The alcohol withdrawal syndrome (AWS) is a common management problem in hospital practice for neurologists, psychiatrists and general physicians alike. Although some patients have mild symptoms and may even be managed in the outpatient setting, others have more severe symptoms or a history of adverse outcomes that requires close inpatient supervision and benzodiazepine therapy. Many patients with AWS have multiple management issues (withdrawal symptoms, delirium tremens, the Wernicke-Korsakoff syndrome, seizures, depression, polysubstance abuse, electrolyte disturbances and liver disease), which requires a coordinated, multidisciplinary approach. Although AWS may be complex, careful evaluation and available treatments should ensure safe detoxification for most patients.

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The Alcohol Withdrawal Syndrome

Background
Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of benzodiazepines' use in the treatment of alcohol withdrawal symptoms.

Objectives
To evaluate the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal.

Search methods
We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions. We also screened references of retrieved articles.

Selection criteria
All randomised controlled trials examining the effectiveness and safety of a benzodiazepine in comparison with a placebo or other pharmacological intervention or other benzodiazepine were considered.

Data collection and analysis
Two reviewers independently assessed trial quality and extracted data.

Main results
Fifty-seven trials, with a total of 4,051 people were included. Despite the considerable number of randomized controlled trials, there was a very large variety of outcomes and of different rating scales and relatively limited quantitative synthesis of data was feasible. Benzodiazepines offered a large benefit against alcohol withdrawal seizures compared to placebo (relative risk [RR] 0.16; 95% confidence interval [CI] 0.04 to 0.69; p = 0.01). Benzodiazepines had similar success rates as other drugs (RR 1.00; 95% CI 0.83 to 1.21) or anticonvulsants in particular (RR 0.88; 95% CI 0.60 to 1.30) and offered a significant benefit for seizure control against non-anticonvulsants (RR 0.23; 95% CI 0.07 to 0.75; p = 0.02), but not against anticonvulsants (RR 1.99; 95% CI 0.46 to 8.65). Changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment were similar with benzodiazepines versus other drugs, although some small studies showed isolated significant differences for other, less commonly, used scales. Data on other comparisons were very limited, thus making quantitative synthesis for various outcomes not very informative.

Authors' conclusions
Benzodiazepines are effective against alcohol withdrawal symptoms, in particular seizures, when compared to placebo. It is not possible to draw definite conclusions about the relative effectiveness and safety of benzodiazepines against other drugs in alcohol withdrawal, because of the large heterogeneity of the trials both in interventions and assessment of outcomes but the available data do not show prominent differences between benzodiazepines and other drugs in success rates.

Benzodiazepines for alcohol withdrawal

Alcohol abuse and dependence represents a serious health problem worldwide with social, interpersonal and legal interpolations. Benzodiazepines have been widely used for the treatment of alcohol withdrawal symptoms. Moreover it is unknown whether different benzodiazepines and different regimens of administration may have the same merits.
 
The objective of this review is to evaluate the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal.

Background: The neuropeptide, oxytocin (OT), has been reported to block tolerance formation toalcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies inhuman subjects indicate that OT administered by the intranasal route penetrates into and exerts eﬀectswithinthebrain.Methods: In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) orplacebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a researchunit for medical detoxiﬁcation using Clinical Institute Withdrawal Assessment for Alcohol (CIWA)score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol WithdrawalSymptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the PennAlcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Proﬁle of MoodStates(POMS)oninpatientdays2and3.Results: All subjects had drunk heavily each day for at least 2 weeks prior to study and had previ-ously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior toplacebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to completedetoxiﬁcation (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scoreson days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxietysubscalescoresonday2(p < 0.01).Conclusions: This is the ﬁrst demonstration that OT treatment may block alcohol withdrawal inhuman subjects. Our results are consistent with previous ﬁndings in rodents that OT inhibits neuroad-aptationtoandwithdrawalfromalcohol.OTcouldhaveadvantagesoverbenzodiazepinesinmanagingalcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will beimportant to test whether OT treatment is eﬀective in reducing drinking in alcohol-dependent outpa-tients.Key Words: Oxytocin, Alcohol Withdrawal, Detoxiﬁcation, Dependence, Tolerance, HumanSubjects.

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Intranasal Oxytocin Blocks Alcohol Withdrawal in Human Subjects

the treatment of substance misuse, addiction and comorbidity with psychiatric disorders primarily focus on their pharmacological management. They are based explicitly on the available evidence and presented as recommendations to aid clinical decision making for practitioners alongside a detailed review of the evidence. A consensus meeting, involving experts in the treatment of these disorders, reviewed key areas and considered the strength of the evidence and clinical implications. The guidelines were drawn up after feedback from participants. The guidelines primarily cover the pharmacological management of withdrawal, shortand longterm substitution, maintenance of abstinence and prevention of complications, where appropriate, in substance misuse, addiction and comorbidity with psychiatric disorders.

Evidence-Based Guidelines for the Pharmacological Management of Substance Misuse, Addiction and Comorbidity: Recommendations from the British Association for Psychopharmacology:

Background In alcohol withdrawal, fixed doses of benzodiazepine are generally recommended as a first-line pharmacologic approach. This study determines the benefits of an individualized treatment regimen on the quantity of benzodiazepine administered and the duration of its use during alcohol withdrawal treatment. Methods We conducted a prospective, randomized, double-blind, controlled trial including 117 consecutive patients with alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , entering an alcohol treatment program at both the Lausanne and Geneva university hospitals, Switzerland. Patients were randomized into 2 groups: (1) 56 were treated with oxazepam in response to the development of signs of alcohol withdrawal (symptom-triggered); and (2) 61 were treated with oxazepam every 6 hours with additional doses as needed (fixed-schedule). The administration of oxazepam in group 1 and additional oxazepam in group 2 was determined using a standardized measure of alcohol withdrawal. The main outcome measures were the total amount and duration of treatment with oxazepam, the incidence of complications, and the comfort level. Results A total of 22 patients (39%) in the symptom-triggered group were treated with oxazepam vs 100% in the fixed-schedule group ( P P P Conclusions Symptom-triggered benzodiazepine treatment for alcohol withdrawal is safe, comfortable, and associated with a decrease in the quantity of medication and duration of treatment.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/211434/ioi10236.pdf

Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial.

BACKGROUND
In alcohol withdrawal, fixed doses of benzodiazepine are generally recommended as a first-line pharmacologic approach. This study determines the benefits of an individualized treatment regimen on the quantity of benzodiazepine administered and the duration of its use during alcohol withdrawal treatment.


METHODS
We conducted a prospective, randomized, double-blind, controlled trial including 117 consecutive patients with alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, entering an alcohol treatment program at both the Lausanne and Geneva university hospitals, Switzerland. Patients were randomized into 2 groups: (1) 56 were treated with oxazepam in response to the development of signs of alcohol withdrawal (symptom-triggered); and (2) 61 were treated with oxazepam every 6 hours with additional doses as needed (fixed-schedule). The administration of oxazepam in group 1 and additional oxazepam in group 2 was determined using a standardized measure of alcohol withdrawal. The main outcome measures were the total amount and duration of treatment with oxazepam, the incidence of complications, and the comfort level.


RESULTS
A total of 22 patients (39%) in the symptom-triggered group were treated with oxazepam vs 100% in the fixed-schedule group (P<.001). The mean oxazepam dose administered in the symptom-triggered group was 37.5 mg compared with 231.4 mg in the fixed-schedule group (P<.001). The mean duration of oxazepam treatment was 20.0 hours in the symptom-triggered group vs 62.7 hours in the fixed-schedule group (P<.001). Withdrawal complications were limited to a single episode of seizures in the symptom-triggered group. There were no differences in the measures of comfort between the 2 groups.


CONCLUSIONS
Symptom-triggered benzodiazepine treatment for alcohol withdrawal is safe, comfortable, and associated with a decrease in the quantity of medication and duration of treatment.

Verena Schweizer

Papers

Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial.

Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal