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The state of pharmacotherapy for the treatment of alcohol dependence

British trials

Without being conclusive either way, in Britain two major studies have provided greater support for naltrexone than for acamprosate. Both studies were plagued by high drop-out rates and poor compliance with treatment, but in the naltrexone study, those patients who did complete the study and largely comply with treatment drank substantially less on naltrexone than on placebo pills. One lesson from both seems to be that among typical British alcohol clinic caseloads, the support available from the staff and/or from families and friends is often insufficient to enable patients to sustain their commitment to treatment.

In conditions typical of NHS alcohol treatment centres, a British study confirmed that taken as directed, naltrexone reduces alcohol consumption. At six centres 175 patients recently abstinent from alcohol, and either receiving or about to receive outpatient treatment, were randomised also to receive 50mg daily of naltrexone for 12 weeks or an identical placebo pill. All but 11 started taking the pills and were included in the analysis. Typically they were men in their late 30s and early 40s and most were not in a stable relationship or in full time work. Before treatment, on average they had been drinking over 16 UK units Just over 10 US drinks each of 13mg. of alcohol a day. Measures taken before treatment and then every two weeks showed that naltrexone did not delay a return to drinking or to heavy drinking, but did (non-significantly) tend to reduce the amount drunk in the last month of the study, a trend partially reflected in biochemical markers of heavy drinking. Patients on naltrexone also experienced significantly less craving for alcohol and by the end of the study nearly two-thirds were judged by their doctors to have improved, about 20% more than in the placebo group. Possible side-effects seen more often in the naltrexone group included nausea and pain, but adverse effects did not result in noticeably more naltrexone patients having to terminate treatment. However, the study excluded patients with serious physical illness, medicated psychiatric conditions, or who also abused other drugs.

These results assumed that the nearly 60% of patients who were lost to the study had resumed heavy drinking. When the analysis was confined to the 70 patients who completed the study and had largely complied with the treatment, there was still no evidence that naltrexone had delayed a return to drinking, but the reduction in the amount subsequently drunk (on average half that in the placebo group) was statistically significant and corroborated by biochemical markers. Other results were similar to that seen in the full sample.

The study's strengths were that it ironed out the idiosyncrasies of treatment at a single unit and enabled an estimate of the added value to be expected from naltrexone as a supplement to routine NHS practice. It confirmed earlier work recording no delay in a return to drinking but a worthwhile reduction in the amount subsequently drunk while patients were taking naltrexone. A different treatment regimen might have further improved outcomes. Naltrexone was introduced only after patients had been abstinent for on average 10–11 days. However, as the featured review observed, the drug seems to work mainly by reducing the experienced rewards of drinking, a mechanism which can only be activated if drinking occurs. Consistent with this theory, the study found that drinking was not delayed but (presumably because they 'got less out of it') patients on naltrexone went on to drink less than those receiving placebo pills.

In contrast, a similar study of acamprosate found no impact on drinking, even among patients who took the pills. At least a week after detoxification at one of 20 specialised British alcohol treatment units, the study randomised 581 alcohol dependent outpatients either to acamprosate three times a day or to placebo tablets, each supplied for six months. The medication was additional to usual treatment. High drop-out and non-compliance rates meant that just a third of the sample completed the study, and by the end fewer than 30% were taking at least 90% of their tablets. Subjects lost to follow-up were assumed to have relapsed.

Acamprosate did not improve abstinence rates among the patients as a whole, nor among certain types of patients thought to respond well to the drug. Even among those who at least took the tablets for the first two weeks, there was no added benefit. Whether taking acamprosate or placebo, both groups drank on most days. Neither did acamprosate prevent relapse to heavy regular or binge drinking by over 80% 12% and 11% abstinent plus 3% and 6% controlled drinking = 15% and 17% one or the other = 85% and 83% presumed or known uncontrolled drinking. of each group, though there was evidence of reduced craving and anxiety. About a month after medication ended, researchers interviewed 385 of the 581 patients. Abstinence rates had remained similar to those seen at the end of the medication period.

In contrast to some earlier research which provided high quality care characteristic of academic centres, apart from the tablets, patients received 'treatment as usual'. For many this seems to have been insufficient to prevent a high rate of pre-medication relapse and subsequent drop-out, making it much harder for acamprosate to demonstrate its worth. Nearly a third 155 + 33 for whom no data and assumed to be drinking. of patients did not remain abstinent for the week before being randomised into the study, a requirement in some other studies. Outcomes in the British study may also have suffered from not starting It was commenced on average 24 days after the start of detoxification, with an interval of over five weeks in some patients. the drug in the immediate post-withdrawal period, when theory suggests its effectiveness should be at its height. Like most previous studies, the UK study did not report on consumption levels but only on whether patients drank or exceeded certain limits. Had consumption been reported, the study might have found that relapses were less frequent and/or less severe on acamprosate than on placebo.

Head-to-head trials

Head-to-head trials of naltrexone versus acamprosate within the same study help to eliminate the possibility that caseload or regimen differences account for their relative impacts. Such studies conducted in Spain, Germany, the USA, and Australia, have consistently favoured naltrexone. Except for the Australian study which applied minimal filters to who could join the study, the caseloads, though often severely dependent, were relatively socially integrated, and all can be assumed to have been relatively highly motivated to tackle their drinking problems.

A Spanish study directly compared acamprosate and naltrexone prescribed to outpatients for a year. The study randomised patients to the treatments, but patients and doctors (not researchers) knew which medications were being taken. The authors argued that full 'blinding' would have meant obliging naltrexone patients to take pills three times a day (the required schedule for acamprosate) when just one a day would have been sufficient, eliminating one of the potential advantages of naltrexone in everyday practice. Other treatments were as close as possible to everyday practice and included consultations between patients and their psychiatrists and weekly abstinence-oriented supportive group therapy plus further pharmacological supports as needed, including disulfiram to terminate relapse.

Patients were required to have a stable family environment to aid compliance and in order to corroborate the patient's progress. Families had to commit to attending the clinic with the patient throughout the study, a condition which meant that 30% of candidate patients had to be excluded from the study. Other exclusion criteria were psychiatric illness or liver disease. All the patients were men. Perhaps because of the study's requirements, they were only moderately severely dependent, nearly all were married, and three-quarters were in full-time employment. On average they had drunk on nearly 9 in 10 days over the past six months and consumed 12 UK units Equivalent to about 96gm. In the article the term "drinks" is used but (see p. 420) this was equivalent to 8gm alcohol. on each of those days.

157 patients entered the study after completing detoxification. At least 10 days had elapsed between their last drink and the start of medication. Retention in the study was good and most therapy sessions were attended. Most patients in the study returned to drinking at some point during the year and naltrexone did not delay this any more than acamprosate, but naltrexone did further delay relapse to heavy drinking (63 days versus 42). The gaps between average time to first drink and to relapse suggest This cannot be established since an average may be composed of widely varying figures but the scope for this is constrained by the fact that the delay cannot have been less than zero. that on acamprosate relapse typically quickly followed a lapse (three days average delay) but that often naltrexone patients tried a drink without relapsing into heavy drinking for several weeks (average delay 19 days). A similar ability to prolong the lapse-relapse interval has been noted in other studies (1 2). By the end of the study 41% of naltrexone patients had not relapsed There is a mistake in table 2 of the source article which assigns these figures to a measure of subjects who did relapse rather than those who did not. compared to just 17% on acamprosate. During the last half the study twice as many naltrexone patients (54%) had maintained abstinence. During the last half the study naltrexone patients had drunk heavily on a third of the days compared to over half the days among acamprosate patients. Perhaps most telling because of their clear clinical significance are the facts that 13 acamprosate patients (16%) refused to continue in the study due to the severity of their relapse, and that half had to be prescribed disulfiram to control relapses resistant to other interventions. On naltrexone the respective figures were 1 and just over a fifth. Naltrexone also reduced craving for alcohol to a significantly greater degree than acamprosate.

In accounting for these findings, the authors speculated that acamprosate might have done better with more severely dependent patients, especially perhaps those drinking to avoid negative states rather than (as may have typically been the case in the Spanish sample) to gain positive reinforcement.

The Spanish study could not assess whether despite falling behind naltrexone, acamprosate nevertheless had some positive effects. The large-scale US COMBINE study was able to do this as well as compare the two medications because it randomised some patients to placebo pills.

For the study 11 clinics screened nearly 5000 applicants. 1383 were alcohol dependent, achieved at least an initial four days without drinking, agreed to join the study, and were randomly allocated to one of nine combinations of abstinence-oriented pharmacological and psychosocial treatments. Though more socially integrated and less severely dependent than some UK alcohol treatment caseloads, patients were heavy drinkers, averaging about 21 UK units About 168gm. most days. Over the 16 weeks of treatment, most were offered nine appointments intended to represent a medical management programme deliverable by non-specialist primary care staff given adequate training and supervision. Typically sessions lasted under 20 minutes and focused on assessing, monitoring and feeding back the medical consequences of the patient's drinking, and promoting adherence to pharmacotherapy. For half these patients, medical care was supplemented by typically 10 sessions of psychological therapy incorporating motivational interviewing, cognitive behavioural, and 12-step elements. For both sets of patients, pharmacotherapy consisted of placebo pills, acamprosate, naltrexone (unusually, not 50mg but 100mg a day), or both medications.

The key question was how far the extra therapies improved on the study's most basic intervention – medical management with inactive placebo pills. Adding psychological therapy improved drinking outcomes to the point where medication failed to create further improvements. But roughly the same gains resulted from adding naltrexone, even without psychological therapy. These were the only supplements which created significant gains. Combining them and even also adding acamprosate did not further improve outcomes, and acamprosate alone did not augment outcomes from the basic intervention. For example, across the 16 weeks of treatment, 58% of patients receiving basic care achieved a "good clinical outcome" – drinking at most moderately with few adverse consequences – compared to 71–78% when either naltrexone or psychological therapy were added. Abstinence and relapse outcomes followed the same pattern as did outcomes a year after treatment, though by this time the differences had faded to the point where none were statistically significant.

An Australian clinic sequentially offered alcohol dependent patients cognitive-behavioural group therapy (weekly for four weeks then every two weeks for the next eight weeks) plus either naltrexone, acamprosate, or both medications, forming three medication groups and a further group which rejected medication and took up the offer of cognitive-behavioural therapy alone. From 603 of these patients, in each group 59 could be matched across gender, age group, prior alcohol detoxification, and dependence severity. All had sustained at least three days without drinking and were not dependent on any other substance. Another paper described the clinic's caseload as "socially disadvantaged, severely dependent". Because patients who rejected medication may have been less committed to curbing their drinking, the most meaningful comparisons are between the three medication groups. These patients on average consumed nearly 19 UK units 150gm. of alcohol each time they drank.

Consistently the combination of naltrexone and acamprosate resulted in the greatest improvements across all outcome measures; generally naltrexone was next best, followed by the acamprosate group, though differences were small and failed to reach statistical significance. In the same order, the proportions of patients who completed the 12-week programme and attended all the therapy sessions were 83%, 80% and 66%. Proportions who completed the programme without drinking were 68%, 66% and 50%. Among patients who did not complete the programme abstinent, the average number of days abstinent were 54, 50, and 45. The average numbers of days to the first lapse to drinking were 37, 26, and 27. The study did not report rates of return to heavy drinking.

Results were similar in a trial in Germany. After inpatient detoxification, 160 alcohol dependent patients were randomly allocated for 12 weeks to naltrexone, acamprosate, naltrexone plus acamprosate, or placebo. All the patients were offered weekly abstinence-oriented, cognitive-behavioural group therapy. Compared to placebo, all the medication options were significantly more effective at avoiding or delaying relapse to heavy drinking. Most effective was the combination of both medications, but not to the degree that there was a statistically significant difference with naltrexone. Least effective of the medications was acamprosate, which did significantly underperform the combined medications. On no measure did naltrexone plus acamprosate significantly better naltrexone alone, but on each there was a slight advantage for the combination at the cost of a heightened incidence of gastrointestinal adverse effects, none of which were serious.

These results were observed among the minority of patients undergoing detoxification at the centre who were prepared to join the study. Presumably only those interested in sustaining their abstinence and fearful of not being able to do so without assistance would have volunteered. Furthermore, they had to have already sustained about two weeks without drinking, to not be using other drugs or have a history of opiate/cocaine abuse, to be free of serious medical/psychiatric conditions, and to not be homeless. The resulting caseload was mainly professionally trained men, most of whom were working. They were however drinking very heavily, on average nearly 32 UK units About 250gm. a day before detoxification. Medication was initiated about five days before they left the detoxification unit. Patients who returned to steady drinking (at least five days) or who drank heavily on a single day were considered relapsed and removed from the study, accounting for 68 patients. A later report of relapse outcomes at three months after the end of the trial (when patients could still take the medications but they knew which drug they were taking) indicated that the combined treatment retained a non-significant advantage compared to the single drug regimens, which were almost exactly equivalent.

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