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Alcohol & Alcoholism Vol. 36, No. 5, pp. 419–425, 2001 NALTREXONE VERSUS ACAMPROSATE: ONE YEAR FOLLOW-UP OF ALCOHOL G. RUBIO*, M. A. JIMÉNEZ-ARRIERO, G. PONCE and T. PALOMO Psychiatric Service, ‘12 de Octubre’ University Hospital, Madrid, Spain (Received 29 December 2000; in revised form 16 March 2001; accepted 2 April 2001) Abstract — Naltrexone and acamprosate reduce relapse in alcohol dependence. They have not yet been compared in a published trial.
The aim of this study was to compare the efficacy of these compounds in conditions similar to those in routine clinical practice. Random
allocation to a year of treatment with naltrexone (50 mg/day) or acamprosate (1665–1998 mg/day) was made in 157 recently detoxified
alcohol-dependent men with moderate dependence (evaluated using the Addictions Severity Index and Severity of Alcohol Dependence
Scale). All were patients whom a member of the family would accompany regularly to appointments. Alcohol consumption, craving
and adverse events were recorded weekly for the first 3 months, and then bi-weekly, by the treating psychiatrist who was not blinded.
At 3-monthly intervals, investigators who were blinded to the treatment documented patients’ alcohol consumption based on patients’
accounts, information given by the psychiatrists when necessary, and reports from patients’ families. Serum gamma-glutamyltransferase
(GGT) was also measured. Efforts were made to sustain the blindness of the investigators. The same investigator did not assess the same
patient twice. The integrity of the blindness was not checked. There was no difference between treatments in mean time to first drink
(naltrexone 44 days, acamprosate 39 days) but the time to first relapse (five or more drinks in a day) was 63 days (naltrexone) versus
42 days (acamprosate) (P = 0.02). At the end of 1 year, 41% receiving naltrexone and 17% receiving acamprosate had not relapsed
(P = 0.0009). The cumulative number of days of abstinence was significantly greater, and the number of drinks consumed at one time and
severity of craving were significantly less, in the naltrexone group compared to the acamprosate group, as was the percentage of heavy
drinking days (P = 0.038). More patients in the acamprosate than the naltrexone group were commenced on disulfiram during the
study. Naltrexone patients attended significantly more group therapy sessions, though this could not explain their better outcome. There
were non-significant trends for the naltrexone group to comply better with medication, to stay in the study longer, and to show greater
improvement over baseline in serum GGT.
the time to relapse, to reduce the number of days of con-sumption and to augment the abstinence period (Pelc et al., Alcoholism is an important and difficult problem from several 1992; Ladewig et al., 1993; Paille et al., 1995; Sass et al., public health perspectives. For a long time, pharmacological 1996; Geerlings et al., 1997; Poldrugo, 1997; Besson et al., 1998; treatments have been limited mainly to the detoxification period Tempesta et al., 2000). However, not all the studies confirm exclusively, and to the use of aversive drugs over the rehabilita- its efficacy compared to placebo (Chick et al., 2000a). This tion period (incorporating the time and process during which compound modulates the GABA-ergic transmission and ‘normal’ levels of intake are attained and maintained). In the decreases postsynaptic potentials in the neocortex, possibly last decade, naltrexone and acamprosate have been proposed via its action on NMDA (N-methyl-D-aspartate) receptors.
for use in the treatment of alcohol dependence. Hypotheses have been drawn up concerning its actions on Naltrexone is an opioid receptor antagonist, with a verified calcium channels as well as on the NMDA receptors reducing efficacy for the reduction of euphoria, alcohol intake and relapse conditioned alcohol-withdrawal craving (Littleton, 1995).
risk by alcohol-dependent or -misusing individuals (Volpicelli The aim of this study was to demonstrate the efficacy and et al., 1992, 1995a,b, 1997; O’Malley et al., 1992; Anton et al., treatment compliance of naltrexone compared to acamprosate 1999; Chick et al., 2000b). These actions seem to be mediated in typical treatment conditions for these patients. An open by the property to block opiate receptors (Ulm et al., 1995), randomized trial has been chosen for two reasons: (1) this is not least in forebrain areas. This antagonism appears to inhibit the experimental situation most similar to daily clinical practice; the actions of endogenous opioids, released because of alcohol (2) if a double-blind trial had been carried out, both drugs intake, upon the mesolimbic pathway, which would otherwise would have to be administered in three doses per day (because produce a rise in dopamine (DA) in the accumbens nuclei of the pharmacokinetics of acamprosate and manufacturer’s (Benjamin et al., 1993; Valenzuela and Harris, 1997; Catafau recommendations). However, taking into account the resist- et al., 1999). Naltrexone efficacy has been demonstrated in ance to treatment compliance in these patients, especially in short-term double-blind studies (6–12 weeks) (O’Malley et al., the medium and long-term, a double-blind trial in which the 1992; Volpicelli et al., 1992, 1995a, 1997; Anton et al., 1999; medication was administered three times a day would place Chick et al., 2000b). However, from the available evidence, naltrexone at a disadvantage since this drug is usually given in naltrexone efficacy has not yet been verified in long-term Long-term efficacy studies (6–12 months) have been carried out, however, on acamprosate, calcium acetyl homotaurinate, a drug marketed in Europe. This has been shown to increase This was a randomized 12-month single-blind trial of *Author to whom correspondence should be addressed at: Servicio dePsiquiatría, Hospital Universitario 12 de Octubre, Avda, Córdoba s/n. 28041, naltrexone versus acamprosate. The treatment conditions were as similar as possible to daily clinical practice.
The participants were alcohol-dependent males who had were ‘open’ groups. Therapy was less structured than in classical requested detoxification in the Addictive Behaviour Unit of relapse prevention programmes. Basic relapse prevention was ‘Doce de Octubre Hospital’. Inclusion criteria were as follows: tackled (dealing with situations of risk, craving and negative (1) male gender aged between 18 and 65 years; (2) meeting emotional states). Abstinence was positively reinforced.
DSM-III-R criteria for alcohol-dependence (American Psy- Patients also received symptom-directed pharmacological treat- chiatric Association, 1987); (3) having a stable family environ- ment for complaints, such as anxiety, depression, insomnia, ment so that the family can help with treatment compliance etc., when these symptoms presented during follow-up. If and provide information during follow-up visits. Exclusion anxiety or depression emerged, sertraline could be prescribed criteria were: (1) presence of another substance use disorder (100–200 mg/day), and for insomnia patients were given hydroxy- (with the exception of nicotine); (2) presence of another psy- zine, an H receptor antagonist of the piperazine family used chiatric disorder diagnosed by SCID for DSM-III-R (SCID); as a hypnotic (50–100 mg/night). In cases of relapses which (3) a medical condition which could hinder treatment com- were difficult to control pharmacologically or psychothera- pliance; (4) impaired liver function [an aspartate aminotrans- peutically, disulfiram was added to the treatment until the ferase (AST) or alanine aminotransferase (ALT) value more than relapse was fully over (2–3 weeks).
three times normal values]; (5) previous treatment withnaltrexone or acamprosate.
After completing detoxification, in the hospital or as an out- Study data on outcome were collected by investigators patient, the subjects were informed about the study objectives.
(at 3, 6 and 12 months) who were blind to the drug taken by They were informed about the two pharmacological treatments, the patients. They used the following sources of data: (1) the naltrexone or acamprosate, elective treatments at the time of patient himself, who was asked not to talk about the type of the study for the treatment of alcohol-dependence, but were medication he was receiving; (2) the psychiatrist appointed to told that the drug they would receive would be chosen at the case, who provided any data required from the clinical random. They would know which drug they would receive.
records, including biochemical results, and who was requested They were told that relapse, or not taking the prescribed not to divulge the treatment prescribed; (3) the patient’s family treatment punctually, would not lead to their being asked to who provided information about drinking and any attempts by leave the trial. However, they would be taken out of the trial if the patient to cease the pharmacological treatment. The degree they did not keep in touch with the investigators for more than of concordance between data from the family and the psy- 15 days (i.e. two consecutive visits). They were also told that chiatrists increased from 80% in the first few months to 95% they could choose to leave the study at any time.
It was hoped that asking the family would help reduce the bias, which could occur if the information were obtained After signing the informed consent, participants were only from the psychiatrist who had prescribed the treatment.
assessed with the following instruments: a structured clinical The investigators never interviewed the same patient at the three interview for DSM-III-R (SCID) (Spitzer et al., 1992); the time points, since, at the end of an interview, they could have Addiction Severity Index (ASI) (McLellan et al., 1980), knowledge of the type of treatment the patient was receiving, Severity of Alcohol Dependence Scale (SADS) (Rubio et al., which could affect future interviews with the same patient.
1998); three analogue scales to measure craving (frequency, Patients and relatives were asked not to tell the investigator duration and intensity) (Anton et al., 1999); and a weekly the name of the treatment they were taking, its appearance, or calendar in which participants recorded all alcohol consumed, how often per day they were taking it. Information from the so that the ‘time-line follow-back’ method could be used to psychiatrist was to complement that obtained from patients document the pattern of consumption during follow-up and their families and consisted mainly of data from clinical (Miller, 1996). The following baseline biological parameters records and results of analyses. The main role of the psy- were determined: serum aspartate aminotransferase (AST), chiatrists in the study was to encourage patients to take the alanine aminotransferase (ALT), gamma-glutamyltransferase medication and to attend psychotherapy sessions.
(GGT), bilirubin, and carbohydrate-deficient transferrin (CDT).
After randomizing the patients (using a random numbers table), patients received either one tablet (50 mg) per day of The primary outcome variables were: days of accumulated naltrexone, or six tablets (or five if of lower body weight) of abstinence and days to first relapse (relapse is defined as the acamprosate (i.e. 1665–1998 mg/day) divided into three doses consumption of more than five drinks or 40 g ethanol per day).
following the manufacturer’s recommendation. Patients Additional outcome variables were number of drinks consumed visited their psychiatrists every 7 days (± 3 days) over the first per week, number of drinks consumed at a time, craving, 3 months, after which they visited every 15 days, till the end abandonment of pharmacological treatment, drop-out from the of the study. In the event of relapse, the frequency of visits was increased in order to help curtail the relapse and to offer thepatient assistance if required. At each visit, entries in the diary of alcohol consumption were checked, together with craving, Pairwise χ2- and t-tests were used to analyse differences and whether the patient continued the treatment. Consumption between the two therapeutic groups, naltrexone versus and compliance data were compared with information given acamprosate. All outcome analyses were conducted under an intention-to-treat analysis plan, with drop-outs regarded as Both groups of patients were offered supportive group relapsed for the abstinence and relapse analyses. Time to therapy, once weekly over the entire study period. The groups relapse and time to first drink were analysed by Kaplan–Meier NALTREXONE VERSUS ACAMPROSATE IN ALCOHOLISM survival analysis. The difference in variables, such as number four in the 4th, one in the 7th and one in the 8th month. The of drinks consumed per day, drinks consumed at one time or reasons for drop-out are shown Fig. 1.
percentage of days abstinent, were analysed by analysis ofcovariance (ANCOVA), taking baseline levels as covariants, and for drop-outs using the last observation carried forward.
At the end of the treatment year the number of abstinent The biological drinking markers, CDT and GGT levels, were patients in the naltrexone group was twice that in the acam- evaluated by both repeated measures and end-point ANCOVA prosate group and the accumulated abstinence was significantly with baseline levels as covariants. A composite craving severity greater in the former (Table 2). The survival until the first score was created, as the average of the three scale scores relapse was longer for naltrexone than acamprosate patients (intensity, duration and frequency). Group differences were (P = 0.02) (Fig. 2). At the end of the study, 41% of the nal- analysed by repeated measures ANCOVA with baseline values trexone group had not relapsed and 54% were abstinent since on the respective scales used as covariants.
the last assessment (6 months), compared to 17 and 27%,respectively, in the group treated with acamprosate. Table 2shows further alcohol consumption data, including the drinks consumed in a session, which was less for patients receivingnaltrexone than those receiving acamprosate. In the group treated with naltrexone fewer patients used disulfiram. If a patient The total number of patients from the different health centres drank some alcohol, relapse occurred on average 12 days later considered for inclusion in the study was 356, of whom 197 in the naltrexone group (SD = 16) whereas it occurred in the were examined at the start of the study (Fig. 1). Of these, some group treated with acamprosate after 6 days (SD = 8).
were not selected: 30% refused to participate; in 30% the A survival curve of time to first alcohol consumption revealed family could not commit themselves to accompany the patient no significant differences between the two groups (the mean to the Centre throughout the follow-up period; 27% had been number of days to the first consumption was 44 for the nal- treated previously with naltrexone or acamprosate; 25% pre- trexone group and 39 for the acamprosate group; P = 0.34).
sented comorbidity of another disorder; and in 15% naltrexone Regarding the composite score, severity of craving, patients was contra-indicated because of impaired liver function. Of receiving naltrexone had significantly lower scores over the 160 subjects selected, three then refused to participate, so 157 were submitted to the pre-treatment analysis.
Randomization gave 77 (naltrexone) and 80 (acamprosate).
Sociodemographic variables respectively were: age (mean ± SD In the naltrexone group there was a trend towards fewer = 43 ± 10; and mean = 44 ± 12 years), married (95 and 92%), drop-outs, fewer attempts to abandon pharmacological treat- employed full time (75 and 75%), secondary education ment, more weeks of completed treatment, and greater attend- (84 and 85%). There was no significant difference between ance at psychotherapy support sessions. The latter reached the groups in any of these variables. There was no significant statistical significance. We considered the hypothesis that the difference between the variables when related to severity of number of days of abstinence could be related to attendance at dependence; in both groups the severity of dependence meas- therapy sessions, rather than to the use of naltrexone or acam- ured with both the ASI and the SADS was moderate (Table 1).
prosate. To test this, we compared the mean number of days of The average period between the last drink and the start of abstinence at 3, 6 and 12 months follow-up, taking the number treatment was 16 days (range 10–22).
of psychotherapy sessions as the covariant (ANCOVA). The A total of 26 patients dropped out during the study (eight results showed that, in the naltrexone group the mean number naltrexone, 18 acamprosate). In the naltrexone group, two of days of abstinence remained constant after the 3rd month, patients dropped out in the 1st month, four in the 3rd month whereas in the acamprosate group the mean number of days and two in the 4th month. In the acamprosate group, two of abstinence decreased over the follow-up period (F = 8.23, dropped out in the 1st month, five in the 2nd, five in the 3rd, Table 1. Severity of alcoholism, recent consumption pattern and The GGT determinations done at 3, 6 and 12 months were biological markers of drinking at study entry compared with baseline levels and ANCOVA showed signifi-cant temporal improvements in the whole sample (F = 52.3, df = 2, P < 0.0001). Table 3 shows the number of days of heavy drinking and the mean values of GGT. There was a non-significant trend for greater improvement in GGT in the naltrexone patients but a significant reduction in percentage ofdays of heavy drinking.
Side-effects were more common in the group receiving naltrexone, the most important of which were: nausea (25 vs 4%, χ2 = 14.1, P = 0.0001), abdominal pain (23% vs 4%, χ2 = 12.9, P = 0.0003), drowsiness (35 vs 2%, χ2 = 27.4, P = 0.0000), nasal congestion (23 vs 1%, χ2 = 12, P = 0.0004), headache (13 vs 6%, χ2 = 2.0, P = 0.15), diarrhoea (1 vs 4%, Fisher test P = 0.3 ) and epigastric discomfort (4 vs 4%, Fisher test P = 0.64). These side-effects gradually disappeared after No significant group differences were detected (P > 0.05). All comparisons were t-tests with df = 155.
Sertraline was prescribed for two patients in whom a Naltrexone was associated with reducing relapse, achieving depressive episode emerged, and hydroxyzine was prescribed more days of accumulated abstinence, reducing the number of to 16 patients because of inability to fall asleep. The distribu- drinks consumed at any one time and reducing craving, com- tion between treatment groups was even, although this was pared to acamprosate. There was a trend for naltrexone to be not the case with prescriptions for disulfiram, which was associated with a greater retention in the treatment programme.
prescribed to significantly more patients in the acamprosate It is difficult to compare our results with those of other studies, group than the naltrexone group (Table 2).
since ours is the first published comparative study of these two % subjects abstinent since last assessment (6 months) No. of subjects who received sertraline to treat depression No. of subjects receiving hydroxyzine to treat insomnia Patients who tried to abandon pharmacological treatmenta Days to first relapse (≥5 drinks per day) No. of days abstinence (accumulated abstinence) aThis information was provided by the family member accompanying the patient.
bKaplan–Meier survival (log-rank) statistic.
NALTREXONE VERSUS ACAMPROSATE IN ALCOHOLISM drinking (Anton et al., 1999). Whichever explanation, the higherdegree of control over their drinking achieved by patients treatedwith naltrexone could explain their lesser use of disulfiramand their achieving more days of abstinence and a greater useof therapy. In our opinion, this effect could be explained asfollows: the craving triggered by consumption is slightly lesswith naltrexone than with acamprosate, which enables thosetreated with naltrexone to stop drinking earlier. Since relapsesare very common in these patients, those treated with naltrexonewould be more capable of interrupting the relapse or diminishingits intensity. This would help to prevent progression in alcoholconsumption and increase the probability that the patient seekshelp from a therapist and, therefore, ultimately, curtail relapse.
This is supported by the fewer absences from therapy in thenaltrexone-treated group. Since naltrexone reduces theintensity of relapse, patients attend more therapy sessions.
Fig. 2. Survival analysis to first relapse.
Although this latter effect has not been found by other authors ᭜, naltrexone; ᭿, acamprosate. *Five or more drinks per day.
(Anton et al., 1999), this could be due to the shorter durationof their studies. Finally, the increased number of attempts to drugs. With regards to other research on naltrexone, in previous abandon treatment with acamprosate may relate to the number studies abstinence rates after 6 weeks were 23–62% (O’Malley of doses required daily, and this could contribute to the smaller et al., 1992; Volpicelli et al., 1992, 1997; Anton et al., 1999; Chick percentage of days of abstinence achieved by these patients.
et al., 2000b). The results of our study, which was four times Anticraving effects of naltrexone were more important than longer than the aforementioned ones, are within this range. The those of acamprosate, although this difference could be due levels of abstinence with acamprosate in placebo-controlled to their different mechanisms of action and the fact that most trials with a 1-year follow-up are between 18 and 35% (Paille patients drank alcohol during the study period. Given that et al., 1995; Sass et al., 1996; Whitworth et al., 1996; Besson et al., acamprosate probably exerts its anticraving action by reducing 1998). In our study, we recorded a rate of 17%. If we extrapo- the intensity of the symptoms of the conditioned withdrawal late these results, it seems that long-term treatment of patients syndrome and naltrexone probably reduces the reinforcing with naltrexone is more beneficial than with acamprosate.
effects of the alcohol, this difference would favour the use of Two hypotheses could explain the benefits of naltrexone naltrexone in patients who are likely to consume some alcohol.
seen in our study. First, it may be that naltrexone increases the This would explain why the patients treated with naltrexone period elapsed before the subject takes the first drink. Prolong- reported less craving than the acamprosate group over the study ing the abstinence period enables the learning of strategies period (Rubio et al., 1999). It is also possible that naltrexone taught in the support therapy and increases feelings of self- would be more effective at reducing craving in patients with efficacy. Second, it may be that naltrexone has an effect on moderate dependence, in whom craving mechanisms related control of alcohol consumption once this has already begun, to positive reinforcement could be over-represented. Since our resulting in a delay in relapse. This could also increase the sample was of patients with moderate dependence, this could The first of these hypotheses was not confirmed, because With regards to the tolerability of both drugs, although the the survival time to the first drink did not differentiate between group treated with naltrexone experienced more side-effects, treatments. In contrast, the action of naltrexone on control these only lasted for the first 2 weeks of the study and there of alcohol consumption is shown in the survival curve to first was no significant difference in the rate of drop-out due to this.
relapse and in the number of drinks consumed at any one time.
This effect has been described in other studies and has been explained by a reduction in the reinforcing effects of ethanol This was an open study, and there is the possibility that the after drinking (O’Malley et al., 1996a,b), or by an improve- investigators did not remain blinded. We tried to prevent the ment in the ability to resist thoughts or cravings to continue investigators from gaining direct information about the type of Table 3. Percentage of days of heavy drinking and serum gamma-glutamyltransferase (GGT) from baseline to 1 year % of days heavy drinking differed between the groups (F = 5.04; df = 1, 140; P = 0.038).
GGT (mean ± SD): not significant.
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Source: http://alcalc.oxfordjournals.org/content/36/5/419.full.pdf