Volume intake and craving in alcohol withdrawal

AIMS: It has been shown that beer consumption is associated with alcohol craving, in contrast to wine or spirits consumption. The present study was undertaken to evaluate whether the daily volume intake of alcoholic beverages is associated with craving in patients undergoing alcohol withdrawal. METHODS: A total of 158 male patients were assessed using the obsessive compulsive drinking scale (OCDS) at admission. The daily volume intake of alcoholic beverages was calculated by adding the volume of all regularly consumed alcoholic beverages, disregarding their alcohol percentage. Lesch's typology was used to classify patients for subgroup analysis. RESULTS: The daily volume intake of alcoholic beverages correlated significantly with the extent of the OCDS (r = 0.33; P < 0.001). With general linear models, we found a significant association of the calculated daily volume intake of all alcoholic beverages with craving (F = 6.426; P = 0.012), but not for the daily ethanol intake. Differentiating the patients according to Lesch's typology a significant association was particularly found in Lesch Type 2 (model of anxiety) patients (F = 11.31; P = 0.001). CONCLUSION: Our results support the hypothesis that volume intake is associated with craving and suggest a role of pathophysiological changes in volume regulating mechanisms (such as vasopressin or ANP) in the neurobiology of alcohol craving, particularly in male patients of Lesch's Type 2 undergoing alcohol withdrawal.     

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.     

Serotonergic anti-depressants and ethanol withdrawal syndrome: a review

AIM: To review laboratory findings on the effects of anti-depressant agents that interact with the serotonergic system on signs of ethanol withdrawal syndrome in rats. METHOD: Adult Wistar rats received a modified liquid diet to produce ethanol dependence. Signs of ethanol withdrawal, locomotor hyperactivity, stereotyped behaviour, tremor, wet dog shakes, agitation, and audiogenic seizures, were evaluated for the first 6 h of ethanol withdrawal. The effects of the anti-depressants fluoxetine, venlafaxine, escitalopram, tianeptine, and extract of Hypericum perforatum (St. John's wort) (HPE) were examined. RESULTS: Some beneficial effects of fluoxetine, tianeptine, HPE, escitalopram and venlafaxine on ethanol withdrawal signs were observed, ranked as follows: fluoxetine = tianeptine > HPE > escitalopram > venlafaxine. CONCLUSIONS: Tianeptine and fluoxetine seem to be potent pharmacologically active agents on ethanol withdrawal syndrome in rats. Thus, these anti-depressants may be useful in treatment of ethanol withdrawal syndrome in patients with alcoholism. In addition to serotonergic effects, interactions with nitrergic, glutamatergic, and adenosinergic systems may also provide a significant contribution to the beneficial effects of these drugs on ethanol withdrawal syndrome.     

Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice

In alcoholic patients, ethanol is often consumed in a repeated cyclic pattern of intoxication followed by abstinence and the emergence of withdrawal symptoms. Repeated cycles of ethanol intoxication and withdrawal lead to a sensitization of central nervous system hyperexcitability as a result of an imbalance between inhibitory GABAergic transmission and excitatory glutamatergic transmission. Symptoms of alcohol withdrawal are usually treated pharmacologically with either benzodiazepines or anticonvulsant medications. However, recent evidence suggests that inhibition of glutamate transmission by stimulation of presynaptic inhibitory metabotropic glutamate receptors (i.e., mGluR2/3 receptors) or inhibition of mGluR5 receptors produces anticonvulsant effects. Therefore, the present study was designed to determine the effects the mGluR2/3 agonist LY379268 and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on ethanol withdrawal-induced seizure activity. Adult male C3H/He mice received chronic 16 h of ethanol vapor exposure in inhalation chambers followed by 8 h of withdrawal daily for 4 consecutive days. During the final (fourth) withdrawal cycle, mice were evaluated hourly for handling-induced convulsions (HIC), and were treated with vehicle, LY379268 (0.3, 1, and 3 mg/kg) or MPEP (1, 3, and 10 mg/kg) treatment at 4 and 8 h into withdrawal. Significant reductions in overall HIC activity were not observed following administration of either compound. These results suggest that inhibition of glutamate transmission by mGluR2/3 agonists or mGluR5 antagonists does not alter HIC activity during withdrawal from repeated ethanol exposure, and as such these compounds may have limited usefulness in the treatment of central nervous system hyperexcitability during alcohol withdrawal.     

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.     

Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal

AIMS: Alcohol withdrawal-enhanced neurotoxicity contributes to the addictive process. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity and learning. In this study, we explored the changes of serum BDNF levels in alcoholic patients at baseline and after one-week alcohol withdrawal. METHODS: Twenty-five alcoholic patients were admitted for alcohol detoxification treatment, and 22 healthy control subjects were also enrolled. We collected blood samples of the patient group on the first and seventh day of alcohol withdrawal, and measured serum BDNF level with sandwich enzyme-linked immunosorbent assay. The severity of withdrawal symptoms was evaluated by the Clinical Institute Withdrawal Assessment-Alcohol, Revised every eight hours. RESULTS: Serum BDNF levels did not differ significantly between alcoholic patients and control subjects. But BDNF levels were found to be significantly increased one week after alcohol withdrawal (from 13.9 +/- 3.8 ng/ml to 15.4 +/- 3.8 ng/ml, P = 0.03). A significant positive correlation was found between baseline BDNF level and baseline withdrawal severity (r = 0.45, P = 0.03). CONCLUSIONS: The present study suggests that elevated serum BDNF levels were found in early alcohol withdrawal, implying that BDNF may involve in neuroadaptation during the period.     

Use of alcoholic beverages in VA medical centers

Background  

Benzodiazepines are the first-line choice for the treatment of alcohol withdrawal syndrome. However, several hospitals continue to provide alcoholic beverages through their formulary for the treatment of alcohol withdrawal. While there are data on the prevalence of this practice in academic medical centers, there are no data on the availability of alcoholic beverages at the formularies of the hospitals operated by the department of Veteran's Affairs.     

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.     

Drugs and health in the Brazilian press: an analysis of articles published in newspapers and magazines

This article analyzes information recently published by the Brazilian press on the use of psychoactive drugs and its implications on health. A sample of 502 newspaper and magazine articles published in 1998 was researched using content analysis. The drugs most frequently featured in the headlines were tobacco (18.1%), coca-derived drugs (9.2%), marijuana (9.2%), alcoholic beverages (8.6%), and anabolic steroids (7.4%). Solvents were featured in only one article, although they are the most commonly used drug in Brazil, second only to alcohol and tobacco. These data indicate an imbalance between the journalistic approach and the epidemiological profile of psychoactive drug consumption in Brazil. Dependence was the most frequent consequence mentioned in the articles (46%), followed by violence (9.2%), withdrawal syndrome (8.0%), and AIDS (6.8%). The focus of the articles varied according to the drug in question. While articles on marijuana focused on its therapeutic use and legalization, those on cocaine-related issues discussed both the damage caused by consumption as well as various interventions (treatment and repression).     

Ethanol for treatment of delirium in alcohol dependent patients on intensive care units in the Netherlands: efficacy not proven

OBJECTIVE: To determine the use of ethanol in Dutch intensive care departments (ICUs) for the treatment of deliriant symptoms in alcohol-dependent patients, and to study the literature data concerning this use. DESIGN: Literature search and questionnaire. METHOD: In Medline a search was performed from 1993 onward with keywords 'intensive care' and 'alcohol'/'alcohol withdrawal syndrome'/'delirium'. All Dutch ICUs received a written questionnaire (n = 247) concerning the use of ethanol in this patient group. RESULTS: According to the literature the syndrome is characterized by autonomous hyperactivity, resulting in tachycardia, tachypnoea, hypertension, perspiration, fever, tremors en fear. In delirium caused by alcohol withdrawal benzodiazepines are advised, sometimes in combination with haloperidol. ICUs sometimes use ethanol, although the effectiveness in preventing or treating withdrawal symptoms has never been ascertained in scientific investigations: in a meta-analysis the conclusion is drawn that the studies are too small and insufficiently objective to determine the effectiveness. The response to the questionnaire was 55% (96/176). From all ICUs, 15 (16%) used ethanol occasionally, and treated an estimated 17% of the admitted alcohol-dependent patients. There was a tendency for large ICUs to use ethanol in these patients more frequently. Each ICU used its own method to calculate the required ethanol dosage. Calculation on the basis of these dosages indicated a plasma ethanol concentration of at most 0.5 promille. CONCLUSION: Because only a small percentage of deliriums on ICUs are caused by alcohol withdrawal, and the effectiveness of ethanol in alcohol-dependent patients with a delirium has never been proven, the use of ethanol in such cases is discouraged.     

Hyperventilation, anxiety, craving for alcohol: a subacute alcohol withdrawal syndrome

Hyperventilation leading to respiratory alkalosis is part of the acute alcohol withdrawal syndrome On the basis of clinical observations and a literature review on withdrawal symptoms the following was hypothesized: (a) hyperventilation is also part of a subacute alcohol withdrawal syndrome and (b) hyperventilation appears together with anxiety and craving for alcohol. These hypotheses were tested in a sample of 37 male alcoholic inpatients, abstinent for periods from several weeks to 9 months. Subjects were administered a questionnaire dealing with drinking history and craving for alcohol during abstinence, the Spielberger Anxiety Inventory and a hyperventilation complaint checklist. Subjects' disposition to hyperventilation was assessed during a physiological measurement session. Results show that hyperventilatory symptoms, anxiety and craving for alcohol appear together. Moreover, the severity of hyperventilatory and anxiety symptomatology is positively correlated with the duration of physically dependent alcohol use but not with the duration of excessive drinking per se, irrespective of age. These results corroborate the hypotheses outlined before.     

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.     

Responses to cardiovascular drugs during alcohol withdrawal

AIM: To present findings on the kinetics and dynamics of cardiovascular drugs during alcohol withdrawal (AW), compared with that observed in remission. METHOD: Studies were reviewed and summarized. RESULTS: A single-dose study in alcoholic patients with propranolol, a beta-adrenergic antagonist, showed that the negative inotropic effect was decreased and the bradycardiac effect increased during AW as compared with during early remission. The hypotensive effect of isosorbid dinitrate, commonly used as a vasodilatator, was weaker at the onset of AW, being associated with the decreased bioavailability of the drug. Verapamil, which is a L-type Ca2+ channel antagonist, produced a bradycardiac effect at the onset of AW, but no effect was observed in early remission. The effect was probably due to changes in L-type Ca2+ channels because no differences in verapamil concentrations between AW and early remission were observed. CONCLUSION: Taken together, AW modifies the dynamics and kinetics of cardiac drugs, which may have an impact on the treatment of alcoholic patients with cardiac diseases.     

Platelet serotonergic binding sites in alcohol-dependent patients.

The serotonin (5-hydroxytryptamine, 5-HT) uptake sites assessed with both [3H]imipramine and [3H]paroxetine, and the 5-HT2A receptors were simultaneously measured in platelets from 24 male subjects meeting the American Psychiatric Association's DSM-IV criteria for alcohol dependence and admitted for inpatient detoxification. Blood samples from alcoholic patients were collected during acute alcohol intoxication (day 0), during withdrawal (day 1), and after 2 weeks of abstinence (day 14). All patients met the criteria for type II alcoholism. Alcohol misuse was found to be associated with an increased number and a lower affinity of [3H]paroxetine binding in comparison to the control values. Abstinence from alcohol for 2 weeks (day 14) resulted in a decrease in the number of 5-HT uptake sites labelled with [3H]paroxetine compared to normal values, together with a significant decrease in the number of 5-HT2A binding sites. The present data indicate that altered serotonergic function existing in alcoholic patients is a reversible phenomenon that normalizes after detoxification and withdrawal.     

Alcohol and the liver: ethanol metabolism and the pathomechanism of alcoholic liver damage]

Ethanol is oxidized in the liver by three different enzyme systems, namely by alcohol dehidrogenase (ADH), the microsomal ethanol oxidizing system and catalase. Alcohol also undergoes a first pass metabolism in the gastric mucosa due to alcohol dehydrogenase. This first pass metabolism of ethanol is decreased in the alcoholic, in the fasted state, in the elderly and during cimetidine therapy leading to elevated alcohol blood-concentrations. Ethanol toxicity is closely related to its metabolism in the liver. Ethanol oxidation by ADH generates reducing equivalents (NADH) and acetaldehyde (AA). The elevated NADH/NAD ratio results in alterations of the intermediary metabolism of lipids, carbohydrates, proteins, purines, hormones and porphyrins. Furthermore, NADH flavours free radical production. The ethanol-associated redox changes are pronounced in the perivenular zone, since this is the area of low oxygen tension and of high ADH activity. In addition to NADH, AA exerts striking toxic effects on the hepatocyte. AA binds to cellular proteins and membranes including the mitochondria, microtubules, glutathion and various enzymes. In addition, AA and lactate stimulate collagen production in fibroblasts. AA-adducts stimulate the production of antibodies against AA-epitopes and could thus aggravate the liver injury. Chronic ethanol consumption results also in the microsomal induction of a specific ethanol-inducible form of cytochrome P--450, the cytochrome P--450IIE1 with high affinity not only to ethanol but also to some drugs (acetaminophen), procarcinogens (nitrosamines) and industrial agents (carbon tetrachloride). The interaction between ethanol metabolism and the metabolism of these compounds including vitamin A may also contribute to hepatic toxicity, since the susceptibility of the alcoholic toward those compounds is enhanced.     

Endogenous breath ethanol concentrations in abstinent alcohol abusers and normals

A highly sensitive gas chromatographic breath assay was used to measure the concentration of endogenous ethanol in the breath of fasting volunteers who had consumed no alcoholic beverages. Normal subjects (n = 15) were studied, as well as withdrawn hospitalized alcohol abusers (n = 13) who had abstained from ethanol for at least two weeks. The mean breath ethanol concentrations were 1.88 nmol/l (SD = 1.06) in the normal subjects and 17.84 nmol/l (SD = 8.81) in the abstinent alcohol abusers. The difference between the two groups was statistically significant (p less than 0.001) and could have arisen either from ingestion of exogenous ethanol (from sources such as tobacco smoke) or from metabolic differences between the two groups.     

Vitamin A utilization status in chronic alcoholic patients

The utilization status of vitamin A (retinol) (treated with oral retinol - 2500 I.U. daily (=250 micrograms) x 5 days - "OROVITE -7", Bencard, England) in 25 patients (M = 23, F = 2; mean age +/- S.D. = 43.88 +/- 12.67; range = 28-70 years), 3 out of 25 patients (12%) were found to be deficient in the vitamin and during treatment further improvement of the blood levels of the vitamin was observed in all except one elderly male patient (age 61 years) and the mean levels on admission (661.04 micrograms/l) was also slightly improved after treatment (662.84 micrograms/l). Night blindness, alcoholic liver disease and hypogonadism are commonly seen in chronic alcoholic patients. Falling plasma levels of the vitamin indicate exhaustion of its hepatic storage. It is therefore suggested that chronic alcoholics should be given vitamin A supplementation along with other polyvitamins during conventional detoxification therapy for ethanol withdrawal syndrome in order to prevent dangerous manifestations of hypovitaminosis A, such as night blindness, cancer, hypogonadism and alcoholic liver disease.     

Alcoholic parents and their children

Summary Some 211 male alcoholic in-patients were compared with a simple random sample of 200 men from Greater Stockholm. The group of male alcoholic in-patients and the random sample were subdivided with respect to alcohol consumption and use of hepatotoxic drugs: (IA) men from the random sample with low or moderate alcohol consumption and no use of drugs (n= 169); (IB) men from the random sample with low or moderate alcohol consumption with use of drugs (n= 31); (IIA) alcoholic in-patients with use of alcohol but no drugs (n= 171); (IIB) alcoholic in-patients with use of alcohol and drugs (n= 40). Earlier and more severe alcohol-related and anti-social problems were found among subjects with an alcoholic parent than among subjects without an alcoholic parent. The highest level of problems was noted for subjects with alcoholism in both parents and among the alcoholic in-patients. Groups which resembled each other were the drug users in the alcoholic group and in the general sample. Both inherited and environmental factors are important determinants and many of these individuals have psycho-social problems as children and adults. The children of those adults who used alcohol in combination with drugs (IIB) had most problems and the most severe problems. In the general population sample, those who used alcohol in combination with drugs (IB) had so many problems in the family and psycho-social problems themselves that they resembled the alcoholic in-patients and especially the group with high alcohol consumption in combination with drugs (IIB). A new finding is that the high-risk groups IB and IIB, who used both alcohol and drugs, had experienced a more disturbed school career and were more aggressive, had more nervous problems, and were more emotionally disturbed than the population studied belonged to a concealed alcoholic group raises the question whether it is really true that every sixth inhabitant of Greater Stockholm has a serious alcohol problem. However, the sample was relatively small, and this implies some uncertainty in the determination of the prevalence. A finding that indicates that the figure is not in fact so far from reality is that 65% of group IB were themselves of the opinion that they drank alcohol often or regarded themselves as alcoholics.     

Reduced alcohol consumption in mice lacking preprodynorphin.

Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the kappa-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower amounts of alcohol in a two-bottle choice test as compared with wild-type littermates. In the same test, knockout mice of both sexes showed a strong reduction of preference for saccharin compared to control mice. In contrast, under conditions of limited (4 h) access (light phase of the light/dark cycle), null mutant mice did not show any differences in consumption of saccharin, but they showed significantly reduced intake of sucrose. To determine the possible cause for reduction of ethanol preference and intake, we studied other ethanol-related behaviors in mice lacking the preprodynorphin gene. There were no differences between null mutant and wild-type mice in ethanol-induced loss of righting reflex, acute ethanol withdrawal, ethanol-induced conditioned place preference, or conditioned taste aversion to ethanol. These results indicate that deletion of preprodynorphin leads to substantial reduction of alcohol intake in female mice, and suggest that this is caused by decreased orosensory reward of alcohol (sweet taste and/or palatability).