Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome

  • Review
  • Overview

Authors


Abstract

Background

Alcohol abuse and dependence represents a very serious health problem worldwide with major social, interpersonal and legal interpolations. Pharmacological treatments presently used are of uncertain effectiveness and there is even more doubt on the comparative effects and value for money.

Objectives

To summarize Cochrane reviews that assess the effectiveness and safety of pharmacological interventions in the treatment of alcohol withdrawal.

Methods

We searched the Cochrane Database of Systematic Reviews (30 November 2010). Two authors independently screened, extracted data, summarised key characteristics of the included reviews and assessed their quality using AMSTAR; the quality of the evidence was summarised according to the GRADE methodology.

Main results

Five reviews, 114 studies, 7333 participants, satisfied criteria for inclusions. The outcomes considered were alcohol withdrawal seizures, adverse events and dropouts. Comparing the five treatments with placebo, benzodiazepines performed better for seizures, three studies, 324 participants, RR 0.16 (95% CI 0.04 to 0.69), moderate quality of evidence. Comparing each of the five treatments versus specific class of drugs, benzodiazepines performed better than antipsychotics for seizures, 4 studies, 633 participants, RR 0.24 (95% CI 0.07 to 0.88) high quality of the evidence. Comparing different benzodiazepines and anticonvulsants among themselves, 28 comparisons, results never reached statistical significance but chlordiazepoxide performed better.
The quality of evidence was high for 3% of the results, moderate for 28%, low for 48% and very low for 20%.

Authors' conclusions

Among the treatments considered, benzodiazepines showed a protective benefit against seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with antipsychotics. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines were possible, because of the heterogeneity of the trials both in interventions and in the assessment of outcomes. Data on potential harms are sparse and fragmented. Results do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS, but anticonvulsants seem to have limited side effects. There is also not enough evidence of effectiveness and safety of baclofen, because only one study consider this treatment and of GHB for which no strong differences were observed in the comparisons with placebo, benzodiazepines and anticonvulsants.

Resumen

Antecedentes

Eficacia y seguridad de las intervenciones farmacológicas para el tratamiento del síndrome de abstinencia de alcohol

El abuso y la dependencia del alcohol representan un problema de salud muy serio a nivel mundial con importantes interpolaciones sociales, interpersonales y legales. Los tratamientos farmacológicos usados actualmente presentan una efectividad incierta y aún hay más dudas en cuanto a los efectos comparativos y al valor monetario.

Objetivos

Resumir las revisiones Cochrane que evalúan la efectividad y la seguridad de las intervenciones farmacológicas para el tratamiento de la abstinencia alcohólica.

Estrategia de búsqueda

 

Criterios de selección

 

Obtención y análisis de los datos

 

Resultados principales

Cinco revisiones, 114 estudios, 7333 participantes, cumplieron los criterios para las inclusiones. Los resultados considerados fueron las crisis convulsivas de la abstinencia alcohólica, los eventos adversos y los abandonos. Al comparar los cinco tratamientos con placebo, las benzodiazepinas actuaron mejor para las crisis convulsivas, tres estudios, 324 participantes, CR 0,16 (IC del 95%: 0,04 a 0,69), pruebas de calidad moderada. Al comparar cada uno de los cinco tratamientos versus una clase específica de fármacos, las benzodiazepinas actuaron mejor que los antipsicóticos para las crisis convulsivas, cuatro estudios, 633 participantes, CR 0,24 (IC del 95%: 0,07 a 0,88) pruebas de alta calidad. Al comparar diferentes benzodiazepinas y anticonvulsivos entre sí, 28 comparaciones, los resultados nunca alcanzaron significación estadística aunque el clordiazepóxido resultó mejor. La calidad de las pruebas fue alta para el 3% de los resultados, moderada para el 28%, baja para el 48% y muy baja para el 20%.

Conclusiones de los autores

Entre los tratamientos considerados, las benzodiazepinas mostraron un beneficio protector contra las crisis convulsivas, en comparación con placebo, y un beneficio potencialmente protector en muchos resultados en comparación con los antipsicóticos. No obstante, no fue posible establecer conclusiones definitivas acerca de la efectividad y la seguridad de las benzodiazepinas debido a la heterogeneidad de los ensayos tanto en las intervenciones como en la evaluación de los resultados. Los datos sobre los daños potenciales son dispersos y fragmentados. Los resultados no aportan pruebas suficientes a favor de los anticonvulsivos para el tratamiento del SAA, aunque los anticonvulsivos parecen tener efectos secundarios limitados. Tampoco hay pruebas suficientes de la efectividad y la seguridad del baclofeno, debido a que sólo un estudio considera este tratamiento y el del GHB para el cual no se observó ninguna diferencia marcada en las comparaciones con el placebo, las benzodiazepinas y los anticonvulsivos.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

Résumé scientifique

Efficacité et sécurité des interventions pharmacologiques pour le traitement du syndrome de sevrage alcoolique

Contexte

L'abus d'alcool et la dépendance à l'alcool sont un très grave problème de santé à l'échelle mondiale qui présente d'importantes conséquences sociales, interpersonnelles et légales. Les traitements pharmacologiques utilisés actuellement ont une efficacité incertaine et les doutes sont encore plus grands concernant les effets comparatifs et la rentabilité.

Objectifs

Résumer les revues Cochrane qui évaluent l'efficacité et la sécurité des interventions pharmacologiques dans le traitement du sevrage alcoolique

Méthodes

Nous avons effectué une recherche dans la base des revues systématiques Cochrane (30 novembre 2010). Deux auteurs ont indépendamment passé au crible et extrait les données, résumé les caractéristiques principales des revues incluses et évalué leur qualité au moyen de la méthode AMSTAR ; la qualité des preuves a été résumée selon la méthodologie GRADE.

Résultats principaux

Cinq revues, 114 études, 7 333 participants, ont répondu aux critères d'inclusion. Les résultats pris en compte étaient les crises convulsives liées au sevrage alcoolique, les événements indésirables et les sorties d'étude. En comparant les cinq traitements à un placebo, les benzodiazépines ont donné de meilleurs résultats pour les crises convulsives, trois études, 324 participants, RR 0,16 (IC à 95 % 0,04 à 0,69), qualité des preuves modérée. En comparant chacun des cinq traitements à une classe de médicaments spécifique, les benzodiazépines ont donné de meilleurs résultats que les antipsychotiques pour les crises convulsives, 4 études, 633 participants, RR 0,24 (IC à 95 % 0,07 à 0,88), preuves de grande qualité. En comparant différentes benzodiazépines et différents anticonvulsivants entre eux, 28 comparaisons, les résultats n'ont jamais atteint une signification statistique, mais le chlordiazépoxyde a donné de meilleurs résultats.
Les preuves étaient de grande qualité pour 3 % des résultats, de qualité modérée pour 28 %, de faible qualité pour 48 % et de très faible qualité pour 20 %.

Conclusions des auteurs

Parmi les traitements étudiés, les benzodiazépines ont démontré un bénéfice protecteur contre les crises convulsives comparé à un placebo et un bénéfice potentiellement protecteur pour de nombreux critères de jugement comparé à des antipsychotiques. Néanmoins, il n'a pas été possible de tirer de conclusions catégoriques concernant l'efficacité et la sécurité des benzodiazépines, en raison de l'hétérogénéité des essais en termes d'interventions et d'évaluation des résultats. Les données sur les préjudices potentiels sont rares et fragmentées. Les résultats ne fournissent pas de preuves suffisantes en faveur des anticonvulsivants pour le traitement du SSA, mais les anticonvulsivants semblent avoir des effets secondaires limités. Les preuves sont également insuffisantes concernant l'efficacité et la sécurité pour le baclofène, car seule une étude examine ce traitement, et pour le GHB pour lequel il n'a été observé aucune différence claire dans les comparaisons avec le placebo, les benzodiazépines et les anticonvulsivants.

摘要

酒精戒斷症候群治療的藥物介入療效與安全性

背景

酒精濫用與依賴在全球造成許多相當嚴重的健康問題,以及主要的社會、人際關係與法律的修竄。目前採用的藥物治療效果不確定,且在比較性效果與金錢價值上有更多疑問。

目的

總結說明評估酒精戒斷治療中藥物介入的療效與安全性的考科藍文獻回顧。

方法

我們搜尋系統性回顧的考科藍資料庫(2010.11.30)。由兩位作者獨立篩選及提取數據,總結所含的回顧文獻的關鍵特點,並用AMSTAR評價其質量;證據的質量依據GRADE方法學來總結。

主要結果

符合納入條件共計,5篇文獻回顧,114篇研究,7333名參與者。考量成果指標為酒精戒斷抽搐、不良事件與中途退出。與安慰劑比較時,五個以benzodiazepines治療,在抽搐的效果較好,其中三個研究,324名參與者,其RR 0.16 (95% CI 0.04到0.69),中度證據品質。與特定藥物等級比較,五個benzodiazepines治療,在抽搐的效果較抗精神病藥物好,4個研究,633名參與者,RR 0.24 (95% CI 0.07到0.88) 具高證據品質。在它們中比較不同的benzodiazepines與鎮痙攣藥,28個比較,結果沒有達到統計顯著性,但chlordiazepoxide效果較好。
高證據品質結果為3%,中度證據品質為28%,低度證據品質為48%,非常低為20%。

作者結論

在所考量的治療中,在與安慰劑比較時,benzodiazepines對於抽搐有保護性的益處,而與抗精神病藥物比較則在許多成果指標上有潛在的保護益處。然而,benzodiazepines相關的療效與安全性可能不會有明確的結論 ,因為試驗的異質性同時存在於介入與成果評估中 。潛在危害的資訊是稀少且分散 。結果對於鎮痙攣藥在AWS的治療上沒有提供充分的證據支持,但鎮痙攣藥似乎有有限的副作用。也沒有足夠的證據支持肌肉鬆弛劑(baclofen )的療效與安全性,因為僅有一個研究考慮此治療方法,具有GHB中,與安慰劑、benzodiazepines與鎮痙攣藥的比較中沒有觀察到強大的差異。

Plain language summary

Safety and effectiveness of medications for the treatment of alcohol withdrawal syndrome

Alcohol abuse and dependence can cause serious health problems as well as interpersonal, social, interpersonal and legal consequences. Dependence on alcohol is evident by reduced control over drinking, tolerance to alcohol and withdrawal symptoms. Alcohol withdrawal syndrome develops after stopping or reducing heavy and prolonged alcohol use. The most common symptoms include sweating, a fast pulse rate, tremor, insomnia, nausea or vomiting, transient hallucinations or illusions, agitation, anxiety and seizures. These are the result of changes in the central nervous system in an attempt to maintain normal function with alcohol consumption. Different types of medications are used to safely reduce the severity of withdrawal and the abuse of alcohol.

Cochrane reviews of randomised controlled trials that examined the effectiveness and safety of medications for alcohol withdrawal syndrome were included in this overview. Participants in the review studies varied in age, gender, nationality, severity of symptoms and treatment as outpatients or inpatients. Five reviews, 114 studies, 7333 participants, were included. We considered the efficacy of the medication on alcohol withdrawal seizures, adverse events as a measure of safety and acceptability of the treatment as dropouts from the study. These outcomes were considered in 72 of the 114 studies. The treatments used were sedative benzodiazepines, anticonvulsants, baclofen, GHB and PAN. Baclofen and GHB mimic alcohol effects and can rapidly reduce symptoms. PAN (psychotropic analgesic nitrous oxide) involves administering low levels of nitrous oxide and oxygen gases so that the individual remains conscious and coherent.

Comparing the five treatments with placebo, benzodiazepines performed better for seizures (three studies, 324 participants, moderate quality of evidence). This was the only treatment with statistically significant findings. Data on potential harms were sparse and fragmented in these studies. Benzodiazepines also performed better than antipsychotics for seizures (4 studies, 633 participants, high quality of evidence).

For the majority of our results, further research is likely to have an important impact on confidence in the estimate of effect. We assessed the quality of the evidence in the included reviews using GRADE, which looks at the quality of evidence for each outcome, taking into consideration the magnitude of the effect, the relevance of the data to the clinical question being asked, the sample size in the relevant trials, the methodological quality of the trials and the consistency of the findings.

Résumé simplifié

Sécurité et efficacité des médicaments pour le traitement du syndrome de sevrage alcoolique

L'abus d'alcool et la dépendance à l'alcool peuvent provoquer de graves problèmes de santé et avoir des conséquences interpersonnelles, sociales et légales. La dépendance à l'alcool se manifeste par un contrôle réduit par rapport à la boisson, une tolérance à l'alcool et des symptômes de sevrage. Le syndrome de sevrage alcoolique se développe après l'arrêt ou la réduction d'une consommation d'alcool importante et prolongée. Les symptômes les plus courants comprennent des sueurs, un pouls rapide, des tremblements, des insomnies, des nausées ou des vomissements, des hallucinations ou des illusions passagères, une agitation, de l'anxiété et des crises convulsives. Ces symptômes sont le résultat de changements du système nerveux central visant à maintenir un fonctionnement normal avec la consommation d'alcool. Différents types de médicaments sont utilisés pour réduire sans risque la gravité du sevrage et l'abus d'alcool.

Les revues Cochrane d'essais contrôlés randomisés qui examinaient l'efficacité et la sécurité des médicaments pour le syndrome de sevrage alcoolique ont été incluses dans cette présentation générale. Les participants des études de revues étaient d'âge, de nationalité et de sexe différents, présentaient une gravité de symptômes variable et étaient traités à l'hôpital ou en tant que patients externes. Cinq revues, 114 études, 7 333 participants, ont été inclus. Nous avons examiné l'efficacité du médicament sur les crises convulsives du sevrage alcoolique, les événements indésirables en tant que mesure de la sécurité et l'acceptabilité du traitement d'après les sorties d'étude. Ces critères d'évaluation ont été examinés dans 72 études sur les 114. Les traitements utilisés étaient des benzodiazépines sédatives, des anticonvulsivants, du baclofène, du GHB et du PAN. Le baclofène et le GHB imitent les effets de l'alcool et peuvent rapidement réduire les symptômes. Le PAN (oxyde nitreux analgésique psychotrope) implique l'administration de faibles niveaux d'oxyde nitreux et de gaz oxygène afin que l'individu reste conscient et cohérent.

En comparant les cinq traitements à un placebo, les benzodiazépines ont donné de meilleurs résultats pour les crises convulsives (trois études, 324 participants, qualité des preuves modérée). Ce traitement a été le seul à fournir des résultats statistiquement significatifs. Les données sur les préjudices potentiels ont été rares et fragmentées dans ces études. Les benzodiazépines ont également donné de meilleurs résultats que les antipsychotiques pour les crises convulsives (4 études, 633 participants, grande qualité des preuves).

Pour la majorité de nos résultats, des recherches supplémentaires sont susceptibles d'avoir un impact important sur la confiance de l'estimation de l'effet. Nous avons évalué la qualité des preuves des revues incluses en utilisant la méthode GRADE qui examine la qualité des preuves pour chaque critères d'évaluation en prenant en compte la quantité d'effet, la pertinence des données pour la question clinique posée, la taille de l'échantillon dans les essais pertinents, la qualité méthodologique des essais et la cohérence des résultats.

Notes de traduction

Traduit par: French Cochrane Centre 4th September, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

淺顯易懂的口語結論

酒精戒斷症候群治療的藥物治療安全性與療效

酒精濫用與依賴會造成嚴重的健康問題以及人際關係、社會、人際關係與法律的後果。由飲酒控制的降低、對酒精的耐受性與戒斷症候群可明顯看出酒精依賴的證據。酒精戒斷症候群於停止或是減少大量飲酒與長期食用酒精後開始發展。最常見的症狀包含有流汗、脈搏快、震顫、失眠、噁心或嘔吐、短暫的幻覺或幻想、激動、焦慮和抽搐發作。這些是中樞神經系統改變,試圖利用酒精消耗維持正常功能的結果。採用了不同的藥物治療類型以安全的降低戒斷的嚴重性與酒精的濫用。

考科藍文獻回顧有檢驗酒精戒斷症候群藥物治療安全性與療效的隨機對照試驗皆包含在此摘要中。迴線回顧所有的研究中的參與者在年齡、性別、國籍、症狀嚴重性與門診或住院治療方式皆不相同。包含5篇系統性文獻回顧,114個研究,7333名參與者。我們考量了藥物治療在酒精戒斷抽搐上的效果,並以不良事件做為安全性的測量,以及由研究中中途退出視為對治療的接受度。這些成果指標在114個研究中的72個中有被考慮。所採用的治療方式為鎮靜用的benzodiazepines、鎮痙攣藥、肌肉鬆弛劑(baclofen)、GHB與PAN。肌肉鬆弛劑(Baclofen)與GHB摹擬了酒精效果且可迅速減少症狀。PAN (psychotropic analgesic nitrous oxide)涉及施打低度的一氧化二氮與氧的氣體,所以個人仍有意識並協調。

與安慰劑組比較,五個治療皆顯示benzodiazepines在抽搐之效果較好(三個研究,324名參與者,中度證據品質)。此為唯一具有統計上顯著性發現的治療。本研究中潛在危害相關的數據稀少且分散。Benzodiazepines在抽搐時效果也較抗精神病藥物好 (4個研究,633名參與者,高度證據品質)。

就我們的結果大多數而言,進一步的研究可能於效果的預估信賴度上有重要的影響。我們使用GRADE評估所包含審閱中的證據品質 ,其觀察了每一成果的證據品質,將效果強度、資訊與所詢問的臨床問題之關聯性、相關試驗中的樣本大小、試驗方法論的品質與發現的一致性皆納入考量。

譯註

翻譯: East Asian Cochrane Alliance
翻譯補助: 台灣衛生福利部/台北醫學大學實證醫學研究中心

Background

Description of the condition

Alcohol abuse and dependence represents a most serious health problem worldwide with major social, interpersonal and legal interpolations. Dependence on alcohol is associated with both physiological symptoms such as tolerance and withdrawal, and behavioural symptoms such as impaired control over drinking (Hasin 1990).

Alcohol withdrawal syndrome (AWS) is a cluster of symptoms that may occur in alcohol-dependent people. The essential feature of alcohol withdrawal is the presence of a characteristics syndrome that develops after the cessation of (or reduction in) heavy and prolonged alcohol use. (DSM-IV-R). The clinical presentation varies from mild to serious and the onset of symptoms typically may appear up to 48 hrs, and actually up to 72 hrs if we consider the uncommon case of delirium tremens after the last alcohol intake. The most common symptoms are autonomic hyperactivity (e.g. sweating or pulse rate greater than 100), tremor, insomnia, nausea or vomiting, transient visual, tactile or auditory hallucinations or illusions, psychomotor agitation, anxiety and seizures (DSM-IV-R). These symptoms involve a wide range of neurotransmitter circuits that are implicated in alcohol tolerance and reflect a homeostatic readjustment of the central nervous system (De Witte 2003; Koob 1997; Nutt 1999; Slawecki 1999). Long-term alcohol consumption affects brain receptors that undergo adaptive changes in an attempt to maintain normal function. Some of the key changes involve reduced brain gamma-aminobutyric acid (GABA) levels and GABA- receptor sensitivity (Dodd 2000; Gillman 1996; Kohl 1998; Petty 1993) and activation of glutamate systems (Tsai 1995), which lead to nervous system hyperactivity in the absence of alcohol. The advances in knowledge of neurobiology and neurochemistry have prompted the use of drugs in the treatment of alcohol dependence and withdrawal that act through these GABA pathways.

Description of the interventions

Withdrawal from alcohol may or may not require pharmacological management, depending on the amount of drinking, the presence of symptoms, the setting of detoxification (SIGN 2003) and the severity of withdrawal symptoms. However, It is important to treat AWS, in order to decrease the severity of symptoms, preventing more severe withdrawal clinical manifestations such as seizures and delirium tremens, and facilitate entry of the patient into a treatment program in order to attempt to achieve and maintain long-term abstinence from alcohol. Symptoms severity-triggered therapy using the revised Clinical Institute Withdrawal Assessment (CIWA-Ar) (Sullivan 1989) is currently recommended for the management of a patient in acute alcohol withdrawal (McKay 2004). Increasing knowledge about the involved neurotransmitter systems has prompted the development of drugs to target them. Different classes of drugs have been used to prevent and treat AWS: benzodiazepine GABAergic medications, which involve mainly the benzodiazepines, the drugs of choice in the treatment of AWS, and non-benzodiazepine GABAergic compounds, which involve carbamazepine, gabapentin, valproic acid, topiramate, Gamma-hydroxybutyric acid (GHB), baclofen, flumazenil etcetera (Leggio 2008). Benzodiazepines are established treatments for AWS (Lejoyeux 1998), but there is a growing interest in testing other medications for the treatment of AWS. Many studies have been conducted, but most of them have not included the most severe forms of AWS. Nevertheless, these studies suggest that it would be worth conducting large RCTs. Benzodiazepines have been shown to be one of the most effective classes of drugs in the management of alcohol withdrawal syndrome. Studies concerning pharmacological therapies of alcohol withdrawal has suggested that benzodiazepines are effective in reducing withdrawal severity, incidence of delirium and seizures with a greater margin of safety and lower abuse potential when compared to other therapies. Anticonvulsants drugs are also indicated for the treatment of alcohol withdrawal syndrome. The effects of GHB and alcohol on the Central nervous System (CNS) was first described in the 1970's and subsequently confirmed (Frau 1995, Colombo 1995, Colombo 1998).

How the intervention might work

Benzodiazepines have been shown to be one of the most effective class of drugs in the management of alcohol withdrawal syndrome (Holbrook 1999; Mayo-Smith 1997). The rationale of the use of benzodiazepine is to modulate central nervous system (CNS) hyperactivity, interacting with GABA receptors, due to the alcohol withdrawal.

In spite of the wide use of anticonvulsants, their exact role for the treatment of alcohol withdrawal has not yet been adequately assessed, and it is unknown whether different anticonvulsants and different regimens of administration (e.g. symptom-triggered versus fixed schedule) may have the same merits (Choi 2005; Gann 2004; Koethe 2007; Mayo-Smith 1997).                

The alcohol-mimicking effects of GHB represents a rationale for using GHB in alcohol addiction treatment and in craving (Gallimberti 1989; Gallimberti 1992)

Baclofen produces its effect via modulating the GABAB receptor, similar to the drug GHB which also has the same mechanism of action and also similar effects. However, there are some pharmacological differences in that baclofen appears to have reduced abuse and dependence potential. Consistent with preclinical evidence, open-label reports demonstrated the ability of baclofen to rapidly reduce symptoms of severe AWS in alcoholic patients.

An alternative method to benzodiazepine sedation has been conceptualised and pioneered in South Africa. This treatment employs psychotropic analgesic nitrous oxide (PAN). PAN treatment involves administering low levels of nitrous oxide plus oxygen to the patient who remains conscious and coherent throughout gas administration (Gillman 1986; Gillman 1998).

In some studies, it was demonstrated that alcohol administration lead to an acute increase in magnesium excretion in the range of 167-260% greater than control subjects.  Furthermore, decreased oral intake secondary to chronic alcoholism would also contribute to decreased magnesium levels (Jermain 1992).  A correlation has also been found in withdrawing alcoholic patients between hypomagnesaemia and sinus tachycardia (Shane 1991).

Why it is important to do this overview

Patients, clinicians and policy makers need to know if there are any important differences between the treatment for alcohol withdrawal in terms of safety and efficacy. This overview is aimed to summarize systematically the available evidence on the pharmacological interventions for alcohol withdrawal.

Objectives

To conduct an overview of Cochane systematic reviews that assessed the effectiveness of any pharmacological treatments, alone or in combination with others, to treat alcohol withdrawal syndrome. Any pharmacological treatment was assessed in terms of effectiveness, acceptability and safety.

Methods

Criteria for considering reviews for inclusion

Types of studies

We included all published Cochrane systematic reviews considering pharmacological interventions aimed to treat alcohol withdrawal syndrome. Cochrane reviews employ rigorous methods
to minimise bias; and are regularly updated (Jadad 1998; Moher 2007; Shea 2007), and so represent a source of high-quality, up to- date evidence. Recent primary clinical trials not yet included in the retrieved reviews were not included.

Types of participants

We considered reviews that included alcohol dependent patients diagnosed in accordance with appropriate standardized criteria (e.g., criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-R) or ICD) (DSM-IV-R) who experienced alcohol withdrawal symptoms regardless of the severity of the withdrawal manifestations. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy.

Types of interventions

- Experimental intervention: Pharmacological interventions alone or in combination with other drugs
- Control Intervention: Placebo; Other pharmacological interventions

Types of outcomes

Efficacy outcomes

  1. Alcohol withdrawal seizures

  2. Alcohol withdrawal delirium

  3. Alcohol withdrawal symptoms as measured by prespecified scales(as the CIWA-Ar score)

  4. Craving as measured by validated scales

Safety outcomes

  1. Adverse events

  2. Severe, life-threatening adverse events

Acceptability outcomes

  1. Dropout and dropout due to adverse events

Search methods for identification of reviews

We searched the Cochrane Database of Systematic Reviews (The Cochrane Library 30 December 2010) using the following selected mesh terms and free text relating to alcohol withdrawal:
1. Alcohol-related disorders [mesh]
2. Alcohol-Induced Disorders, Nervous System [mesh]
3. Substance Withdrawal Syndrome [mesh]
4. ((alcohol) NEAR/3 (disorder* or withdr* or abstinen* or abstain* or detox* or neuropathy or delirium))
5. #1 or #2 or #3 or #4

Data collection and analysis

Selection of reviews

Two authors independently screened the titles and abstracts of all the reviews, obtained through the search strategy. All potentially eligible reviews were obtained as full articles and two authors independently assessed them for inclusion. In doubtful or controversial cases, all identified discrepancies were discussed between the authors.

Data extraction and management

We extracted data from included reviews. The data extraction form summarise key characteristics of the review, including objectives, information on participants, interventions examined, outcomes assessed and comparisons performed. The data extraction form also summarises the results of the review for each outcome. One author extracted data and a second investigator verified the extracted data. We resolved differences by discussion and consensus.

Assessment of methodological quality of included reviews

Quality of Included Reviews

We assessed the quality of included systematic reviews using AMSTAR: A MeaSurement Tool to Assess Reviews (Shea 2007). AMSTAR assesses the degree to which review methods avoided bias by evaluating the methods against 11 distinct criteria. Each item on AMSTAR is rated as yes (clearly done), no (clearly not done), can't answer, or not applicable see Appendix 1.

One author (SM) assessed the quality of the included reviews using AMSTAR, and a second investigator (LA) verified this assessment.
We resolved differences by discussion and consensus. We did not use the quality of the reviews as an inclusion criteria, but we identified and discussed differences in quality between reviews, and used the quality assessment to interpret the results.

Quality of evidence in Included reviews

- Assessment of the quality of the evidence

We assessed the quality of the evidence in included reviews according to the methodology described by the GRADE working group (Atkins 2004;Schünemann 2006). This approach involves assessing the quality of evidence for each outcome, taking into consideration the magnitude of the effect, the relevance of the data to the clinical question being asked, the sample size in the relevant trials, the methodological quality of the trials and the consistency of the findings. In the GRADE system, evidence is classified as “high”, “moderate”, “low” or “very low”. see Appendix 2

Data synthesis

Statistical presentation of results from reviews
We used a range of approaches to present the results of included reviews. Where available, we extracted and report pooled effect sizes for outcomes meta-analysed in reviews; or effect sizes from their included studies. We present results according to the statistical information available in each included review.

Results

Description of included reviews

Of the 86 records identified, 76 were excluded on the basis of title, ten were considered for inclusion. Five were excluded for the following reasons: four (Fox 2003; Pani 2010; Roessner 2010a; Roessner 2010b) because type of interventions and type of outcomes considered did not satisfied the inclusion criteria and one (Smith 2009) because the outcomes did not satisfied the inclusion criteria. Five Cochrane reviews were included in this overview (Amato 2010; Gillman 2007; Leone 2010; Liu 2011; Minozzi 2010), see Figure 1 for the flow chart of included reviews and Table 1 and Table 2 for the main characteristics of included review. Regarding the Leone 2010 review, in this overview we considered only results from the six studies assessing interventions for alcohol withdrawal. All the reviews included randomised controlled trials (RCTs) examining the effectiveness, safety and overall risk-benefit of pharmacological interventions in comparison with placebo or other pharmacological treatment; in all the reviews, patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy. The interventions considered were benzodiazepines, anticonvulsants, baclofen, GHB, PAN alone or in combination with other drugs compared with placebo, other pharmacological interventions and, for benzodiazepines and anticonvulsants, among themselves. The sum of studies included in the reviews is of 139, but 25 studies were included in more than one review, so the number of single included studies is 114 with a total of 7333 participants, see Table 3 for a list of the comparisons carried out.

Figure 1.

Flow chart of reviews

Table 1. Main characteristics of included reviews
ReviewData published/assessed as updateData SearchPopulationInterventions

Comparisons

Interventions

Total studies consideredN° Excluded studiesN° Included studiesN° Participants
Anticonvulsants for alcohol withdrawalCLIB issue 3, 2010

Searches performed in December 2009;

 

Alcohol dependent patients who

experienced alcohol withdrawal symptoms

Anticonvulsants drugs alone or combined with other drugs

 

Placebo; Other pharmacological interventions;

Different anticonvulsants

9135564151
Benzodiazepines for alcohol withdrawalCLIB issue 3, 2010Searches performed in December 2009

Alcohol dependent patients who

experienced alcohol withdrawal symptoms

Benzodiazepines alone or combined with other drugs

 

Placebo; Other pharmacological interventions; Different benzodiazepines9127644331
Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapsesCLIB issue 2, 2010

Searches performed in September 2008;

 

Alcohol dependent patients in therapy with GHB to prevent or to treat AWS.

Gamma-hydroxybutyric acid (GHB) at any dosage

 

Placebo; Other pharmacological treatment352213648
Baclofen for alcohol withdrawalCLIB issue 1, 2011

Searches performed in September 2010;

 

Alcohol dependent patients who

experienced alcohol withdrawal symptoms

BaclofenBenzodiazepine (diazepam)87137

Psychotropic analgesic nitrous oxide (PAN) for alcoholic withdrawal

states

CLIB issue 2, 2007

Searches performed in May 2005;

 

Voluntary consenting subjects in alcohol withdrawal. Trials

which include participants with alcoholic delirium were excluded

PAN individually titrated to the clinical needs of each patient as measured by their individual responses to the gas. Oxygen (placebo) and/or benzodiazepine regimen.15105212
Table 2. Country of origin of studies included in the reviews
ReviewAsiaAustralia/New ZealandEuropeNorth AmericaSouth Africa
23  Anticonvulsants for alcohol withdrawal1433180
24  Benzodiazepines for alcohol withdrawal3126322
26  Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses 001300
54. Baclofen for alcohol withdrawal00100
25 . Psychotropic analgesic nitrous oxide for alcoholic withdrawal states00005
Table 3. Comparisons carried out in the studies included in the five reviews considering treatments for alcohol withdrawal
AuthorTreatmentControl
Addolorato 1999 GHB 50mgDiazepam (benzodiazepine)
Addolorato 2005Diazepam (benzodiazepine)Baclofen (muscle relaxant)
Adinoff 1994Diazepam (benzodiazepine)

Placebo

Clonidine (alpha adrenergic)

Alprazolam (benzodiazepine

Agricola 1982 Carbamazepine (anticonvulsant)Tiapride (antipsychotic)
Alldredge 1989Phenytoin (anticonvulsant)Placebo
Ansoms 1991Lometazepam (benzodiazepine)Zopiclone (anxyolitic)
Anton 1997Diazepam (benzodiazepine)Abecamil (benzodiazepine)
Bailly 1992Diazepam (benzodiazepine)Propranol (beta-blocking))
Balldin 1986Carbamazepine (anticonvulsant) + Chlorprothixene (antipsychotic)Clonidine (alpha adrenergic)
Baumgartner 1987Chlordiazepoxide (benzodiazepine)Clonidine (alpha adrenergic)
Baumgartner 1991Chlordiazepoxide (benzodiazepine)Clonidine (alpha adrenergic)
Bjorkvist 1976Carbamazepine (anticonvulsant)Placebo
Blanchard 1985Phenobarbital (anticonvulsant)Placebo
Bonnet 2003Gabapentin (anticonvulsant)Placebo
Borg 1986Oxazepam  (benzodiazepine)

Amobarbital (anticonvulsant)

Melperone (antipsychotic)

Brown 1972Chlordiazepoxide (benzodiazepine)Diazepam (benzodiazepine)
Burroughs 1985Chlordiazepoxide  (benzodiazepine)

Placebo

Chlormethiazole (anticonvulsant)

Bromocriptine (dopamine agonist)

Ceccanti 1996GHB 50mgOxazepam  (benzodiazepine)
Chance 1991Phenytoin (anticonvulsant)Placebo
Choi 2005Lorazepam  (benzodiazepine)Topiramate (anticonvulsant)
Croissant 2009Chlormethiazole (anticonvulsant)Oxcarbazepine (anticonvulsant) + Tiapride (antipsychotic)
Daeppen 2002Oxazepam (benzodiazepine) symptom triggeredOxazepam (benzodiazepine) fixed-schedule
Day 2004Diazepam (benzodiazepine)Chlordiazepoxide (benzodiazepine)
De Rooster 1983Nitrous oxide plus oxygenBarbiturates plus benzodiazepine
Dencker 1978Chlormethiazole (anticonvulsant)Piracetam (CNS stimulant)
Dion 1968Chlordiazepoxide  (benzodiazepine)Magnesium sulphate (anticonvulsant)
Elsing 1996GHB 50mgChlormethiazole (anticonvulsant)
Elsing 2009GHB 50mgChlormethiazole (anticonvulsant)
Favre 2005Diazepam (benzodiazepine)Cyametazine (antipsychotic)
Fey 1993Nitrous oxideBenzodiazpine
Flygenring 1984Carbamazepine (anticonvulsant)Barbital (anticonvulsant)
Funderburk 1978Chlordiazepoxide (benzodiazepine)Ethanol
Gallimberti 1989GHBPlacebo
Gann 2004Chlormethiazole (anticonvulsant)Placebo
Gillman 1986Nitrous oxideDiazepam (benzodiazepine)
Gillman 2004Nitrous oxideDiazepam (benzodiazepine)
Gillmer 1973Oxazepam  (benzodiazepine)Benzoctamine (anxyolitic)
Glatt 1966Chlormethiazole (anticonvulsant)Placebo
Golbert 1967Chlordiazepoxide (benzodiazepine)

Placebo

Promazine (anticonvulsant)

Alcohol

Paraldehyde (anticonvulsant) + Chloral hydrate (sedative)

Janks 1992Nitrous oxideBenzodiazepine
Jauhar 2000Chlordiazepoxide (benzodiazepine)Diazepam (benzodiazepine)
Kaim 1969Chlordiazepoxide (benzodiazepine) 

Placebo

Chlorpromazine (antipsychotic)

Hydroxyzine (anxyolitic)

Thiamine  (vitamine B1)

Kaim 1972Chlordiazepoxide (benzodiazepine) 

Placebo

Paraldehyde (anticonvulsant)

Pentobarbital (anticonvulsant)

Perhenazine (antipsychotic)

Kalyoncu 1996Diazepam (benzodiazepine)Carbamazepine (anticonvulsant)
Koethe 2007Oxcarbazepine (anticonvulsant)Placebo
Kolin 1981Diazepam (benzodiazepine)Alprazolam (benzodiazepine)
Koppi 1987Meprobamate (anticonvulsant)Caroverine (spasmolytic)
Kramp 1978Diazepam (benzodiazepine)Barbital (anticonvulsant)
Krupitsky 2007Diazepam (benzodiazepine)

Placebo

Topiramate (anticonvulsant)

Memantine (anticonvulsant)

Lamotrigine (anticonvulsant)

Kumar 2009Lorazepam (benzodiazepine)Chlordiazepoxide (benzodiazepine) 
Lambie 1980Valproate (anticonvulsant)Placebo
Lapierre 1983Chlordiazepoxide  (benzodiazepine)Chlormethiazole (anticonvulsant)
Lenzenhuber 1999Flunitrazepam (benzodiazepine)GHB
Lepola 1984Chlordiazepoxide  (benzodiazepine)Tiapride (antipsychotic)
Longo 2002Chlordiazepoxide  (benzodiazepine)

Sodium valproate (anticonvulsant)

Depakote (anticonvulsant)

Loranzepam (benzodiazepine)

Lucht 2003Diazepam (benzodiazepine)

Chlormethiazole (anticonvulsant)

Carbamazepine (anticonvulsant)

Madden 1969Chlormethiazole (anticonvulsant)Trifluoperazine (antipsychotic)
Malcom 1989Oxazepam  (benzodiazepine)Carbamazepine (anticonvulsant)
Malcom 2002Lorazepam  (benzodiazepine)Carbamazepine (anticonvulsant)
Malcom 2007Lorazepam  (benzodiazepine)Gabapentin (anticonvulsant)
Manhem 1985Chlormethiazole (anticonvulsant)Clonidine (adrenergic agonist)
Mariani 2006Gabapentin (anticonvulsant)Phenobarbital (anticonvulsant)
Martin 1975Diazepam (benzodiazepine)

Placebo

Clobazam (benzodiazepine)

MC Grath 1975Chlordiazepoxide  (benzodiazepine)Chlormethiazole (anticonvulsant)
McLendon 1980Chlordiazepoxide (benzodiazepine) Placebo
Mendels 1985Chlordiazepoxide (benzodiazepine) Halazepam (benzodiazepine)
Mielke 1976Diazepam (benzodiazepine)

Placebo

Clorazepate (benzodiazepine)

Miller 1984Diazepam (benzodiazepine)Lorazepam  (benzodiazepine)
Mukherjee 1983Chlordiazepoxide (benzodiazepine) Clobazam (benzodiazepine)
Murphy 1983Chlormethiazole (anticonvulsant)

Placebo

Tiapride (antipsychotic)

Myrick 2009Lorazepam  (benzodiazepine)Gabapentin (anticonvulsant)
Naranjo 1983Lorazepam (benzodiazepine)Placebo
Nava 2007GHB 50mg    Diazepam (benzodiazepine)
Nimmerichter 2002GHB 50mg and 100mgChlormethiazole (anticonvulsant)
O'Brien 1983Diazepam (benzodiazepine)Lorazepam (benzodiazepine)
Overall 1973Chlordiazepoxide  (benzodiazepine)Mesoridazine (antipsychotic)
Palestine 1976Chlordiazepoxide  (benzodiazepine)Haloperidol (antipsychotic)
Pena-Ramos 1977Chlordiazepoxide  (benzodiazepine)Thioridazine (antipsychotic)
Pena-Ramos 1979Chlordiazepoxide  (benzodiazepine)Thioridazine (antipsychotic)
Radouco-Thomas 1989Chlordiazepoxide  (benzodiazepine)

Phenobarbital (anticonvulsant)

Tetrabamate (anticonvulsant)

Rathlev 1994Phenytoin (anticonvulsant)Placebo
Reoux 2001Divalproex (anticonvulsant)Placebo
Ritola 1981Carbamazepine (anticonvulsant)Chlormethiazole (anticonvulsant)
Ritson 1986Diazepam (benzodiazepine)Lorazepam  (benzodiazepine)
Robinson 1989Chlormethiazole (anticonvulsant)Clonidine (adrenergic agonist)
Rosenthal 1998Phenobarbital (anticonvulsant)Valproate (anticonvulsant)
Rothstein 1973Diphenylhydantoin (anticonvulsant)

Chlordiazepoxide (benzodiazepine)

+ Thiamine  (vitamine B1)

Runion 1978Chlordiazepoxide (benzodiazepine)Hydroxyzine (anxyolitic)
Saitz 1994Chlordiazepoxide (benzodiazepine) fixed-scheduleChlordiazepoxide (benzodiazepine) symptom-triggered
Saletu 1983Lopirazepam (benzodiazepine)Prazepam (benzodiazepine)
Sampliner 1974Phenytoin (anticonvulsant)Placebo
Santo 1985Tetrabamate (anticonvulsant)Tiapride (antipsychotic)
Schick 2005Carbamazepine (anticonvulsant)Oxcarbazepine (anticonvulsant)
Seifert 2004Carbamazepine (anticonvulsant)Chlormethiazole (anticonvulsant)
Sellers 1977Chlordiazepoxide (benzodiazepine) 

Placebo

Propranol (beta-blocking))

Sellers 1983Diazepam (benzodiazepine)Placebo
Solomon 1983Chlordiazepoxide (benzodiazepine)Lorazepam (benzodiazepine)
Spies 1996Flunitrazepam (benzodiazepine) + Clonidine (adrenergic agonist)

Flunitrazepam (benzodiazepine) + Haloperidol (antipsychotic)

Chlormethiazole (anticonvulsant) +

Haloperidol (antipsychotic)

Spies 2003Flunitrazepam (benzodiazepine) + Clonidine (adrenergic agonist) + Haloperidol (antipsychotic) infusion-titratedFlunitrazepam (benzodiazepine) + Clonidine (adrenergic agonist) + Haloperidol (antipsychotic) bolus-titrated
Stanhope 1989Carbamazepine (anticonvulsant)Placebo
Stuppaeck 1992Oxazepam  (benzodiazepine)Carbamazepine (anticonvulsant)
Stuppaeck 1998Oxazepam  (benzodiazepine)Vigabatrin (anticonvulsant)
Teijeiro 1975Heminiurine (anticonvulsant)Phenobarbital (anticonvulsant) + Ferbamate (tranquillizes)
Thompson 1975Diazepam (benzodiazepine)Paraldehyde (anticonvulsant)
Tubridy 1988Alprazolam (benzodiazepine)Chlormethiazole (anticonvulsant)
Wilson 1985Chlordiazepoxide (benzodiazepine)Alprazolam (benzodiazepine)
Worner 1994Diazepam (benzodiazepine)Propranol (beta-blocking))

Methodological quality of included reviews

The methodological quality of the included reviews was good: all provided an a priori design; the literature search was comprehensive in all the reviews, none used the status of publication as an inclusion criteria; all provided a list of included and excluded studies, described the characteristics of included studies, assessed and documented the methodological quality of primary studies, used quality assessment results to formulate conclusions; all but one (Leone 2010) combined the results in an appropriate way (took heterogeneity into consideration); one did not perform meta-analysis because only one study was included; all stated conflict of interest. The only flaw of the included reviews related to the assessment of publication bias: three reviews (Amato 2010; Liu 2011; Minozzi 2010) planned to assess it but two (Amato 2010; Minozzi 2010) reported that funnel plot (plot of the effect estimate from each study against the sample size or effect standard error) was not used to assess the potential for bias related to the size of the trials, because all the included studies had small sample size and not statistically significant results and for one (Liu 2011) it was not possible to assess it because only one study was included ; two reviews did not appraise publication bias. See Table 4

Table 4. Quality of included reviews using AMSTAR
Amstar criteriaAmato 2010Gillman 2007Leone 2010Minozzi 2010Liu 2010
1. a priori’ designyesyesyesyesyes
2. duplicate extractionyesyesyesyesyes
3. literature search comprehensive yesyesyesyesyes
4 status of  publication used as criterianonononono
5. included and excluded list providedyesyesyesyesyes
6. studies characteristics providedyesyesyesyesyes
7. quality assessed and documentedyesyesyesyesyes
8. quality impacted conclusionsyesyesyesyesyes
9. methods for combining appropriateyesyesnoyesna
10. publication bias assessedNonononoyes
11. conflicts of interest statedyesyesyesyesyes

Effect of interventions

The following results refer to primary outcomes chosen for this overview, for results related to all the outcomes considered in the five reviews, refer to the single reviews.

The outcomes considered are only primary (most relevant) outcomes and are categorized as efficacy, safety and acceptability outcomes.

  • The efficacy outcome considered is: alcohol withdrawal seizures

  • The safety outcome considered is: adverse events

  • The acceptability outcome considered is: dropout

We present the results showing the GRADE Summary of findings tables that allow to see in a single table both results and their quality.

Comparing the five considered treatments with placebo, results were statistically significant in favour of the treatment only in one comparison: benzodiazepines performed better for seizures, results come from three studies, 324 participants, RR 0.16 (95% CI 0.04 to 0.69), and the quality of evidence was moderate. Figure 2 shows the summary of results for these comparisons.

Figure 2.

Summary of findings table: treatments versus placebo

Comparing the five treatments versus specific class of drugs, results reached the statistical significance only in one comparison: benzodiazepines performed better than antipsychotics for seizures, 4 studies, 633 participants, 633 participants, RR 0.24 (95% CI 0.07 to 0.88) with high quality of the evidence. Figure 3 shows the summary of results for these comparisons.

Figure 3.

Tratments versus specific class of drugs

Comparing different benzodiazepines see Table 5 and anticonvulsants see Table 6 among themselves, results never reached statistical significance but, between benzodiazepines, chlordiazepoxide. performed better.

Table 5. Results of the comparisons between different benzodiazepines
Outcome or SubgroupStudiesParticipants

Effect Estimate

R R (Random, 95% CI)

Alcohol withdrawal seizures
Chlordiazepoxide vs Alprazolam11000.44 [0.15, 1.35]
Chlordiazepoxide vs Diazepam1240.33 [0.01, 7.45]
Chlordiazepoxide vs Lorazepam.1500.20 [0.01, 3.97]
Lorazepam vs. Diazepam1403.00 [0.13, 69.52]
Adverse events
Chlordiazepoxide vs Clobazam1400.80 [0.25, 2.55]
Chlordiazepoxide vs. Diazepam2343.00 [0.14, 63.15]
Chlordiazepoxide vs. Halazepam1800.53 [0.05, 5.57]
Lorazepam vs. Diazepam2962.56 [0.35, 18.62]
Chlordiazepoxide vs Alprazolam 11003.00 [0.13, 71.92]
Diazepam vs Abecamil1480.33 [0.04, 2.98]
Dropouts
Alprazolam vs. Diazepam2600.25 [0.01, 5.03]
Chlordiazepoxide vs. Diazepam2416.00 [0.37, 96.85]
Chlordiazepoxide vs. Halazepam1922.75 [0.80, 9.51]
Chlordiazepoxide vs Clobazam1540.81 [0.32, 2.01]
Chlordiazepoxide vs Lorazepam1580.38 [0.08, 1.74]
Lorazepam vs. Diazepam31561.20 [0.54, 2.65]
Table 6. Results of the comparisons between different anticonvulsants
Outcome or SubgroupStudiesParticipants

Effect Estimate

R R (Random, 95% CI)

Adverse events
Carbamazepine versus Chlormethiazole21213.10 [1.01, 9.50]
Carbamazepine versus Barbital1611.81 [0.70, 4.68]
Chlormethiazole versus Pentobarbital1272.80 [0.12, 63.20]
Dropouts
Carbamazepine versus Chlormethiazole21210.50 [0.16, 1.54]
Carbamazepine versus Barbital1600.07 [0.00, 1.23]
Carbamazepine versus Oxcarbazepine1293.20 [0.14, 72.62]
Chlormethiazole versus Pentobarbital1271.39 [0.28, 7.05]
Pentobarbital versus Paraldehyde1960.37 [0.03, 3.97]

Discussion

Summary of main results

The reviews considered many outcomes, we decided to consider in this report only the primary outcomes one related to efficacy (alcohol withdrawal seizures), one related to safety (adverse events) and one related to acceptability (dropouts). Adopting these criteria we present in this overview results from 3 outcomes, considered in 72 out the 114 studies included. Comparing the five considered treatments with placebo, results were in favour of benzodiazepines for seizures, comparing treatments versus specific class of drugs, benzodiazepines performed better than antipsychotics for seizures, although this result is not impressive considering that neuroleptics are well known pro convulsants drugs; finally comparing different benzodiazepines and anticonvulsants among themselves, results never reached statistical significance but, between benzodiazepines, chlordiazepoxide performed better.

Overall completeness and applicability of evidence

Based on these considerations, the overall results need to be interpreted with caution. For the majority of our results, those classified as moderate (28%) or low (48%) quality, further research is likely to have an important or a very important impact on confidence in the estimate of effect and may change the estimate. Furthermore, for the 20% of evidence classified as very low any estimate of effect is very uncertain. Moreover, we could not examine dose-response effects since patients were not treated with even similar doses of various treatments across RCTs. In this overview we selected only three outcomes, mainly because these were the outcomes considered by the majority of the studies and because they are all considered relevant outcomes. Weare aware that doing that we can loose useful information that in any case can be found in the original reviews. However, looking at the other outcomes in the original reviews the final judgment on the efficacy of the considered interventions is unchanged. One critical point is the choice of seizures as measure of efficacy, we are aware that it would be better to consider the overall withdrawal syndrome, unfortunately this outcome was not considered in the majority of included studies and, when considered, the way in which the data are reported varied between the studies, preventing the possibility of a cumulative analysis and this is the reason why we decided to consider seizures in this report, nevertheless these data, although not very informative, are available in the single reviews.

Quality of the evidence

The quality of evidence, rated utilising the GRADE methodology, was not so good: only two out of the 60 results (3%) are based on an high quality of evidence, both were in the comparisons between benzodiazepines and antipsychotic and only one of them reached the statistically significance, showing that benzodiazepines performed better than antipsychotics for seizures. 28% had a moderate quality of evidence, two out these 17, reached the statistically significance: one in favour of benzodiazepine versus placebo for seizures and the other one in favour of GHB versus other drugs for dropouts. 29/60 (48%) results had a low quality of evidence and 12 (20%) a very low quality. The percentages of results of low or very low quality became higher if we consider only the comparisons of different benzodiazepines and different anticonvulsants among themselves: 61% low and 32% very low.

Potential biases in the overview process

None known

Agreements and disagreements with other studies or reviews

The results of the overview are in agreement with the main results of the included reviews

Authors' conclusions

Implications for practice

With all the limits discussed above, our implications for practice are the following: Between the four treatments considered, benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, in particular seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with antipsychotics drugs. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines were possible, because of the heterogeneity of the trials both in interventions and in the assessment of outcomes. Data on potential harms are sparse and fragmented. Results do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS, but anticonvulsants seem to have limited side effects.
There is also not enough evidence of effectiveness and safety of baclofen, because of only one study consider this treatment and of GHB for which no strong differences were observed in the comparisons with placebo, benzodiazepines and anticonvulsants.

Implications for research

Most of the available evidence are of moderate quality, suggesting the need for further research. Particularly, since benzodiazepines showed a potential benefit, further studies should test alternative drugs against them, and should investigate which benzodiazepine performed better for the treatment of alcohol withdrawal syndrome and the relative dose-response effect. To make a substantial contribution to the available evidence, new studies should enrol a large number of participants (at least 400) and consider few, important outcomes, related to the efficacy, safety and acceptability of the considered interventions, in order to allow cumulative synthesis. Adverse events for safety and dropouts for acceptability are probably the right outcomes to be considered, for efficacy the overall withdrawal syndrome should be studied. The overall withdrawal syndrome usually is an outcome assessed with scales and consistency on rating continuous outcomes in the same scales should also be achieved in order to obtain comparable information from all relevant studies.

Acknowledgements

We will thank Simona Vecchi for developing the search strategy and Zuzana Mitrova for her help and assistance during the review process.

Appendices

Appendix 1. AMSTAR Checklist criteria

AMSTAR criteria

  1. Was an ’a priori’ design provided? [Yes−the research question and inclusion criteria were established before conducting the review];

  2. Was there duplicate study selection and data extraction? [Yes−at least two people working independently extracted the data and the method was reported for reaching consensus if disagreements arose];

  3. Was a comprehensive literature search performed?[Yes−at least two electronic sources were searched; details of the databases, years searched and search strategy were provided; the search was supplemented by searching of reference lists of included studies, and specialised registers, and by contacting experts];

  4. Was status of publication used as an exclusion criterion? [Yes−the authors stated that they excluded studies from the review based on publication status. No−authors searched for reports irrespective of publication type. They did not exclude reports based on publication from the systematic review];

  5. Was a list of studies (included and excluded provided)? [Yes−a list was provided];

  6. Were the characteristics of the included studies provided? [Yes−data on participants, interventions and outcomes were provided, and the range of relevant characteristics reported];

  7. Was the scientific quality of the included studies assessed and reported? [Yes−predetermined methods of assessing quality were reported];

  8. Was the scientific quality of the included studies used appropriately in formulating conclusions?[Yes−the quality (and limitations) of included studies was used in the analysis, conclusions and recommendations of the review];

  9. Were the methods used to combine the findings of studies appropriate?[Yes−if results were pooled statistically, heterogeneity was assessed and used to inform the decision of statistical model to be used. If heterogeneity was present, the appropriateness of combining studies was considered by review authors];

  10. Was the likelihood of publication bias assessed? [Yes−publication bias was explicitly considered and assessed];

  11. Was the conflict of interest stated? [Yes−sources of support were clearly acknowledged].

For all items except item 4, a rating of ’yes’ is considered adequate. For item 4, a rating of ’no’ (that is, the review did not exclude unpublished or grey literature) is considered adequate. A review
that adequately meets all of the 11 criteria is considered to be a review of the highest quality. For this overview we will consider reviews that achieve scores of between 8 to 11 high quality; scores
of 4 to 7 medium quality; and scores of 0 to 3 low quality. One investigator will assess the quality of the included reviews using AMSTAR, and a second investigator will verify this assessment.

Appendix 2. GRADE Criteria

Definitions are as follows:

  • High – Further research is very unlikely to change confidence in the estimate of effect.

  • Moderate – Further research is likely to have an important impact on confidence in the estimate of

  • effect and may change the estimate.

  • Low – Further research is very likely to have an important impact on confidence in the estimate of

  • effect and is likely to change the estimate.

  • Very low – Any estimate of effect is very uncertain

Decrease grade if:

  • Serious (-1) or very serious (-2) limitation to study quality

  • Important inconsistency (-1)

  • Some (-1) or major (-2) uncertainty about directness

  • Imprecise or sparse data (-1)

  • High probability of reporting bias (-1)

Increase grade if:

  • Stong evidence of association - significant relative risk of >2 (<0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1)

  • Very strong evidence of association - significant relative risk of >5 (<0.2) based on direct evidence with no major threats to validity (+2)

  • Evidence of a dose response gradient (+1)

  • All plausible confounders would have reduced the effect (+1)

History

Protocol first published: Issue 6, 2010
Review first published: Issue 6, 2011

Contributions of authors

Designing the review: All authors; Screening search results: Amato, Minozzi; Screening retrieved papers against inclusion criteria,: Amato Minozzi; Extracting data from paper: Amato, Minozzi; Analysis of data: Amato, Minozzi, Davoli; Writing the review: Amato and Minozzi; Appraising quality of papers: Minozzi: Providing general advice on the review: Davoli

Declarations of interest

None

Sources of support

Internal sources

  • Department of Epidemiology, Lazio region, Italy.

External sources

  • No sources of support supplied