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The Efficacy of Tiapride and Carbamazepine Combination Therapy in Reducing Alcohol Withdrawal Symptoms: a Systematic Review and Meta-Analysis

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The Efficacy of Tiapride and Carbamazepine Combination Therapy in Reducing Alcohol Withdrawal Symptoms: a Systematic Review and Meta-Analysis Published online: 2018-12-06 Review Thieme Messer Thomas, Latifi Sahar. The Efficacy of Tiapride … Phar- macopsychiatry 2018; 00: 00–00 The Efficacy of Tiapride and Carbamazepine Combination Therapy in Reducing Alcohol Withdrawal Symptoms: A Systematic Review and Meta-Analysis Authors Sahar Latifi1, Thomas Messer2 Affiliations ABSTRACT 1 Resident of Psychiatry and Psychotherapy, Danuvius The combination of tiapride (TIA) and carbamazepine (CBZ) as Klinik GmbH, Pfaffenhofen an der Ilm, Technischen an alternative treatment option to benzodiazepines and clome- Universität München, Bavaria, Germany thiazole has been investigated by several investigations. We 2 Head of Department, Professor of Psychiatry and Psycho- performed a systematic review and meta-analysis to further therapy, Danuvius Klinik GmbH, Pfaffenhofen an der Ilm, explore the efficacy of this combination in order to render more Technischen Universität München, Bavaria, Germany definite answers whether this combination can be recommend- able in the clinical practice. We systematically searched elec- Key words tronic databases including PubMed (MEDLINE), EMBASE, OVID, tiapride, carbamazepine, systematic review, alcoholism, Cochrane, Google Scholar, and Scopus for human studies. Sta- withdrawal symptoms tistical homogeneity was checked by χ2 test and I2 using Cochran heterogeneity statistic. Our analysis showed a sig- received 24.06.2018 nificant efficacy of the combination of TIA and CBZ in reducing revised 06.11.2018 alcohol withdrawal syndrome (AWS) (p < 0.0001, z-value: 4.07). accepted 08.11.2018 The cumulative analysis illustrated that the favorable efficacy of this combination therapy has been consistent over time. Our Bibliography study shows that the combination of TIA/CBZ is an effective DOI https://doi.org/10.1055/a-0795-3689 treatment in management of AWS in patients with alcohol ab- Published online: 6.12.2018 stinence. However, the safety of this combination could not be Pharmacopsychiatry 2019; 52: 209–216 proven, so we recommend its prescription after an informed © Georg Thieme Verlag KG Stuttgart · New York consent. ISSN 0176-3679 Correspondence Sahar Latifi, MD Danuvius Klinik GmbH Technischen Universität München Krankenhausstraße 68 85276 Pfaffenhofen an der Ilm, Bavaria Germany [email protected] This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Introduction leads to the nervous system hyperactivity [4]. In fact, GABA has an Alcohol withdrawal syndrome (AWS) can cause a life-threatening inhibitory effect that suppresses neural activity and thereby it plays condition that increases the concerns for the necessity of suitable an important role in developing the tolerance and inducing the and rapid treatments. It has been shown that chronic alcohol con- withdrawal syndrome in patients with long-term exposure to alco- sumption induces neuroadaptive changes that involve mainly the hol [5]. Recent studies have also shown that a genetic variation in gamma-aminobutyric acid (GABA) receptors central noradrena- GABAA receptor subunits affects the risk for developing alcoholism line, dopamine, and glutamate receptors [1, 2]. Studies have shown [6]. Furthermore, an increased level of dopamine has been report- that a reduced neurotransmission in GABAA and an enhanced neu- ed in patients with AWS [7]. The involvement of other neuromod- rotransmission in glutamatergic pathways results in an imbalance ulators, such as serotonin and corticotropin-releasing factor, has between inhibitory and excitatory neurotransmitters [3], which also been described, which presents the AWS as a complex phe- Latifi S, Messer T. Tiapride and Carbamazepine in Alcohol Withdrawal: A Review … Pharmacopsychiatry 2019; 52: 209–216 209 Review Thieme nomenon affecting multiple nerve systems [8]. Triggering this com- study was to review the literature addressing the efficacy and safety plex matrix of receptors and neurotransmitters to reduce the with- of the combination therapy with CBZ and TIA in treatment of AWS. drawal symptoms has been a challenging theme in the recent re- We also performed a meta-analysis to examine the results of the rel- searches. In this field, many combinations of medications have been evant studies in order to render more definite answers if this combi- studied. The most common treatment options are clomethiazole nation in the clinical practice is recommendable. To our knowledge, and benzodiazepines. Bonnet et al. [9] compared the efficacy of this is the first meta-analysis addressing the efficacy of this combi- clomethiazole and clonazepam in a prospective observational study nation therapy in patients with alcohol dependence. that revealed no significant difference between these 2 medica- tions. A new study by Sychla et al. [10] showed that both diazepam and clomethiazole were equally effective and safe; however, clome- Methods thiazole showed a faster effect, so patients treated with clomethi- azole were treated significantly shorter. Furthermore, benzodiaz- Study design and data collection epines have become worldwide the first choice of treatment of AWS This study is a systematic review that summarizes the findings of pre- because clomethiazole-induced respiratory insufficiency has lim- vious researches addressing the efficacy and safety of CBZ and TIA ited its use in clinical practice [11]. A new study in Germany by Ver- in treatment of alcohol withdrawal symptoms. We also performed a thein et al. [12] showed that oxazepam is as effective as clomethi- meta-analysis to compare the outcomes of relevant literature. We azole in treatment of AWS. Although benzodiazepines are pre- systematically searched electronic databases including PubMed scribed vastly in management of AWS [13], many side effects such (MEDLINE), EMBASE, OVID, Cochrane, Google Scholar, and Scopus as memory deficits and interactions with other drugs have been for human studies with the following keywords: “triapride” AND/OR reported frequently [14, 15]. The benzodiazepine-induced additive “carbamazepin” AND “alcohol withdrawal” OR “alcohol dependence” sedation in combination with alcohol can cause respiratory suppres- OR “alcohol abuse.” The references of the retrieved articles were also sion [16]. Furthermore, benzodiazepines can cause additional ad- scanned to detect the relevant literature. All potential published diction problems that also should be taken into consideration [17]. studies up to May 2018 have been reviewed. Although some beneficial effects of long-term prescription of ben- zodiazepines in patients with alcohol dependence have been re- Study eligibility criteria ported [18], they must be prescribed cautiously in clinical practice. The relevant studies evaluating the effect of the combination ther- Leggio et al. [19] reported that the addictive properties of benzo- apy with TIA and CBZ have been considered as eligible. The inclu- diazepines increase the focus on non-benzodiazepine GABAergic sion criteria were studies on human subjects, existence of adequate medications such as carbamazepine (CBZ), which shows promising comparative data, and application of standard instruments for as- effects in clinical studies. sessment of withdrawal symptoms for proper comparison. Primary CBZ is an anticonvulsive that is typically used for the treatment search of databases with mentioned keywords revealed 290 of seizure disorders and neuropathic pain. However, it has been articles, whereby after exclusion the irrelevant article after initial shown to be effective, safe, and well-tolerable in treatment of AWS screening, 7 studies could be selected. The main reasons for exclu- [20–22]. Prince and Turpin [23] reported the beneficial effect of sion were irrelevance of basic theme, lack of adequate comparative CBZ in patients with alcohol dependence, but adverse effects (for data, lack of application a standard method for assessment the example, dizziness, drowsiness, nausea, and vomiting as the most AWS, lack of use of a combination therapy of TIA and CBZ (applica- frequent side effects) and drug interactions may limit its useful- tion of monotherapy), and use of other anticonvulsants in combi- ness. CBZ is a potent inducer of hepatic cytochrome CYP3A4 and nation with TIA. Among the selected articles, 2 studies were case is also known to be an inducer of CYP1A2, 2B6, and 2C9/19, so it reports (on only 1single case), so these studies have been also ex- may reduce plasma concentrations of medications mainly metab- cluded because of lack of the comparative data. olized by these cytochromes (for example aripiprazole and tacroli- mus) through accelerating their metabolism. Assessment of alcohol withdrawal symptoms Tiapride (TIA) is a dopamine D2 and D3 receptor antagonist. It is Most of the involved studies have used the Clinical Institute With- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. used to treat a variety of disorders including dyskinesia, negative drawal Assessment for Alcohol (CIWA) for the evaluation of AWS. symptoms of psychosis, and agitation and aggression in the elderly CIWA or CIWA-Ar (revised version), is a 10-item scale that is used [24]. A combination of CBZ and TIA has been shown to effectively re- to assess the severity of alcohol withdrawal symptoms. This instru- duce the withdrawal symptoms without inducing an additive seda- ment assesses the 10 common symptoms of alcohol withdrawal tion [25]. Since dopamine hyperactivity has been linked with AWS, (nausea and
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