Single Dose Studies

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3.3.1. Studies with 3-mo Active Treatment Period

Four studies covering treatment periods of 3 mo were performed between 1982 and 1992. Three reported significantly better outcomes on acamprosate than on placebo.

This was the first double-blind, placebo-controlled study using acamprosate with alcohol-depend-net patients. Eight-five patients were tested on a dosage of 25 mg acamprosate per kg body weight, but not less than 1500 mg nor more than 2500 mg per day. Psychosocial supportive treatment was permitted. Of the 70 patients who completed the study, 61% of those on acamprosate maintained abstinence and had normalization of GGT and mean corpuscular volume (MCV) versus 32% on placebo (p = 0.02). The success of this study stimulated the subsequent extensive development program with the drug.

This study in 569 patients from 31 centers in France had as a primary outcome criterion normalization of GGT in alcohol-dependent patients. All patients received 1332 mg acamprosate or matching placebo. Psychosocial supportive treatment was permitted and patients were followed for 3 mo without treatment and after medication was ceased. At the end of the active treatment period, GGT levels in patients treated with acamprosate were significantly lower than those of patients on placebo (p < 0.016). In addition, tongue trembling significantly improved in more patients on acamprosate than on placebo. Data on drinking behavior were not reported. The authors noted that patients of lower body weight experienced more favorable outcome on acamprosate. This was viewed as evidence of a possible dose-related effect with the study drug. The results were considered to be compelling significant confirmation of efficacy, and authorization was granted to market the drug in France in 1989.

This single-center study included 127 patients—45 alcohol abusing and 82 alcohol dependent— distributed equally between treatment groups, with 90 patients completing the 3-mo treatment period. Outcome criteria included absolute abstinence and objective markers such as GGT and red cell MCV, but not duration of abstinence. The study medication was dose-adjusted according to the following regimen: Patients below 60 kg body weight received 1332 mg acamprosate daily and those above 60 kg received 1998 mg acamprosate daily or matching placebo. At the end of the study, 21 patients on placebo and 18 on acamprosate were abstinent and improvements in GGT and MCV were comparable in both treatment groups. The study therefore failed to demonstrate any therapeutic advantage of acamprosate.

This dose ranging study comparing outcomes among 1998 mg and 1332 mg acamprosate and matching placebo confirmed the efficacy of acamprosate and is discussed in detail in the above section on dose ranging studies.

3.3.2. Studies with 6 mo Active Treatment Period

Between 1988 and 2000, nine of the placebo-controlled studies performed with acamprosate tested the drug over a 6-mo active treatment period. The European studies were conducted in eight different countries, whereas the other study was conducted in the United States Despite some differences in methodology, primary outcome criteria were reasonably consistent across projects and evaluated the time to first drink, proportion of patients relapsing, abstinence period throughout the study period, and CAD. European study protocols permitted a liberal approach for concomitant psychosocial intervention, allowing institutional practices of the different participating centres, whereas the study in the United States used a manual-driven psychosocial intervention for all patients. Eight studies had follow-up periods (varying between 1.5 and 6 mo) after termination of active study medication.

Five of the eight European studies reported significantly better outcome in the main criteria of efficacy in favor of acamprosate.

This study reported on outcome of 102 alcohol-dependent patients from 5 treatment centers. As in the Rousseaux study (12), the daily dose of acamprosate was adjusted as follows: Patients below 60 kg body weight received 1332 mg acamprosate, whereas those above 60 kg received 1998 mg acamprosate. Attrition rates were high, with 79% of patients on placebo and 56% of those on acamprosate dropping out before the end of the 6-mo period. Patients on acamprosate demonstrated significantly longer CAD (60 vs 40 d) and a higher rate of complete abstinence (24% vs 4%). Measures of clinical global impression, depression, anxiety, craving, and psychological and physiological dependence did not reveal differences between treatment groups.

3.3.2.2. Ladewig et al. (Switzerland 1989-1991) (14,15)

During 1989, four acamprosate studies with treatment periods of 6 mo (and five studies with treatment periods of 12 mo—see below) were started in different European countries. The study by Ladewig et al. (14) in Switzerland was the smallest of these and reported results in 61 alcohol-dependent patients from 3 centers. As in the 1987 Rousseaux (12) and the 1988 Pelc (9) studies, the study medication was dose-adjusted according to body weight below or above 60 kg for 1332 mg or 1998 mg acamprosate, respectively. The 6-mo treatment period was followed by a 6-mo drug-free follow-up period. Patients on acamprosate had significantly longer CAD (121 vs 78 d). Thirty-eight percent of acamprosate patients and 24% of placebo patients were abstinent at the end of the treatment period. Although the difference in proportions remained during the follow-up period, the statistical difference disappeared.

This study in northern Italy included alcohol-dependent patients who participated in a postwithdrawal community-based alcohol-treatment program. Acamprosate dose were adjusted according to body weight and use of concomitant disulfiram was allowed. Two hundred forty-six patients were analyzed, including 112 patients completing the 6-mo treatment period and 101 finishing the 6 mo of drug-free follow-up. Patients treated with acamprosate experienced a higher rate of abstinence at the 3-and 6-mo treatment periods, longer CAD at 6 mo (99 vs 70 d) and 12 mo follow-up (168 vs 120 d), and longer time to first relapse (150 vs 61 d). Disulfiram did not appear to influence the outcome.

Three hundred thirty alcohol-dependent patients from 18 centers in southern Italy participated in this study of 6-mo treatment with 3 mo follow-up. After 6 mo of treatment, 25% dropped out. Patients on acamprosate had significantly higher continuous-abstinence rates, longer CADs, and longer periods before the first relapse occurred. Whereas most studies on acamprosate assessed outcome according to measures of abstinence (proportion and duration), this study also reported outcome in terms of alcohol consumption during periods of relapse. Some significant, ableit limited, differences in the quantity and frequency of drinking in those patients who relapsed were reported suggesting that patients on acam-prosate consumed less alcohol during relapse periods. As with most other studies in the acamprosate development program, differences between treatment groups could be not detected for depression and anxiety levels or measurements associated with craving or desire to drink.

3.3.2.5. Geerlings et al. (The Benelux Countries 1990-1992) (18)

Two hundred sixty-two patients from Belgium, the Netherlands, and Luxembourg participated in this study, which was characterized by a 6-mo follow-up period after the 6-mo active treatment phase. The drug dose was adjusted to body weight and, as with all other studies, abruptly terminated at the end of the active study period, (i.e., without any tapering down of dosage). Drug compliance based on pill count was 86%. The study suffered from high attrition rates (64% over the first 6 mo and another 16% over the second 6-mo follow-up period), but, nevertheless, demonstrated significant treatment effects in favor of acamprosate. The therapeutic advantage seemed to have been maintained during the drug-free follow-up period, although the number of subjects at the end of the period were too small to statistically conclude this.

3.3.2.6. Chick et al. (United Kingdom 1990-1993) (5)

This study comprised patients up to 7 wk after an acute withdrawal treatment, a longer period than any of the other studies. Hence, 32% of the 581 patients included in the study had already relapsed after the required withdrawal treatment and before their inclusion into the study. All patients on acamprosate received 1998 mg/d. Sixty-five percent had dropped out after 6 mo and general compliance to drug-taking was considered low by the authors, with 57% of patients taking 90% of the total pills. No therapeutic advantage of acamprosate over placebo to reduce relapse was observed. Interestingly, patients treated with acamprosate had significantly lower craving scores after 2 and 4 wk of treatment and lower levels of anxiety after 4 wk. The authors noted that this study differed from other acam-prosate studies in that patients suffered more social problems, received less psychosocial support, and were more likely to be episodic drinkers. Although none of the patients who relapsed during the washout period attained complete abstinence, no specific responder profile could be identified.

3.3.2.7. Borg et al. (Sweden 1991-1993) (Unpublished Data, Merck/Lipha, France)

This small study of only 14 patients was designed for close daily monitoring of patients during 6 mo of treatment, rather than intended as a comparative study with the objective to demonstrate treatment differences. Over the 6-mo treatment period, alcohol consumption was measured three times per week, serum analyses for alcohol markers conducted weekly, and urine analysis for ethanol and 5-hydroxytryptophol performed daily. Ten patients completed the study. Abstinence varied between 73% and 100% of treatment days, but the sample was too small to detect possible differences between treatment groups.

The 288 patients in this study began daily acamprosate (1998 mg) or matching placebo concomi-tantly with the start of acute withdrawal treatment. This earlier introduction of acamprosate in the treatment regimen was hypothesized to potentially enhance drug efficacy, because plasma steady state for acamprosate takes approximately 5 d to develop. The study confirmed significantly longer CAD and longer periods of abstinence after the last relapse with acamprosate. In addition, the measure of continuous abstinence revealed some trend in favor of acamprosate, although this was not statistically significant. Nonetheless, the study failed to suggest some clinical advantage of starting acamprosate earlier, although this possibility merits a direct study. Finally, no adverse interaction occurred between acamprosate and the early-withdrawal treatment regimens.

3.3.3. Studies with a 12-mo Active Treatment Period

3.3.3.1. Paille et al. (France 1989-1992) (Published 1995) (6)

This dose ranging study was discussed in Section 3.2.1.

Three hundred two alcohol-dependent patients from 14 centers participated in this study of 12 mo treatment and 6 mo follow-up. Study medication was dose adjusted for body weight. Patients on ben-zodiazepines for more than 1 mo prior to the study were permitted to continue this practice during the study, and new prescriptions of concomitant oxazepam and temazepam were allowed for periods not exceeding 2 wk. Thirty percent of patients dropped out during the first 6 mo, 14% during the second 6 mo, and 9% during the last 6 mo. The proportion of abstinent patients, time to first relapse, and CAD were all showed a significant advantage for acamprosate during the active treatment period. During the follow-up period, the difference between the two groups became less marked.

Four hundred forty-eight alcohol-dependent patients from five treatment centers with similar psychosocial treatment programs participated in this study of 12 mo treatment and 12 mo follow up. As with most studies, acamprosate dosage was adjusted for body weight. Sixty percent of patients dropped out during the treatment year (per trimester: 34%, 15%, 6%, and 5%, respectively) and a further 7% dropped out during the follow-up year. Following the "intent to treat" principle, patients who received concomitant neuroleptics (65), antidepressants (34), and benzodiazepines (23) were distributed equally across groups and were maintained in the study despite this protocol violation. The study confirmed the efficacy of acamprosate. Those treated with acamprosate had a greater rate of abstinence, a longer time to first relapse, and a longer CAD than placebo-treated subjects.

3.3.3.4. Besson et al. (Switzerland 1989-1993) (21)

The particular interest of this study lies in the fact that both the acamprosate and placebo treatment groups were stratified into two subgroups: patients who chose to have concomitant open-label disulfi-ram treatment and patients who did not. Patients on disulfiram had daily visits and observed disulfiram administration, suggesting more medical contact than patients not opting for disulfiram. One hundred eighteen patients participated in the study (12 mo treatment, 12 mo follow up), with 67% dropping out the first year and 17% in the second year. No adverse interaction between acamprosate and disulfiram was noted. The study outcome confirmed significantly better results on acamprosate than placebo. Analysis of the strata indicated that acamprosate and disulfiram produced the best outcome, disulfiram or acamprosate the second most positive, and no medication the worst outcome. 3.3.3.5. Sass et al. (Germany 1990-1992) (22)

This intensively documented study of 272 alcohol-dependent patients recruited from 12 centers was considered a pivotal study in the official European application for marketing authorization for acam-prosate. Patients received 12 mo of active treatment and 12 mo follow-up. Counseling and psychotherapy differed among sites but, in general, was rather intensive, consisting of 1 h sessions every week for 18 wk, followed by two weekly group sessions. Fifty-one percent dropped out during the first year and 11% in the second year. Similar outcome criteria for drinking behavior as mentioned in the above studies clearly demonstrated the efficacy of acamprosate. No differential effect on craving, however, could be detected, and extensive psychological assessments did not indicate differences between treatment groups. Interestingly, analysis of complete abstinence demonstrated an advantage for acamprosate-treated patients during the drug-free follow-up year. This may suggest a stabilization of abstinent behavior in the acamprosate patients. Psychological assessments at the end of the double-blind period did not suggest any rebound phenomena after the abrupt termination of study medication. Subsequent analyses of this study data by the authors failed to identify a clear responder profile for acamprosate.

4. OPEN STUDIES

Several open-label studies have been performed for acamprosate. These include the following:

• A 2-wk study in 591 patients to investigate tolerance of coprescription with psychotropic medications (tetra-bamate, meprobamate, and oxazepam) commonly used in France during acute detoxification. No adverse drug interactions were recorded (23).

•Six multicenter studies in six countries to compare the efficacy of acamprosate with different types of psychosocial programmes and determine tolerance to acamprosate. One of these studies was recently published and the data confirmed the good safety profile of acamprosate (6).

• A study with 248 patients in the Netherlands (7) to contrast the outcomes of acamprosate treatment in three groups: one without any psychosocial support, another with minimal intervention, and the last with a brief intervention. No significant differences were found among the groups.

5. SAFETY DATA

Side effects reported with acamprosate are rare and transient. These include minor gastrointestinal effects such as diarrhea in 10% of patients, nausea and abdominal discomfort in fewer than 10% of patients, and minor skin irritations in fewer than 10% of patients. Decreases as well as increases in libido have been observed in a few patients. The only symptom consistently associated with overdose has been diarrhea. No interactions between acamprosate and any other medications (e.g., disul-firam, antidepressants, anxiolytics, neuroleptics, or hypnotics) have been identified so far. Acamprosate is contraindicated in patients with renal insufficiency and those with known hypersen-sitivity against the drug.

6. REVIEW

The global interpretation of the evidence from the double-blind, placebo-controlled studies with acamprosate confirms that acamprosate has a moderate but fairly consistent effect in reducing relapse in alcohol dependence. Most studies reported that acamprosate increased abstinent rates, increased cumulated abstinence periods, and prolonged periods between withdrawal and first relapse. Acam-prosate was also associated with lower patient dropout from treatment. Furthermore, no physical or psychological dependence was observed. Craving or desire to drink was occasionally reported to be less on acamprosate, although more studies are needed. Most studies that measured mood (anxiety and depression) did not report any significant medication effects. None of the analyses published to date has succeeded in identifying a particular responder profile. Data from most studies showed a perceivable drug effect within 1 mo of treatment. However, the minimum required duration of acamprosate treatment has not been clearly established. The more consistent or lasting effects may be achieved when acamprosate is administered for 6-12 mo. All double-blind study projects employed some form of psychosocial support, but no consistent evidence has emerged on any particular requirements of such support during acamprosate treatment. In one open study, results suggested that patients without significant psychosocial support may do as well as those receiving manual-driven minimal or brief interventions. The majority of studies incorporated used regimens of dose adjustment according to body weight. Although official authorization to prescribe the medication in several countries follow this treatment schedule, there seems to be no clear evidence that this is indeed necessary. The documented safety and tolerance profile of acamprosate is exceptionally good. Dose ranging studies indicated better outcome with 1998 mg acamprosate when two tablets are taken three times a day. Although taking six tablets daily may be a practical problem to some patients, high levels of compliance have been recorded in most studies.

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