11.4.1
Context
These medications are most obviously suited to the maintenance and action stages of change, but there is latitude in their use given the low risk when taken with alcohol. Acamprosate and naltrexone are ranked three and six respectively in the Mesa Grande, but these high rankings should be interpreted cautiously as they reflect a high volume of studies finding consistently positive but small effects. There are a number of medications acting upon endogenous neurochemical systems that play some role in mediating the reinforcement potential of
psychoactive substances, the craving for a psychoactive drug effect or the attenuation of the unpleasant
consequences of withdrawal.
A range of medications, including antipsychotics, tricyclic and SSRI antidepressants, dopamine agonists and serotonin antagonists, have been investigated. None of these have evidence for effectiveness in the treatment of alcohol misuse or dependence in the absence of psychiatric co-morbidity (Berglund, Thelander and Jonsson, 2003 p260-268) and will not be considered further.
This section is focused on naltrexone and acamprosate, which are both used as components of relapse
prevention. Many of the trials have been conducted in North America, where an abstinence model dominates, so it is not always straightforward to generalise results to the UK, where these medications may be used with people who are not motivated to aim for abstinence.
11.4.2
Evidence
A meta-analysis (Carmen et al., 2004) included 33 trials but was only able to compare acamprosate and
naltrexone on abstinence. The duration of studies ranged from three to 24 months and all the studies included psychosocial support. Compared to placebo, the odds ratio of acamprosate being associated with abstinence was significant at 1.88, while naltrexone failed to reach significance at 1.26. The data available did not allow the
meta-analysis to test claims that either drug is an anti- craving agent.
One study (Rubio et al., 2001) randomly allocated patients to acamprosate or naltrexone and followed up at 12 months. Participants had good family support and attended an unstructured relapse prevention group. The naltrexone group did significantly better on most outcome measures, including accumulated abstinence, time to relapse and the need for additional medication. There were more side-effects with naltrexone but only half as many dropouts.
In a study combining both drugs (Kiefer et al., 2003), the combination treatment did better than acamprosate but not naltrexone only.
11.4.3
Naltrexone (Nalorex
®)
Naltrexone is an opioid antagonist, which is thought to be effective by blocking endogenous opioid pathways stimulated by alcohol use (Sinclair, 2001). In psychological terms, the positive reinforcement of alcohol use is
diminished; opioid pathways are only one way in which alcohol exerts its reinforcing effects, so the overall theoretical importance of blocking opioid systems is modest. Berg et al. (1996) have published a favourable risk-benefit analysis of naltrexone. Naltrexone is not yet licensed in the UK for alcohol treatment.
Volpicelli et al. (1992) studied 70 alcohol-dependent subjects in a placebo-controlled trial where all subjects received standard rehabilitation treatment. At 12 weeks, 54 per cent of the placebo-treated subjects had relapsed, compared to 23 per cent of naltrexone subjects. This significant group difference occurred, in part, because those subjects in the naltrexone group who took a drink did not continue drinking; in other words, their drinking did not constitute a full-blown relapse.
O’Malley et al. (1992) carried out a similar study with 97 participants comparing coping skills and supportive therapy with adjunctive naltrexone or placebo. The naltrexone-treated subjects drank on significantly fewer days (approximately 50 per cent) and consumed significantly fewer units of alcohol (approximately 25–50 per cent) than the placebo-treated group. Sixty-one percent of subjects receiving naltrexone and supportive therapy achieved three months of continuous abstinence, compared to only 28 per cent in the coping skills group. However, of those subjects who did relapse, those who
had received coping skills therapy did better than those who had supportive therapy.
Combining naltrexone with a psychosocial treatment, Monterosso et al. (2001) achieved a low attrition rate, 18 per cent, and significantly fewer heavy drinking days – five per cent for naltrexone against nine per cent for controls. Sinclair (2001) showed progressive decreases in craving which persisted after finishing medication. However, Chick et al. (2000a) found no difference for naltrexone
compared to standard treatment.
11.4.4
Acamprosate (Campral
®)
The action of acamprosate on neurochemical systems is unclear (Littleton, 1995). It is probably not a simple GABA agonist, which would make it susceptible to the same problems of dependence as benzodiazepines, but more likely it is able to mimic GABA or inhibit the action of stimulant amino acids such as glutamate at the NMDA receptor. Not everyone benefits from acamprosate and most of the trials include a psychosocial intervention. Paille et al. (1995) conducted one of a number of major multicentre trials that demonstrated the efficacy of acamprosate. In a placebo-controlled trial of acamprosate as an adjunct to post-detoxification rehabilitation, subjects received a high dose (2g daily), low dose (1.3g daily) or placebo for 12 months – two-thirds of placebo subjects, but only half of acamprosate subjects dropped out by one year. There was a dose-related increase in time to first drink (153 vs 135 vs 102 days) and total abstinence days (223 vs 198 vs 173) for the three groups.
Whitworth et al. (1996) recruited 455 subjects to a placebo-controlled, multicentre trial. All participating centres used similar psychosocial rehabilitation programmes. At one year 18.3 per cent of the acamprosate-treated subjects and 7.1 per cent of placebo-treated subjects had achieved continuous abstinence from alcohol. Sass et al. (1996), in a similar trial of 272 subjects, achieved a better outcome with 44.8 per cent of acamprosate-treated subjects continuously abstinent for one year against 25.3 per cent of placebo- treated subjects. They also found acamprosate subjects had longer periods (224 vs 163 days) before relapse. Against the trend of benefits from psychosocial components to treatment, De Wildt et al. (2002) found that neither minimal motivational enhancement nor brief cognitive behavioural therapy improved drinking
outcomes as compared to acamprosate alone. Against the trend of acamprosate efficacy, the major UK trial (Chick et al., 2000b) found no difference between active drug and placebo. This was attributed to the delay between detoxification and starting acamprosate. In a meta-analysis of 17 studies that included 4,087
individuals, continuous abstinence rates were significantly higher at six months for the acamprosate patients. The effect sizes at three, six and 12 months were 1.33, 1.50 and 1.95 respectively, giving a 13.3 per cent superiority to acamprosate over placebo (Mann et al., 2004). Similarly, Berglund, Thelander and Jonsson (2003, p268–69) present 16 studies involving 4,158 participants, showing an effect size of 0.26 for their meta-analysis. Chick, Lehart and Landron (2003) reviewed 15 studies and calculated a 50 per cent reduction in drinking for those taking acamprosate compared to placebo. Pelc et al. (1997) have published a favourable risk-benefit report for acamprosate.
11.4.5
Project COMBINE
Project COMBINE (Anton et al., 2006) was designed to evaluate the efficacy of two relapse prevention
medications in various combinations with behavioural treatment. A total of 1,383 recently abstinent individuals with a primary diagnosis of alcohol dependence were recruited and randomised to one of eight treatment conditions where tablets were taken: naltrexone, acamprosate, naltrexone plus acamprosate, or placebo, all with medical management and with or without “combined behavioural intervention”. A ninth group received no tablets and no medical management, only the combined behavioural intervention.
Medical management was usually delivered by nurses or doctors over nine sessions and essentially comprised boosting motivation, encouraging support for abstinence and ensuring adherence to the pharmacotherapy. Combined behavioural intervention was delivered by professionals who had competence in psychosocial treatments. It was an integrated and flexible package of up to 20 sessions, including motivational interviewing, coping skills, 12-Step facilitation and community support. At 12-month follow-up the main outcome measure, percentage of days abstinent, increased from 23–30 per cent to 59–69 per cent. Participants receiving naltrexone fared better than other groups, but overall it is difficult to see clinically significant differences between the nine
interventions. In contrast to most other studies, there was no evidence of benefit from acamprosate. Relapse into heavy drinking days (>2 drinks for women and >5 for men) was somewhat less in all the medication groups, including placebo, but again there were no striking between-group differences. The claim that naltrexone with medical management could be delivered in healthcare settings to people who might otherwise receive no treatment is best seen as one of several options for generic health settings. Cost-effectiveness data is needed to guide any policy based on Project COMBINE findings.
11.4.6
Conclusions
• Both naltrexone and acamprosate show minor
positive effects in relapse prevention when used in conjunction with psychosocial interventions (IA)
• Naltrexone is most clearly indicated to help individuals
who have lapsed or “slipped” and acamprosate is best suited to supporting abstinence among those who fear craving will lead to a lapse (III)
• There is considerable variation in outcomes,
suggesting trial methodologies or treatment delivery are an important influence on outcome (IA)
• There are too few studies to compare naltrexone
against acamprosate.