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Treatment of the alcohol withdrawal syndrome is the first step towards the rehabilitation of alcohol-dependent patients. The objectives of treatment are relief of symptoms, prevention of complications and a smooth transition into a long-term rehabilitation programme. Recently, progress has been made in the clinical management of the alcohol withdrawal syndrome through standardization of the assessment using the CIWA-A scale and frequent monitoring of clinical findings, recognition of the efficacy of non-pharmacological interventions (i.e. standardized supportive care) and simplification of pharmacotherapy by optimizing the use of long-acting benzodiadepines via a loading dose technique. Benzodiazepines, because of their cross-tolerance with ethanol, wide margin of safety and low potential for physical dependence and tolerance, are very effective and are the drugs of choice for the treatment of the alcohol withdrawal syndrome.

Alcohol is used in most cultures despite knowledge of the physical, psychological and social problems associated with its abuse. Behavioural impairment is a function of several factors, including blood alcohol concentration (BAC) and the rate of alcohol metabolism by alcohol dehydrogenase and the microsomal ethanol-oxidizing system. Their availability and activity depend upon alcohol use history, ethnicity, other drug use and gender. Adverse social consequences related to alcohol intoxication include impaired driving, acts of aggression and violence towards self and others, and various types of accidents. About 40% of all fatal traffic accidents in Canada and the US in 1986-1987 were alcohol-related. Similar statistics have been reported in the UK and Europe (e.g. Sweden). The risk of a fatal car accident increases exponentially with a driver's BAC, prompting recommendations to lower the legal BAC limit for driving and piloting aircraft. Risks of falls, drownings, and fires and burns may also be increased by alcohol intoxication. At least 22% of work-related accidents may have involved alcohol use. These data are probably conservative estimates as under-reporting of alcohol use is likely. Alcohol facilitates aggressive behaviours, but it is difficult to separate the pharmacological effect from psychosocial effects or some other common factor (e.g. low CSF levels of the serotonin metabolite 5-H1AA have been reported in alcoholics, suicide attempters, violent offenders). In addition, alcohol interacts with other drugs to increase or decrease their behavioural and therapeutic effects. An acutely high BAC inhibits the metabolism of other CNS depressants (e.g. benzodiazepines), but long-term alcohol use increases the metabolism of most drugs. A potential amethystic agent, to block or reverse alcohol's effects, has been identified in preclinical studies (Ro15-4513, an imidazobenzodiazepine). Some clinical studies indicated that naloxone, lithium, ibuprofen, zimeldine and catecholamine agonists may reduce ethanol-induced behavioural or cognitive effects but the results have not been consistently replicated. More research is needed to determine the potential clinical use of amethystic agents and other pharmacotherapies in the prevention and treatment of problem behaviours associated with alcohol abuse and intoxication.

Self-report of daily alcohol consumption has been used as the dependent variable in clinical trials to assess the effects of two serotonin uptake inhibitory drugs, zimelidine and citalopram. The validity of the dairy data was established by correlating concentration of ethanol in daily urine samples with number of reported standard alcoholic drinks (r = 0.62 for the 934 subject-days in the zimelidine study; r = 0.54 for the 3,103 subject-days in the citalopram study, both p less than 0.0001). The effects of factors other than inaccurate reporting, such as the range of values for reported daily drinks and subjects' drinking patterns, on the correlation coefficients for all subject-days and for individual subjects in the citalopram study are discussed. Sampling 50% or fewer of the 84 days of the citalopram study for each subject is economically advantageous and did not significantly change the values of the correlation coefficients or the rank positions of subjects but did increase the 95% confidence intervals for the correlation coefficients, indicating less certainty about the actual correlation coefficients and, therefore, the accuracy of a subject's self-report. The ability of urine ethanol concentration to validate objectively diaries of alcohol consumption is limited by factors that must be considered but are likely to be out of the investigator's control.

The mechanism of the interaction between ethanol and diazepam is not known. Six healthy male subjects (aged 21 to 32 yr) were randomly assigned in a balanced crossover study to each of two treatments, 28 days apart: (1) diazepam 10 mg intravenously over 20 min, preceded by 60 min with ethanol 0.7 gm/kg (diluted to 20% v/v) orally over 15 min and followed for 8 hr by ethanol 0.15 gm/kg/hr to maintain the blood alcohol concentrations between 800 to 1,000 mg/l; (2) diazepam 10 mg intravenously over 20 min. The area under the curve (AUC) for total diazepam increased in all subjects (30.1 +/- 10.7%, mean = SD, p < 0.02) after ethanol. Since AUCfree diazepam also rose in all (mean - 26.5 +/- 17.3%) and AUC of the metabolite N-desmethyldiazepam fell (mean = 50.5 +/- 11.7%, p < 0.01) there had been inhibition of hepatic intrinsic clearance of free drug. The susceptibility of individuals to inhibition of N-desmethylation by ethanol is qualitatively determined by total drug concentrations. Estimation of free diazepam concentration coupled with measurement of metabolite affords a qualitative and quantitative evaluation of the mechanism of this interaction.

All patients in alcohol withdrawal should have a full assessment for detecting medical complications. The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A) scale permits a quantitative assessment for following the clinical course and therapeutic response in patients in withdrawal. Most patients with mild withdrawal symptoms do not require hospitalization and respond to non-pharmacologic supportive care. Early initiation of treatment with supportive nursing care and, if necessary, benzodiazepines usually will prevent progression to serious withdrawal reactions and provide the patient with sufficient symptomatic relief. Pharmacotherapy can be considerably simplified by using the loading dose technique, i.e., giving diazepam every 1-2 hr initially until the patient shows signs of clinical improvement and/or mild sedation. If long half-life drugs (e.g., diazepam) are used, further therapy is rarely needed and complications are prevented. Short-acting benzodiazepines can also be given in a similar fashion in the milder clinical syndrome. Phenytoin should only be given to patients with a preexisting seizure disorder. Phenothiazines, barbiturates, paraldehyde, and antihistamines have no role in the treatment of withdrawal because of their toxicity or lack of efficacy. Haloperidol is effective in the control of hallucinations in patients also treated with a benzodiazepine. The treatment of alcoholic intoxication and withdrawal is only the first step toward full rehabilitation.

Alcohol withdrawal therapy can be simplified with a loading dose of diazepam, taking advantage of the kinetic tapering afforded by the drug's long t 1/2s and its metabolites, and of the effectiveness of nonpharmacologic maneuvers. In a double-blind trial, 50 inpatients in moderate to severe alcohol withdrawal received 20 mg oral diazepam and supportive care (n = 25) or placebo and supportive care (n = 25) every 2 hr until they were asymptomatic. Fifty-six percent of patients responded to placebo within 5 +/- 2.9 hr (mean +/- SD), whereas 72% responded to initial diazepam within 6.3 +/- 3.9 hr. Patients treated with diazepam had more rapid and greater improvement than those treated with placebo. Patients who did not respond to six doses of diazepam received further (unblinded) diazepam, 20 mg, every 1 to 2 hr. All patients who did not initially respond (n = 18) improved after more diazepam. Thus all patients who received diazepam (n = 36), during the experimental phase or subsequently, were effectively treated. There were no adverse effects. The median number of 20-mg diazepam doses to treat alcohol withdrawal were three, given over a period of 7.6 hr (range = 1 to 12 and 0.33 to 45 hr). Complications occurred only in those who received placebo during the experimental phase, indicating that delay in therapy may be responsible for the appearance of complications in alcohol withdrawal.

Effects of ethanol on serotonergic neurotransmission were investigated in crude mitochondrial fraction (P2 fraction) from rat brain hippocampus and hypothalamus. The [14C]5-HT preloaded P2 fraction was exposed to 45 mM KCl to induce 5-hydroxytryptamine release in vitro. Ethanol in vitro did not produce any significant inhibition of [14C]5-HT release until its concentration was greater than 100 mM. The K+-evoked 45Ca uptake of hippocampal P2 fraction was unaffected by 100 mM. However, 200 mM ethanol inhibited approximately 63% of K+-evoked 45Ca uptake. Chronic ethanol (10 g/kg/day) for 6 days inhibited [14C]5-HT release from hippocampus whereas it did not affect [14C]5-HT release from hypothalamus. Results indicate that chronic ethanol treatment may decrease serotonergic neurotransmission in selective brain regions. The reduction in 5-hydroxytryptamine release was the result of inhibition in "stimulus-secretion" coupling mechanism.

The disposition of chlordiazepoxide, diazepam, oxazepam and lorazepam was studied before and after disulfiram administration to normal subjects and alcoholic patients. Similar studies to determine the effect of ethanol administration on diazepam and oxazepam disposition were also performed. After disulfiram, decreases in the plasma clearance of chlordiazepoxide (54%, p < 0.05; diazepam, 41% p < 0.05) and their active metabolites were observed. Oxazepam and lorazepam have no important active metabolites and the effect of disulfiram on their net disposition was minimal. In normal subjects ethanol (> 800 mg/l maintained for 8 h) increased the AUC free diazepam (26.6 +/- 17.3% mean +/- SD, p < 0.05) and decreased the AUC for N-desmethyldiazepam (50.5 +/- 11.7%, p < 0.05) indicating inhibition of diazepam N-desmethylation. In contrast, there was no significant change in the disposition of oxazepam in four healthy subjects after a single oral dose of ethanol. Thus, disulfiram and ethanol appear not to inhibit the metabolic disposition of oxazepam or lorazepam, benzodiazepine derivatives principally biotransformed by glucuronidation. On pharmacokinetic grounds oxazepam and lorazepam may be the drugs of choice if benzodiazepine therapy is required in chronic alcoholics.

Rats were trained to remain on a motor-driven belt until they reached a criterion of not exceeding 1% error (1.2 s off the belt) in a 2 min trial. Upon completion of training, animals were treated with nifedipine and/or ethanol and were tested for degree of impairment after an i.p. injection of 2 g/kg ethanol solution on test days. Chronic nifedipine treatment enhances the acute ethanol effects on motor impairment and delays the acquisition of tolerance to ethanol. Results suggest modification of brain calcium channel activities could delay the development of tolerance to ethanol and may prevent ethanol-induced organic brain damage.

The acute interaction of zimelidine (Z) with ethanol (E) was examined in six healthy men aged 20 to 37 yr who randomly received each of four treatments 1 wk apart: Z, 200 mg by mouth, preceded by 1 hr and followed for 7 hr of oral E in juice dosed to maintain blood alcohol concentrations between 800 and 1000 mg/l; placebo Z and E; Z and juice; and placebo Z and juice. E decreased the rate of biotransformation of Z to norzimelidine (NZ) by 46%, but the AUCs of Z, NZ, and their total concentration over 8 hr were not altered by E. Acetaldehyde concentrations did not change and no aversive alcohol-sensitizing reaction was detected. E-induced impairments in memory, body sway, and a manual tracking task were further enhanced by Z, as was the E-induced decrease in friendliness. Data suggest Z and E interact kinetically and dynamically and suggest a mechanism whereby Z may decrease E intake in man.

A shortened 10-item scale for clinical quantitation of the severity of the alcohol withdrawal syndrome has been developed. This scale offers an increase in efficiency while at the same time retaining clinical usefulness, validity and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal.

Although acute tolerance to the psychomotor impairment caused by alcohol has been documented in single-dose studies, the pharmacodynamic effects of continued alcohol administration in humans have not been well studied. Six nonalcoholic men received alcohol to achieve and maintain breath alcohol levels of 80-100 mg/dl for 6 hr. The men suffered an initial impairment in word recall but improved over the next 6 hr. Measures of standing steadiness and manual tracking did not show evidence of the development of tolerance. This lack of tolerance was reflected in subjects' self-assessments of sedation and intoxication.

We have studied the interaction of viqualine, a 5-hydroxytryptamine (5-HT) uptake inhibitor, with ethanol in 16 healthy men aged 20 to 34 years. The subjects were randomly assigned to receive ethanol dosed to maintain blood alcohol concentrations of 17-22 mmol.l-1 (n = 8) or orange juice (n = 8) on each of two test days one week apart and preceded, in random order, by 3 days of viqualine 75 mg bd or placebo. Ethanol had no effect on steady-state viqualine concentrations or the inhibition of 5-HT uptake. Viqualine did not affect acetaldehyde concentrations or cause an aversive alcohol-sensitizing reaction. The deleterious effects of ethanol on word recall, manual tracking, body sway, and self-ratings of intoxication, sedation, and performance were not modified by the presence of viqualine. Within each beverage group performances and self-ratings on viqualine and placebo days were not different. The first dose of viqualine was associated with transient nausea. Viqualine and ethanol do not interact kinetically or dynamically on the variables examined in this study.

1 Free fractions of diazepam, propranolol and warfarin were determined in 15 male chronic alcoholics in alcohol withdrawal. 2 On admission the mean free fraction of diazepam was 25% above and propranolol 44% below the limits of normal range, while the mean warfarin free fraction was in high normal range. One week later mean free fraction of diazepam declined by 20% while propranolol and warfarin increased by 24% and 19% respectively (P less than 0.05). 3 Propranolol free fraction and alpha 1-AGP concentrations were highly correlated (linear r = -0.83, P less than 0.001). In contrast the sources of variation in diazepam and warfarin free fraction were more complex and less certain. 4 Statistically significant changes of drug free fractions in serum of chronic alcoholics were observed during alcohol withdrawal. The extent and direction of these changes differed for various classes of drugs and their potential causes appear to be quite different. 5 Clinically important changes in drug effect may be present acutely, within the dosing interval, as a result of altered drug binding. These are more likely when the clinical response is closely related to drug concentration and will occur within the dosing interval due to larger fluctuations in free drug concentration, even though the average free drug concentration will remain unchanged. 6 Total drug level changes will be observed during alcohol withdrawal even in absence of detectable changes of drug metabolism.