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Jhanwar A., Patidar OP., Sharma RN, Chourishi A., Jain A., A Double Blind Study For Efficacy of Diazepam and Baclofen In The Treatment Of Alcohol Withdrawal Syndrome.. J Pharm Biomed Sci 2014; 04(06):482-488.

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A Double Blind Study For Efficacy Of Diazepam and Baclofen In The Treatment

Of Alcohol Withdrawal Syndrome

Anshul Jhanwar1,*

,O.P.Patidar2,R.N.Sharma

3,Ashutosh Chourishi

3,Abhay Jain

4

Affiliation:-

1Demonstrator, Pharmacology, J.M.C., Jhalawar (Raj),

India 2Associate professor, Medicine, J.M.C., Jhalawar (Raj),

India 3Professor, Pharmacology, R.D.G.M.C., Ujjain (M.P.),

India 4Professor, Psychiatry, R.D.G.M.C., Ujjain (M.P.), India

The name of the department(s) and institution(s) to which the work should be attributed: R.D.Gardi Medical College,Ujjain (M.P),India

*To whom it corresponds:- Dr. Anshul Jhanwar, III/2, Doctor’s residence, Medical College Campus, Jhalawar, Dist- Jhalawar (Raj.)– 326001, India Email - dranshul123@gmail.com Mobile – 07726097704 Abstract Aim: To compare the efficacy of Baclofen and Diazepam in alcohol withdrawal syndrome. Materials and Methods: This was a 15 days, randomized, parallel, double blind comparative study. Fourty eight in-patients were randomized in two groups (Group I (Baclofen =24), mean age = 33±6.76 and Group II (Diazepam = 24), mean age = 35±8.16. All patients with mild to moderate AWS were enrolled for study after obtaining informed written consent. The patients were administered either Baclofen 10mg or Diazepam 10mg tablets at the dose of one tablets twice a day for five days followed by one tablet once a day for the next five days. The in-patient unit offered a 10-day in-patient stay with flexibility to allow negotiation of the discharge date between day 10 and day 15.

Statistics: The data were analyzed by using the statistical software SPSS, version 16.0.The continuous variables were analyzed by using the Student t-test while categorical data was analyzed by using the Chi-square (x2) test. The results were presented as median (range) and number (percentage) for continuous variables. Main outcome measures: Primary variables were CIWA-Ar total score (The revised Clinical Institute Withdrawal Assessment for Alcohol). Clinical trial registry: India (CTRI) number: CTRI/2011/08/001938. Results: In both groups, from 2nd to 3rd day all participants had achieved a clinically relevant improvement of their withdrawal symptoms. There was drastic reduction on the scores of CIWA-Ar scale from baseline to day 10 & day 15. These changes were statistically highly significant (p < 0.001), which shown that both drugs were efficacious in the treatment of acute mild to moderate AWS. But there were no statistically significant differences between both of the treatment groups on day 10 & day 15 in all efficacy measures, so that the results obtained with them can be considered as equal. Side-effects were slightly more common in the Diazepam group than in Baclofen group. Conclusions: From the present study it can be concluded that, Baclofen is equivalent in efficacy to Diazepam in the treatment of mild to moderate AWS.

Keywords: Baclofen, Diazepam,CIWA-Ar Scale,

Alcohol withdrawal syndrome.

Research Article

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INTRODUCTIONlcoholism is a major public health problem, defined as a pattern of uncontrolled drinking leading to medical, legal and

psychosocial adverse consequences. Alcohol withdrawal syndrome (AWS) refers to symptoms that may occur when a person who has been drinking too much alcohol every day, and suddenly stops or decreases drinking alcohol1,2.The major withdrawal symptoms are insomnia, anxiety, headache, git upset, palpitations, anorexia, hallucinations and seizures.In India, it is estimated that 75 million people are alcohol users. Of these, there has been a noted prevalence of 19.78% - 21.4% of alcohol use and 5% of alcohol dependence in Indian population3,4.

The spectrum of withdrawal symptoms and the time range for the appearance of these symptoms after cessation of alcohol use are listed in Table 1. Generally, the symptoms of alcohol withdrawal relate proportionately to the amount of alcoholic intake and the duration of a patient's recent drinking habit. Most patients have a similar spectrum of symptoms with each episode of alcohol withdrawal. The goals are to treat the immediate withdrawal symptoms, prevent complications and provide long-term preventive therapy. Pharmacological treatment of alcohol withdrawal syndrome involves the use of medications that are cross tolerant with alcohol.

Table 1. Symptoms of alcohol withdrawal syndrome.

At present, benzodiazepines (eg, Diazepam, 0.5-0.75 mg/kg/day) are the drugs of choice in the treatment of AWS, particularly for preventing or treating seizures and delirium. However, 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 is often the case in alcoholics. Moreover, benzodiazepines could have addictive properties, which

constitute a limitation to their use in subjects affected by substance abuse disorders5.

Baclofen is a stereoselective -aminobutyric acidB (GABAB) receptor agonist use at present to control spasticity.However, recent lines of experimental evidence have suggested the ability of Baclofen to suppress alcohol withdrawal signs in rats accordingly6-10. Recent preliminary data have shown how Baclofen rapidly suppressed AWS severity in human alcoholics, even when manifested in its severe form complicated by

delirium tremens11-16. The low toxicity of Baclofen makes it a promising agent. Along with treatment, a "drying-out" period should be appropriate. No alcohol is allowed during this time. The study we report here compares Baclofen with Diazepam. Both drugs were evaluated for effects on acute withdrawal symptoms, craving for alcohol, and rebound phenomena after treatment discontinuation.

OBJECTIVE OF TRIAL

The main objectives of the trial for clinical management of AWS was to compare the efficacy of Baclofen and Diazepam in terms of decreasing the severity of symptoms, preventing more severe withdrawal clinical manifestations such as seizure and delirium, and facilitate entry of the patient into a treatment program in order to attempt to achieve and maintain long-term abstinence from alcohol.

MATERIAL AND METHODS STUDY DESIGN The type of study was interventional. The study was 15 days, randomized, controlled, parallel-group, double-blind clinical trial conducted at department of psychiatry in collaboration with department of pharmacology in Ruxmaniben Deepchand Gardi Medical College, Surasa, Ujjain. The study was performed in accordance with Good Clinical Practice (GCP) guidelines. All patients

A

Symptoms Time of appearance after cessation of

alcohol use Minor withdrawal symptoms: insomnia,

tremulousness, mild anxiety, gastrointestinal upset, headache, diaphoresis, palpitations, anorexia.

6 to 12 hours

Alcoholic hallucinosis: visual, auditory, or hallucinations

12 to 24 hours

Withdrawal seizures: generalized tonic-clonic seizures

24 to 48 hours

Alcohol withdrawal delirium (delirium tremens): hallucinations (predominately visual),

disorientation, tachycardia, hypertension, low-grade fever, diaphoresis

48 to 72 hours

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provided written informed consent prior to any study-related procedures. ETHICAL APPROVAL The study was approved by the Medical Ethical Committee of the R. D. Gardi Medical College, Ujjain. Before starting enrollment of the patients the study was registered in Clinical trial registry – India (CTRI), National Institute of Medical Statistics (ICMR), New Delhi. The CTRI registration number is CTRI/2011/08/001938. Study was updated periodically in CTRI dataset. STUDY POPULATION: Total 64 patients of alcohol withdrawal were admitted consecutively between July 2011 to July 2012 for alcohol detoxification at our in-patient psychiatric department of R.D. Gardi Medical College. Out of them only 48 patients satisfied the inclusion criteria and were asked for informed consent. They were all males in the age group of 18-60 years of age. INCLUSION CRITERIA

Age between 18 and 60, no gender limitation. Agree to abstain for alcohol for duration of

study. Willing to participate and be able to provide

informed consent. Meets criteria for alcohol dependence (DSM-IV-

TR) (American Psychiatric Association, 1994) and mild-to-moderate alcohol withdrawal syndrome.

Have a clinically withdrawal assessment prior to study.

Subject must be medically acceptable for study treatment. Consideration includes no past or present physical disorder that is likely to deteriorate during participation.

Not have any other psychiatric condition or psychotropic medication 15 days prior to entering the study.

EXCLUSION CRITERIA

Current diagnosis of any other substance dependence syndrome other than alcohol dependence (excluding nicotine & caffeine dependence).

Diagnosis of schizophrenia, bipolar disorder, or dementia.

History of hepatic encephalopathy, ascites, diabetes, or renal disease.

Pregnant and lactating females.

Subject with known sensitivity of previous adverse reaction to Baclofen, Diazepam.

METHODOLOGY

Before admission of patients in de-addiction ward for this study a screening visit was required. During the screening visit, medical history was recorded, a neurological exam and brief physical exam were performed, and CAGE questionnaire was administered. Following this, each subject included in this study gave written informed consent relating to documentation of data on personal history and course of alcohol withdrawal for scientific purposes. In this study only in-patients were taken. The in-patient detoxification unit offered a 10-day in-patient stay with flexibility to allow negotiation of the discharge date between day 10 and day 15. A validated interview was carried out on admission. On the day of admission each patient was undergo detailed psychiatric, neurological and medical examinations. A detailed proforma was made to assess the patients on these points. RANDOMIZATION AND BLINDING

After giving written informed consent, subjects who met all screening requirement were randomized to receive the either Baclofen (Group-I) or Diazepam (Group-II) tablet on a double-blind basis. Patients were allocated in chronological order and randomized into two groups by even and odd method. The Diazepam and Baclofen tablets were indistinguishable, having the same physical characteristics (e.g. size, colour, appearance). Study medications for both groups were dispensed in temper proof, packets that were similar in appearance. Label on the packets contained study code, patient’s serial number, manufacturing date and expiry date and space for date of dispensing. Hence, neither the patient nor the investigator was aware of the medication received by the patients. Only the pharmacist preparing the study medication was aware of the allocation. INTERVENTIONS

The patients were administered either Baclofen 10 mg (Group-I) or Diazepam 10 mg (Group–II) tablets at the dose of one tablets twice a day for five days followed by one tablet once a day for the next five days. At admission and also during the study period, alcohol abstinence was checked by a Breathalyzer at least once every day.

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FOLLOW-UP AND ASSESSMENT

To quantify the severity of alcohol withdrawal syndrome, and to monitor and medicate patients going through withdrawal, CIWA-Ar (The revised Clinical Institute Withdrawal Assessment for Alcohol) scale is used, which is a validated 10-item clinical rating scale focusing on subjective and objective symptoms of withdrawal. The withdrawal symptoms which included in this scale are: 1. Nausea & vomiting, 2. Tremor, 3. Paroxysmal sweats, 4. Anxiety, 5.Agitation, 6.Tactile disturbances, 7.Auditory disturbances, 8.Visual disturbances, 9.Headache, fullness in head, 10.Orientation and clouding of sensorium. In this scale each item rated of 0 to 7 (except orientation which is 0 to 4). The maximum score is 67. CIWA-Ar scores of 8 points or fewer correspond to mild withdrawal, scores of 9 to 15 points correspond to moderate withdrawal, and scores of greater than 15 points correspond

to severe withdrawal symptoms (This scale adapted from Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Selleres EM). CIWA-Ar scale was used to assess alcohol withdrawal symptoms on days 1 upto day 10 and post medication at day 15. Patients were evaluated every day for improvement of alcohol withdrawal symptoms and observed for any adverse events or relapse of symptoms.

STATISTICS The data were analyzed by using the statistical software SPSS, version 16.0. The continuous variables were analyzed by using the Student t-test. The results were presented as median (range) and number (percentage) for continuous variables. The p-value >0.05 (t<2) was required to declared not statistical significant at 5% level.

RESULTS The ITT group consisted of 46 participants. Twenty-three patients were randomized to each group as shown in Fig. 1. There were no significant differences between the treatment groups in terms of socio-demographic and all study parameters that were measured at baseline. In both groups, withdrawal symptoms improved with almost no residual symptoms on day 3. In the morning on day 3, all participants had achieved a clinically relevant improvement of their withdrawal symptoms on CIWA-Ar. Thus, the main effect of both treatments occurred within the first 48 hours. From day 3 onwards, participants

showed few, mild symptoms of withdrawal. There was no major deterioration during the rest of the study period. There was drastic reduction on the scores of CIWA-Ar scale, from baseline to day 10 & day 15. These changes were statistically highly significant (p ˂ 0.001), which showed that both the drugs were efficacious in the treatment of acute mild to moderate alcohol withdrawal syndrome as shown in Table 2.

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Table 2. Comparison of CIWA-Ar from baseline values.

S.no Scale Group B.L.

**SD±Mean Day 10

SD±Mean *t –value

Day 15 SD±Mean

t –value

1. CIWA-Ar

score

Group –1 (Baclofen)

12.47 ± 1.59 2.08 ± 0.90 27.86 1.43 ± 0.66 31.4

Group-2 (Diazepam)

12.55 ± 1.60 2.12 ± 0.81 28.22 1.74 ± 0.95 28.5

* t-values 3, it means highly significant, p 0.001. **Standard deviation

In accordance with the study protocol, participants did not receive any active drug on days 11 to day 15. In group-1 there was no change in CIWA-Ar when the active medication was completely tapered off, i.e. no rebound effects were seen with Baclofen. But in group-2 there was rebound insomnia, when the active medication

(Diazepam) was completely tapered off, but this was not statistically significant. There were no statistically significant differences between the both treatment groups on days 10 and 15 in all efficacy measures like tremors (Table 3), sweating (Table 4), and anxiety (Table 5).

Table 3. Changes from baseline to day 10 and day 15 in tremors (mean SEM).

Days Group - I

Baclofen (n=24) (mean *SEM) Group – II

Diazepam (n=24) (mean SEM) P -value t- value

Day –10 3.18 0.16 3.24 1.4 0.10 0.04

Day- 15 2.9 0.24 2.87 1.8 0.10 0.02

* Standard error of mean

Table 4. Changes from baseline to day 10 and day 15 in sweating (mean SEM).

Days Group - I

Baclofen (n=24) (mean SEM)

Group – II

Diazepam (n=24) (mean SEM)

P -value t- value

Day –10 2.20 0.21 2.1 0.20 0.10 0.35

Day- 15 2.47 0.27 2.5 0.19 0.10 0.1

Table 5. Changes from baseline to day 10 and day 15 in anxiety (mean SEM).

Days Group - I

Baclofen (n=24) (mean SEM) Group – II

Diazepam (n=24) (mean SEM) P -value t- value

Day –10 2.36 0.24 2.65 0.16 0.10 1

Day- 15 2.35 0.49 2.60 0.70 0.10 0.5

Statistical analysis revealed no differences in treatment with Baclofen and Diazepam, so that the results obtained with these treatment schemes can be considered to be equal. The p-value > 0.05, (t<2) was required to declared not statistical significant at 5% level.

All the “t” values were < 2, hence p value were > 0.05, so there were no statistical significant difference in the all the efficacy measures, between the both treatment groups at day 7 & day 15 (Table 6). So that the results obtained with these treatment schemes can be considered as equal.

Table 6. Changes from baseline to day 10 and day 15 in CIWA-Ar Total score (mean SEM).

Days Group - I

Baclofen (n=24) (mean SEM)

Group – II

Diazepam (n=24) (mean SEM) P -value t- value

Day –10 10.39 0.37 10.33 0.36 0.10 0.12

Day- 15 11 0.35 10.8 0.38 0.10 0.39

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DISCUSSION AND CONCLUSIONS Pharmacotherapy is only one part of the therapeutic strategy in the treatment of alcoholism. A short and effective management of withdrawal symptoms not only reduces the inconvenience for a patient, but also saves costs. Diazepam is a well-proven therapy for the treatment of mild to moderate alcohol withdrawal syndrome. This study was aimed to determine the efficacy of Baclofen compared to conventional Diazepam in the treatment of mild to moderate alcohol withdrawal syndrome. All participants included in our study had a mild to moderate alcohol withdrawal syndrome at baseline, with a CIWA-Ar score of 12 points. The ideal medication for the detoxification of alcohol-dependent patients would suppress withdrawal rapidly, suppress drinking behaviors, not interact with alcohol, cause little or no ataxia or incoordination, and have a low potential for abuse. Baclofen fulfills some of these criteria. Addolorato G et al (2002) conducted a first open clinical study and showed how baclofen rapidly suppressed symptoms of severe AWS. Caputo F et al. (2002) evaluated the efficacy of baclofen in a double-blind randomised controlled study, which enrolled 39 alcohol-dependent patients randomly divided into two groups.The study results indicated that the percentage of dropouts was lower in the baclofen group respect to the placebo group. In both the treatment groups there was a significant reduction in withdrawal symptoms, although the difference between the two treatment groups was not found to be statistically significant. In both treatment groups, the withdrawal syndrome did not last longer than 3 days. At the end of day 2, participants showed no more than one or two mild symptoms (such as tremor, sweating or restlessness). Therefore, we believe that acute withdrawal can be treated within 2 or 3 days with effective medication. From the present study it can be concluded that, Baclofen is equivalent in efficacy to Diazepam in the treatment of alcohol withdrawal syndrome. Because Baclofen has less interaction with alcohol, therefore it may be used safely in alcohol withdrawal syndrome. Additional studies are needed to ascertain Baclofen’s utility as a treatment for preventing alcohol withdrawal or relapse to drinking after a period of abstinence.

LIMITATIONS OF STUDY Only male participants were present in the study. Small population included in the study. Patients with severe AWS were not included in the study.

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Article citation:

Jhanwar A., Patidar OP., Sharma RN, Chourishi A., Jain A. A double blind study for efficacy of Diazepam and Baclofen in the treatment of Alcohol withdrawal syndrome. J Pharm Biomed Sci 2014; 04(05):482-488. Available at www.jpbms.info.

Source of support: None

Competing interest / Conflict of interest The author(s) have no competing interests for financial support, publication of this research, patents and royalties through this collaborative research. All authors were equally involved in discussed research work. There is no financial conflict with the subject matter discussed in the manuscript.

Copyright © 2014 Jhanwar A., Patida OP., Sharma RN, Chourishi A., Jain A. This is an open access article distributed under the Creative

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