The Pharmacotherapy of Alcohol Dependence: A State of the Art Review

The psychopharmacology of alcohol dependence is today poised at interesting crossroads. Three major drugs Naltrexone, Disulfiram and Acamprosate have been tried and tested in various trials and have many meta-analyses each to support them. While Naltrexone may reduce craving, Acamprosate scores on cost effectiveness worldwide with Disulfiram being an alcohol deterrent drug. Studies support, refute and criticize the use of each of these drugs. Combining one or more of them is also a trend seen. The most important factor in efficacy has been the combination of psychosocial treatment with medication. Studies from the early 1970s to date have been reviewed and the findings presented in a manner useful for the busy clinician to judge the best pharmacological option in the management of alcohol dependence. The role of depot disulfiram, naltrexone, and medications like Topiramate and SSRIs under research for alcohol dependence, are also addressed.

in India (Grover, Bhateja and Basu, 2007). This is a little lower than the three to fi ve per cent estimate for major world populations (Murray and Lopez, 1997;Makela, Martikainen and Nihtila, 2005). It has also been seen that only 8-10% of total alcohol dependence patients are treated in specialty settings and less than 10% receive pharmacotherapy (Finney, Hahn and Moos, 1996). Today, with a better understanding of the basic neurobiological components of alcohol dependence, we have pharmacological agents targeted at improving drinking behavior, enhancing abstinence and preventing relapse as well as reducing the amount of alcohol people drink when they relapse (Swift, 1999;Rosenthal, 2006).
There are currently three US FDA approved medications for the relapse prevention of alcohol dependence. These are Disulfiram, Naltrexone and Acamprosate. This paper shall review the clinical experiences with these drugs, discuss the more recent trends in combination therapies and also briefl y describe some new promising experimental pharmacological therapies for the treatment of alcohol dependence.

Naltrexone
Naltrexone is an opioid receptor antagonist approved by the US FDA in 1994 that reduces heavy drinking by diminishing the rewarding neurobiological effects of alcohol (Harris and Erickson, 1979;Gianoulakis, 1993;Anton, 2008). It acts via reducing dopamine release in response to alcohol from the dopamine reward pathways in the ventral tegmental area and the nucleus accumbens (Gessa, et al., 1985;Heimer and Alheid, 1991;Benjamin, et al., 1993). It is also known to reduce the release of endogenous opioids like endorphins in response to alcohol (Herz, 1997).
Naltrexone is known to reduce craving for alcohol in both alcohol dependent patients (Monti, et al., 1999) and social drinkers (Davidson, et al., 1996;Richardson, et al., 2008). There are also a number of reviews and meta-analyses that support naltrexone as a treatment for alcohol dependence, along with 29 published randomized placebo controlled trials, some supportive and some not (Garbutt, et al., 1999;Melchior and Hoes, 1999;Kranzler, 2000;Streeton and Wheelan, 2001;Richardson, et al., 2008). Two pivotal early trials were the fi rst to illustrate the effi cacy of naltrexone in the management of alcohol dependence (Volpicelli, et al., 1992;O'Malley, et al., 1992). A recent review has reported modest favorable effects of naltrexone on heavy drinkers. In a majority of the studies reviewed, Naltrexone reduces signifi cantly the rates of drinking in heavy drinkers by 30-60%. It reduces craving signifi cantly though abstinence is seen usually in 25-35% cases. . Another meta-analysis, a Cochrane collaborative, found a decrease in the rate of relapse in alcohol dependence in case of short-term studies (< 12 weeks), but the effect on increasing abstinence was small. Medium term trials (> 12 weeks) are too limited in number (eight studies) to show benefi ts for relapse prevention but do show increased time to the consumption of the fi rst drink and decreased craving over time (Srisurapanont and Jarasuraisin, 2005). The dosage used in most studies is 50-100mg per day. More often than not, naltrexone was used in combination with cognitive behavioral therapy, supportive individual or group psychotherapy and relapse prevention therapy. Naltrexone alone has been shown to reduce heavy drinking rates in a smoking cessation program (King, et al., 2009) while it has also been shown to improve the cost effectiveness of cognitive behavioral therapy in alcohol dependence (Walters et al., 2009). Naltrexone also has a favorable safety profi le. It does not reduce seizure threshold nor have any fatalities been reported with naltrexone overdose. It has not been associated with pleasurable effects, does not result in tolerance and has no abuse potential (Swift, et al., 1994;Croop, Faulkner and Labriola, 1997; no recent citable studies done in the author's knowledge). The frequency of side effects with naltrexone is low, with nausea and vomiting being the most commonly reported, followed by headache, low energy, decreased alertness, depression and anxiety. These side effects resolve in one to two days after starting naltrexone, or after a few doses, or on reducing the daily dosage (Croop, Faulkner and Labriola, 1997). Though naltrexone carries a black box warning of possible hepatotoxicity, there are no reports of hepatotoxicity with the recommended daily dosages (Yen, et al., 2006). In fact, liver enzymes which are raised often reduce with naltrexone due to decreased alcohol consumption (Berg, et al., 1996;Yen, et al., 2006).
From the clinical perspective, it is essential to note that though naltrexone has been used widely in the management of alcohol dependence there are always potential barriers to naltrexone response. Among these, the most common are medication non-adherence and heterogeneity of the alcohol dependent patient population. There are also probably different endophenotypes of alcoholism whereby some patients would respond differentially to naltrexone. We are already aware of naltrexone responders associated with response to alcohol in the laboratory (King, et al., 1997), family history of alcoholism (Jaffe, et al., 1996) and genotypes (Oslin, et al., 2003).
A long acting extended release injectable formulation of Naltrexone (encapsulated naltrexone 380mg in bio-degradable microspheres) was approved by the European FDA in 1996 for the treatment of alcohol dependence. The preparation was shown to maintain therapeutic levels for a month after injection. It also had reduced side effects and less chance of hepatic toxicity as it eliminated fi rst pass metabolism in the liver (Garbutt, et al., 2005). Most studies with the preparation in keeping with oral naltrexone fi nd reduction in the time to relapse in alcohol dependent patients (Johnson, et al., 2004;Kranzler, et al., 2004).

Acamprosate
Acamprosate (calcium acetylhomotaurinate) is a synthetic compound with a chemical structure similar to the amino acid neurotransmitter GABA and amino acid neuromodulator taurine. It is available as 333mg tablets with recommended dosages being two 333mg tablets thrice a day. It has been used to treat over 1.5 million patients since its introduction in 1989 and is currently available and prescribed in over 28 countries (Mason, 2001). It is hypothesized that acamprosate acts via modulation of glutamatergic hyperactivity associated with chronic alcohol induced changes (De Witte et al., 2005). Acute alcohol intake disrupts the normal balance between neuronal excitation and inhibition regulated by GABA, glutamate and other receptor systems. This results in an exaggeration of the inhibitory processes. During chronic alcohol consumption, neuroadaptation occurs via up regulation of excitatory NMDA receptors. Abrupt removal of alcohol leaves the up regulated NMDA system unopposed in a state of hyperactivity. Acamprosate may act at the regulatory sites on both ionotropic and metabotropic NMDA receptors and normalizes this hyper excitability to re-establish homeostasis (Hoffman, 2003;De Witte, 2004).
The US FDA approval of acamprosate was based on three trials that showed acamprosate's effi cacy in reducing relapse and maintaining abstinence in patients with alcohol dependence (Paille, et al., 1995;Sass, et al., 1996;Pele, et al., 1997). A number of reviews and meta-analyses have demonstrated moderate effi cacy of acamprosate in the management of patients with alcohol dependence (Bouza, et al., 2004;Mason, 2005). The clinical effi cacy of acamprosate was evaluated in a systematic review of published clinical trials up to 1997 with a consistent fi nding being 30-50% increase in non drinking days (Wilde and Wagstaff, 1997). A relatively recent meta analysis of 22 studies also reported the same effect (Mann et al., 2004). In summary, there is good evidence to support increased abstinence and decreased drinking days with acamprosate compared to placebo in the treatment of alcohol-dependent patients. The strongest effect of acamprosate is seen in recently detoxifi ed alcohol dependents with very good data supporting its effi cacy in long term studies.
In addition, all clinical trials support a favorable safety and tolerability profi le of acamprosate. It has no abuse potential and the only side effect noted in all studies and on an overdose is diarrhea while hypercalcemia may be seen in chronic overdose cases only (Mason, 1996;Mann, 2004). Studies have also shown acamprosate to be a cost effective treatment (Schadlich and Brecht, 1998). However, in India, Disulfi ram is cheaper than either Naltrexone or Acamprosate. Hence Disulfi ram is the more cost effective treatment. Worldwide, though, Naltrexone and Acamprosate are cheaper than Disulfi ram, and Disulfi ram is not easily available in many nations.

Combined Naltrexone and Acamprosate Therapy
Some authors have suggested a clinical rationale for combining Naltrexone and Acamprosate therapy in the management of alcohol dependence as they act on different neurotransmitter systems (Mason, 2005;Kranzler, 2006). Clinical trials have proved that the above combination is better than acamprosate alone, though not better than naltrexone alone, especially in terms of fi rst relapse. These were also the fi rst studies to suggest that combined therapy is better than monotherapy in the treatment of alcohol dependence (Kiefer et al., 2003;Feeney et al., 2006). More recent researches may be underway but have not been published at this point of time in the author's knowledge.

Disulfi ram
Disulfi ram, an aldehyde dehydrogenase inhibitor, has been approved by US FDA in 1951 as an aversive therapy for the management of alcohol dependence. It blocks the oxidation of ingested alcohol at the acetaldehyde stage and prevents its rapid metabolism to acetate. Thus when a disulfi ram treated patient ingests even small amounts of alcohol, acetaldehyde accumulates as a result of the disulfi ram-ethanol reaction and causes tachycardia, hypotension, diaphoresis, fl ushing, dyspnea, nausea and vomiting. These symptoms act as a deterrent to alcohol ingestion (Savas and Gullu, 1997). Disulfi ram is available as 250mg tablets with the recommended dosage being 250-500mg per day. Disulfi ram is often not recommended as the fi rst line medication for newly diagnosed alcohol dependent patients but is reserved for treating patients who have previously failed one or more courses of treatment or those who are motivated to achieve complete abstinence (Fuller, et al., 1986). With the advent and emergence of Naltrexone and Acamprosate, there has been a decline in Disulfi ram use with it slipping to a second line treatment in many centers for the treatment of alcohol dependence. Safety concerns may also be the reason for this as many alcoholic patients try to consume alcohol even when on Disulfi ram and hence may cause themselves unnecessary harm.
Several reviews support the effi cacy of supervised use of Disulfi ram in the management of alcohol dependence (Banys, 1988;Brewer, 1995;Suh et al., 2006). This background alone ought to make everyone in the world of alcoholism treatment aware of disulfi ram's potential especially for the large and often demoralizing number of patients that do not respond to other treatments. There is no doubt that supervised disulfi ram therapy is an integral component of any alcohol treatment program (Chick and Brewer, 1999). There are also a large number of limitations with respect to disulfi ram research. In a review of studies published between 1948 and 1971 it was seen that among 42 studies only one had an adequate research design. The limitations still hold, with no randomized double blind trials being ever conducted on Disulfi ram in this reviewer's knowledge. Lack of double blinded controlled and randomized clinical trials with disulfi ram is another hindrance. The reason for this is that awareness that the patient is on disulfi ram is an essential for the action of disulfi ram in order to enhance its effi cacy and hence most studies are open ones (Lundwall and Baekeland, 1971; Hughes and Cook, 1997; Fuller and Gordis, 2004). It has been noted that disulfi ram is most effective when supervised and used in alcoholism with the help of a close family member (Brewer, 2005).
Disulfi ram is an old drug, long out of patent protection. It is thus cheap and marketed by manufacturers of the generic drug who do little advertising and research. There is also a ready availability of funding for naltrexone and acamprosate research which means that researchers with projects on these drugs are more likely to study acamprosate or naltrexone than disulfi ram. Fears of disulfi ram hepatotoxicity are often exaggerated. There is about one case in 25000 patient years (Poulsen, 1992;Brewer and Hardt, 1999;Martin and Beresford, 2007). Death from disulfi ram is also very rare (Brewer, 2005). Disulfi ram can be readily prescribed with Acamprosate and Naltrexone and is shown to improve the effi cacy of Acamprosate (Beeson et al., 1998;Suh et al., 2006). There have been cases where disulfi ram has been continued safely for over 15 years (Brewer, 1993;Garbutt, 2009).
A long acting depot preparation of Disulfi ram in the form of a Disulfi ram implant is also available. It was introduced in the 1950s and is still used in some parts of the world. In various studies, it shows a similar pharmacological and clinical profi le like oral Disulfi ram (Johnsen and Marland, 1991;1992). No current research evidence is available on this preparation.

Comparison of the Three Drugs
There are only a few studies that provide a head on between the above three drugs. Naltrexone has been proven superior to Acamprosate in one of the earliest studies comparing the two drugs (Rubio et al., 2001). An Indian study has shown Naltrexone to be superior to Disulfi ram (Naidu et al., 2000); while a retrospective chart review has shown acamprosate to be superior to naltrexone (Basu et al., 2005). No major recent studies add to this literature and future research in this area is warranted.
The author of this article has been involved in recent work on Disulfi ram. In similar studies the author and others have shown disulfi ram to be superior to naltrexone, acamprosate and topiramate in separate studies. They, along with others, have also shown disulfi ram to be superior to naltrexone in the management of adolescents with alcohol dependence.

Topiramate
Though not US FDA-approved, there are various reports of topiramate being effective in the management of alcohol dependence. It is a drug that has been used successfully in epilepsy and migraine. It is postulated to be effective in the management of alcohol dependence as it reduces dopamine release after alcohol consumption due to its ability to enhance GABA mediated inhibition through non benzodiazepine receptors (White et al., 2000; Johnson et al., 2003). There is also a possible glutamate antagonism mechanism at the alpha amino 3 hydroxy

Future Probable Pharmacological Agents
Several other classes of drugs, not yet currently approved, are under active study for use in alcohol dependence. Selective serotonin reuptake inhibitors (SSRIs) that augment brain serotenergic function have shown to reduce alcohol consumption in animal studies. Findings with alcohol dependent patients are inconsistent but these drugs are the main stay in the management of depression with alcohol dependence. Type A alcoholics (late onset, less severe dependence, less psychopathology) show a favorable response to these drugs. The two drugs that have been studied so far are Sertraline and Fluoxetine in one study each ( Pharmacotherapy for alcohol dependence is always delivered in a psychosocial context that may affect the outcome of the treatment. The rigorous study of different psychotherapeutic treatments for alcohol dependence has shown several distinct approaches to be effective. Many psychosocial interventions for alcohol dependence, including Alcoholics Anonymous, can be integrated successfully with pharmacotherapy. Psychosocial interventions, ranging from brief medical management to more intensive individualized psychotherapies, have all been shown to produce positive outcomes in certain studies, depending on the specifi c medication and the study context. Particularly successful combinations may include the use of behavioral marital therapy plus a disulfi ram contract for patients taking that medication, and the combination of naltrexone or acamprosate with cognitive-behavioral therapy or psychosocial support. Ongoing research examining the optimal combinations of medications with different psychosocial treatments for alcohol dependence may further inform the fi eld (Weiss and Kueppenbender, 2006).

STEP 1
Assess each patient of alcohol dependence with regard to family support, past history of relapses, treatments received and response towards various treatments.

STEP 2
Choose between Disulfi ram, Naltrexone and Acamprosate on the basis of history.
• DISULFIRAM -more cost-effective in the Indian setting and especially when co-morbid cocaine dependence is present. • NALTREXONE -when comorbid opioid dependence is present with intense craving symptoms. • ACAMPROSATE -when side effects due to Disulfi ram were previously experienced or lack of response to other two drugs.

STEP 3
Combine the drug therapy with appropriate psychosocial interventions. DISULFIRAM with Marital and Family Therapy. NALTREXONE or ACAMPROSATE with Cognitive Behavioral Therapy.

Concluding Remarks
Today the pharmacology scenario with respect to alcohol dependence is more promising than ever. The molecules used regularly in the management of alcohol dependence have been widely researched such that the sharp clinician can ascertain their use for specific patient populations when needed. Further studies involving comparisons of various different drugs across various settings and subsets of the alcoholic population are needed to clear any lacunae that remain.

Thumb rule for clinicians
It is important for clinicians treating alcohol dependence to note the following: • Naltrexone and Acamprosate, though effective, only reduce craving and do not deter the patient from taking alcohol. He may still drink while on these drugs with no untoward effects. • Disulfi ram, though underused, is cheaper than the above two drugs but very effective as an alcohol deterrent as fear of a disulfi ram ethanol reaction forces the patient to be off alcohol when on the drug. • Combination therapy of disulfi ram with any of the other drugs thereby acting on different neurobiological systems may be optimal for the effective management of alcohol dependence. • The use of psycho-education about disulfi ram and its actions is very essential to get the best effects out of the medication.

Take home message
The pharmacotherapy of alcohol dependence is keenly poised today. We have different drugs (Naltrexone, Disulfi ram and Acamprosate) with varying mechanisms of action aimed at different populations which, when used judiciously, can bring about good results along with psychosocial interventions in the management of alcohol dependence. Newer agents like Topiramate and SSRIs are being investigated for their role in alcohol dependence.

Confl ict of interest
None declared. No funding, speaker fees or research grant received.