Tiapride: A Review of its Pharmacology and Therapeutic Potential in the Management of Alcohol Dependence Syndrome

Abstract

Synopsis Tiapride, an atypical neuroleptic agent, is a selective dopamine D2-receptor antagonist with little propensity for causing catalepsy and sedation. It shows preferential activity at receptors previously sensitised to dopamine and those located extrastriatally. Tiapride demonstrates anti-dyskinetic activity reflecting antidopaminergic actions, and also anxiolytic activity mediated by mechanisms that are poorly understood. Unlike the benzodiazepines, tiapride does not affect vigilance and has a low potential for interaction with alcohol (ethanol), and possibly for abuse. Tiapride facilitates management of alcohol withdrawal, but its use inpatients at risk of severe reactions in acute withdrawal should be accompanied by adjunct therapy for hallucinosis and seizures. Since it may prove difficult to identify such patients and there is also a small risk of neuroleptic malignant syndrome (particularly with parenteral administration), the usefulness of tiapride in this setting is likely to be limited. Nevertheless, relativ e freedom from the complications associated with benzodiazepine therapy suggest a possible role for the drug in the treatment of individuals suitable for alcohol detoxification as outpatients. Preliminary clinical studies in alcoholic patients following detoxification have shown that tiapride ameliorates psychological distress, improves abstinence, and reduces drinking behaviour, and in the short term facilitate s reintegration within society. These benefits were associated with reduced consumption of health care resources. However, the potential risk of tardive dyskinesia at the dosage employed (300 mg/day) requires evaluation and necessitates medical supervision. Thus, with its lack of adverse effects on vigilance and low propensity for interaction with alcohol and possibly for abuse, tiapride will probably find particular use in the management of alcoholic patients suitable for detoxification in an outpatient setting; and, if initial findings are confirmed in large well-designed trials, in the short term (<6 months) therapy of reformed alcoholic patients under medical supervision. Pharmacodynamic Properties Tiapride, an atypical neuroleptic agent, is a selective adenylate cyclase-independent dopamine D2-receptor antagonist which lacks affinity for dopamine D1-receptors. It possesses only weak sedative and cataleptic effects and is particularly active at receptors previously sensitised to dopamine; this latter property is considered responsible for its antidyskinetic effects. In vivo, tiapride binds preferentially to extrastriatal dopamine receptors in the rat brain, particularly in the hippocampus. Antagonism of dopamine activity by tiapride is generally weak in normal animals, but is often much greater under conditions where the dopaminergic system is altered by pharmacological manipulation or selective tissue destruction. The anxiolytic activity of tiapride has been demonstrated in several animal models, including those involving alcohol (ethanol) withdrawal. The mechanism(s) responsible for the anxiolytic properties of tiapride have not been fully elucidated, but it is distinct from the antidopaminergic activity of the drug. Tiapride does not appear to cause physical or psychological dependence. It does not possess antiepileptic properties, but conversely does not lower the epileptogenic threshold. In common with other dopaminergic antagonists, tiapride causes hyperprolactinaemia, although the effects of prolonged tiapride administration on circulating prolactin levels have not been assessed. Pharmacokinetic Properties The pharmacokinetic profile of tiapride requires further definition, particularly in terms of pharmacodynamic-pharmacokinetic relationships. Indeed, the maximum dosage recommended by the manufacturer for the treatment of delirium during acute alcohol withdrawal (1800 mg/day) exceeds those assessed in pharmacokinetic studies by at least 5- to 6-fold. Bioavailability of tiapride is about 75% following oral or intramuscular administration. Peak plasma tiapride concentrations are achieved within about 0.4 to 1.5 hours when given by either route, and steady-state occurs 24 to 48 hours after initiating 3 times daily administration. The drug is rapidly distributed and does not bind appreciably to plasma proteins. Tiapride is mainly eliminated by renal excretion, principally in the unchanged form. The elimination half-life is approximately 3 to 4 hours, and may increase with age and declining renal function. Therapeutic Potential in Alcohol Dependence Syndrome Tiapride has demonstrated clinical efficacy in patients undergoing acute alcohol withdrawal, although there are methodological deficiencies in most trials which limit their interpretation. The drug appeared to prevent development of delirium, but no conclusions could be drawn regarding its effects on hallucinosis and it is ineffective against seizures. Tiapride resolved or reduced gastrointestinal and psychological distress, most autonomic manifestations, and sleep disturbances without adversely affecting vigilance. In comparative clinical trials, the overall efficacy of tiapride was superior to that of placebo, and approached, or was comparable to that of benzodiazepines or chlormethiazole. Tiapride has also demonstrated efficacy in preliminary investigations which assessed alcoholic patients during rehabilitation (up to 6 months following detoxification). It improved abstinence, drinking behaviour, self-esteem, psychological distress and social complications, which was reflected in reduced consumption of health care resources among patients with symptoms of depression or anxiety. No interaction between tiapride and alcohol was evident among those who resumed drinking. Furthermore, although dependence liability was not specifically assessed, there was no indication of drug abuse (in accordance with the results of animal studies). Tolerability Tiapride was generally well tolerated in clinical trials. The most frequently reported adverse events (>1%) were drowsiness, extrapyramidal syndromes, dizziness and orthostatic hypotension. Compared with the overall population that have received tiapride, alcoholic patients undergoing therapy with this drug appear less likely to experience drowsiness or extrapyramidal syndromes, but appear more prone to orthostatic hypotension (particularly those treated parenterally). Serious adverse events are reported to occur rarely (1.7 per 100 000 treatment months). There have been only 4 reports of tardive dyskinesia, and these were in elderly patients undergoing ‘long term’ therapy. For patients undergoing acute alcohol withdrawal with tiapride the most worrisome serious event appears to be malignant neuroleptic syndrome (25 case reports); it is difficult to differentiate between this and delirium. In comparative clinical trials, the tolerability of tiapride was similar to that of other established therapies for acute alcohol withdrawal, although sedation was less marked compared with diazepam. The tolerability of tiapride 300 mg/day for up to 6 months was comparable to that of placebo during rehabilitation after alcohol withdrawal. Dosage and Administration For the treatment of delirium or pre-delirium during alcohol withdrawal, intravenous or intramuscular tiapride 400 to 1200 mg/day given 4- to 6-hourly is recommended, increased to 1800 mg/day if required. No other dosage recommendations are available for the facilitation of alcohol withdrawal. However, recommended dosages for the treatment of agitation and aggressiveness are 200 to 300 mg/day for 1 to 2 months, or longer with medical supervision. Higher dosages are recommended for the treatment of abnormal movements (300 to 800 mg/day) and may be necessary for alleviation of tremor during alcohol withdrawal. Tiapride 300 mg/day has proved beneficial in the treatment of patients following alcohol detoxification. The dosage should be reduced in patients with renal insufficiency. © 1994, Adis International Limited. All rights reserved.