Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

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Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



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Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
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Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Reviews
Year : 2010 | Month : August | Volume : 4 | Issue : 4 | Page : 2947 - 2955

Pharmacotherapy of Alcohol Dependence

MOHAN L, SHANKAR PR, RAUT P, GYAWALI S

*Dept. of Clinical Pharmacology & Therapeutics Kasturba Medical College Manipal, India **Dept. of Clinical Pharmacology & Therapeutics KIST Medical College Lalitpur, Nepal *** Dept. of Clinical Pharmacology & Therapeutics Pt. Jawaharlal Nehru Memorial Medical College Raipur, India **** Dept. of Pharmacology Manipal College of Medical Sciences Pokhara, Nepal

Correspondence Address :
Dr. P. Ravi Shankar
Dept. Of Clinical Pharmacology
KIST Medical College
P.O. Box 14142
Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com

Abstract

Alcohol is a commonly used psychoactive substance all over the world and responsible for a significant proportion of mortality and morbidity. The treatment of alcohol dependence consists of two phases, detoxification and rehabilitation. Pharmacotherapy is being investigated to enhance abstinence and prevent relapse and complement interventions at a psychosocial level.
Alcohol activates dopamine in the nucleus accumbens and mediates positive reinforcement and reward. The US Food and Drug Administration (FDA) have approved three medications, disulfiram, naltrexone and acamprosate for the treatment of alcohol dependence. The selective serotonin reuptake inhibitors (SSRIs) particularly fluoxetine and citalopram have been evaluated. Buspirone and Ondansetron have also been tried for alcohol dependence.
Combination of naltrexone and acamprosate has shown promising results. It is essential to develop clinically useful pharmacological treatments, which can be evaluated using large-scale clinical trials. Clinical trial methodologies to evaluate combination treatments and using medications along with psychosocial treatments are required.

Keywords

Alcohol; Dependence; Detoxification; Pharmacotherapy; Rehabilitation

Alcohol is a commonly used psychoactive substance all over the world. In Nepal, alcohol has been consumed since a long time. The substance has deep-rooted religious, cultural and traditional dimensions and social implications (1). Alcohol use is common among both genders and around 25% of respondents were found to be dependent on alcohol in a survey in a town of Eastern Nepal (2).

Brief epidemiology:
Up to 25% of accidents in the workplace and around 60% of total accidents at work may be associated with alcohol (3). Almost one third of Americans consume enough alcohol to be considered at risk for alcohol dependence and there are more than 100,000 deaths each year from alcohol related diseases and injures (4). In Australia, alcohol accounted for an estimated 3668 deaths and 95917 hospital admissions in the financial year 1996-97 (5). In Korea, a recent study had established that 10.2% of the adult population had a lifetime prevalence of alcohol dependence and this makes the condition, the second most common psychiatric disorder in Korea (6). In India, about 15-20% of people consume alcohol and the number of drinkers has increased to about one in twenty and about five million people are addicted to alcohol (7).
Alcohol dependence:
The criteria for alcohol dependence have been defined by the fourth edition of the Diagnostic and Statistical Manual of Mental disorders (8). Among the criteria are tolerance, characteristic withdrawal symptoms on stopping use, abandonment of important social, occupational or recreational activities because of alcohol ingestion and continued use of alcohol despite problems. Alcohol dependence is a chronic disorder, which results from a variety of genetic, psychosocial and environmental factors (9).

Management of alcohol dependence:
The treatment of alcohol dependence consists of two phases, detoxification and rehabilitation. The initial detoxification phase deals with the acute withdrawal symptoms while rehabilitation attempts to prevent relapse and develop long-term abstinence (10). Psychosocial treatments have been shown to be effective in reducing alcohol consumption and maintaining abstinence. However, 40 to 70% of patients relapse and start drinking within a year following treatment (11).
Pharmacotherapy is being investigated to enhance abstinence and prevent relapse and complement interventions at a psychosocial level. Recent advances in neurobiology have identified the effects of alcohol on various neurotransmitter systems and these can be targets for drugs (10). Alcohol dependence is a heterogeneous condition.

Neurobiology of alcohol dependence:
Alcohol changes the 3-dimensional structure of proteins. The ion channels, neurotransmitter receptors and enzymes involved in signal transduction are particularly sensitive (12). Dopamine, serotonin, gamma amino butyric acid (GABA), glutamic acid, adenosine, neuropeptide Y, nor-epinephrine, cannabinoid receptors and opioid peptides are affected (13).
The dopamine system plays a central role in the biology of alcoholism. Alcohol activates releases dopamine in the nucleus accumbens and mediates positive reinforcement and reward (14). Alcohol use increases release of endorphins and indirectly activates the dopaminergic reinforcement and reward system (15).
Alcohol is a depressant of the central nervous system (CNS) and potentates GABAergic inhibition. On chronic exposure, there is a compensatory up regulation of glutamatergic and down regulation of the GABA system, which can result in an increased tolerance for alcohol (16).

Medications for treating alcohol dependence:
The US Food and Drug Administration (FDA) have approved three medications, disulfiram, naltrexone and acamprosate for the treatment of alcohol dependence (4). (Table/Fig 1) shows pharmacokinetics of selected drugs used in management of alcohol dependence while (Table/Fig 2) shows dosage, adverse effects, contraindications and precautions regarding use of selected drugs for management of alcohol dependence

Aversive agents: Disulfiram
Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH) which catalyses oxidation of acetaldehyde to acetic acid. Blood levels of acetaldehyde increases and a characteristic disulfiram-ethanol reaction (DER) is produced (17). A number of studies have been performed with disulfiram; however controlled clinical trials have failed to establish clearly the benefit of disulfiram in enhancing abstinence (18).
The usual dose is 250 mg per day and the maximum dose is 500 mg per day. On consuming alcohol while on disulfiram adverse reaction like palpitations, flushing, nausea, vomiting and headache may develop (4). Myocardial infarction, congestive cardiac failure, respiratory depression and even death can occur. The drug is contraindicated in patients on metronidazole, with psychosis or cardiovascular disease. It is also not recommended in patients with severe pulmonary disease, chronic renal failure, diabetes, peripheral neuropathy, seizure, liver cirrhosis or more than 60 years of age. Disulfiram is converted to 5-ethyl N, N-diethylthiocarbamate sulphoxide (DETC-MeSO) and this metabolite is responsible for inactivating ALDH (19). A number of factors can influence the metabolism of disulfiram and other medications metabolised by the same cytochrome P-450 enzymes can inhibit disulfiram metabolism (20). DETC-MeSO is potent and its pharmaceutical characteristics may make a transdermal or a sustained release formulation feasible (17). The variability in metabolism can also be reduced. Further development of this metabolite as a drug can be considered. Disulfiram implants can improve compliance. However, the bioavailability of disulfiram following implantation is variable (18).

Serotonergic agents:
The selective serotonin reuptake inhibitors (SSRIs) particularly fluoxetine and citalopram have been most extensively evaluated (17). Naranjo and coworkers in 1990 first reported on the effects of fluoxetine on alcohol consumption in heavy drinkers (21). Fluoxetine 60 mg/day decreased average daily alcohol consumption by around 17% compared to base line. Further studies have shown conflicting results (17).
In 1987, Naranjo et al reported that citalopram 40 mg daily reduced number of drinks and increased number of abstinent days in non-depressed, early stage problem drinkers. However further studies have shown diverse results (17). The diversity of subject samples may be partly responsible for the variable effects of SSRIs.
Fluoxetine is usually started at a dose of 20 mg per day and may be increased to 60mg daily as needed. Nausea, headache and sexual dysfunction may be among the adverse effects.
Other agents acting on serotonergic receptors:
Buspirone and ondansetron have also been tried for alcohol dependence (18). Ondansetron is usually given in a dose of 4 μg per kg body weight twice daily and malaise, fatigue, headache, dizziness and anxiety are the major side effects. The therapy is however more expensive compared to other agents.

Drugs acting on the opioid receptors:
Naltrexone is an opioid receptor antagonist and has been approved for the treatment of alcohol dependence by the US FDA [10, 18]. Two small, double-blind, placebo-controlled trials had shown a reduced rate of drinking relapse, reduced craving and less frequent drinking in patients treated with naltrexone (22) (23). A systematic review of 11 trials found that naltrexone reduced short term relapse rates in alcohol dependent patients when combined with psychosocial treatments (24). However, more recent RCTs working at longer term outcomes have reported mixed results (4).
Naltrexone may act by blocking the μ opioid receptors, which reduces alcohol’s reinforcing effects. The recommended dose is 50 mg daily in a single dose (4). The drug undergoes extensive hepatic first pass metabolism to Q-naltrexol, which is a weaker antagonist but has a longer half life (25). The drug is generally well tolerated. Non-specific symptoms like headache, flu–like symptoms, nausea and anorexia have been reported (25). Naltrexone blocks the action of opioid analgesics and is contraindicated in patients on long-term opioid therapy for chronic pain or heroin dependence.
Compliance may be a limiting factor in naltrexone treatment (26). Sinclair had suggested that naltrexone is useful to prevent relapse rather than to maintain absolute abstinence (27). The most common side effects are nausea, headache, anxiety and sedation (28). Dose dependent hepatotoxicity may be a problem and the drug is contraindicated in patients with hepatitis or liver failure (10). In April 2006, the US FDA approved an extended-release (30 day) injectable suspension of naltrexone (29).
It has been suggested that patients with high level of alcohol craving are more likely to benefit from naltrexone treatment (30). Naltrexone not only blocks the opioid receptors but also indirectly increases the hypothalamo pituitary adrenal (HPA) activity and results in higher level of ACTH and cortisol (31).

Nalmefene
Nalmefene has similar properties and a similar mechanism of action to naltrexone (32). A RCT had used nalmefene in dosage of 20 or 30 mg orally daily and observed that the drug significantly reduced relapse in heavy drinking (32). Out side of research studies, the drug is available only in an injectable form.
NMDA/GABA receptor modulator:

Acamprosate
Acamprosate (calcium acetyl homotaurinate) blocks the glutaminergic NMDA receptors and activates GABAA receptors and is approved by the FDA for treating alcohol dependence (4). Acamprosate has a structure similar to GABA and enhances GABA transmission by increasing the number of sites for GABA uptake (25). The drug also affects the calcium channels which increase in number as alcohol dependence develops (33).
The drug is available in 333 mg enteric-coated tablets and dosing is by weight. For an adult weighing above 60 kg the dose is six tablets orally in three divided doses along with meals (25). For adults under 60 kg the dose is four tablets daily. Only 10% of acamprosate is absorbed and 90% is excreted unchanged in urine.
The side effects are mainly confined to the gastrointestinal system and can be minimized by gradually increasing the dose. Low frequencies of rash, pruritus, paresthesiae, decreased libido and confusion have been reported (25). Transient diarrhea is the most common adverse effect and occurs in about 10% of patients.
The calcium component may inactivate tetracyclines during concurrent use. The safety of the drug in pregnancy or lactation has not been established (25). Like naltrexone and disulfiram the FDA pregnancy category is C. The drug is contraindicated in patients with renal insufficiency or advanced cirrhosis but may be safely taken by patients with liver dysfunction.
Acamprosate has been studied in over 3000 patients and evidence of the efficacy in rehabilitation of alcoholics is generally consistent (17). The drug has a prominent role to play in treating alcohol dependence. Chick and coworkers have raised the possibility that certain subgroups of alcoholics may be more responsive to treatment with acamprosate (34).
Chronic exposure to alcohol causes compensatory up regulation of the glutamatergic and down regulation of the GABA system and causes increased tolerance. Abrupt alcohol withdrawal causes a hyper excitable state. This is perceived as disagreeable by the patients. Acamprosate is an antiglutamatergic agent and reduces motivation to drink by suppressing alcohol withdrawal symptoms (10). Acamprosate may have other beneficial effects such as substituting for deficits in negative feedback signals and reducing the development of tolerance and sensitization to alcohol (35).

Lithium:
The exact mechanism of action is not known but it affects phosphoinositide signaling and enhances serotonin action in the brain (18). Garbutt and coworkers concluded that lithium lacks efficacy in treating primary alcohol dependence.

Combination of naltrexone and acamprosate:
Combining these two drugs is attractive for several reasons. The drugs have different mechanisms of action (36). Combination of two drugs would act simultaneously on two different aspects of craving and have a synergistic effect. Naltrexone reduces the quantity of ingested alcohol by decreasing the priming effect of initial intake or alcohol associated cues while acamprosate increases the probability that currently abstinent subjects remain abstinent (36).
A study observed that co administration significantly increased the rate and extent of absorption of acamprosate (37). A RCT observed that the combination was pharmacologically and behaviourally safe (38). The COMBINE study had shown good initial results (39). The study will answer important questions regarding the effectiveness of the drugs alone and in combination as well as that of psychosocial treatment. Combination treatment seems to be well tolerated and no serious adverse effects were reported. An increased incidence of diarrhoea and nausea has been seen perhaps due to a pharmacokinetic interaction.

Future perspectives:
It is essential to develop clinically useful pharmacological treatments, which can be evaluated using large-scale clinical trials. Clinical trial methodologies to evaluate combination treatments especially involving multiple medications and using medications along with psychosocial treatments are required (17). Small scale, exploratory studies to develop new candidate medications or formulations are however important. Combining medications with participations in self help groups may be a challenge (40). Factors which may predict poor compliance with treatment and appropriate efforts to remedy these will be important. The optimal duration of treatment is not well defined. The role of pharmacotherapy in efforts at secondary prevention should also be defined. Alcoholics with co morbid drug use disorders and with other disorders are not included often in drug trials. This can form a population for future studies.

Conclusion

Changes are taking place in the pharmacotherapy of alcoholism. Pharmacotherapy should be combined with concurrent counselling through professional or self-help programmes. Acamprosate and naltrexone are the best choices for relapse prevention. Disulfiram shows limited efficacy and may be used less frequently. SSRIs can be used in alcoholics with co morbid disorders. Topiramate and ondansetron show promise in treating alcohol dependence. The biology of addiction and dependence is being elucidated and this may lead to more effective drug treatments.

References

1.
Kumar S, Pokharel B, Nagesh S, Yadav BK. Alcohol use among physicians in a medical school in Nepal. Kathmandu Univ Med J 2006; 4: 460-464.
2.
Niraula SR, Shyangya P, Jha N, Paudel RK, Pokharel PK. Alcohol use among women in a town of eastern Nepal. JNMA J Nepal Med Assoc 2004; 43: 244-249.
3.
World Health Organization. WHO Global status reports on alcohol 2004. http://whqlibdoc.who.int/publications/2004/9241562722_(425KB).pdf, Accessed on June 10, 2009.
4.
Williams SH. Medications for treating alcohol dependence. Am Fam Physician. 2005; 72: 1775-1780.
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