| Abstract|| |
Background: Benzodiazepines (BDZs) have been the treatment of choice for alcohol withdrawal syndrome (AWS); however, they are associated with several side effects and also have abuse potential. In some studies, the use of baclofen has been effective in reducing symptoms of alcohol withdrawal symptoms.
Aim: The objective of this study was to compare the efficacy of baclofen and benzodiazepine (lorazepam) in reducing symptoms of AWS.
Materials and Methods: It was a single-center, randomized, open-label study. Patients with alcohol dependence syndrome were enrolled in the study and randomized into two groups using computer-generated random table number. Baclofen (experimental group, 10 mg three times a day) and BZDs (control group, lorazepam, 8–12 mg/day in divided doses) were orally administered for reducing symptoms of alcohol withdrawal. Both groups received Vitamin B1 (100 mg/day through intramuscular route) and psychotherapeutic interventions. The severity of alcohol dependence was assessed by using the Severity of Alcohol Dependence Questionnaire, and alcohol withdrawal was assessed with the Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar).
Results: Sixty-six patients were randomized (baclofen n = 34, benzodiazepine (BZD) group n = 32). Two patients (one patient in each group) had complicated withdrawal symptoms and were dropped from the final analysis. There was a significant reduction in alcohol withdrawal symptoms in both groups. There were no significant differences in CIWA-Ar scores between the two groups. Both the drugs were well-tolerated.
Conclusion: Baclofen and lorazepam are comparable in efficacy and tolerability in reducing symptoms of AWS.
Keywords: Alcohol withdrawal, baclofen, lorazepam
|How to cite this article:|
Gulati P, Chavan BS, Sidana A. Comparative efficacy of baclofen and lorazepam in the treatment of alcohol withdrawal syndrome. Indian J Psychiatry 2019;61:60-4
| Introduction|| |
Alcohol dependence is a major public health problem in India, with an estimated 34%–42% of adult Indian population reports having used alcohol in their lifetime; 5%–7% have been estimated to be abusers of alcohol and 10–20 million persons have been estimated to be in need of treatment for alcohol dependence.
Clinical management of alcohol dependence involves initial discontinuation of alcohol intake by alcohol-dependent patients, which leads to a condition known as alcohol withdrawal syndrome (AWS). In its mild-to-moderate forms, symptoms such as increase in blood pressure and pulse rate, tremors, hyperreflexia, irritability, and anxiety usually develop within 6–24 h after the last drink and may subside within few days. However, delirium tremens may develop in patients consuming excessive amount of alcohol for many years and may lead to death in about 5%–10% of the cases, if not managed properly.,
Although benzodiazepines (BZDs) have been the drugs of choice in the treatment of AWS, their use is associated with several side effects, such as risk of excessive sedation, memory deficits, and respiratory depression in patients with liver impairment, as is often the case in patients of alcohol dependence. Moreover, BZDs have addictive properties, which constitute a limitation to their use in subjects affected by substance use disorders., Consequently, the discovery of new potentially useful drugs for the treatment of AWS is of considerable practical importance. Baclofen has emerged as an effective drug in the treatment of alcohol dependence, with its role in reducing craving and hence decreasing alcohol consumption., In addition, in two studies, baclofen has been found to reduce the severity of alcohol withdrawal symptoms comparable to diazepam – a property that established pharmacotherapies for alcohol dependence, i.e., naltrexone and acamprosate, have not demonstrated., In one of these studies in which 5 patients of alcohol dependence syndrome (ADS) who had CIWA-Ar score more than 20, a single dose of baclofen 10 mg resulted in rapid disappearance of alcohol withdrawal symptoms in all patients along with rapid improvement in well-being and resolution of psychological distress., In the second study, 37 patients with AWS were enrolled in the study and randomly divided into two groups. Eighteen patients received baclofen (30 mg/day for 10 consecutive days) and 19 patients received diazepam. It was found that both baclofen and diazepam significantly decreased CIWA-Ar score and there was no significant difference between the two drugs. In addition, there is a published report of a case of severe AWS complicated by delirium tremens being successfully treated with baclofen. It is hypothesized that baclofen use results in attenuation of alcohol withdrawal symptoms by the activation of gamma-aminobutyric acid-B receptors, resulting in a reduction of AWS-associated, enhanced function of N-methyl-d-aspartate-mediated glutamate excitatory neurotransmission.
In a recent review to assess the efficacy and safety of baclofen in patients with AWS, it was concluded that although baclofen was found to be efficacious, safe, and well-tolerated for the treatment of AWS, the evidence for recommending baclofen for AWS was insufficient. However, only one study had met the inclusion criteria for this review out of seven shortlisted studies. As this study was outpatient department based, use of alcohol or other psychoactive substance by the patients between assessments cannot be ruled out with certainty, even though an objective assessment of blood alcohol concentration was used; however, blood alcohol levels may have returned to permissible limits by the time assessments were made. Due to limited but promising research on the use of baclofen in treating AWS and to overcome potential limitations of an outpatient study, the current study was planned to compare the efficacy of baclofen with a benzodiazepine (in this study, lorazepam was chosen as this is the short-acting BDZ and most commonly used drug for AWS in our center) in the treatment of AWS in an inpatient setting.
| Materials and Methods|| |
Patients were enrolled from those attending the Department of Psychiatry of Government Medical College and Hospital (GMCH), Chandigarh, India. A total of 66 patients with the diagnosis of alcohol dependence as per ICD-10 criteria, fulfilling inclusion and exclusion criteria and willing to participate in the study, were enrolled. Participants were assigned randomly into two groups – baclofen group (experimental group [EG]) and lorazepam group (control group [CG]) using computer-generated random number table.
- Age 18–65 years
- Patients meeting diagnostic criteria for alcohol dependence as per ICD-10 classification.
- Presence of serious physical illness such as renal dysfunction, seizure disorder, and cardiac disease (as assessed by thorough physical examination, history, and routine laboratory screening)
- Presence of another current coexisting major psychiatric disorder
- Presence of another current drug dependence except nicotine and caffeine
- Patients with a history of hypersensitivity reaction with these drugs in the past
- Patients with a history of complicated withdrawals, and
- Patients not willing to participate.
It was a randomized, open-label study conducted at the Department of Psychiatry, GMCH, Chandigarh, India, from October 2011 to May 2013. After taking informed consent, participating patients were admitted in the ward for detoxification and efforts were made to complete the detoxification in 7- to 10-day period. Inpatient facility at the institute provides strict security measures barring entry of any psychoactive substance in the ward. Participants enrolled in the study were assessed for their pattern of alcohol use, major health problems due to alcohol consumption, and occurrence of withdrawal symptoms in the past, by using a semi-structured Pro forma by the principal investigator. Sociodemographic data (age, socioeconomic status, marital status, level of education, and occupation) and previous history of detoxification were also recorded. The amount of alcohol consumed by the patient was converted into absolute grams of alcohol. Participants in both the groups were assessed for severity of alcohol dependence by using the Severity of Alcohol Dependence Questionnaire (SADQ) at baseline. Severity of withdrawal symptoms was evaluated with CIWA-Ar for alcohol by the principal investigator in the morning at a fixed time before administration of medication. Medications were dispensed at fixed intervals by nursing staff.
All routine laboratory investigation including liver function tests were done to rule out any serious medical complication at baseline as shown in [Table 1].
|Table 1: Routine investigations, including markers of alcohol consumption, at baseline (values in mean±standard deviation)|
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For detoxification, patients in the baclofen group were given three doses of 10 mg of baclofen (EG). Patients of lorazepam group were detoxified with lorazepam (CG, 8–12 mg/day in divided doses). The other interventions during the detoxification including the administration of Vitamin B1 (100 mg/day through intramuscular route) and psychotherapy, in the form of Motivational Enhancement Therapy and Relapse Prevention by qualified clinical psychologist, were same for both the groups. If required, zolpidem up to 10 mg/day was used as hypnotic in patients of baclofen group for managing sleep disturbances. In case of complicated withdrawals in either of the group, the patient was dropped from the study and managed as per the standard protocol for complicated withdrawals. Adverse effects of treatment in both the groups were monitored by using a checklist. The study protocol was approved by the Institutional Ethics Committee, and the defined guidelines of Central Ethics Committee for Biomedical Research on human participants by ICMR were adhered to, in addition to the principles enunciated in the “Declaration of Helsinki.”
Chi-square test was used to compare the demographic profile and variables related to alcohol (nominal data) in both groups. ANOVA was used to compare ordinal variables within both the groups. Data analysis was performed using the SPSS 14 version software (SPSS Inc., Chicago, IL, USA) statistical software package for Windows. Analyzed data are represented in percentage, mean, and standard deviation. The level of statistical significance was P < 0.05.
| Results|| |
A total of 66 patients were enrolled, with 34 patients in the baclofen group (EG) and 32 patients in the lorazepam group (CG). Two patients (one patient in baclofen and one patient in lorazepam group went in to delirium on day 2) developed complicated withdrawal during detoxification, and hence, they were dropped from the final analysis and were managed as per the standard protocol in the department. Rest of the patients (n = 64) completed the detoxification period during the admission, with 33 patients in EG and 31 in CG, and were included in the final analysis for comparison of the efficacy of two drugs in the management of alcohol withdrawal.
Sociodemographic profile of the patients
Both the groups had comparable sociodemographic profile and did not have any statistically significant difference as shown in [Table 2].
Both the groups were comparable on average alcohol consumption and duration of regular use of alcohol. Patients in both the groups had moderate-to-severe alcohol dependence as measured by SADQ, and hence required pharmacotherapy for the management of withdrawal symptoms. There was no statistical difference between the two groups on these parameters as shown in [Table 3].
[Figure 1] shows a comparison of withdrawal symptom profile in the two groups using CIWA-Ar scale. There was a comparable decrease in total scores in both the groups with completion of detoxification at day 8 in both the groups. Symptoms of headache, tremor, anxiety, nausea, and paroxysmal sweats were most commonly reported symptoms during detoxification, and there was no statistical difference in scores between the two groups. Blood pressure, pulse, and respiratory rate were regularly recorded in both the groups and there was no difference. Other symptoms in CIWA-Ar scale were infrequent and insufficient for statistical comparison between the groups. Zolpidem was required as hypnotic by 15 patients (45.4%) of EG during detoxification.
|Figure 1: Total Clinical Institute Withdrawal Assessment for Alcohol, revised score of two groups during detoxification|
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Only one patient in the baclofen group (EG) reported sedation which subsided on its own and did not require any dose modification. None of the patients in lorazepam group (CG) reported any side effect.
| Discussion|| |
The present study was conducted to evaluate the efficacy of baclofen in the management of AWS against the standard treatment with BZD (lorazepam). Before the initiation of treatment, both the groups had comparable severity of withdrawal symptoms (total as well as individual item-wise score) as measured by CIWA-Ar. The results showed that in both the groups, it was possible to complete the detoxification within 8 days and there was no difference in the total as well as individual item withdrawal scores during the period of 8 days. A similar outcome was reported in an earlier study in which baclofen was compared to diazepam for controlling withdrawal symptoms.
These findings highlight the potential of baclofen in the treatment of alcohol withdrawals instead of benzodiazepines even though benzodiazepines have been the drug of choice for the same. This will help to decrease the chances of benzodiazepine dependence as many patients underreport benzodiazepines' self-use and continue to receive them for insomnia or anxiety even after acute symptoms of alcohol withdrawal subside., Furthermore, patients of alcohol dependence have a high potential of benzodiazepine abuse and dependence during their lifetime due to comorbid psychiatric disorders. In addition, the use of benzodiazepines is associated with several side effects, such as risk of excess sedation, memory deficits, and respiratory depression in patients with liver impairment, as mentioned earlier. The use of baclofen will avert these complications as such adverse effects do not occur with baclofen and also it has been tolerated well by patients as shown in current and previous studies.,,,
Use of baclofen has low abuse potential as its use was neither associated with craving nor did it cause any symptoms after being discontinued in patients who were on regular treatment.,, Baclofen has also been well-tolerated by alcohol-dependent patients with cirrhosis. Hence, it can be used safely for detoxification in patients with associated liver dysfunction, in whom benzodiazepines are either contraindicated or need dose modification due to their predominant metabolism by the liver. As mentioned above, both total severity score and individual item score of withdrawal symptom were comparable in the two groups in the present as well as previous study; hence, baclofen can be used for detoxification and the same molecule can be continued as an anticraving drug for relapse prevention. Although the present study was conducted using the sound methodology, having stringent inclusion and exclusion criteria, with all the patients being admitted during the entire course of detoxification, certain limitations need to be considered while interpreting the results. The study was open label, carried out at a single center, with a small sample size without inclusion of a placebo arm. Further, the findings would have been more helpful through the use of more robust statistical tests including RMANOVA and confidence interval to see less common risk associated with medication. Results cannot be generalized to all patients of alcohol dependence as most patients in the current study had moderate dependence. In future, multicentric studies using blinding techniques with larger samples are required to overcome these limitations. Furthermore, studies using higher doses of baclofen than those used currently can be conducted to find any dose–response relationship for greater therapeutic effect.
| Conclusion|| |
Findings of the current study show that both baclofen and lorazepam are comparable in efficacy and tolerability in reducing the symptoms of AWS. Since, BDZs have abuse potential and also require dose modification in patients with significant liver dysfunction, baclofen can be considered as detoxification agent in patients with ADS and the same molecule can be continued as anti-craving agent for relapse prevention.
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Conflicts of interest
There are no conflicts of interest.
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Dr. Ajeet Sidana
Department of Psychiatry, Government Medical College and Hospital, Chandigarh
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]