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    Introduction
    Patients and Methods
    Discussion
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 Table of Contents    
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 53  |  Issue : 1  |  Page : 25-29
Status of disulfiram in present day alcoholic deaddiction therapy


Department of Pharmacology, Fr. Muller Medical College, Mangalore - 575 002, India

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Date of Web Publication13-Jan-2011
 

   Abstract 

Aim: Assessment of safety and efficacy profile of disulfiram (DSM) in the alcoholic de-addiction regimen.
Objectives: a . Assessment of Adverse Drug Reaction (ADR) profile; b. Evaluation of effectiveness of various de-addiction regimen; c. Defaulters and dropouts
Patients and Methods: Fifty-one patients in a de-addiction center were investigated on 0 th , 30 th and 60 th day along with psychiatric evaluation, ADR surveillance was made. Statistical analysis was done thereafter.
Results: 125 mg DSM given OD for 2 months. 76.5% patients had taken full course of treatment, 45% didn't complain of any ADR. Of ADR reported 27.4% had drowsiness, 21.4% tiredness, 7.8% skin manifestation.
Conclusion: DSM is the main drug among naltrexone, acamprosate, nalmefene and other drugs used in alcoholic de-addiction. Relative and effectiveness is lost by the degree of dropouts and hence relapses. Low-dose DSM had decreased adverse effects with 76.5% patients taking the full course of treatment. DSM alters liver functions as there were significant changes in the lab parameters of SGPT(P=0.007), SGOT(P=0.001), GGT(P=<0.001) between first and third samples. Occurrence of ADR is not the cause of default; patients find it confusing to differentiate between the symptoms of alcohol withdrawal and those due to ADR of DSM.

Keywords: Adverse drug reaction, alcohol de-addiction, de-addiction regimen, disulfiram, drug default

How to cite this article:
Palatty PL, Saldanha E. Status of disulfiram in present day alcoholic deaddiction therapy. Indian J Psychiatry 2011;53:25-9

How to cite this URL:
Palatty PL, Saldanha E. Status of disulfiram in present day alcoholic deaddiction therapy. Indian J Psychiatry [serial online] 2011 [cited 2014 Sep 18];53:25-9. Available from: http://www.indianjpsychiatry.org/text.asp?2011/53/1/25/75557



   Introduction Top


Alcoholism is one of the major health and social problems faced in developing countries. Although there are various drugs, none of them proved to be efficacious in the long run owing to the cost, adverse effects and the inadequate compliance for the long term management of alcohol de-addiction. For naltrexone and acamprosate, though approved in the West, their cost effects are a burden for the lower and middle class in the Indian society. Disulfiram (DSM) proved to be an effective drug for Indian setting. [1] But its compliance rates are considerably affected due to the large number of adverse effects [2] contributing to the high percentage of default rates. [3] Although majority of adverse effects was noted by Poulsen et al, [4] they also stated that it could not be differentiated from sobriety or manifestations of alcohol abuse. Since efficacy of a medication depends on its mode of action, seriousness of illness and its toxicity, this cross-sectional study is aimed at noting the efficacy of 125 mg OD DSM in contrast to the study conducted on 250mg OD DSM by Srinivasan et al, [5] on patients, initially in the hospital and later at the home setup under supervision. This study concentrated mainly on adverse effects, change in laboratory parameters and compliance rates. Comparison was also done on the complaints before and after administration of DSM.


   Patients and Methods Top


This cross-sectional study was conducted on alcohol-dependent patients who were undergoing detoxification for alcoholic de-addiction therapy in a private hospital for 40 days. Nitrazepam was given initially 10mg BD for 9 days for detoxification. DSM was given for the rest of the days.

Inclusion criteria

  • DSM IV criteria, alcohol-dependent patients.
  • Alcoholics 20-60 years of age with normal liver function test's after detoxification.
Exclusion criteria

  • Relapse cases.
  • Liver Function Test's above normal range.
Patients satisfying inclusion criteria were examined and routine investigations like complete hemogram, lipogram, blood glucose, serum electrolytes, Liver Function Test and occult blood in stool along with psychiatry evaluation before the administration of DSM and on the 30 th and 60 th days of DSM administration.

Patients received 125mg of DSM OD after lunch initially under supervision of hospital staff and later by the family members, to enhance the compliance rates. Patients were followed up regularly during hospital stay for the first 30 days and later weekly up to the 60 th day. At each follow up, drug adverse effects, alcohol consumption and default rate was noted. Combined psychotherapy had been provided. Patients received symptomatic treatment.

Outcome measures

  • Days of abstinence
  • Dropout rate (>5 alcoholic drinks/40g alcohol in 24hr).
  • Adverse effects complained
  • Alterations in the lab parameters
Statistical analysis was done using SPSS Package, Kruskal-Wallis Test, Wileoxon-Segned rank sum test, ANOVA (fishers test) and students paired-t-test.


   Discussion Top


The results of this study indicated that there were few adverse drug reactions (ADR) with DSM [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], and [Figure 7]. This may be due to either fallacious reporting or symptoms present in sobriety which was aggravated with DSM and those were tiredness, depression, nausea and anxiety. There were four cases of skin reactions that got aggravated after DSM therapy. This is similar to the findings by Zawar and Nerliers [6] vide [Figure 8] [Figure 9], where a thirty-three year old male developed pustular lesions after 42-43 days of DSM therapy. A forty seven year old male had an aggravation of psoriatic lesion after 32 days of DSM therapy shown in [Figure 10]. No instance of psychosis which is common in India [7] was noted with 125 mg DSM when compared to the study conducted by Srivasan et al. [5] In our study, psychiatric clinical examination was done on admission, 30 th , and 60 th days. Among these, 5 of them had depressive symptoms, 16 had hallucination and 10 of them had both the symptoms vide [Figure 1]. Now, we would recommend MINI plus scale for a comprehensive psychiatric evaluation. Alcohol is known to derange the psyche-Korsakoff's psychosis. There were significant changes in lab parameters of SGPT(P=0.007), SGOT(P=0.001), GGT(P=<0.001), MCV(P=0.001), serum cholesterol (P=0.002), serum HDL(P=0.05), serum LDL(P=0.014) especially between first and third samples showing in DSM playing an important role in altering liver functions. [Figure 4] shows the comparision of individual lab parameters that were statistically significant. [Figure 5] shows SGOT having significant change in samples between 0-30 th day and 0-60 th day. In [Figure 6], the variation in GGT values between 0-30 th , 30 th -60 th , and 30 th -60 th days were significant as per Wileoxon-Segned rank sum test. MCV values between 0-30 th , 30 th - 60 th , and 30 th -60 th days were significant based on students paired-t-test as shown in [Figure 7]. The ADR was not of severe magnitude that necessitated withdrawal of drug or institution of life saving measures which was similar to the findings of Liskow et al, [8] and contrary to Borup et al. [9] No hepatic dysfunction was noted though it is a well known ADR for which liver function tests were done during DSM treatment as per recommendations by Wright et al, at 2 week interval at initial 2 months and later at 3-6 month interval. [10] It may be due to careful selection of patients, low dose of DSM and short period of assessment.
Figure 1: Histogram of Adverse Drug Reaction

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Figure 2: DSM Default Rate

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Figure 3: Prevalence of ADR

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Figure 4: Group-comparison values of individual lab parameters

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Figure 5: Comparison between SGOT samples taken on 0, 30th, and 60th day

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Figure 6: Comparison between GGT samples taken on 0, 30th, and 60th day

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Figure 7: Comparison between MCV samples taken on
0, 30th and 60th day


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Figure 8: Patient having a pustule in the anterior abdomen wall along left mid-clavicular line

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Figure 9: Pustular lesion from a close view

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Figure 10: Patient with DSM induced aggravated skin reaction

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DSM was well tolerated and had lesser dropout rate. The reason for dropouts includes easy availability of alcohol, failure of supervision and deceleration of motivation. Patients find it difficult to differentiate between the symptoms of alcohol withdrawal and those due to ADR of DSM. Therefore could not be the reason for dropout. None of the patients blamed ADR in particular, for the default which is similar to the findings of Srinivasan et al, [5] and contrary to Borup et al. [9] The dropout rates can be reduced by increasing motivation by combined psychotherapy and reassurance. Although Nitrazepam was used for the detoxification in the study, its influence in the de-addiction therapy per se is minimal. [11]

The effect of various drugs like Naltrexone, DSM, Acamprosate, Fluoxetine and serotonergic agents like Ondansetron used in the present day alcoholic de-addiction therapy is literary disappointing. SSRI like fluoxetine has no effect on drinking behaviour per se, but it may treat underlying depression leading to drinking. Dopaminergic antagonists - neuroleptics have not unequivocally proved its worth. Benzodiazepines are effective as an adjuvant and are not the mainstay treatment in de-addiction therapy. Studies showed that Ondansetron is useful only in cases of early onset of alcohol dependence and Topiramate is more efficacious than placebo but not as a long-term treatment option. [12] The complex interplay of various systems like dopamine, opiod, serotonin, glutamate, GABA on addiction makes its treatment, a daunting possibility. This is reflected in the varied drugs that are used in alcohol de-addiction i.e. nalmefene, tiapiride, metronidazole, lithium, and ondansetron. Topiramate is advocated as chemoprophylaxis of alcohol dependence. [13] Certain studies showed that Topiramate improved the psychomotor functions in alcohol-dependent individuals. [14] Presently DSM, Naltrexone and Acamprosate are approved drugs for alcohol de-addiction therapy. [15] Naidu et al, in their study, concluded that Naltrexone had less craving for alcohol along with significant decline of GGT level when compared to DSM. [16] Also Naltrexone had better outcome in reducing relapse rates when compared to that of Acamprosate. [17] A study by Staffen et al, [18] showed that DSM was better than Naltrexone and Acamprosate both on cost, efficacy and in reduction of alcohol craving and binge drinking. [19],[20],[21] Thus playing an important role in long term management in alcohol de-addiction along with effective psychotherapy and counseling unlike to the writings of Mann and Williams. [22] Other studies supporting for long term DSM management and it being better than other treatment protocols are Petrakis et al, [23] and De Souza. [24]

This study revealed that low dosage had decreased adverse effects. Although there were some ADR, 76.5% of patients had taken full course of treatment and thereby it shows that ADR weren't the reason for default and DSM achieved better compliance without losing its primary deterrent action and psychological effects. [25] Since usage of DSM needs repeated physician's advice and active decision process by the patient, fear and experience of DSM-Ethanol reaction further helps him to continue sobriety. DSM-Ethanol reaction noted in this dosage was of mild intensity which could be taken care at a primary care setting.

To increase the efficacy of de-addiction management, combination of pharmacotherapy acting on various neuronal pathways can be tried along with DSM. One such methodology is usage of DSM implants alone or in combination with Naltrexone for higher abstinence rates. [26] Long-term acting injectables are another way to look forward in order to avoid supervision and achieve long-term compliance rates. Molecular and behavioral advances can be utilized interfering with alcohol metabolism based on genetic characteristics of the individuals. The concerns with alcohol addiction are wide and appropriate regulations and treatment protocols have to be formulated mainly by Addictive Medicine, a specialty subject which is the need of the hour. [27]


   Conclusion Top


  • DSM remains the main drug in the present day de-addiction regimen. It is relatively safe at 125mg without its deterrent effect being hampered. Moreover it's safe and effective.
  • DSM as an unsupervised domiciliary therapy for the larger part of 6 the months therapy is a cause for concern as there is a point where deceleration in motivation, overwhelming temptation and easy availability crack the de-addiction course leading to relapse. Supervised domiciliary therapy for a 6-month period along with active participation at psychosocial and alcoholic anonymous meetings is advocated.
  • Occurrence of ADR is not the reason for default.
  • Patient finds it confusing to differentiate ADR from symptoms of alcohol manifestation.
  • DSM-Ethanol reaction at this dosage can be managed at primary care setting.
  • Use of long acting DSM, injectables, implants, combination of drugs, pharmacotherapy based on genetic characters is another option to look for.


 
   References Top

1.Avinash De Souza - Studies of family supervised disulfiram, naltrexone and acamprosate in the Indian setting. Proceedings of 3rd Berlin Stapleford. International Addiction Conference on latest developments in effective medical treatments for addiction; Berlin March 18 - 19th 2006 avinashdes999@yahoo.com  Back to cited text no. 1
    
2.Christensen JK, Rψnsted P, Vaag UH. Side effects after disulfiram: Comparison of disulfiram and placebo in a double-blind multicentre study. Acta Psychiatr Scand 1984;69:265-73.  Back to cited text no. 2
    
3.Borup C, Kaiser A, Jenson E. Long term antabuse treatment: Tolerance and reasons for withdrawal. Acta Psychiatr Scand Suppl 1992;369:47-9.  Back to cited text no. 3
    
4.Enghusen Poulsen H, Loft S, Andersen JR, Andersen M. Disulfiram therapy--adverse drug reactions and interactions. Acta Psychiatr Scand Suppl 1992;369:59-65.  Back to cited text no. 4
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7.Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf 1999;20:427-35.  Back to cited text no. 7
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8.Liskow B, Nickel E, Tunley N, Powell BJ, Penick EC. Alcoholics' attitudes toward and experiences with disulfiram. Am J Drug Alcohol Abuse 1990;16:147-60.  Back to cited text no. 8
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12.Castro LA, Baltieri DA. The pharmacologic treatment of the alcohol dependence]. Rev Bras Psiquiatr 2004;26:S43-6. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez/ [last accessed on 2008 Aug 28].   Back to cited text no. 12
    
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16.Naidu H, Thacore AS, Koshy MK. Naltrexone in alcohol dependence: A comparison with disulfiram. Indian J Psychiatry 2000;41:43-4.  Back to cited text no. 16
    
17.Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: A double-blind, placebo-controlled study. Arch Gen Psychiatry 2003;60:92-9.  Back to cited text no. 17
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18.Niederhofer H, Staffen W. Comparision of disulfiram and placebo in treatment of alcohol dependence of adolescents. Drug Alcohol Rev 2003;22:295-7. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez/ [last accessed on 2008 Aug 28].  Back to cited text no. 18
    
19.Laaksonen E, Koski-Jδnnes A, Salaspuro M, Ahtinen H, Alho H. A randomized, multicentre, open - label, comparative trial of disulfiram, naltrexone and acamprosate in treatment of alcohol dependence. Alcohol Alcohol 2008;43:53-61. Available from: http://alcalc.oxfordjournals.org/cgi/content/full/agm136v2 [last accessed on 2007 Oct 27].  Back to cited text no. 19
    
20.Ehrenreich H, Krampe H. High effectiveness of long term disulfiram in a structured outpatient rehabilitation programme: Proceedings of 3rd Berlin Stapleford: International Addiction Conference on latest developments in effective medical treatments for addiction; Berlin. Available from: www.znv.de/bartels.html [last accessed on 2006 Mar 18].  Back to cited text no. 20
    
21.De Souza A, De Souza A. A one-year pragmatic trial of naltrexone vs. disulfiram in the treatment of alcohol dependence. Alcohol Alcohol 2004;39:528-31.  Back to cited text no. 21
    
22.Williams SH. Medications for treating alcohol dependence. Am Fam Physician 2005;72:1775-80. Available from: http://www.aafp.org/afp/20051101/1775.html [last accessed on 2008 Aug 28].  Back to cited text no. 22
    
23.Petrakis I, Ralevski E, Nich C, Levinson C, Carroll K, Poling J, et al. Naltrexone and disulfiram in patients with alcohol dependence and current depression. J Clin Psychopharmacol 2007;27:160-5. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez/ [last accessed on 2008 Aug 28].  Back to cited text no. 23
    
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DOI: 10.4103/0019-5545.75557

PMID: 21431004

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