Invited Review Pharmacotherapy of Alcoholism: Gaps in Knowledge And

Alcohol & Alcoholism Vol. 35, No. 6, pp. 537Ð547, 2000

INVITED REVIEW

PHARMACOTHERAPY OF ALCOHOLISM: GAPS IN KNOWLEDGE AND OPPORTUNITIES FOR RESEARCH HENRY R. KRANZLER*

Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030, USA

(Received 8 December 1999; in revised form 11 June 2000)

Abstract — During the past decade, renewed interest in medications to prevent relapse in alcoholics has yielded a number of promising candidates. Although two of these medications, naltrexone and acamprosate, are currently in clinical use in a number of countries, overall, their effectiveness appears to be limited. Disulfiram, the deterrent medication that was approved 50 years ago for the treatment of alcoholism, has not consistently been shown to be efficacious. However, since inadequate dosing and other modifiable factors may limit its deterrent effects, the identification of a more potent metabolite of disulfiram appears to warrant further evaluation. Studies of serotonergic agonists for treatment of alcoholism have also yielded inconsistent results. There is evidence, however, that subgroups of alcoholics may respond well to such medications, suggesting that treatment matching may enhance their efficacy. In addition, nalmefene, a compound with effects similar to naltrexone, as well as a sustained release formulation of naltrexone, may enhance the beneficial effects of opioid antagonist therapy. Despite these developments, much remains to be learned about the pharmacotherapy of alcoholism. The ongoing development and evaluation of novel medications should be given a high priority. However, such basic issues as the optimal dosing strategy and duration of treatment for existing therapies are not known. Similarly, combination therapy, involving either multiple medications or the combination of medication with specific psychotherapies, has not been well studied. The utility of specific pharmacotherapies in women, different ethnic/racial groups, adolescent and geriatric patients, and individuals with co-morbid alcohol and drug use disorders (including nicotine dependence) is also largely unknown, as is the appropriateness of medication therapy for treatment of early problem drinkers. The ultimate aim of these efforts is the development of algorithms for the pharmacological treatment of heavy drinking, which incorporate the characteristics of the patient and of pharmacological and psychosocial treatments with demonstrated efficacy. Although a general framework for such an effort currently exists, much detail is needed before it will be of widespread clinical value.

INTRODUCTION (Rosenthal, 1979), which limits the validity of general conclusions. Among the major challenges in alcoholism treatment is the The brief overview that follows will be extended in prevention of relapse into heavy drinking. Individual and group subsequent sections to provide a more detailed review of the counselling and 12-step programmes are basic elements in the existing literature, including the limitations of that literature. rehabilitation of patients with alcohol dependence. Although Since there are few studies of combined treatments for alcohol medications are commonly used to treat withdrawal from dependence, they will also be presented as an integral part alcohol, their role in the rehabilitation of alcoholic patients of the detailed review. The final section of the article is a remains limited. Pharmacological agents can be used in several discussion of the opportunities that exist for research on the ways to prevent alcoholic relapse. Whereas deterrent drugs pharmacotherapy of alcoholism. make the ingestion of alcohol unpleasant, others appear to Renewed interest in medications to treat alcoholism, evident reduce alcohol intake by reducing the reinforcing effects of over the past decade, has begun to bear fruit, as witnessed by alcohol or by reducing the urge or craving to ingest alcohol. the approval in 1994 by the US Food and Drug Administration This review is intended to highlight promising areas of (FDA) of naltrexone for treatment of alcohol dependence. investigation and gaps in the literature on pharmacological Disulfiram, a deterrent agent, was approved for the treatment and combined treatments for alcohol dependence. Although of alcoholism nearly 50 years earlier (Hald and Jacobsen, medications are increasingly being used to treat co-morbid 1948). Its use, however, has not been widespread and, although psychopathology in alcoholics (Kranzler and Rounsaville, some small-scale studies have shown it to be superior to 1998), this review will focus on alcoholism pharmacotherapy placebo, the largest controlled trials have failed to demonstrate independent of such co-morbidity. This review is not intended its efficacy. Although naltrexone was approved in the USA to be comprehensive, since space does not permit a discussion for treatment of alcohol dependence based upon the results of of all pharmacological agents that have been examined for two controlled trials showing the medication to be superior to treatment of alcohol dependence. In addition, it must be rec- placebo in the prevention of alcoholic relapse, this medication ognized that many studies that yield negative results are never has also failed to achieve widespread use in the USA. Although published, an important issue termed ‘the file drawer problem’ there are probably a number of reasons for this lack of commer- cial success, some recent studies have shown poor tolerability and/or poor compliance with the medication. *Author to whom correspondence should be addressed at: University of Recently a multicentre study of acamprosate was completed Connecticut Health Center, 263 Farmington Avenue, MC2103, Farmington, in the USA, with the results reported recently in preliminary CT 06030, USA. form (Mason and Goodman, 2000). Acamprosate is the most

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© 2000 Medical Council on Alcoholism 538 H. R. KRANZLER intensively studied medication for treatment of alcohol However, behavioural efforts that may be of value include the dependence (Mason and Ownby, 2000). Although the drug use of incentives provided to the patient, contracting with has not yet been approved for use in the USA, its approval in the patient and a ‘significant other’ to work together to ensure countries throughout Europe suggests that it is likely to compliance, providing regular reminders and other informa- become the second medication approved in the USA for treat- tion to the patient, and behavioural training and social support ment of alcohol dependence in the ‘new era’ of alcoholism (Allen and Litten, 1992). Azrin et al. (1982) found that a trial pharmacotherapy. programme of stimulus control training, role playing, com- In the face of all of this promise, the lack of clear guidelines munication skills training and recreational and vocational for the use of medication, alone or in combination with specific counselling improved outcome in disulfiram-treated patients psychosocial treatments, substantially limits the clinical value compared with those receiving placebo. Chick et al. (1992) of pharmacotherapy for alcoholism treatment. Furthermore, assessed the efficacy of supervised disulfiram treatment as an despite growing interest by the pharmaceutical industry in adjunct to out-patient treatment of alcoholism. During a 6-month medication development for alcohol dependence, funding for treatment period, patients received disulfiram 200 mg/day or such research remains far below that of other therapeutic areas placebo under the supervision of an individual nominated in psychiatry, such as the treatment of major depression or by the patient. Under these circumstances, disulfiram sig- psychosis. The main source in the USA for funding research nificantly increased abstinent days and decreased total drinks on the pharmacotherapy of alcoholism remains the National consumed; these effects were confirmed by parallel changes in Institute on Alcohol Abuse and Alcoholism (NIAAA). γ-glutamyltransferase levels. Consistent interest and high levels of industrial support for Because there is an increased risk of side-effects and toxic medication development internationally are essential for a hazards as the dosage of disulfiram is increased, the daily dosage more rapid development of the field. prescribed in the USA has been limited to 250Ð500 mg/day. However, by titrating the dose of disulfiram in relation to a challenge dose of ethanol, Brewer (1984) found that a sub- REVIEW OF THE LITERATURE ON MEDICATIONS stantial number of patients required in excess of 1 g/day of FOR RELAPSE PREVENTION IN ALCOHOLICS disulfiram to produce the DER. This suggests that for many patients, the standard approach to treatment with disulfiram is Deterrent medications inadequate to yield an aversive reaction when combined These alter the body’s response to alcohol, making its in- with alcohol, thereby limiting its potential value as a deterrent gestion unpleasant. Disulfiram (Antabuse), the only deterrent medication. It is possible that by enhancing compliance and medication approved in the USA for the treatment of alcoholism, optimizing the dosage of disulfiram, its efficacy in alcoholism inhibits aldehyde dehydrogenase (ALDH), the enzyme that treatment may be substantially increased. catalyses the oxidation of acetaldehyde to acetic acid. If alcohol The requirement that disulfiram undergoes a complex is ingested after this enzyme is inhibited, blood acetaldehyde process of bioactivation before it can inhibit ALDH (Yourick levels rise, which produce the disulfiramÐethanol reaction and Faiman, 1991) may explain the need for a higher dosage (DER). The DER is an aversive reaction that varies in intensity in some patients. S-ethyl N,N-diethylthiocarbamate sulphoxide both with the dose of disulfiram and the volume of alcohol (DETC-MeSO), a metabolite of disulfiram, appears to be consumed; it is the prospect of such a reaction that is thought responsible for inhibition of ALDH (Hart and Faiman, 1992). to deter drinking. At the dosage that is used clinically, faulty bioactivation in Despite the apparent logic of such an approach, there is some individuals may yield too low a concentration of DETC- limited evidence for the efficacy of disulfiram in the treatment MeSO to inhibit ALDH. There are a number of factors that can of alcoholism. In a multicentre, cooperative study conducted interfere with bioactivation. First, bioactivation of disulfiram in the Veterans Administration (Fuller et al., 1986), more than appears to be inhibited by one of its metabolites (Yourick and 600 male alcoholics were assigned randomly to groups receiving Faiman, 1987). Furthermore, some alcoholics, due to liver dis- disulfiram (either 1 mg/day or 250 mg/day), or to a control ease, have reduced levels of the cytochrome P-450 enzymes group. Patients assigned to the disulfiram groups were told that are required for bioactivation (Guengerich and Turvey, they were being given the drug, but neither patients nor 1991). Following pretreatment with disulfiram, alcoholics staff knew the dosage. Results showed that, irrespective of the with liver disease showed a diminished response to an alcohol medication group, complete abstinence in the 1-year treatment challenge, compared to alcoholics without liver disease (Wicht trial was related to medication compliance. There were no sig- et al., 1995). In addition, the potential exists for competitive nificant differences among the three groups in terms of length inhibition of disulfiram bioactivation by the co-administration of time to first drink, unemployment rate, social stability, or of a variety of widely used medications that are also meta- number of men totally abstinent. However, among patients bolized by the relevant cytochrome P-450 enzymes (Madan who resumed drinking, those taking disulfiram 250 mg/day et al., 1995). had significantly fewer drinking days than patients in the other The clinical use of DETC-MeSO, the metabolite of disulfiram two groups, a finding that may have arisen by chance (given that directly antagonizes the activity of ALDH should, there- the large number of statistical analyses). fore, eliminate much of the variability in response observed Careful efforts to enhance compliance with disulfiram may with disulfiram. Furthermore, the metabolism of disulfiram serve to augment the deterrent effects of the medication. The produces several intermediates that are potentially toxic (Erve use of disulfiram by subcutaneous implantation (Wilson et al., 1998). Since DETC-MeSO is the end product of disulfiram et al., 1980) does not appear to yield blood levels that are metabolism, none of these intermediates are produced from adequate to produce a DER (Bergstrom et al., 1982). it, so that it may also be better tolerated than the parent PHARMACOTHERAPY OF ALCOHOLISM 539 compound. Finally, DETC-MeSO is potent and has favourable evaluated are the selective serotonin reuptake inhibitors pharmaceutical characteristics, which make feasible its use as (SSRIs), particularly fluoxetine and citalopram. A summary a transdermal or sustained release formulation, which may be of the studies of citalopram and fluoxetine is provided in useful in the enhancement of compliance with the medication. Tables 1 and 2, respectively. In summary, although the literature on disulfiram does not Both acute (Amit et al., 1985) and chronic (Naranjo et al., support its widespread use in the treatment of alcoholism, the 1984) administration of zimelidine, an SSRI that was removed drug may be useful in the treatment of alcoholics with whom from clinical trials due to toxicity, have shown that the drug special efforts are made to enhance compliance. Further develop- reduces ethanol consumption. Other SSRIs that have been ment of DETC-MeSO, which potently inhibits ALDH, may tested in humans to determine their effects on alcohol con- help to better define an appropriate role for deterrent therapy sumption include fluoxetine (Naranjo et al., 1990; Gerra et al., in the treatment of alcohol dependence. 1992; Gorelick and Paredes, 1992; Kranzler et al., 1995; Kabel and Petty, 1996), citalopram (Naranjo et al., 1987, 1992, 1995; Medications that directly reduce alcohol consumption Balldin et al., 1994; Tiihonen et al., 1996), viqualine (Naranjo These appear to influence several neurotransmitter systems et al., 1989), and fluvoxamine (Kranzler et al., 1993; Angelone that underlie the reinforcing or discriminative stimulus effects et al., 1998). of ethanol: endogenous opioids; catecholamines, especially Naranjo et al. (1990) were the first to report on the effects dopamine; serotonin, and excitatory amino acids (e.g. of fluoxetine on alcohol consumption in heavy drinkers. They glutamate) (Kranzler, 1995). Although it is likely that these found that fluoxetine 60 mg/day reduced average daily alcohol systems interact in complex ways to produce the reinforcing consumption by ~17% from baseline levels; treatment with effects of ethanol, efforts to develop medications for alco- fluoxetine 40 mg/day or placebo had no effect. When alcoholics holism treatment have focused on agents that are relatively on an in-patient unit were given the opportunity to drink alcohol, selective for specific neurotransmitter systems. fluoxetine pretreatment (80 mg/day) initially reduced alcohol Serotonergic medications. In contrast to the extensive consumption, but the effect lasted only 1 week (Gorelick and preclinical literature that links serotonergic neurotransmission Paredes, 1992). Using a cross-over design, Gerra et al. (1992) to alcohol consumption, data on the effects of serotonergic compared the effects of fluoxetine 40 mg/day, acamprosate, medications on human drinking behaviour are more limited, and placebo in family-history-positive (FHP) and family- and the results are less consistent (Kranzler and Anton, 1994). history-negative (FHN) alcoholics. They found that both active The serotonergic medications that have been most extensively medications were superior to placebo in reducing the number

Table 1. Placebo-controlled trials of fluoxetine (FLX)

Reference Country Study typea Total n Study durationb Commentc

Naranjo et al. (1987) Canada 3,P 29 4 weeks FLX 60 mg/day (but not 40 mg/day) reduced drinks/day Gerra et al. (1992) Italy 3,C 28 1 month FLX 40 mg/day reduced drinks/day in family-history-positive patients only Gorelick and Paredes (1992) USA 2,P 20 4 weeks FLX to a maximum of 80 mg/day transiently reduced drinks/day Kranzler et al. (1995) USA 2,P 101 12 weeks FLX 60 mg/day was comparable to placebo on all drinking outcomes Janiri et al. (1996) Italy 2,P 50 2 months FLX 20 mg/day increased proportion abstinent Kabel and Petty (1996) USA 2,P 28 12 weeks FLX 60 mg/day was comparable to placebo on all drinking outcomes aStudy types: 3,P, 3-arm, parallel groups; 3,C, 3-group cross-over; 2,P, 2-arm, parallel groups. bTreatment period (for cross-over studies this is the duration of each treatment received). cOnly statistically significant differences reported.

Table 2. Placebo-controlled trials of citalopram (CIT)

Reference Country Study typea Total n Study durationb Commentc

Naranjo et al. (1987) Canada 3,C 39 4 weeks CIT 40 mg/day increased abstinent days and decreased drinks/day Naranjo et al. (1992) Canada 2,C 16 1 week CIT 40 mg/day increased abstinent days and decreased drinks/day Balldin et al. (1994) Sweden 2,C 30 5 weeks CIT 40 mg/day increased drinks/day for lighter drinkers only Naranjo et al. (1995) Canada 2,P 62 12 weeks CIT 40 mg/day decreased drinks/day for first week only Tiihonen et al. (1996) Finland 2,P 62 4 months CIT 40 mg/day increased study retention and improved drinking outcomes (by informant report)

aStudy types: 3,C, 3-group, cross-over; 2,C, 2-group cross-over; 2,P, 2-arm, parallel groups. bTreatment period (for cross-over studies this is the duration of each treatment received). cOnly statistically significant differences reported. 540 H. R. KRANZLER of drinks consumed. However, the effect of fluoxetine was sig- compared to placebo treatment. Balldin et al. (1994) found an nificant only in the FHP patients, while acamprosate produced effect of citalopram only among heavy drinkers at the lower a significant reduction only in the FHN patients. Kranzler end of the range of alcohol consumption in their patient et al. (1995) conducted a placebo-controlled trial of fluoxetine sample. Recently, Pettinati et al. (2000) applied an approach 60 mg/day in combination with coping skills psychotherapy in similar to that employed by Kranzler et al. (1996) to examine ambulatory alcoholics. These investigators found no overall the interaction of alcoholic subtype with medication effects in advantage to the active drug on drinking outcomes. In a further a placebo-controlled trial of sertraline. These investigators analysis of the data, Kranzler et al. (1996) found that, among found that low risk/severity alcoholics drank on fewer days the subgroup of patients with high levels of both pre-morbid and were more likely to be abstinent in the 12-week treatment vulnerability and alcohol-related problems, fluoxetine appeared trial if they received sertraline than if they were treated with to reduce the beneficial effects of coping skills training. Kabel placebo. In contrast, high risk/severity alcoholics showed and Petty (1996) showed no effect of fluoxetine 60 mg/day, better outcomes on these measures when treated with placebo, compared with placebo, among severe alcoholics recruited compared with sertraline, though these effects did not reach from an alcoholism treatment programme at a Veterans Affairs statistical significance. These findings suggest that prospect- Medical Center. ive studies that aim to match alcoholic subtypes with SSRI The other SSRI whose effects on alcohol consumption have treatment may define a role for such medications in the treat- been extensively examined is citalopram. Naranjo et al. (1987) ment of heavy drinking or mild alcohol dependence. first reported that citalopram 40 mg/day reduced the number Opioid antagonists. Both naltrexone and nalmefene are of drinks consumed per day and increased the number of opioid antagonists with no intrinsic agonist properties. Of abstinent days in a sample of non-depressed, early-stage these medications, naltrexone has, by far, been studied problem drinkers. In this study, citalopram 20 mg/day showed more extensively. A summary of published studies of opioid no such effect. Subsequently, these investigators (Naranjo antagonists for treatment of alcohol dependence is shown in et al., 1992) studied the effects of citalopram in a sample of Table 3. non-depressed, alcohol-dependent subjects. Using a cross- Naltrexone was approved by the US FDA in 1985 for over study design, they found that, compared with placebo, the treatment of opioid dependence and in 1994 for the treat- citalopram 40 mg/day significantly decreased alcoholic drinks ment of alcohol dependence. Due to poor compliance with the and increased abstinent days. However, when citalopram medication, naltrexone maintenance treatment of opioid 40 mg/day was combined with a brief psychosocial inter- dependence has been generally unsuccessful in practice. A vention in a subsequent study, an advantage for the active drug notable exception to this is its use in opioid-dependent profes- over placebo on the number of daily alcoholic drinks was sionals, where it can be combined with contingency contract- found only during the first week of treatment (Naranjo et al., ing to enhance compliance (Stine and Kosten, 1997). Limited 1995). In this 12-week treatment trial, the overall reduction compliance with the medication may also limit naltrexone’s in drinking was comparable for the citalopram and placebo effectiveness in alcoholism treatment. groups (Naranjo et al., 1995). Balldin et al. (1994) compared In a study of 70 alcohol-dependent veterans, Volpicelli et al. the effects of citalopram 40 mg/day with placebo during a (1992) found that naltrexone 50 mg/day was a useful adjunct 5-week trial in a sample of heavy drinkers. Overall, there to an intensive day treatment programme in the prevention was no difference between treatment groups. However, when of relapse to heavy drinking. Naltrexone significantly delayed the data were reanalysed based on the pretreatment level of the time to consumption of the first drink following alcohol consumption, there was an advantage of the active detoxification, and hindered the progression of drinking from medication on daily alcohol intake in the less heavy drinking initial sampling to operationally defined relapse. Study subjects subgroup. Tiihonen et al. (1996) compared citalopram 40 mg who drank while taking naltrexone reported less euphoria, with placebo in a 3-month study. These investigators found that which may indicate that naltrexone blocked the endogenous study retention was significantly better in the active medication opioid system’s contribution to alcohol’s ‘priming effect’ group, as was the collateral informant report of the patients’ (Volpicelli et al., 1995). In a laboratory study of non-problem condition. There was also a trend for decreased alcohol con- drinkers, naltrexone was found to reduce the reinforcing (i.e. sumption and γ-glutamyltransferase levels in the citalopram stimulant) effects and increase the unpleasant (i.e. sedative) group. Although these investigators found no relationship properties of initial alcohol consumption (Swift et al., 1994). between alcoholic subtype and medication response, it is un- These findings were replicated and extended by O’Malley likely that the small size of the study sample provided adequate et al. (1992), who examined the utility of naltrexone in com- statistical power to identify such an interaction. bination with either supportive therapy or relapse prevention One possible explanation for the variable findings in studies skills training. This study appears to be unique, in that it of SSRIs to reduce drinking behaviour is the diversity of sub- systematically examined combination therapy, i.e. both the ject samples. The majority of studies by Naranjo and colleagues pharmacologic and the psychotherapeutic components of treat- were conducted in heavy drinkers who were not seeking ment were varied. Interestingly, in addition to the main effect treatment for alcoholism. These and some subsequent studies of the medication, naltrexone interacted differentially with suggest that SSRIs are efficacious only in heavy drinkers or the psychotherapeutic intervention. Naltrexone was more in certain subgroups of alcoholics. For example, Gerra et al. efficacious in preventing the initiation of drinking when paired (1992) found an effect of fluoxetine only in alcoholics with a with supportive therapy than when used in combination with positive family history of alcoholism. In contrast, Kranzler coping skills training. On the other hand, once the subject et al. (1996) found that high risk/severity alcoholics had sampled alcohol, naltrexone plus coping skills/relapse pre- poorer drinking outcomes when treated with fluoxetine, vention training was better at preventing a full-blown relapse. PHARMACOTHERAPY OF ALCOHOLISM 541

Table 3. Placebo-controlled trials of opioid antagonists for alcohol dependence

Referencea Study typeb Total n Study durationc Commentd

Volpicelli et al. (1992) 2,P 70 12 NTX 50 mg/day orally delayed time to first drink and reduced risk of heavy drinking O’Malley et al. (1992) 2,P 101 12 NTX 50 mg/day orally resulted in fewer drinking days and heavy drinking days. NTX and ST particularly efficacious in preventing initiation of drinking; NTX and CBT particularly efficacious in preventing replapse to heavy drinking Oslin et al. (1997) 2,P 44 12 NTX 50 mg/day orally reduced risk of relapse to heavy drinking Volpicelli et al. (1997) 2,P 97 12 NTX 50 mg/day orally = PLA in ITT analysis. In highly compliant subjects, NTX prevented drinking and heavy drinking and reduced total drinks Hersh et al. (1998) 2,P 64 8 NTX 50 mg/day orally = PLA on drinking and cocaine use in subjects with co-morbid alcohol and cocaine use disorders Kranzler et al. (1998) 2,P 20 8 Sustained release NTX injection reduced frequency of heavy drinking Anton et al. (1999) 2,P 131 12 NTX 50 mg/day orally reduced drinking frequency and drinks/drinking day and delayed relapse to heavy drinking Kranzler et al. (2000) 3,P 183 12 NTX 50 mg/day orally associated with more adverse effects, poorer medication compliance and greater attrition from treatment than PLA; NTX = NEF = PLA on drinking outcomes Mason et al. (1994) 3,P 21 12 NALM 40 mg/day orally superior to NALM 10 mg/day orally or PLA in prevention of relapse to heavy drinking Mason et al. (1999) 3,P 105 12 NALM 20 mg/day orally = NALM 80 mg/day orally; together NALM- treated subjects less likely to relapse to heavy drinking aAll studies were conducted in the US and were single-site studies. bStudy types: 2,P, 2-arm, parallel groups; 3,P, 3-arm, parallel groups. cTreatment period only (weeks). dOnly statistically significant differences reported. CBT, cognitiveÐbehavioural therapy; ITT, intention-to-treat; NALM, nalmefene; NTX, naltrexone; PLA, placebo; ST, supportive therapy.

Analysis by these investigators of the reasons for relapse during More recently, Hersh et al. (1998) failed to show an advant- this initial study period supports the notion that naltrexone age for naltrexone over placebo on measures of substance use differentially affects alcohol craving and urges, its reinforcing or craving among patients with co-morbid alcohol and cocaine properties, the experience of intoxication, and the chances use disorders. Kranzler et al. (1998) found that alcoholics of continued drinking following a relapse (O’Malley et al., treated with a sustained-release formulation of naltrexone had 1996a). These investigators also found that naltrexone may be detectable plasma concentrations of the drug for more than 30 most beneficial among alcoholics with higher levels of craving days following injection. Furthermore, the active formulation and poorer cognitive functioning (Jaffe et al., 1996). was superior to placebo in reducing the frequency of heavy During a post-treatment follow-up period, O’Malley et al. drinking in these patients. However, in another study by Kranzler (1996b) found that the beneficial effects of naltrexone et al. (2000) comparing oral naltrexone with the serotonergic diminished gradually over time. Furthermore, abstinence during antidepressant nefazodone, neither active medication was treatment strongly predicted whether subjects met criteria superior to placebo on measures of alcohol consumption. In fact, for alcohol abuse or dependence at a 6-month, post-treatment in that study, naltrexone treatment resulted in significantly follow-up visit. These findings suggest that patients who are more adverse effects, poorer medication compliance, and a unable to remain abstinent during acute treatment might greater rate of early discontinuation of treatment than placebo. benefit from naltrexone treatment for longer than the 12-week Despite these negative results, Anton et al. (1999) found that, duration of treatment in these initial studies. when combined with cognitiveÐbehavioural psychotherapy, Subsequently, Oslin et al. (1997), in a study of older naltrexone was superior to placebo on a variety of measures: veterans, found that naltrexone was superior to placebo in percentage of days abstinent, number of drinks per drinking reducing the risk of relapse. However, Volpicelli et al. (1997) day, and time to relapse to heavy drinking during the 12-week found no overall advantage to naltrexone over placebo in the treatment trial. The observed effects were, however, generally treatment of alcohol dependence. These investigators found that small in magnitude. Furthermore, time to the first alcoholic compliance with naltrexone treatment was variable, and that drink and the likelihood of abstinence throughout the trial did only among highly-compliant subjects was the active medication not differ significantly by group, nor did objective measures of significantly better than placebo with respect to the percentage heavy drinking (i.e. γ-glutamyltransferase and carbohydrate- of patients who drank, the percentage of patients who relapsed, deficient transferrin). and total drinks consumed. These findings, together with the A pilot study by Mason et al. (1994) showed an advantage evidence of a major effect of compliance in studies of disulfiram, for the opioid antagonist nalmefene 40 mg/day over nalmefene underscore the need for a better understanding of factors that 10 mg/day or placebo in the prevention of relapse to heavy underlie medication compliance among alcoholics. Furthermore, drinking in a small sample of alcohol-dependent subjects. well-informed efforts to enhance medication compliance are Subsequently, these investigators (Mason et al., 1999) essential, if medication therapy is to be of value in the routine compared nalmefene (20 mg/day or 80 mg/day) with placebo clinical care provided to alcoholics. treatment in a larger sample of alcohol-dependent subjects. 542 H. R. KRANZLER They found no difference between the two active treatment Three placebo-controlled studies of acamprosate for alcohol groups, though when combined, nalmefene-treated subjects dependence have also been conducted in Belgium. Roussaux were significantly less likely to relapse to heavy drinking than et al. (1996) found no difference in drinking outcomes or bio- were placebo-treated subjects. Outcomes on other, related chemical measures in a 3-month, placebo-controlled trial with measures of risk of heavy drinking were consistent with this 127 alcoholics recruited from an in-patient setting. However, finding. However, although the study was designed as a three- acamprosate was shown to enhance treatment retention and arm trial, unfortunately, the data are not presented separately the maintenance of abstinence among alcoholics in a 6-month for the nalmefene groups, so that it is not possible to assess the study by Pelc et al. (1996). In a second study, Pelc et al. relative effects of the two dosages vis-à-vis one another or in (1997) compared two dosages of acamprosate (1332 mg/day relation to placebo. or 1998 mg/day) to placebo in a 90-day multicentre study in In summary, naltrexone appears to produce a modest effect 188 alcohol-dependent patients. Both acamprosate-treated on drinking behaviour among alcoholics. The small effect groups had significantly better outcomes than placebo-treated may explain why significant medication effects have not been patients on abstinent days, proportion of patients achieving observed in some published studies. Furthermore, the number abstinence for the entire trial, time to first alcoholic drink, of patients treated in double-blind studies of the drug has been and liver enzyme levels. Although there were some trends for comparatively few, and longer-term outcome studies are the higher dosage of acamprosate to be superior to the lower lacking. A number of studies are currently underway to further dosage of that medication, these did not reach statistical evaluate the range of patient groups for which naltrexone is significance. efficacious, its optimal duration of use and the most appropriate In a multicentre study in Belgium, The Netherlands, and psychosocial treatments to be used in combination with the Luxembourg, alcoholics were treated with either acamprosate medication. In addition, based upon promising initial results in or placebo for 6 months and were then followed up for an the treatment of alcoholism obtained with the opioid antagonist additional 6 months (Geerlings et al., 1997). Acamprosate- nalmefene (Mason et al., 1994, 1999), further research with that treated patients were significantly more likely to complete treat- medication is underway. Sinclair (1998) has argued that for ment and to remain abstinent during the treatment period than opioid antagonists to be efficacious in alcoholism treatment, were placebo-treated patients. The beneficial effects, although they must be administered to individuals who are actively evident at follow-up, did not reach statistical significance drinking, rather than in the context of relapse prevention. during the post-treatment period. Additional empirical evaluation of this hypothesis is warranted. In a multicentre study in Austria (Whitworth et al., 1996), Acamprosate (calcium acetylhomotaurinate). This amino alcoholic patients were treated with acamprosate or placebo acid derivative is another promising therapeutic agent. It is for 12 months and then followed up for an additional 12 approved for use in a number of European countries and a months. During treatment, acamprosate-treated patients were multicentre trial was recently completed in the USA. Table 4 significantly less likely to return to drinking, an effect that summarizes placebo-controlled trials of acamprosate for persisted during the post-treatment follow-up. Sass et al. alcohol dependence. A detailed summary of acamprosate studies (1996) conducted a multicentre study in Germany, which also was recently compiled by Mason and Ownby (2000). included 12-month treatment and post-treatment follow-up Acamprosate affects both γ-aminobutyric acid (GABA) and periods. These investigators found that acamprosate was excitatory amino acid (i.e. glutamate) neurotransmission. Based superior to placebo with respect to treatment retention. upon its profile of clinical effects, Littleton (1995, 1996) has Patients receiving the active medication were also more likely argued that acamprosate works by decreasing craving related to remain abstinent during both the active treatment and to conditioned alcohol withdrawal. While ‘craving’ has long follow-up periods. been criticized as a non-specific, overused term (Kozlowski Poldrugo (1997) reported the results of a multicentre study of and Wilkinson, 1987), Littleton (1995, 1996) has elaborated a acamprosate in Italy, in which patients were randomly assigned theory of the phenomenon that is based on empirical findings to receive either acamprosate or placebo for 6 months, and from both the laboratory and the clinic. were followed for 6 months after treatment was discon- Initially evaluated in a single-centre trial in France, tinued. Acamprosate significantly enhanced treatment reten- acamprosate was shown over a 3-month treatment period to be tion, and the percentage of acamprosate-treated patients that twice as effective as placebo in reducing the rate at which was continuously abstinent during active treatment was alcoholics returned to drinking (Lhuintre et al., 1985). Sub- nearly double that of the placebo group. In this study, sequently, a 3-month, multicentre study in France (Lhuintre significantly more patients in the acamprosate group were et al., 1990) showed that treatment with acamprosate continuously abstinent during the post-treatment follow-up produced a greater reduction in γ-glutamyltransferase level period as well. Another multicentre study conducted in Italy than placebo treatment; however, data on drinking behaviour was recently reported by Tempesta et al. (2000). These per se were not reported. A large, multicentre study in France investigators treated 310 patients with either acamprosate or (Paille et al., 1995) showed a doseÐresponse relationship for placebo for 6 months, followed by a 3-month post-treatment the medication over 12 months of active treatment, followed follow-up period. Acamprosate-treated patients relapsed to by 6 months of single-blind placebo. Overall, in this study, drinking significantly later in the trial than did placebo patients. acamprosate was associated with significantly better rates of The active treatment group was also more likely to maintain clinic attendance and more abstinent days, with the high-dose continuous abstinence, though this effect was not statistically acamprosate showing the best outcomes, the placebo group significant during the follow-up period. Cumulative days of the poorest outcomes, and the low-dose acamprosate group abstinence also favoured the acamprosate group, an effect that intermediate on these measures. persisted during the post-treatment period. Among patients PHARMACOTHERAPY OF ALCOHOLISM 543

Table 4. Acamprosate treatment of alcohol dependence: placebo-controlled trials

Reference Country Study typea Total n Study durationb Commentc

Lhuintre et al. (1985) France S,2 85 3/0 ACA (25 mg/kg/day) more likely to remain abstinent than PLA Lhuintre et al. (1990) France M,2 569 3/0 ACA (1332 mg/day) had lower GGT level than PLA Gerra et al. (1992) Italy S,3 28 1/0 ACA (1332 mg/day) that was negative for alcoholic family history had a lower mean quantity of alcoholic drinks Pelc et al. (1996) Belgium M,2 102 6/0 ACAd had greater treatment retention, fewer days drinking, was more likely to remain abstinent, and had greater reduction in GGT level than PLA. Paille et al. (1995) France M,3 538 12/6 ACA (1332 or 1998 mg/day) had greater treatment retention, fewer drinking days, and greater likelihood of normal GGT than PLA. Effects on study retention and abstinence persisted during F/U Roussaux et al. (1996) Belgium S,2 127 3/0 ACAd had drinking and related outcomes comparable to those of PLA Sass et al. (1996) Germany M,2 272 12/12 ACAd had greater treatment retention and fewer days drinking and were more likely to remain abstinent than PLA. Effects on drinking persisted during F/U Whitworth et al. (1996) Austria M,2 448 12/12 ACAd had fewer days drinking and were more likely to remain abstinent than PLA. Effects on drinking persisted during F/U Geerlings et al. (1997) Benelux M,2 262 6/6 ACAd had greater treatment retention, fewer days drinking and a greater likelihood of remaining abstinent than PLA Poldrugo et al. (1997) Italy M,2 246 6/6 ACAd had greater treatment retention, fewer days drinking, greater likelihood of remaining abstinent, and lower rate of abnormal GGT than PLA. Difference in likelihood of abstinence persisted druing F/U Pelc et al. (1997) Belgium M,3 188 3/0 ACA (1332 or 1998 mg/day) had greater treatment retention, fewer days drinking, was more likely to remain abstinent, and had greater reduction in GGT and ASAT levels than PLA Besson et al. (1998) Switzerland M,2 110 12/12 ACAd had fewer days drinking and were more stratified likely to remain abstinent during treatment. on optional Patients receiving disulfiram and ACA had the use of DSF best outcomes; those receiving neither drug had the poorest outcomes. Patients receiving either ACA or DSF had intermediate outcomes Chick et al. (2000) UK M,2 581 6/1 ACA (1998 mg/day) had drinking outcomes comparable to those of PLA. Transient beneficial effects were seen on desire to drink and on anxiety symptoms in ACA Tempesta et al. (2000) Italy M,2 330 6/3 ACA (1998 mg/day) had delayed relapse to drinking, fewer days drinking, and greater likelihood of remaining abstinent than PLA. Among patients who drank during treatment, ACA had fewer drinking episodes and a lower mean quantity of alcohol consumption than PLA. Lower drinking frequency persisted during F/U aStudy types (all but one are parallel-group studies: Gerra et al. (1992) was a 3-group, cross-over study): S,2 = single-centre, two-arm; M,2 = multicentre, two-arm; M,3 = multicentre, three arm; bTreatment period/follow-up period (months); cOnly statistically significant differences reported; dDosage was dependent on body weight (1332 mg/day for subjects weighing <60 kg, 1998 mg/day for subjects weighing ≥60 kg); eDuration of each of three treatments received; ACA = acamprosate group; ASAT = aspartate aminotransferase; DSF = disulfiram; F/U = follow-up period; GGT = gamma-glutamyltransferase; PLA = placebo group. who drank during treatment, treatment with acamprosate was felt that random assignment on this variable was not feasible. associated with fewer drinking episodes and a lower mean Acamprosate was shown to be superior to placebo on quantity of alcohol consumption than placebo. measures of total abstinence and on cumulative abstinent days. Recently, Besson et al. (1998) compared acamprosate with Interestingly, although only exploratory given the study design, placebo in a 12-month, multicentre study in Switzerland. the group receiving both acamprosate and disulfiram showed Although patients were randomly assigned to receive acam- a significantly greater percentage of abstinent days than any prosate or placebo, stratification was used for patients who of the other three groups. One explanation offered by the were taking disulfiram concomitantly, since the investigators investigators for the marked effect of combination therapy was 544 H. R. KRANZLER that acamprosate reduced the need to drink, whereas disulfiram Despite the fact that a number of medications have been enhanced the cognitive effects of self-control over drinking. shown to be of value in the treatment of alcohol dependence, Additional studies of this combination therapy appear pharmacotherapy has not yet had a demonstrably large effect warranted. on alcoholism treatment. This is due, in part, to a widely held Finally, a recent publication describes the results of a view among the public and large segments of the alcoholism multicentre comparison of acamprosate with placebo in 581 treatment community that alcohol dependence is not a medical alcoholics conducted in the UK (Chick et al., 2000). This disorder. From this follows the belief that the disorder is not study included a 6-month active treatment period, followed amenable to pharmacological treatment, nor is it desirable to by a 1-month post-treatment follow-up period. Unlike other complicate the process of recovery by the introduction of multicentre studies of acamprosate, this protocol allowed medication. Moreover, the pharmaceutical industry has been patients to be randomly assigned to medication group for as slow in developing medications to treat alcoholism, due to its long as 5 weeks after the initiation of detoxification. Con- scepticism over the potential profitability of such medications. sequently, nearly a third of patients had relapsed to drinking These factors have seriously limited research activity in this by the time of randomization. This may explain the failure to area, despite a systematic effort by the US National Institute find any beneficial effects on drinking behaviour as a function of Alcohol Abuse and Alcoholism (NIAAA) to develop of medication condition. Transient beneficial effects of acam- medications for relapse prevention. prosate were observed on desire to drink and on anxiety symptom It has been argued that a consistent foundation of psycho- ratings. Subgroup analysis failed to show a differential effect social treatment is necessary for the evaluation of medication of the medication based on the typology proposed by Lesch effects in substance abuse trials (Carroll, 1997). The main and Walter (1996) as a useful predictor of treatment response. reasoning behind this argument is that manual-guided psycho- Together, studies in more than 3000 patients provide therapy reduces error variance, so that medication effects are generally consistent evidence of the efficacy of acamprosate in more readily observable. However, virtually all research on alcoholism rehabilitation. Whereas studies of acamprosate the pharmacotherapy of alcoholism, while increasingly attentive have not used standardized psychotherapeutic approaches, the to the need for systematic attention to the psychosocial treat- consistent, though modest, advantage of the active medication ment provided to study patients, has focused on main effects can be expected when the medication is used in routine of medications. This is so, despite evidence that the nature and clinical settings. However, as greater efforts are made to use intensity of psychosocial treatment can directly affect the specific psychosocial therapies as a platform for pharmaco- efficacy of medications in the treatment of substance abuse therapy, greater medication effects may emerge. Furthermore, (O’Malley et al., 1992; McLellan et al., 1993). Project Combine, since acamprosate has a benign side-effect profile, with a large multicentre study supported by NIAAA, can be expected gastrointestinal symptoms being most prominent, it appears to provide information on the effects of acamprosate and to have a prominent role to play in the treatment of alcohol naltrexone in alcohol dependence, using more or less intensive dependence. However, further studies are needed to determine therapies. However, there are numerous other combinations of whether subgroups of alcoholics may be more responsive to medication and psychotherapy, the interactive effects of which treatment with acamprosate (cf. Lesch and Walter, 1996; Chick are of considerable theoretical and clinical importance, which et al., 2000). This is underscored by the findings of Gerra warrant intensive study. et al. (1992), who found that acamprosate was efficacious in It is clear that the development of clinically useful reducing the number of drinks consumed only in patients with pharmacological treatments will require large-scale clinical no family history of alcoholism. trials, which provide for statistical power adequate to draw valid conclusions on the efficacy of medications. This is particularly true in the evaluation of combination treatments, OPPORTUNITIES FOR RESEARCH both those involving multiple medications and those examin- ing the interaction of medications with well-defined psycho- Two recent, critical reviews evaluated the literature on the therapeutic treatments. Such large-scale studies also hold pharmacotherapy of alcoholism (Moncrieff and Drummond, promise for the elucidation of patient features that may predict 1997; Garbutt et al., 1999). These reviews underscored the response to individual and combined treatments. need for methodological rigor in the conduct of research in However, small-scale, exploratory studies remain important this field. Other authors (Kranzler et al., 1997) have provided for the development of new candidate medications or guidelines for resolving some of the methodological com- formulations. Although there is consistent evidence that plexities that are inherent in treatment trials with alcoholics. In acamprosate is efficacious in reducing the number of days addition, Moncrieff and Drummond (1998) reviewed the most drinking, its effects are modest. In contrast, while the effects highly cited controlled clinical trials (including, but not limited of naltrexone in some studies have been robust, evidence of to, pharmacotherapy studies). These authors developed a re- its efficacy has been less consistent. Consequently, there is a liable scoring system, with which they evaluated the methodo- pressing need to identify medications with unique modes of logical quality of 25 trials. In contrast to these reviews, the action, as well as those with greater potency than existing focus of the present article is on gaps in knowledge and medications in producing effects that may be of value in potential strategies to address them. As such, it depends on the alcoholism treatment. Once such medications are identified, author’s subjective appraisal of the importance of the issues their potential must be demonstrated in preliminary clinical that exist and the articles to be considered, rather than specific trials, before they are subjected to large-scale investigation. criteria for the identification of studies for review and for For example, evidence that disulfiram must undergo bio- rating the quality of the research findings. transformation to produce aversive effects when alcohol is PHARMACOTHERAPY OF ALCOHOLISM 545 consumed (Yourick and Faiman, 1991) suggests that DETC- relapse. Little is known concerning the efficacy of medications MeSO, the active metabolite of disulfiram (Hart and Faiman, to reduce drinking in individuals who drink heavily, but who 1992), may be more efficacious as a deterrent than are not alcohol dependent, or who meet criteria for alcohol the parent compound. Since the safety of this metabolite has dependence but have not experienced substantial problems been demonstrated in preclinical toxicologic studies, it is now related to their drinking. In short, the role of pharmacotherapy possible to evaluate its effects in humans. Obviously, however, in secondary prevention efforts remains to be defined. evidence of its safety and efficacy in small-scale clinical Alcoholics with co-morbid drug use disorders are often ex- studies is needed before large-scale evaluation of DETC- cluded from alcoholism treatment trials. This is ironic, given MeSO is warranted. the high degree of overlap in the prevalence of alcohol and Given the likely advantage of combining medication and drug use disorders (Kessler et al., 1997). In view of the press- psychosocial treatments (O’Malley et al., 1992; McLellan et al., ing clinical need represented by co-morbid drug use disorders, 1993), attention to the factors that influence the integration of a sustained effort is needed to identify medications, alone and these approaches is also important. Combining medications in combination, that are efficacious and effective in such with self-help group participation may represent a particular dually dependent groups. In addition, optimal combinations of challenge (Meza and Kranzler, 1996). Abstinence-oriented medications and psychosocial treatments are needed for this groups such as Alcoholics Anonymous often see deterrent population. agents such as disulfiram as supportive of their goal of total The ultimate goal of these efforts to develop medications abstinence. As a consequence, group members may be willing for the treatment of alcohol dependence is a series of to work with physicians around the issue of proper dosage, algorithms for characterization and pharmacological treatment compliance, and early detection of side-effects. The use of of heavy drinkers/alcoholics, including a variety of medications medications to reduce the risk of relapse through direct effects combined with specific psychosocial treatments. Guidelines on craving or drinking behaviour may also be potentially for initiation, maintenance and discontinuation of treatment additive or synergistic to self-help efforts. The factors that and for managing poor or partial response are necessary. Con- influence the acceptability of medication therapy to both self- sideration of combination therapy should include combination help groups and the alcohol treatment community should, of medication and psychosocial treatment, as well as com- therefore, be an important focus of research. bination pharmacotherapy. Ultimately, such information will It is likely that efforts to identify factors that predict be useful in the elaboration of algorithms for the pharmaco- poor compliance and appropriate efforts to remedy these will logical treatment of heavy drinking and alcohol dependence, be of value generally in the pharmacotherapy of alcoholism. In which incorporate the characteristics of the patient, as well as addition to efforts that focus on medication compliance, the medications and psychosocial treatments that have been research is needed to identify other factors that influence the shown to be efficacious. Although a general framework for efficacy and effectiveness of medications with demonstrated such an effort currently exists, much detail remains to be utility in relapse prevention. Specifically, it is unclear for added before these algorithms will be of widespread clinical which patient groups acamprosate and naltrexone are most value. useful and which dosage schedules and concomitant psychosocial treatments are optimal. Although the literature on Acknowledgements — The preparation of this manuscript was supported in the selective serotonin reuptake inhibitors has not been part by US National Institutes of Health Grants R01-AA11062, K02-AA00239, P50-AA03510 and M01-RR06192. The manuscript is a revised version of a consistently positive, these medications may have a role in the lecture delivered at the Ninth Congress of the International Society for treatment of some heavy drinkers or alcoholics. Clarification of Biomedical Research in Alcoholism, Copenhagen, Denmark, June, 1998. 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