy in 18% of intoxicated tiapride/carbamazepine patients. A change of medication in this group was necessary only when primarily intoxicated patients had reached the non-intoxicated range. CONCLUSIONS: Treatment with tiapride/carbamazepine in alcohol-intoxicated patients proved to be safe.     

DETOXIFICATION: THE USE OF BENZODIAZEPINES

The use of benzodiazepines in the management of alcohol withdrawalin chemically dependent alcoholics is reviewed. Benzodiazepinesare safer than earlier sedative drugs used for this purpose,such as barbiturates, chloral hydrate and paraldehyde. Differencesin efficacy between individual benzodiazepines are slight, butbenefits and disadvantages of longer acting (diazepam and chlordiazepoxide)drugs and shorter acting (lorazepam and oxazepam) are compared.Long-term outcome is commented on.     

Naltrexone exerts a favourable effect on plasma lipids in abstinent patients with alcohol dependence

Epidemiological studies suggest that abstinence periods in some patients with alcohol dependence may increase their cardiovascular risk via proatherogenic changes in plasma lipid levels. Because of this, drugs administered in withdrawal therapy should not exacerbate these effects. The aim of this study was to estimate the influence of naltrexone, carbamazepine, and lithium carbonate on plasma lipid levels in 160 alcohol-dependent males during withdrawal therapy. Plasma concentrations of total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides (TGL) were determined every 2 weeks for 20 weeks. Pharmacotherapy (naltrexone 50 mg, carbamazepine 600-800 mg, lithium carbonate 500-1000 mg once per day or placebo) was given within the framework of a double-blind study between the fourth and twentieth weeks of the study. The results of 116 patients who maintained abstinence during the whole 20-week observation period were analysed. In patients treated with naltrexone significant decreases in TC (239 +/- 58 vs 216 +/- 52 mg/dl; P < 0.01) and TGL (125 +/- 68 vs 86 +/- 33 mg/dl; P < 0.02) concentrations after 16 weeks of pharmacotherapy were observed. In patients treated with carbamazepine, significant increases in TC (224 +/- 39 vs 243 +/- 54 mg/dl, P < 0.04) and HDL (40 +/- 10 vs 44 +/- 8 mg/dl, P < 0.01) after 16 weeks of pharmacotherapy were observed. After 16 weeks of pharmacotherapy, patients treated with naltrexone had lower mean TC (P < 0.03) and LDL-C (P < 0.01) concentrations than patients treated with carbamazepine, lower mean LDL-C levels than patients treated with lithium carbonate (149 +/- 54 vs 164 +/- 57 mg/dl, P < 0.01), and lower TGL concentrations than patients of the remaining pharmacotherapy groups. We conclude that naltrexone, by its hypolipaemic effect, could be useful for withdrawal therapy in alcoholic patients, because it may decrease the cardiovascular risk in abstinent patients with alcohol dependence by lipid mechanisms.     

REDUCED BINOCULAR DEPTH INVERSION IN PATIENTS WITH ALCOHOLISM

Binocular depth inversion represents an illusion of visual perception,serving to invert the perception of implausible hollow objects,e.g. a hollow face into a normal face. Such inversion occursfrequently, especially when objects with a higher degree offamiliarity (e.g. photographs of faces) are displayed. Cognitivefactors are assumed to override the binocular disparity cuesof stereopsis. The hypothesis was tested that during mild andmoderate alcohol withdrawal, and severe and mild alcohol intoxication,the central nervous system is unable to correct implausibleperceptual hypotheses. Measurements of binocular depth inversionin perception of three-dimensional objects were performed in10 patients with severe alcohol intoxication, in 10 subjectswith mild alcohol intoxication, in nine patients with moderatealcohol withdrawal treated with carbamazepine, in 10 patientswith moderate alcohol withdrawal without any pharmacologicaltreatment, in 11 patients with mild alcohol withdrawal and in10 healthy volunteers. The binocular depth inversion scoreswere highly elevated in the severely intoxicated patients groupand in the group with moderate withdrawal symptoms without carbamazepinetreatment, in comparison to the healthy volunteers. The datademonstrate a strong impairment of binocular depth inversionin moderate alcohol withdrawal and during severe alcohol intoxication.This supports the view that these states may be accompaniedby a disorganization of the interaction between sensory inputand top-down component. The effects of carbamazepine are discussed.     

A double-blind randomized placebo-controlled trial of lofexidine in alcohol withdrawal: lofexidine is not a useful adjunct to chlordiazepoxide

Lofexidine is an alpha-adrenoceptor agonist which has proved useful in opiate withdrawal and which, through its attenuation of noradrenergic activity, might be a valuable adjunct in the management of alcohol withdrawal. The objective of this study was to compare the clinical effectiveness and patient retention with adjunctive lofexidine versus placebo in the treatment of alcohol withdrawal under chlordiazepoxide cover. This was done in a prospective double-blind randomized placebo-controlled trial with 72 alcohol-dependent adults referred and admitted for in-patient alcohol detoxification. The adjunctive lofexidine group experienced significantly more severe withdrawal symptoms, greater hypotensive problems, more adverse effects, and no better rates of retention in treatment. Lofexidine provides no discernible benefit as an adjunctive medication (to chlordiazepoxide) in alcohol detoxification and, on the basis of our study, appears to be contra-indicated.     

替吉奥联合顺铂治疗晚期胃癌近期疗效观察

目的观察替吉奥胶囊（S-1）联合顺铂治疗晚期胃癌的近期疗效和毒副反应。方法初治和复治的晚期胃癌53例,替吉奥胶囊每天80mg／m2,2次／d,口服14d,停药7d;顺铂75mg／ml,d1～3静脉滴注,21d为1个周期,2周期后评价疗效。结果总有效率为67．9％（36／53）,主要毒副反应为胃肠道反应,Ⅲ～Ⅳ度的白细胞减少占13．2％（7／53）。结论替吉奥胶囊联合顺铂方案治疗晚期胃癌是有效、安全的。     

An attempt to evaluate diagnostic and prognostic significance of blood endogenous ethanol in alcoholics and their relatives

Endogenous ethanol in the blood of human subjects was measured by gas chromatography. In healthy males, 12-13-year-old boys (sons of alcoholic and nonalcoholic fathers), and alcoholic inpatients (after cessation of all drugs), the endogenous ethanol levels ranged from 0 to 4.3 mg/l. The results showed no significant differences between the groups. At the period of alcohol withdrawal reactions the concentrations of endogenous ethanol were minimal in patients with delirium tremens and maximal in patients with mild alcohol withdrawal syndrome, the dynamics of this parameter being dependent on the severity of the alcohol withdrawal syndrome and the nature of the drugs prescribed.     

替吉奥联合顺铂治疗晚期胃癌近期疗效观察

目的观察替吉奥胶囊(S-1)联合顺铂治疗晚期胃癌的近期疗效和毒副反应。方法初治和复治的晚期胃癌53例,替吉奥胶囊每天80mg/m2,2次/d,口服14d,停药7d;顺铂75mg/m2,d1~3静脉滴注,21d为1个周期,2周期后评价疗效。结果总有效率为67.9%(36/53),主要毒副反应为胃肠道反应,Ⅲ~Ⅳ度的白细胞减少占13.2%(7/53)。结论替吉奥胶囊联合顺铂方案治疗晚期胃癌是有效、安全的。     

Clinical performance of a levonorgestrel-releasing intracervical contraceptive device during the first year of use

One-hundred-and-ninety-eight women used a new type of levonorgestrel-releasing intracervical contraceptive device (LNG-ICD) designed to release 20 μg levonorgestrel/day. The insertion took place within 7 days of menstruation. Clinical performance during the first year of LNG-ICD use was evaluated. Seven pregnancies occurred during the study period; one in an epileptic woman using carbamazepine, 300 mg/day, and the other six in healthy women after unnoticed expulsion of the ICD. Sixteen spontaneous expulsions occurred. The most common reasons for removal were side effects, including bleeding disturbances, hormonal side effects and other medical reasons. The continuation rate was 72.6 per cent after one year. Three pelvic infections were observed.     

Summary of the Dutch College of General Practitioners' practice guideline 'Delirium in elderly people'

The Dutch College of General Practitioners' practice guideline 'Delirium in elderly people' contains a number of key messages. These are: Consider the diagnosis of delirium in the case of changes in consciousness and attention, incoherent thinking or disorientation, if this picture developed over a short period of time (hours to days) and if the symptoms vary over the 24-hour period. Delirium is provoked by one or more somatic disorders; investigation and treatment of these disorders is an essential part of managing delirium. It is often difficult to distinguish delirium from dementia and depression. Although delirium is generally reversible, the prognosis in the elderly is relatively poor. If delirium is accompanied by fear or agitation, haloperidol is the drug of first choice, but in delirium induced by alcohol withdrawal or benzodiazepine withdrawal, a short-acting benzodiazepine such as lorazepam or oxazepam is indicated. Part of the treatment, but also prevention of delirium is focused on inducing factors that can provoke a delirium, such as medication with an anticholinergic effect, polypharmacy, inadequate nutrition, dehydration, sleep deprivation, immobility and sensory handicaps.     

Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain

To test acamprosate's role as an aid in preventing relapse after detoxification, 296 alcohol-dependent patients entered a prospective, multicentre, randomized, double-blind, parallel comparison of acamprosate treatment consisting of two 333 mg tablets given three times daily for 180 days with matching placebo treatment. Unlike previous studies, acamprosate was prescribed from the start of alcohol withdrawal, rather than after the detoxification process. During the treatment period, 110 patients dropped out. The two treatment groups were balanced with regard to baseline values and reasons for discontinuation. There was no difference between the groups in the severity of withdrawal symptoms as measured by the CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol scale). Acamprosate given during withdrawal did not cause unwanted effects. The cumulative abstinence duration (CAD, main end-point) was 19 days longer in the acamprosate treatment group than the placebo treatment group (analysis of variance on ranks, P = 0.0006) and the stable recovery duration, defined as the number of abstinent days between the last relapse into any drinking and the end of the trial, was 16 days longer in the acamprosate treatment group (P = 0.021). Continuous abstinence, estimated by survival analysis on time to first relapse, was achieved by 35% of acamprosate-treated patients and 26% of placebo-treated patients (log rank P = 0.068). The geometric mean of the ratio final/baseline values for serum carbohydrate-deficient transferrin was 0.802 (placebo) and 0.733 (acamprosate) (P = 0.059). The geometric mean of the ratio final/baseline values for serum gamma-glutamyltransferase was 0.496 (placebo) and 0.415 (acamprosate) (P = 0.024) which corroborated the greater abstinence reported by the acamprosate group.     

Adverse effects of benzodiazepines

The growing realisation that the benzodiazepines have potential for causing serious harm has caused concern due to their wide and common use. This paper is a review of the adverse effects of benzodiazepines, and concentrates on four areas of particular concern: drug dependence with the consequent withdrawal symptoms; psychological effects while on the drugs; use by the elderly; and tolerance to the drug effects. Although the phenomenon of a benzodiazepine withdrawal syndrome is generally accepted, there is still controversy over the frequency amongst users. A number of major studies are reviewed here, and the main methodological issues are discussed. These include definition of the withdrawal symptoms, selection of subjects, and use of double-blind, placebo-controlled conditions. The studies investigating psychological impairment with benzodiazepine use deal mainly with motor performance and co-ordination, although there is a large group of studies looking at the effect of the drugs on memory. Although the studies reviewed make a considerable contribution to the understanding of the effects of benzodiazepines, they focus on physiological and specific psychological variables, rather than more global measures of functioning and behaviour. It is suggested here that this emphasis needs to change in order to obtain a clearer picture of how benzodiazepines affect quality of life. Future studies should also be prospective in design, and include clear criteria for the selection of subjects and for the definition of withdrawal symptoms.