Naltrexone for the treatment of alcoholism: a meta-analysis of randomized controlled trials

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1 International Journal of Neuropsychopharmacology (2005), 8, Copyright f 2005 CINP DOI: /S Naltrexone for the treatment of alcoholism: a meta-analysis of randomized controlled trials Manit Srisurapanont and Ngamwong Jarusuraisin Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Amphur Muang, Chiang Mai 50200, Thailand REVIEW ARTICLE Abstract Many trials of naltrexone have been carried out in alcohol-dependent patients. This paper is aimed to systematically review its benefits, adverse effects, and discontinuation of treatment. We assessed and extracted the data of double-blind, randomized controlled trials (RCTs) comparing naltrexone with placebo or other treatment in people with alcoholism. Two primary outcomes were subjects who relapsed (including heavy drinking) and those who returned to drinking. Secondary outcomes were time to first drink, drinking days, number of standard drinks for a defined period, and craving. All outcomes were reported for the short, medium, and long term. Five common adverse effects and dropout rates in shortterm treatment were also examined. A total of 2861 subjects in 24 RCTs presented in 32 papers were included. For short-term treatment, naltrexone significantly decreased relapses [relative risk (RR) 0.64, 95% confidence interval (CI) ], but not return to drinking (RR 0.91, 95% CI ). Short-term treatment of naltrexone significantly increased nausea, dizziness, and fatigue in comparison to placebo [RRs (95% CIs) 2.14 ( ), 2.09 ( ), and 1.35 ( )]. Naltrexone administration did not significantly diminish short-term discontinuation of treatment (RR 0.85, 95% CI ). Naltrexone should be accepted as a short-term treatment for alcoholism. As yet, we do not know the appropriate duration of treatment continuation in an alcohol-dependent patient who responds to short-term naltrexone administration. To ensure that the real-world treatment is as effective as the research findings, a form of psychosocial therapy should be concomitantly given to all alcohol-dependent patients receiving naltrexone administration. Received 9 March 2004; Reviewed 25 July 2004; Revised 20 September 2004; Accepted 5 October 2004 Key words: Alcohol, alcohol use disorder, meta-analysis, naltrexone, opioid antagonists. Introduction Alcoholism (alcohol dependence and abuse) is a common health problem. Its health, social, and economic consequences are usually devastating. Although many individuals do achieve long-term sobriety with therapy, others continue to relapse and deteriorate despite multiple courses of treatment. Due to the limited success of psychosocial treatment programmes (Berglund et al., 2003), several pharmacological agents have been studied in people with alcoholism. Disulfiram has only limited clinical utility for those with high motivation, good health, and good cooperation. Even in highly motivated individuals, disulfiram may partially improve alcohol-dependent patients in some respects, e.g. drinking frequency and Address for correspondence: M. Srisurapanont, M.D., Professor of Psychiatry, Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Amphur Muang, Chiang Mai 50200, Thailand. Tel.: (66-53) Fax: (66-53) or (66-53) amount of alcohol consumption (Garbutt et al., 1999). While the results of some studies showed that lithium reduced drinking in alcohol-dependent patients with mood disorders (Fawcett et al., 1984; Merry et al., 1976), a randomized controlled trial (RCT) failed to demonstrate any benefit of this drug in either depressed or non-depressed patients (Dorus et al., 1989). The efficacy of selective serotonin reuptake inhibitors (SSRIs) remains to be tested in placebo-controlled, randomized trials with large sample sizes. Acamprosate is a promising medication, but it has not been widely approved (Overman et al., 2003). The interaction of alcohol and the opioid system has not been fully understood because the interaction between ethanol and the mechanistic processes associated with opioid production, secretion, and binding is relatively complex (Herz, 1997). However, most animal studies suggest that the competitive binding of opioid antagonists to opioid receptors may have the propensity to diminish the rewarding effects by decreasing the dopamine released in the mesolimbic

2 2 M. Srisurapanont and N. Jarusuraisin pathway (Spanagel and Zieglgansberger, 1997). Due to these findings, many clinical trials have investigated both the harm and benefit of opioid antagonists in people with alcoholism. Among them, naloxone has a very short half-life and, therefore, very limited clinical utility. Nalmefene has been examined in at least two RCTs, but is not yet approved (Mason et al., 1994, 1999). Naltrexone is the agent studied most, and it has been approved for the treatment of alcoholism in several countries. We, therefore, proposed to systematically review its benefits, adverse effects, and discontinuation of treatment for alcoholism. Methods Inclusion criteria This review included all double-blind RCTs that compared naltrexone with placebo and/or other treatment in people with alcohol dependence or abuse. Subjects with alcohol dependence or abuse had to be diagnosed by the use of clearly defined diagnostic systems, e.g. DSM-III, DSM-III-R, DSM-IV, and ICD- 10. All data of the patients were included regardless of age, gender, nationality, comorbidity, and hospitalization status. No language or publication restriction was applied. Outcomes Two primary outcomes were subjects who relapsed (including heavy drinking) and those who returned to drinking. We assigned these outcomes as being primarily beneficial because they are of concern for most researchers, clinicians, and patients. In addition, as dichotomous data, they can be interpreted and understood easily. Secondary outcomes were time to first drink, drinking days (in % or number), number of standard drinks for a defined period (e.g. week, study duration, and drinking day), and craving. As alcoholism is a chronic disease with a high relapse rate, all outcomes were reported for the short- (up to and including 12 wk), medium- (more than 12 wk and up to and including 12 months) and long-term (more than 12 months). For any outcome assessed more than once in a particular term, we extracted results of the longest duration only. The analysis also included short-term adverse effects and discontinuation of treatment because of their importance in this treatment period. The five new-onset adverse clinical events most frequently found in the largest comparison, but not in a randomized trial of naltrexone, were examined (Croop et al., 1997). They comprised nausea, headache, dizziness, fatigue, and nervousness. Locating trials To look into the comparative trials, we used four electronic databases (MEDLINE, EMBASE, CINHAL, and the Cochrane Central Register of Controlled Trails) in September The terms used to identify articles were [naltrexone or narcotic antagonist or opioid antagonist] and [alcohol or ethanol]. To identify further reports, we checked the references of this preliminary list of selected studies along with references of other relevant review papers. Du Pont Pharmaceutical, the only producer of naltrexone, was contacted for information about unpublished trials. Of all papers found, only RCTs comparing naltrexone with placebo and/or other treatment in people with alcohol dependence or abuse were included. Quality assessment of included trials and data extraction We assessed the methodological quality of each trial included by examining its randomization (Schulz et al., 1995). Trial characteristics and the data relevant to the reviewed outcomes were extracted and recorded in a data record form. If the data in each study were relevant to two primary, four secondary, five adverse, or dropout outcomes presented in figures, they would be extracted. Because treatment or the controlled group of some studies was divided into a number of subgroups (mostly due to the difference of concomitant treatment), a continuous outcome of these subgroups could not be combined as an outcome of the whole group. In this case, the outcome of the subgroup receiving the most rigorous treatment, e.g. highest dose of drug treatment and most intensive psychotherapy, was used to represent the group. Statistical analysis A relative risk (RR) with 95% confidence interval (CI) was an effect measure used for dichotomous outcomes. A number-needed-to-treatment (NNT) and number-needed-to-harm (NNH) were also computed for outcomes, with a significantly different benefit and more adverse effects respectively. A weighted mean difference (WMD) with 95% CI was used to synthesize the outcomes of time to first drink and drinking days. The outcomes relevant to standard drinks and craving were likely to be measured by various units (e.g. standard drinks per week, per month, or per drinking day) or scales (e.g. a

3 Naltrexone for alcoholism 3 visual analogue scale or specially designed rating scales for craving) and, therefore, combined by using standardized mean differences (SMDs) with 95% CIs. The data synthesis was done on an intention-totreat basis. Because the results obtained from a random effect model of data synthesis might be more generalized, this model was used throughout the review for calculating RRs, WMDs, and SMDs (DerSimonian and Laird, 1986). The inconsistency of data was examined by looking at the graphical display of the results and also by using an I-square (I 2 ) (Higgins et al., 2003). As recommended, an I 2 of 75% or more indicates high inconsistency of data. To test the robustness of the results, relative to features of the primary studies (those carried out only in individuals with alcoholism), a sensitivity analysis was performed to examine the results including and excluding the studies conducted in alcohol-dependent patients with comorbidity. The statistical analysis was performed by the use of Review Manager 4.2 (Cochrane Collaboration, Oxford, England). Results Study inclusion and characteristics Our searches found 28 RCTs of naltrexone in people with alcohol dependence or abuse. We excluded four studies not using the double-blindness design (Lee et al., 2001; Rubio et al., 2001, 2002) and a clearly defined diagnostic system (Huang et al., 2002). Twenty-four papers were identified as original articles presenting main findings of 24 RCTs (see Table 1). Eight papers were classified as duplicated reports presenting only additional data or representing the data (Anton et al., 2001; Jaffe et al., 1996; Modesto- Lowe et al., 1997; O Malley et al., 1996a,b; Oslin et al., 1997a; Rohsenow et al., 2000; Volpicelli et al., 1995) of six original papers (Anton et al., 1999; Hersh et al., 1998; Monti et al., 2001; O Malley et al., 1992; Oslin et al., 1997b; Volpicelli et al., 1992). Although some data presented in duplicated papers were also included in this review, the following parts referenced only the original articles to cause less confusion. It was noted that a nested sequence of three trials presented in a paper was considered as a trial, since the subjects in all three trials were the same (O Malley et al., 2003). In this study, the investigators started by conducting a 10-wk RCT comparison of naltrexone+primary care management (PCM) and naltrexone+cognitive behavioural therapy (CBT) and placebo, followed by two 24-wk RCTs in those responding to first trial treatment. The total number of subjects included in this review was Of those, 1709 were assigned to receive naltrexone treatment. All trials diagnosed the subjects by using DSM-III-R or DSM-IV. Apart from 82 patients with dual alcohol and cocaine dependence or abuse in two trials (Carroll et al., 1993; Hersh et al., 1998) and six individuals with alcohol abuse in a study (Chick et al., 2000), all other subjects were alcohol-dependent patients. All were aged 18 yr or more. The sample sizes of most trials were between in each arm. While one study had only nine subjects in each arm (Carroll et al., 1993), two trials had subjects in each arm (Guardia et al., 2002; Krystal et al., 2001). Only a few studies stated clearly the locations or countries in which the studies were carried out. According to the investigators affiliations, it was understood that 14 studies were conducted in North American (including Puerto Rico), seven in Europe, one in Asia, and two in Australia. Of 24 RCTs, only five provided the details of techniques used for randomization (Balldin et al., 2003; Kiefer et al., 2003; Latt et al., 2002; O Malley et al., 2003; Volpicelli et al., 1997). With regard to study duration, only eight trials were carried out for longer than 12 wk (Anton et al., 1999; Balldin et al., 2003; Heinala et al., 2001; Knox and Donovan, 1999; Landabaso et al., 1999; Monti et al., 2001; O Malley et al., 1992, 2003). Of the 24 RCTs included in this review, only two did not have a placebo arm (Carroll et al., 1993; Landabaso et al., 1999). Apart from three trials (Galarza et al., 1997; Landabaso et al., 1999; Oslin et al., 1997b), naltrexone in all studies was administered daily at a dose of 50 mg/d. It was noted that one trial gave naltrexone continuously in the first 3 months and as targeted medication (only when alcohol consumption was likely) in the last 3 months (Heinala et al., 2001). All trials clearly defined the psychosocial treatment concomitantly given with naltrexone. While a trial gave a simple psychosocial treatment called medical advice (Latt et al., 2002), each of the remainder gave at least one form of intensive psychosocial treatment, e.g. coping skills and CBT. Regarding the outcome measures, those related to drinking behaviour were reported in figures in most trials. Seven (Ahmadi and Ahmadi, 2002; Chick et al., 2000; Kiefer et al., 2003; Kranzler et al., 2000; Monti et al., 2001; Morris et al., 2001; O Malley et al., 1992) and three trials (Hersh et al., 1998; Kiefer et al., 2003; Morris et al., 2001) presented the outcomes of subjects with relapses and return to drinking in graphs and p values respectively. Therefore, these data could not be included in the analysis. Functional outcomes were presented in only one trial (Knox and Donovan, 1999). No trial reported the outcome of patient satisfaction,

4 4 M. Srisurapanont and N. Jarusuraisin Table 1. Characteristics of RCTs comparing naltrexone with placebo or other treatment in people with alcoholism Authors Methods Subjects Interventions O Malley et al. (1992) Volpicelli et al. (1992) Carroll et al. (1993) Galarza et al. (1997) Oslin et al. (1997b) Volpicelli et al. (1997) Hersh et al. (1998) Anton et al. (1999) Knox and Donovan (1999) Landabaso et al. (1999) Chick et al. (2000) 12-wk study with 6-month follow-up after the completion of 12-wk treatment in the USA 12-wk study in the USA Double-blind, 12-wk study in the USA 4-wk study in Puerto Rico 12-wk study in the USA 12-wk study in the USA 8-wk study in the USA 12-wk study with a 14-wk follow-up after the completion of 12 wk treatment in the USA 6-month study in the USA Double-blind, 24-month study in Spain multicentre, 12-wk study in the UK dependence (DSM-III-R), yr old dependence (DSM-III-R); yr old Outpatients with dual alcohol and cocaine dependence or abuse (DSM-III-R), no age specified dependence (DSM-IV); yr old; male only Patients with alcohol dependence (DSM-III-R); yr old dependence (DSM-III-R); yr old Patients with dual alcohol and cocaine dependence or abuse (DSM-III-R); yr old dependence (DSM-III-R); yr old Patients with alcohol dependence (DSM-IV); yr old Patients with alcohol dependence (DSM-IV); mean age=30.6 yr old dependence or abuse (DSM-III- R); yr old 50 mg/d naltrexone+coping skills (n=29) vs. 50 mg/d naltrexone+supportive therapy (n=23) vs. placebo+coping skills (n=25) vs. placebo+ supportive therapy (n=27); no intervention given during follow-up period 50 mg/d naltrexone (n=35) vs. placebo (n=35); all received rehabilitation treatment 50 mg/d naltrexone (n=9) vs. disulfiram (n=9); all received weekly individual psychotherapy Naltrexone (undefined dose) (n=10) vs. placebo (n=10); all received regular psychosocial treatment 100 mg/d naltrexone on Monday/Wednesday and 150 mg naltrexone on Friday (n=21) vs. placebo (n=23); all received weekly group therapy and bi-weekly case management 50 mg/d naltrexone (n=48) vs. placebo (n=49); all received individual psychotherapy and counselling 50 mg/d naltrexone (n=31) vs. placebo (n=33); all received individual relapse prevention psychotherapy 50 mg/d naltrexone (n=68) vs. placebo (n=63); all received weekly CBT; no intervention given during follow-up period 50 mg/d naltrexone (n=31) vs. placebo (n=32); all received 21 d in-patient chemical dependency treatment followed by a 6-month outpatient programme 25 mg/d naltrexone+an aversive agent (n=15) vs. an aversive agent alone (n=15); 6-month naltrexone treatment; 12-month aversive therapy 50 mg/d naltrexone (n=90) vs. placebo (n=85); all received the usual psychosocial treatment programme

5 Naltrexone for alcoholism 5 Table 1 (cont.) Authors Methods Subjects Interventions Johnson et al. (2000) Kranzler et al. (2000) Heinala et al. (2001) Krystal et al. (2001) Monti et al. (2001) Morris et al. (2001) Ahmadi and Ahmadi (2002) Gastpar et al. (2002) Guardia et al. (2002) Latt et al. (2002) Balldin et al. (2003) 8-wk study in the USA 11-wk study in the USA 12-wk regular treatment study with 20-wk targeted medication treatment in Finland 12-wk study in the USA 12-month study in the USA 12-wk study in Australia 12-wk study in Iran multicentre, 12-wk study in Germany multicentre, 12-wk study in Spain multicentre, 12-wk study in Australia multicentre, 6-month study in Sweden dependence (DSM-IV) with age of alcoholic onset <25 yr old, age yr old Patients with alcohol dependence (DSM-III-R); yr old dependence (DSM-IV); yr old dependence (DSM-IV), >18 yr old dependence (DSM-IV), mean age of 39.2 yr old Outpatients alcohol dependence (DSM-III-R), yr old dependence (DSM-IV), yr old; male only Out- and in-patients with alcohol dependence (DSM-III-R); mean age (SD)=42.7 (9.7) yr dependence (DSM-IV); yr old Patients with alcohol dependence (DSM-IV); yr old dependence (DSM-IV); yr old 50 mg/dnaltrexone+ondansetron 4 mg/kg (n=10) vs. placebo (n=10); all participants received group CBT 50 mg/d naltrexone (n=61) vs mg/d nefazodone (n=59) vs. placebo (n=63); all received coping skill training First 12 wk, 50 mg/d naltrexone (n=63) vs. placebo (n=58) +either cognitive coping skill (n=67) or supportive psychotherapy (n=54); for 20 wk duration, naltrexone (undefined dose) given only when alcohol drinking was likely (targeted medication) 50 mg/d naltrexone for 12 months (n=209) vs. 50 mg/d naltrexone for 3 months followed by a placebo for 9 months (n=209); all received 12-step facilitation counselling 50 mg/d naltrexone (n=64) vs. placebo (n=64) for 12 wk; all received 1 2 wk of CET+CST or ERC 50 mg/d naltrexone (n=55) vs. placebo (n=56); all received group psychoeducation and social support 50 mg/d naltrexone (n=58) vs. placebo (n=58); all received individual counselling and relapse prevention programme 50 mg/d naltrexone (n=87) vs. placebo (n=84); all received psychosocial alcoholic treatment programme 50 mg/d naltrexone (n=101) vs. placebo (n=101); all received rehabilitation treatment 50 mg/d naltrexone (n=56) vs. placebo (n=51); all received medical advice 50 mg/d naltrexone+cbt (n=25) vs. 50 mg/d naltrexone+supportive therapy (n=31) vs. placebo+cbt (n=30) vs. placebo+supportive therapy (n=32) [continued overleaf

6 6 M. Srisurapanont and N. Jarusuraisin Table 1 (cont.) Authors Methods Subjects Interventions Keifer et al. (2003) O Malley et al. (2003) multicentre, 12-wk study in Germany Open-label, 10-wk study followed by 24-wk, randomized, doubleblind, placebo-controlled study in treatment responders in the USA Patients with alcohol dependence (DSM-IV); yr old dependence (DSM-III-R); yr old 50 mg/d naltrexone (n=40) vs mg/d acamprosate (n=40) vs. naltrexone+acamprosate (n=40) vs. placebo (n=40); all received group CBT First 10 wk, 50 mg/d naltrexone+pcm (n=93) vs. 50 mg/d naltrexone+cbt (n=97); 24 wk follow-up (in treatment responders only), naltrexone+pcm (n=26) vs. placebo+pcm (n=27) and naltrexone+cbt (n=30) vs. placebo+cbt (n=30) CBT, cognitive behavioural therapy; CDP, controlled drinking programme; CET, cue-exposure treatment; CST, communication skills training; ERC, education and relaxation control; PCM, primary care management. Study or subcategory (first-named author) Naltrexone n/n Placebo n/n RR (random) 95% CI Weight % RR (random) 95% CI 01 Number of subjects with relapses Volpicelli (1992) 8/35 Oslin (1997b) 3/23 Volpicelli (1997) 17/48 Anton (1999) 26/68 Gastpar (2002) 34/84 Guardia (2002) 8/101 Latt (2002) 19/56 Subtotal (95% CI) Total events: 115 (naltrexone), 173 (placebo) Test for heterogeneity: χ 2 = 8.86, df = 6 (p = 0.18), I 2 = 32.3% Test for overall effect: Z = 3.65 (p = ) 19/35 8/21 26/49 38/63 36/87 19/101 27/ ( ) 0.34 ( ) 0.67 ( ) 0.63 ( ) 0.98 ( ) 0.42 ( ) 0.64 ( ) 0.64 ( ) 02 Number of subjects with return to drinking O'Malley (1992) 30/52 42/52 Volpicelli (1992) 16/35 20/35 Oslin (1997b) 6/21 8/23 Volpicelli (1997) 27/48 32/49 Anton (1999) 36/68 42/63 Chick (2000) 74/90 69/85 Kranzler (2000) 43/61 41/63 Gastpar (2002) 41/84 45/ ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Subtotal (95% CI) Total events: 273 (naltrexone), 299 (placebo) Test for heterogeneity: χ 2 = 8.91, df = 7 (p = 0.26), I 2 = 21.4% Test for overall effect: Z = 1.64 (p = 0.10) ( ) Favours naltrexone Favours placebo Figure 1. Short-term comparisons between naltrexone and placebo in respect of subjects with relapses and those who return to drinking. health-related quality of life, cost, or mortality rates. Apart from three studies (Johnson et al., 2000; Heinala et al., 2001; Monti et al., 2001), all placebo-controlled trials with a short-term study duration reported the dropout rates. Eleven placebo-controlled trials, with a short-term study duration, reported at least one of five interestingly adverse effects (Ahmadi and Ahmadi, 2002; Chick et al., 2000; Gastpar et al., 2002; Guardia et al., 2002; Hersh et al., 1998; Kranzler et al., 2000; Krystal et al., 2001; Latt et al., 2002; Monti et al., 2001; O Malley et al., 1992; Oslin et al., 1997b). Two RCTs were carried out in patients with dual cocaine and alcohol dependence or abuse (Carroll et al., 1993; Hersh et al., 1998). Both of these trials reported only secondary outcomes. However, according to the treatment comparison, only the results of short-term, placebo-controlled RCTs could be combined with others (Hersh et al., 1998). We, therefore,

7 Naltrexone for alcoholism 7 performed sensitivity analyses of the short-term outcomes that compared naltrexone with placebo with regard to time to first drink, drinking days, standard drinks, headache, dizziness, fatigue, and discontinuation of treatment. It was found that the inclusion or exclusion of the outcomes obtained from Hersh s study were not much different in respect of data inconsistency or significant/non-significant differences of outcome measures. The data of that study were, therefore, included in the following presentation. Naltrexone vs. placebo Figure 1 shows short-term comparisons between naltrexone and placebo in respect of subjects who relapsed and those who returned to drinking. In the first 12 wk of treatment, naltrexone significantly diminished the risk of relapse (RR 0.64, 95% CI ), but not the risk of return to drinking (RR 0.91, 95% CI ). No significant difference between groups and no significant heterogeneity of data were found in any secondary outcomes of short-term treatment (see Table 2). Of five adverse effects of interest, only nausea, dizziness, and fatigue were significantly more frequent in the naltrexone-treated group, with RRs (95% CIs) of 2.14 ( ), 2.09 ( ), and 1.35 ( ) respectively (see Figure 2). Figure 3 shows short-term comparisons between naltrexone and placebo regarding discontinuation of treatment. Discontinuation of treatment rates were not significantly different between groups (RR 0.85, 95% CI ). For medium-term treatment, no significant difference between groups was found in respect of relapse. Two secondary outcomes were significantly different, in which naltrexone was superior in increased time (days) to first drink and decreased craving (see Table 2). Naltrexone ( other treatment) vs. placebo/other treatment (see Table 2) Naltrexone+ondansetron vs. placebo Only a secondary outcome of standard drinks was available, with a significant preference towards naltrexone+ondansetron treatment. Naltrexone vs. acamprosate vs. naltrexone+acamprosate vs. placebo Only a short-term, placebo-controlled trial was carried out to compare naltrexone vs. acamprosate vs. naltrexone+acamprosate (Kiefer et al., 2003). Because the study findings were presented only in graphs, no RR, WMD, or SMD could be computed. Naltrexone vs. nefazodone No significant difference between groups was found in respect of return to drinking, time to first drink, drinking days, standard drinks, and craving. Naltrexone vs. intensive psychosocial treatment alone Because disulfiram mainly works through its behavioural but not pharmadynamic effects, we classified disulfiram administration as an intensive psychosocial treatment. In this small-sample-size study (n=9 in each arm), naltrexone was significantly inferior to disulfiram regarding time to first drink and drinking days. Naltrexone+intensive psychosocial treatment vs. intensive psychosocial treatment alone Because most trials applied a form of intensive psychosocial treatment and we have already included those study findings in the section under naltrexone vs. placebo, only the data comparison between naltrexone+intensive psychosocial treatment vs. intensive psychosocial treatment alone (without a placebo) is included in this section. Only medium- and long-term comparisons were reported in one trial (Landabaso et al., 1999). The intensive psychosocial treatment used in that trial was an aversive agent (not specified). Medium- and longterm adjuncts of naltrexone significantly decreased the risks of relapse and return to drinking. Naltrexone+intensive psychosocial treatment vs. naltrexone+simple psychosocial treatment Both short- and medium-term outcomes were available in three placebo-controlled trials (Balldin et al., 2003; O Malley et al., 1992, 2003). While the intensive psychosocial treatment was CBT, the simple psychosocial treatment was supportive psychotherapy (Balldin et al., 2003; O Malley et al., 1992) and PCM (O Malley et al., 2003). A short-term adjunct of intensive psychotherapy was not superior in any respect of primary or secondary outcomes. For a medium-term adjunct of intensive psychosocial treatment, no superiority was found on the risks of relapse and return to drinking. However, the intensive psychosocial adjunct significantly increased time (days) to first drink and decreased craving.

8 8 M. Srisurapanont and N. Jarusuraisin Table 2. Effects of naltrexone treatment, apart from short-term, primary outcome comparisons with placebo Outcome comparison (studies) Total number of patients Test for heterogeneity Mean effect size (95% CI) Naltrexone vs. placebo (short-term secondary outcomes only) Time to first drink (Anton et al., 1999; 511 I 2 =0 % WMD x0.06 (x1.04 to 0.93) Guardia et al., 2002; Hersh et al., 1998; Kranzler et al., 2000) Drinking days (Hersh et al., 1998; 489 I 2 =61.5% WMD x1.96 (x5.47 to 1.56) Kranzler et al., 2000; Latt et al., 2002; O Malley et al., 1992; Volpicelli et al., 1997) Standard drinks (Anton et al., 1999; 772 I 2 =65.3% SMD x0.21 (x0.46 to 0.04) Chick et al., 2000; Guardia et al., 2002; Hersh et al., 1998; Kranzler et al., 2000; O Malley et al., 1992) Craving (Anton et al., 1999; Kranzler et al., 2000; O Malley et al., 1992; Volpicelli et al., 1997) 400 I 2 =34.1% SMD x0.10 (x0.35, 0.15) Naltrexone vs. placebo (medium-term) Relapses (Balldin et al., 2003) 118 na RR 1.01 (0.92 to 1.11) Time to first drink (Balldin et al., 2003) 55 na WMD (29.83 to 40.17)* Drinking days (Balldin et al., 2003; 440 I 2 =58.3% WMD x6.92 (x18.09 to 4.25) Krystal et al., 2001) Standard drinks (Krystal et al., 2001) 385 na SMD 0.03 (x0.17 to 0.23) Craving (Balldin et al., 2003) 55 na SMD x0.88 (x1.44 to x0.33)* Naltrexone+ondansetron vs. placebo (short-term) (Johnson et al., 2000) Standard drinks 20 na SMD x4.19 (x5.88 to x2.50)* Naltrexone vs. nefazodone (short-term) (Kranzler et al., 2000) Return to drinking 120 na RR 1.04 (0.82 to 1.32) Time to first drink 120 na WMD 0.70 (x0.96 to 2.36) Drinking days 120 na WMD 4.40 (x4.95 to 13.75) Standard drinks 120 na SMD 0.09 (x0.27 to 0.45) Craving 120 na SMD 0.28 (x0.08 to 0.64) Naltrexone vs. intensive PST alone (short-term) (Carroll et al., 1993) Time to first drink 18 na WMD x5.60 (x7.94 to x3.26)* Drinking days 18 na WMD (22.18 to 22.42)* Standard drinks 18 na SMD 0.90 (x0.08 to 1.88) Naltrexone+intensive PST vs. intensive PST alone (medium-term) (Landabaso et al., 1999) Relapses 30 na RR 0.33 (0.14 to 0.80)* Return to drinking 30 na RR 0.33 (0.14 to 0.80)* Naltrexone+intensive PST vs. intensive PST alone (long-term) (Landabaso et al., 1999) Relapses 30 na RR 0.60 (0.40 to 0.91)* Return to drinking 30 na RR 0.60 (0.40 to 0.91)* Naltrexone+intensive PST vs. naltrexone+simple PST (short-term) Relapses (O Malley et al., 2003) 190 na RR 0.87 (0.61 to 1.22) Return to drinking (O Malley et al., 242 I 2 =85.4% RR 1.19 (0.54 to 2.61) 1992, 2003) Drinking days (O Malley et al., 1992) 47 na WMD x0.10 (x5.87 to 5.67) Standard drinks (O Malley et al., 1992, 237 I 2 =0 % SMD 0.2 (x0.23 to 0.28) 2003) Craving (O Malley et al., 1992, 2003) 137 I 2 =0 % SMD x0.09 (x0.35 to 0.16)

9 Naltrexone for alcoholism 9 Table 2 (cont.) Outcome comparison (studies) Total number of patients Test for heterogeneity Mean effect size (95% CI) Naltrexone+intensive PST vs. naltrexone+simple PST (medium-term) Relapses (Balldin et al., 2003; O Malley 96 I 2 =76.6% RR 0.81 (0.44 to 1.47) et al., 1992) Return to drinking (O Malley et al., 40 na RR 0.97 (0.69 to 1.35) 1992) Time to first drink (Balldin et al., 2003) 56 na WMD (31.69 to 42.31)* Drinking days (Balldin et al., 2003) 56 na WMD x12.00 (x25.37 to 1.37) Craving (Balldin et al., 2003) 56 na SMD x0.61 (x1.15 to x0.07)* Naltrexone+CBT vs. placebo+cbt in naltrexone+cbt responders (medium-term) (O Malley et al., 2003) Return to drinking 60 na RR 0.76 (0.46 to 1.28) Standard drinks 60 na SMD 0.19 (x0.32, 0.69) Craving 60 na SMD 0.20 (x0.30 to 0.71) Naltrexone+PCM vs. placebo+pcm in naltrexone+pcm responders (medium-term) (O Malley et al., 2003) Return to drinking 53 na RR 0.80 (0.58 to 1.12) Standard drinks 53 na SMD x0.21 (x0.75, 0.33) Craving 53 na SMD 0.02 (x0.52 to 0.56) CI, confidence interval; CBT, cognitive behavioural therapy; PCM, primary care management; PST, psychosocial treatment; RR, relative risk; SMD, standardized mean difference; WMD, weighted mean difference; na, not applicable. * Indicates significance difference. Naltrexone+psychosocial treatment vs. placebo+psychosocial treatment (in short-term treatment responders) In one trial, a 24-wk follow-up study was extended to examine the effects of discontinued naltrexone administration in those patients responding to 10-wk treatment (O Malley et al., 2003). The intervention comparisons in this extension period were: (i) naltrexone+cbt vs. placebo+cbt and (ii) naltrexone +PCM vs. placebo+pcm. No difference between groups was found in the return to drinking, standard drinks, and craving. Discussion In comparison to recent meta-analyses (Carmen et al., 2004; Kranzler and Kirk, 2001; Streeton and Whelan, 2001), this review included a larger number of subjects and studies. In addition, it comprises only studies with high methodological quality by including those using a double-blindness design and clearly defined diagnostic systems. The review findings support a number of conclusions. First, according to its RR of 0.64 (in comparison to placebo), short-term treatment of naltrexone for alcoholism decreases the risk of alcohol relapse by 36% (NNT=7). However, this review cannot find its short-term efficacy in preventing return to drinking. In addition, only the benefits on time to first drink and craving, but not alcoholic relapse and return to drinking, can be seen after the patients receive more than 12 wk naltrexone treatment. Second, alcoholdependent patients treated with naltrexone have 114% (NNH=8), 109% (NNH=12), and 35% (NNH=17) greater risk of nausea, dizziness, and fatigue respectively. Third, naltrexone cannot lower the risk of discontinued treatment in alcohol-dependent patients. In addition, approx. 36% (302/841) of those taking naltrexone may discontinue their treatment in the first 12 wk. Last, regarding psychosocial treatment adjunct to naltrexone; although intensive psychosocial treatment (e.g. CBT) may not show a short-term advantage over simple psychosocial treatment, its superiority in increasing time to first drink and decreasing craving may be seen after 12 wk of therapy. Some positive findings found only in studies with a small sample size should be viewed with caution, and they need further investigation. Those include the efficacy of naltrexone in dual diagnosis of alcoholism and cocaine dependence or abuse (Hersh et al., 1998), the superiority of naltrexone plus an aversive agent to an aversive agent alone (Landabaso et al., 1999), the equi-efficacy of naltrexone and nefazodone (Kranzler et al., 2000), the equi-efficacy of naltrexone and acamprosate (Kiefer et al., 2003), the efficacy of naltrexone

10 10 M. Srisurapanont and N. Jarusuraisin Study or subcategory (first-named author) Naltrexone n/n Placebo n/n RR (random) 95% CI Weight % RR (random) 95% CI 01 Nausea O'Malley (1992) 17/52 7/52 Oslin (1997b) 3/21 4/23 Chick (2000) 27/90 13/85 Kranzler (2000) 20/61 9/63 Monti (2001) 14/64 5/64 Morris (2001) 19/55 10/56 Ahmadi (2002) 20/58 9/58 Gastpar (2002) 6/84 1/87 Subtotal (95% CI) Total events: 126 (naltrexone), 58 (placebo) Test for heterogeneity: χ 2 = 3.49, df = 7 (p = 0.84), I 2 = 0% Test for overall effect: Z = 5.28 (p < ) ( ) 0.82 ( ) 1.96 ( ) 2.30 ( ) 2.80 ( ) 1.93 ( ) 2.22 ( ) 6.21 ( ) 2.14 ( ) 02 Headache Oslin (1997b) Hersh (1998) Chick (2000) Kranzler (2000) Morris (2001) Ahmadi (2002) Gastpar (2002) Guardia (2002) Latt (2002) 6/21 9/31 37/90 28/61 17/55 14/ 58 9/84 8/55 6/23 15/33 40/85 29/63 16/56 6/58 9/87 8/101 1/101 16/ ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Subtotal (95% CI) Total events: 136 (naltrexone), 138 (placebo) Test for heterogeneity: χ 2 = 13.89, df = 8 (p = 0.08), I 2 = 42.4% Test for overall effect: Z = 0.23 (p = 0.82) ( ) 03 Dizziness O'Malley (1992) 18/52 8/52 Hersh (1998) 10/31 5/33 Chick (2000) 10/90 11/85 Kranzler (2000) 16/61 8/63 Morris (2001) 6/55 0/56 Ahmadi (2002) 7/58 1/58 Gastpar (2002) 8/84 2/87 Subtotal (95% CI) Total events: 75 (naltrexone), 35 (placebo) Test for heterogeneity: χ 2 = 8.55, df = 6 (p = 0.20), I 2 = 29.8% Test for overall effect: Z = 2.97 (p = 0.003) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 04 Fatigue Oslin (1997b) Hersh (1998) Chick (2000) Kranzler (2000) Morris (2001) Ahmadi (2002) Gastpar (2002) 6/21 11/31 10/90 36/61 15/55 7/84 6/21 6/33 9/85 33/63 8/56 13/58 5/58 3/ ( ) ( ) ( ) ( ) ( ) ( ) ( ) Subtotal (95% CI) Total events: 98 (naltrexone), 70 (placebo) Test for heterogeneity: χ 2 = 6.32, df = 6 (p = 0.39), I 2 = 5.1% Test for overall effect: Z = 2.24 (p = 0.03) ( ) 05 Anxiety/Nervousness Chick (2000) Morris (2001) Ahmadi (2002) 12/90 7/85 11/55 11/56 14/58 10/ ( ) ( ) ( ) Subtotal (95% CI) Total events: 37 (naltrexone), 28 (placebo) Test for heterogeneity: χ 2 = 0.69, df = 2 (p = 0.71), I 2 = 0% Test for overall effect: Z = 1.13 (p = 0.26) ( ) Favours naltrexone Favours placebo Figure 2. Short-term comparisons between naltrexone and placebo in respect of subjects with adverse effects. +ondansetron for early-onset alcoholism (Johnson et al., 2000), and the superiority of disulfiram when compared to naltrexone (Carroll et al., 1993). The available evidence is limited in many respects. First, many trials had a relatively short study duration. Of 24 RCTs available, only eight of them had a study duration of longer than 12 wk. Second, most studies had a small sample size. For a power of 80% and a significant criterion of 0.05, a two-arm study needs at least 87 subjects in each arm to detect the degree of medium-effect size of treatment in a dichotomous outcome (Cohen, 1992). Of all RCTs, only three had at least 87 subjects in each arm (Guardia et al., 2002; Krystal et al., 2001, O Malley et al., 2003). Third, there has been too little evidence to suggest that the widely used medications for alcoholism, naltrexone or acamprosate, are in anyway superior to any other one. Although a 12-month RCT found naltrexone superiority in some outcomes (e.g. decreasing the risk of alcohol relapse), due to its single-blind study design, these results should be viewed with caution (Rubio et al., 2001). Due to the small sample size (n=40 in

11 Naltrexone for alcoholism 11 Study or subcategory (first-named author) Treatment n/n Control n/n RR (random) 95% CI Weight % RR (random) 95% CI O'Malley (1992) Volpicelli (1992) Galarza (1997) Oslin (1997b) Volpicelli (1997) Hersh (1998) Anton (1999) Knox (1999) Chick (2000) Kranzler (2000) Morris (2001) Ahmadi (2002) Gastpar (2002) Guardia (2002) Latt (2002) Kiefer (2003) 15/52 11/35 5/10 7/21 13/48 11/31 9/68 15/31 53/90 25/61 17/55 12/58 28/84 40/101 23/56 21/52 14/35 4/10 10/23 13/49 14/33 14/63 18/32 49/84 13/63 23/56 33/58 33/87 42/101 17/51 18/40 30/ ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Total (95% CI) Total events: 302 (treatment), 348 (control) Test for heterogeneity: χ 2 = 27.50, df = 15 (p = 0.02), I 2 = 45.5% Test for overall effect: Z = 1.81 (p = 0.07) Favours naltrexone Favours placebo Figure 3. Short-term dropouts between naltrexone and placebo groups ( ) each arm), a type II error could not be ruled out in a double-blind RCT that found the equi-efficacy of naltrexone and acamprosate (Kiefer et al., 2003). Fourth, psychosocial benefits of naltrexone treatment are rarely measured. Apart from a trial that minimally explores functioning (Knox and Donovan, 1999), no study examines the satisfaction of the patient, healthrelated quality of life, cost, and mortality. Last, the problem of a high dropout rate is common in most studies, e.g. an overall short-term dropout rate of 36% in naltrexone-treated patients (Figure 3). Whatever the reason for that study attrition, a high dropout rate affects the validity of the results. Some experts take the view that high dropout rates are a minor flaw of RCTs and cannot be completely corrected by the use of an intention-to-treat analysis (Hardon et al., 1996; Peduzzi et al., 2002). A major limitation of this review is the inability to synthesize data presented only in graphs or p values with those being presented in figures. With concern that these data may have an impact on the main conclusion that naltrexone is efficacious for preventing alcohol relapse, we qualitatively examined the trial results relevant to short-term primary outcomes. While four trials reported that naltrexone was significantly superior to placebo in decreasing relapse (Ahmadi and Ahmadi, 2002; Kiefer et al., 2003; Morris et al., 2001; O Malley et al., 1992), three RCTs did not find a difference (Chick et al., 2000, Kranzler et al., 2000; Monti et al., 2001). According to these results, the data in these studies should not be able to reverse the main conclusion of this review. A minor limitation of the review appears to be the inconclusive definitions and measurements used for assessing alcoholic treatment outcomes, e.g. the definitions of alcoholic relapse or heavy drinking. The review findings could implicate the treatment of alcoholism in some respects. First, naltrexone at the dose of 50 mg/d should be accepted as a short-term treatment for alcoholism. However, as yet, we do not know the appropriate duration of treatment continuation in an alcohol-dependent patient who responds to short-term naltrexone administration. Second, because psychosocial treatment was given in almost all trials included, to ensure that the real-world treatment would be as effective as the research findings, a form of psychosocial treatment should be concomitantly given to all alcohol-dependent patients receiving naltrexone administration. Although the adjunct of intensive psychosocial treatment, e.g. CBT, may not be superior to that of simple psychosocial treatment, its advantages in increasing time to first drink and decreasing craving may be seen after 12 wk of therapy. Last, naltrexone administration cannot lower the risk of discontinued treatment in alcohol-dependent patients. Approximately 36% of those taking naltrexone still discontinue their treatment in the first 12 wk. A naltrexone-treatment programme should, therefore, include strategies to improve treatment adherence, e.g. concomitant psychosocial treatment. In addition, management of the common adverse effects of naltrexone should be given, e.g. informing about naltrexone-induced nausea, dizziness, and fatigue. Acknowledgements This review was conducted within the framework of the Cochrane Collaboration Drugs and Alcohol Group (CCDAG). We thank the editors and staff of the CCDAG for their database searches and helpful comments on previous versions of this review. Previous

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