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.
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.
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).
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.
KeywordsAlcohol Dependence Tardive Dyskinesia Neuroleptic Malignant Syndrome Alcohol Withdrawal Alcoholic Patient
Unable to display preview. Download preview PDF.
- Cheymol G, Mouillé P. Étude des effets anti-arythmisants de dérivés du métoclopramide. Archives Internationales de Pharmacodynamic et de Therapie 215: 150–159, 1975Google Scholar
- Chivers JK, Gommeren W, Jenner P, Leysen J, Marsden CD, et al. Comparison of in vivo and in vitro actions of tiapride in rodents. Abstract. British Journal of Pharmacology 79 (Suppl.): 398P, 1983Google Scholar
- Costall B, Naylor RJ. Assessment of the test procedures used to analyse neuroleptic action. Review of Pure and Applied Pharmacological Sciences 1: 3, 1980Google Scholar
- Costall B, Naylor RJ. Experimental studies of dopamine function in movement disorders. Neurotransmitter systems and their clinical disorders, Academic Press, London, 1977Google Scholar
- Costall B, Naylor RJ, Nohria V. Use of the mouse circling model to demonstrate enhanced striatal actions for oxiperomide and tiapride following denervation. British Journal of Pharmacology 66: 121P, 1979Google Scholar
- Crown S, Crisp AH. Crown-Crisp Experiential Index. Hodder & Stoughton, 1979Google Scholar
- Csernansky JG, Csernansky CA, Hollister LE. 3[H]-Sulpiride labels mesolimbic non-dopaminergic sites that bind antidepressant drugs. Ex-perientia 41: 1419–1421, 1985Google Scholar
- DeFigueiredo R. Action du tiapride dans les manifestations aigues du sevrage alcoolique. Semaine des Hôpitaux de Paris 59: 2551–2554, 1983Google Scholar
- Delamaire D, Carpentier MC, Eudier F, Derouet J, Bourel M. Essai ambulatoire du tiapridal après sevrage alcoholique hospitalier. Etude randomisée de cinquante et une hépatopathies alcooliques en double insu. Semaine des Hôpitaux de Paris 62: 3109–3114, 1986Google Scholar
- Fontaine J, Reuse JJ. Pharmacological analysis of the effects of substituted benzamides on the isolated guinea-pig ileum. Study of metoclopramide, sulpiride, bromopride, tiapride, and sultopride. Archives Internationales de Pharmacodynamie et de Therapie 235: 51–61, 1978Google Scholar
- Goreliek DA. Serotonin uptake blockers and the treatment of alcoholism. In Galanter M (Ed.) Recent developments in alcoholism, Vol. 7, pp. 267–281, Plenum Press, New York, 1989Google Scholar
- Gross MM, Lewis E, Hastey J. Acute alcohol withdrawal syndrome. In Kissin B, Begleiter H (Eds) The biology of alcoholism, Vol. 3, pp. 191–263, Plenum Press, New York, 1974Google Scholar
- Gross MM, Lewis E, Nagarajan M. An improved quantitative system for assessing the acute alcoholic psychoses and related states (TSA and SSA). In Gross MM (Ed.) Alcohol intoxication and withdrawal: experimental studies, advances in experimental medicine and biology, Vol. 35, pp. 365–376, Plenum Press, New York, 1973Google Scholar
- Jenner P, Theodorou A, Marsden CD. Specific receptors for substituted benzamide drugs in brain. In Rotrosen & Stanley (Eds) The benzamides: pharmacology, neurobiology, and clinical aspects, advances in biochemical psychopharmacology, Vol. 35, pp. 109–141, Raven Press, New York, 1982Google Scholar
- Joshi R, Sivaganesanathan A. Tiapride versus metoclopramide: comparison after minor gynaecological surgery. European Journal of An-aesthesiology 10: 109–112, 1983Google Scholar
- Laboratoires Delagrange Synthélabo, Investigator’s Brochure, September 1991Google Scholar
- Laboratoires Delagrange Synthélabo, tiapride prescribing information, France, 1993Google Scholar
- Laporte P, Bonnafoux D, Coffinet P. Conduit du sevrage. A propos du traitement de 150 alcooliques chroniques. Semaine des Hôpitaux de Paris 55: 399–402, 1979Google Scholar
- Lepóla U, Kokko S, Nuutila J, Gordin A. Tiapride and chlordiazepoxide in acute alcohol withdrawal. A controlled clinical trial. International Journal of Clinical Pharmacology Research 5: 321–326, 1984Google Scholar
- Lescut J, Verzele R, Hanon D. Intérêt du tiapride chez l’ethylique chronique. Lille Medical 17: (Suppl.): 73–77, 1979Google Scholar
- Lin CW, Wilk S. A comparison of the effect of substituted benzamides in radioreceptor binding assays with their effects on brain dopaminergic systems in vivo. In Rotrosen & Stanley (Eds) The benzamides: pharmacology, neurobiology, and clinical aspects, advances in biochemical psychopharmacology, Vol. 35, pp. 51–60, Raven Press, New York, 1982.Google Scholar
- Mercier J, Scotto-di-Tella AM, Menguy A. Quelques données expérimentales sur le tiapride. Semaine des Hôpitaux de Paris 53: 84–88, 1977Google Scholar
- Mikawa I, Saito Y, Yokoyama O. Hemodynamics and urinary excretion of tiapride in patients with renal function disorders. [Translated into English from Japanese.] Kiso to Rinsho 18: 553–558, 1984Google Scholar
- Mouillé P, Cheymol G. Effets cardiovasculaire et hémodynamiques de dérivés du métoclopramide. Archives Internationales de Pharmacodynamic et de Therapie 215: 139–149, 1975Google Scholar
- Murphy DJ, Shaw GK, Clarke I. Tiapride and chloraiethiazole in alcohol withdrawal: a double-blind trial. Alcohol and Alcoholism 18: 227–237, 1983Google Scholar
- Naranjo CA, Ozdemir V, Bremner KE. Diagnosis and pharmacological treatment of alcoholic patients. CNS Drugs 1: ((in press)), 1994Google Scholar
- Renaudin C, Lemant P. Essai comparatif de l’atrium 300 et du tiapride per os dans le traitement du syndrome de sevrage alcoolique. Psychologie Médicale 13: 161–168, 1981Google Scholar
- Rey E, d’Athis Ph, Richard MO, de Lauture D, Olive G. Pharmacokinetics of tiapride and absolute bioavailability of three extravascular forms. International Journal of Clinical Pharmacology, Therapy and Toxicology 20: 62–67, 1982aGoogle Scholar
- Rondanelli R, Regazzi MB, Cristiani D, Ciardelli L. Cinética délia tiapride e biodisponibilità relativa di due preparad per os. Rivista Italiana di Biologia e Medicina 3: 237–244, 1983Google Scholar
- Schuckit MA. Alcohol and alcoholism. In Wilson et al. (Eds) Harrison’s principles of internal medicine, 12th ed., pp. 2146–2151, McGraw-Hill, New York, 1991Google Scholar
- Shaw JM, Kolesar GS, Sellers EM, Kaplan HL, Sandor P. Development of optimal treatment tactics for alcohol withdrawal. I. Assessment and effectiveness of supportive care. Journal of Clinical Psychopharmacol-ogy 1: 382–389, 1981Google Scholar
- Steele JW, Faulds D, Sorkin EM. Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation. Drugs and Aging 3: 460–478, 1993Google Scholar
- Strolin-Benedetti M, Donath A, Malnoe A. Étude pharmacocinétique et métabolique du tiapride chez l’homme. Semaine des Hôpitaux de Paris 53: 69–71, 1977Google Scholar
- Tenant Jr FS. Editorial. Disufiram will reduce medical complications but not cure alcoholism. Journal of the American Medical Association 19: 1489, 1986Google Scholar
- Tollefson GD, Montague-Claouse J, Tollefson SL. Treatment of comorbid generalized anxiety in a recently detoxified alcoholic population with a selective serotonergic drug (buspirone). Journal of Clinical Psycho-pharmacology 12: 19–26, 1992Google Scholar
- Wadworth AN, Heel RC. Remoxipride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in schizophrenia. Drugs 40: 863–879, 1990Google Scholar
- WHO (World Health Organization). The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva, World Health Organization, 1992Google Scholar