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

  1. Laura Amato*,
  2. Silvia Minozzi,
  3. Marina Davoli

Editorial Group: Cochrane Drugs and Alcohol Group

Published Online: 15 JUN 2011

Assessed as up-to-date: 28 MAR 2011

DOI: 10.1002/14651858.CD008537.pub2


How to Cite

Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD008537. DOI: 10.1002/14651858.CD008537.pub2.

Author Information

  1. ASL RM/E, Department of Epidemiology, Rome, Italy

*Laura Amato, Department of Epidemiology, ASL RM/E, Via di Santa Costanza, 53, Rome, 00198, Italy. amato@asplazio.it.

Publication History

  1. Publication Status: New
  2. Published Online: 15 JUN 2011

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Table 1. Main characteristics of included reviews

ReviewData published/assessed as updateData SearchPopulationInterventionsComparisons

Interventions
Total studies consideredN° Excluded studiesN° Included studiesN° Participants

Anticonvulsants for alcohol withdrawalCLIB issue 3, 2010Searches 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 2009Alcohol 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, 2010Searches 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, 2011Searches 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, 2007Searches 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))

 
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

 
Table 5. Results of the comparisons between different benzodiazepines

Outcome or SubgroupStudiesParticipantsEffect 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 SubgroupStudiesParticipantsEffect 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]