Alcohol & Alcoholism Vol. 36, No. 5, pp. 419-425, 2001
`
`NALTREXONE VERSUS ACAMPROSATE: ONE YEAR FOLLOW-UP OF ALCOHOL
`
`DEPENDENCE TREATMENT
`
`G. RUBIO*, M. A. JIMENEZ-ARRIERO, G. PONCEand T. PALOMO
`
`Psychiatric Service, ‘12 de Octubre’ University Hospital, Madrid, Spain
`
`(Received 29 December 2000;in revisedform 16 March 2001; accepted 2 April 2001)
`
`Abstract — Naltrexone and acamprosate reduce relapse in alcohol dependence. They have not yet been comparedin a publishedtrial.
`The aim ofthis study was to comparetheefficacy of these compoundsin conditions similar to thosein routine clinical practice. Random
`allocation to a year oftreatment with naltrexone (50 mg/day) or acamprosate (1665-1998 mg/day) was madein 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 memberof the family would accompanyregularly to appointments. Alcohol consumption, craving
`and adverse events were recorded weekly forthe first 3 months, and then bi-weekly, by the treating psychiatrist who wasnot blinded.
`At 3-monthly intervals, investigators who were blindedto the treatment documentedpatients’ 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 madeto 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 timeto first drink
`(naltrexone 44 days, acamprosate 39 days) but the timeto 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 wassignificantly greater, and the numberof drinks consumedat one time and
`severity of craving weresignificantly less, in the naltrexone group comparedto 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 therapysessions, thoughthis couldnot 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
`improvementoverbaseline in serum GGT.
`
`INTRODUCTION
`
`Alcoholism is an important and difficult problem from several
`public health perspectives. For a long time, pharmacological
`treatments have been limited mainly to the detoxification period
`exclusively, and to the use of aversive drugs over the rehabilita-
`tion period (incorporating the time and process during which
`‘normal’ levels of intake are attained and maintained). In the
`last decade, naltrexone and acamprosate have been proposed
`for use in the treatment of alcohol dependence.
`Naltrexone is an opioid receptor antagonist, with a verified
`efficacy for the reduction of euphoria, alcohol intake and relapse
`risk by alcohol-dependentor -misusing individuals (Volpicelli
`et al., 1992, 1995a,b, 1997; O’Malley et al., 1992; Anton etal.,
`1999; Chick et al., 20006). These actions seem to be mediated
`by the property to block opiate receptors (Ulm et al., 1995),
`not least in forebrain areas. This antagonism appearsto inhibit
`the actions of endogenousopioids, released because of alcohol
`intake, upon the mesolimbic pathway, which would otherwise
`produce a rise in dopamine (DA) in the accumbensnuclei
`(Benjamin et al., 1993; Valenzuela and Harris, 1997; Catafau
`et al., 1999). Naltrexone efficacy has been demonstrated in
`short-term double-blind studies (6-12 weeks) (O’Malleyetal.,
`1992; Volpicelli et al., 1992, 1995a, 1997; Anton et al., 1999;
`Chick et al., 2000b). However, from the available evidence,
`naltrexone efficacy has not yet been verified in long-term
`studies.
`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
`
`*Author to whom correspondence should be addressed at: Servicio de
`Psiquiatria, Hospital Universitario 12 de Octubre, Avda, Cordobas/n. 28041,
`Madrid, Spain.
`
`the time to relapse, to reduce the number of days of con-
`sumption and to augment the abstinence period (Pelc et al.,
`1992; Ladewig et al., 1993; Paille et al., 1995; Sass et al.,
`1996; Geerlingset al., 1997; Poldrugo, 1997; Bessonet al., 1998;
`Tempesta et al., 2000). However, not all the studies confirm
`its efficacy compared to placebo (Chick et a/., 2000a). This
`compound modulates the GABA-ergic transmission and
`decreases postsynaptic potentials in the neocortex, possibly
`via its action on NMDA (N-methyl-D-aspartate) receptors.
`Hypotheses have been drawn up concerning its actions on
`calcium channels as well as on the NMDAreceptors reducing
`conditioned alcohol-withdrawal craving (Littleton, 1995).
`The aim of this study was to demonstrate the efficacy and
`treatment compliance of naltrexone compared to acamprosate
`in typical treatment conditions for these patients. An open
`randomizedtrial has been chosen for two reasons: (1) this is
`the experimental situation mostsimilar to daily clinical practice;
`(2) if a double-blind trial had been carried out, both drugs
`would have to be administered in three doses per day (because
`of the pharmacokinetics of acamprosate and manufacturer’s
`recommendations). However, taking into account the resist-
`ance to treatment compliance in these patients, especially in
`the medium and long-term, a double-blind trial in which the
`medication was administered three times a day would place
`naltrexone at a disadvantage since this drug is usually given in
`a single daily dose.
`
`PATIENTS AND METHODS
`
`Design
`This was a randomized 12-month single-blind trial of
`naltrexone versus acamprosate. The treatment conditions were
`as similar as possible to daily clinical practice.
`
`419
`
`APOTEX EXHIBIT 1006
`APOTEX EXHIBIT 1006
`Apotex v. Alkermes
`Apotex v. Alkermes
`IPR2025-00514
`IPR2025-00514
`
`© 2001 Medical Council on Alcohol
`
`

`

`420
`
`G. RUBIOetai.
`
`The participants were alcohol-dependent males who had
`requested detoxification in the Addictive Behaviour Unit of
`‘Doce de Octubre Hospital’. Inclusion criteria were as follows:
`(1) male gender aged between 18 and 65 years; (2) meeting
`DSM-III-R criteria for alcohol-dependence (American Psy-
`chiatric Association, 1987); (3) having a stable family environ-
`ment so that the family can help with treatment compliance
`and provide information during follow-up visits. Exclusion
`criteria were: (1) presence of another substance use disorder
`(with the exception of nicotine); (2) presence of another psy-
`chiatric disorder diagnosed by SCID for DSM-III-R (SCID);
`(3) a medical condition which could hinder treatment com-
`pliance; (4) impaired liver function [an aspartate aminotrans-
`ferase (AST) or alanine aminotransferase (ALT) value more than
`three times normal values];
`(5) previous treatment with
`naltrexone or acamprosate.
`After completing detoxification, in the hospital or as an out-
`patient, the subjects were informed aboutthe study objectives,
`They were informed about the two pharmacological treatments,
`naltrexone or acamprosate, elective treatments at the time of
`the study for the treatment of alcohol-dependence, but were
`told that the drug they would receive would be chosen at
`random, They would know which drug they would receive.
`They were told that relapse, or not taking the prescribed
`treatment punctually, would not lead to their being asked to
`leave the trial. However, they would be taken outofthetrial if
`they did not keep in touch with the investigators for more than
`15 days(i.e. two consecutive visits). They were also told that
`they could choose to leave the study at any time.
`
`Procedure and assessments
`
`After signing the informed consent, participants were
`assessed with the following instruments: a structured clinical
`interview for DSM-III-R (SCID) (Spitzer et a/., 1992); the
`Addiction Severity Index (ASI) (McLellan et al., 1980),
`Severity of Alcohol Dependence Scale (SADS) (Rubio et al,,
`1998); three analogue scales to measure craving (frequency,
`duration and intensity) (Anton et al., 1999); and a weekly
`calendar in which participants recorded all alcohol consumed,
`so that the ‘time-line follow-back’ method could be used to
`document
`the pattern of consumption during follow-up
`(Miller, 1996). The following baseline biological parameters
`were determined: serum aspartate aminotransferase (AST),
`alanine aminotransferase (ALT), gamma-glutamyltransferase
`(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
`naltrexone, or six tablets (or five if of lower body weight) of
`acamprosate (i.e. 1665-1998 mg/day) divided into three doses
`following the manufacturer’s recommendation. Patients
`visited their psychiatrists every 7 days (+ 3 days) overthe first
`3 months, after which they visited every 15 days, till the end
`ofthe study. In the event ofrelapse, the frequency ofvisits was
`increased in order to help curtail the relapse and to offer the
`patient assistance if required. At each visit, entries in the diary
`of alcohol consumption were checked, together with craving,
`and whether the patient continued the treatment. Consumption
`and compliance data were compared with information given
`by the family.
`Both groups of patients were offered supportive group
`therapy, once weekly over the entire study period. The groups
`
`were ‘open’ groups. Therapy was less structured than in classical
`relapse prevention programmes. Basic relapse prevention was
`tackled (dealing with situations of risk, craving and negative
`emotional states). Abstinence was positively reinforced.
`Patients also received symptom-directed pharmacologicaltreat-
`ment for complaints, such as anxiety, depression, insomnia,
`etc., when these symptoms presented during follow-up. If
`anxiety or depression emerged, sertraline could be prescribed
`(100-200 mg/day), and for insomnia patients were given hydroxy-
`zine, an H, receptor antagonist of the piperazine family used
`as a hypnotic (50-100 mg/night). In cases of relapses which
`were difficult to control pharmacologically or psychothera-
`peutically, disulfiram was added to the treatment until the
`relapse was fully over (2-3 weeks).
`
`The ‘blind’ investigators
`Study data on outcome were collected by investigators
`(at 3, 6 and 12 months) who were blind to the drug taken by
`the patients. They used the following sources of data: (1) the
`patient himself, who was asked not to talk about the type of
`medication he wasreceiving; (2) the psychiatrist appointed to
`the case, who provided any data required from the clinical
`records, including biochemical results, and who was requested
`not to divulge the treatment prescribed; (3) the patient’s family
`whoprovided information about drinking and any attempts by
`the patient to cease the pharmacological treatment. The degree
`of concordance between data from the family and the psy-
`chiatrists increased from 80% in the first few months to 95%
`in the final 3 months.
`It was hoped that asking the family would help reduce the
`bias, which could occur if the information were obtained
`only from the psychiatrist who had prescribed the treatment.
`The investigators never interviewed the samepatientat the three
`time points, since, at the end of an interview, they could have
`knowledge of the type of treatment the patient was receiving,
`which could affect future interviews with the same patient.
`Patients and relatives were asked notto tell the investigator
`the nameofthe treatment they were taking, its appearance, or
`how often per day they were taking it. Information from the
`psychiatrist was to complement that obtained from patients
`and their families and consisted mainly of data from clinical
`records and results of analyses. The main role of the psy-
`chiatrists in the study was to encourage patients to take the
`medication and to attend psychotherapy sessions.
`
`Outcome measures
`
`The primary outcome variables were: days of accumulated
`abstinence and daysto first relapse (relapse is defined as the
`consumption ofmorethan five drinks or 40 g ethanol per day).
`Additional outcome variables were numberof drinks consumed
`per week, number of drinks consumed at a time, craving,
`abandonmentofpharmacological treatment, drop-out from the
`study and 3-monthly serum GGT.
`
`Statistical analysis
`Pairwise x?- and ¢-tests were used to analyse differences
`between the two therapeutic groups, naltrexone versus
`acamprosate. All outcome analyses were conducted under an
`intention-to-treat analysis plan, with drop-outs regarded as
`relapsed for the abstinence and relapse analyses. Time to
`relapse and timeto first drink were analysed by Kaplan—Meier
`
`

`

`Fig. 1. Retention inthe study.
`
`Completed study
`Withdrawn because
`Withdrawn
`Withdrawn
`because of not|because of|of refusal to continue
`committing
`side effects
`after relapse
`themselves to
`attending
`weekly
`
`Recruitedinitially
`Selected n=160
`
`Naltrexone
`Acamprosate|on=5
`
`

`

`422
`
`G. RUBIOetai.
`
`Table 1. Severity of alcoholism, recent consumption pattern and
`biological markers of drinking at study entry
`
`Naltrexone Acamprosate
`group
`group
`(n=77)
`(n = 80)
`
`
`
`Mean SD MeanParameter SD
`
`
`
`
`
`The GGT determinations done at 3, 6 and 12 months were
`compared with baseline levels and ANCOVA showedsignifi-
`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 of
`days of heavy drinking.
`Side-effects were more common in the group receiving
`naltrexone, the most important of which were: nausea (25 vs
`4%, ¥?=14.1, P=0.0001), abdominal pain (23% vs 4%,
`42 = 12.9, P=0.0003), drowsiness (35 vs 2%, y?= 27.4,
`P=0,0000), nasal congestion (23 vs 1%, x2 = 12, P= 0.0004),
`headache (13 vs 6%, x? = 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
`the first 2 weeks of the study.
`
`29
`0.70
`52
`87
`
`5
`0.14
`19
`20
`
`28
`0.71
`51
`87
`
`Severity of Alcohol Dependence Scale
`Addiction Severity Index
`Composite craving severity score
`Percentage of days drinking in
`past 6 months
`5.1
`12.2
`5.0
`12.3,
`No. of drinks per drinking day
`101
`125
`98
`110
`Gamma-glutamyltransferase (IU/1)
`19
`84
`21
`81
`Aspartate aminotransferase (IU/l)
`31
`67
`30
`64
`Alanine aminotransferase (IU/1)
`20
`26
`17
`25
`Carbohydrate-deficient transferrin (U/l)
`5
`16
`3
`15
`Days betweenlast drink and
`start of study medication
`
`6
`0.12
`22
`21
`
`No significant group differences were detected (P > 0.05). All
`comparisons were ¢-tests with df= 155.
`
`DISCUSSION
`
`Sertraline was prescribed for two patients in whom a
`depressive episode emerged, and hydroxyzine was prescribed
`to 16 patients because ofinability to fall asleep. The distribu-
`tion between treatment groups was even, although this was
`not the case with prescriptions for disulfiram, which was
`prescribed to significantly more patients in the acamprosate
`group than the naltrexone group (Table 2).
`
`Naltrexone wasassociated with reducing relapse, achieving
`more days of accumulated abstinence, reducing the number of
`drinks consumed at any one time and reducing craving, com-
`pared to acamprosate. There was a trend for naltrexone to be
`associated with a greater retention in the treatment programme.
`It is difficult to compare our results with those ofotherstudies,
`since ours is the first published comparative study ofthese two
`
`Table 2. Outcomeafter 1 year
`
`Parameter
`
`Subjects who completed study
`% subjects abstinent since last assessment (6 months)
`No. of subjects prescribed disulfiram
`No. of subjects whoreceivedsertraline to treat depression
`
`No. of subjects receiving hydroxyzine to treat insomnia
`Patients whotried to abandon pharmacological treatment*
`Subjects who relapsed during the study
`
`Naltrexone group
`(n=77)
`
`Acamprosate group
`(n = 80)
`
`n
`
`69
`41
`17
`1
`
`7
`28
`32
`
`Mean
`
`%
`
`90
`54
`22
`1
`
`9
`36
`41
`
`SD
`
`n
`
`62
`22
`42
`1
`
`9
`37
`14
`
`Mean
`
`%
`
`78
`27
`52
`1
`
`11
`46
`17
`
`SD
`
`Analysis ‘y? (df = 1)
`
`4.14, P=0.14
`14.5, P = 0.0002
`15.3, P = 0.0002
`0.0, P=0.9
`(Fisher test, P = 0.74)
`0.20, P= 0.6
`1.57, P=0.21
`10.89, P = 0.0009
`
`t (df = 155)
`
`No. of weeks of study completed
`
`44
`
`1.92, df = 1, 154,
`P=0.53
`No. of therapy sessions attended
`43
`5
`32
`8
`6.8, df= 1, 154,
`P=0.01
`
`
`6
`
`35
`
`6
`
`Mean
`
`SD
`
`Mean
`
`SD
`
`F, df, P
`
`Daysto first alcohol consumption
`
`Daysto first relapse (25 drinks per day)
`
`No. of drinks consumed at one time
`
`No. of days abstinence (accumulated abstinence)
`
`44
`
`63
`
`4
`
`243
`
`2.19, df=1
`P=0.34>
`6.96, df= 1,
`P=0.02>
`7.01, df= 1, 141,
`P=0.01
`5.76, df = 1, 140,
`P=0.03
`6.2, df= 1, 139,
`12.1
`15.3
`10.1
`11.3
`Composite craving severity score
`P=0.01
`
`36
`
`38
`
`6
`
`115
`
`39
`
`42
`
`9
`
`180
`
`28
`
`32
`
`7
`
`129
`
`@This information wasprovided by the family member accompanyingthe patient.
`>Kaplan—Meiersurvival (log-rank)statistic.
`
`

`

`
`
`%withoutrelapse*
`
`monthsof follow-up
`
`Fig. 2. Survival analysis to first relapse.
`@, naltrexone; Ml, acamprosate. *Five or more drinks per day.
`
`107 + 90
`
`% of days heavy drinking differed between the groups (F = 5.04; df= 1, 140; P = 0.038).
`GGT (mean + SD): not significant.
`
`‘Table 3. Percentage of days of
`
`heavy drinking and serum gamma-glutamyltransferase (GGT)
`
`from baseline to | year
`
`Baseline period
`(90 days)
`
`1-3 months
`follow-up (90 days)
`
`follow-up (90 days)
`
`6-12 months
`follow-up (180 days)
`
`% of days
`heavy
`drinking
`
`Group
`
`altrexone
`|Acamprosate
`
`96
`96
`
`GGT
`n=157
`
`110 + 98
`125+ 101
`
`% of days
`heavy
`drinking
`
`23
`48
`
`GGT
`n= 139
`
`76 + 42
`90 + 75
`
`% of days
`heavy
`drinking
`
`44
`52
`
`GGT
`n= 133
`
`85 + 46
`99 + 72
`
`% of days
`heavy
`drinking
`
`33
`53
`
`GGT
`n=131
`
`87 + 62
`
`

`

`424
`
`G. RUBIOetai.
`
`pharmacological treatment taken by the patients, although it
`Catafau, A. M., Etcheberrigaray, A., Pérez de los Cobos, J.,
`Estorch, M., Guardia, J. and Flotats, A. (1999) Regional cerebral
`is possible that they could have guessed the treatment from
`blood flow changes in chronic alcoholic patients induced by
`the patients’ side-effects. However,
`this can also occur in
`naltrexone challenge during detoxification. Journal of Nuclear
`double-blindtrials, except in studies with total integrity of the
`Medicine 40, 19-24.
`double-blindedness (Moncrieff and Drummond, 1997). Objective
`Chick, J., Howlett, H., Morgan, M. Y., Ritson, B. and UKMASinves-
`tigators (2000a) United Kingdom Multicentre Acamprosate Study
`outcome criteria are not subject to bias: in our study, GGT
`(UKMAS): a 6-month prospective study of acamprosate versus
`(whichis a helpful, but not perfect, marker ofdrinking) appeared
`placebo in preventing relapse after withdrawal from alcohol. Alcohol
`to corroborate a better reported outcome in the naltrexone
`and Alcoholism 35, 176-187.
`group, but the advantagefailed to reach statistical significance.
`Chick, J., Anton, R., Checinski, K., Croop, R., Drummond, C., Farmer, R.,
`Some of the advantages of naltrexone seen in this study
`Labriola, D., Marshall, J., Moncrieff, J., Morgan, M., Peters, T.
`and Ritson, B. (20005) A multicentre, randomized, double-blind,
`could be explained bythe fact that the participants were patients
`placebo-controlled trial of naltrexone in the treatment of alcohol
`with moderate alcohol dependence. Impaired liver function
`dependenceor abuse. Alcohol and Alcoholism 35, 587-593.
`as an exclusion criterion will have ruled out some of the most
`(1997)
`Geerlings, P. J., Ansoms, C. and van den Brink, W.
`severe cases. Possibly, the latter would have responded better
`Acamprosate and prevention of relapse in alcoholics. European
`Journal ofAddiction Research 3, 129-137.
`to acamprosate than to naltrexone.
`(1993)
`Ladewig, D., Knecht, Th., Lehert, P. H. and Fend, A.
`At the start of the study, the psychiatrists did not know
`Acamprosat — ein stabilisierungsfktor in der langzeitentwohnung
`which pharmacological treatment would be most effective
`von alkoholabhangigen. Therapeutische Umschau 50, 182-187.
`and,
`therefore, had a similar attitude towards encouraging
`Littleton, J. (1995) Acamprosate in alcohol dependence: how doesit
`compliance with both treatments. However, as the study pro-
`work? Addiction 90, 1179-1188.
`McLellan, A. T., Luborsky, L., Woody, G. E. and O’Brien, C. P.
`gressed and subjects treated with naltrexone appeared to have
`(1980) An improved diagnostic evaluation instrument for substance
`a better outcome, the psychiatrist may have made moreeffort
`abusepatients: the Addiction Severity Index. Journal ofNervous and
`to encourage compliance with naltrexone treatment, which
`Mental Disease 168, 26-33.
`could, at least hypothetically, have then introducedabias.
`Miller, W. R. (1996) Form 90: A Structured Assessment Interview for
`Our assessment of the degree of compliance to the
`Drinking andRelatedBehaviors Test Manual: NIAAA Project Match
`Monograph Series, vol. 5, Mattson, M. E. and Marshall, L. A. eds,
`pharmacological treatment was conducted by questionnaires
`pp. 14-22. National Institute on Alcoholism and Alcohol Abuse,
`corroborated by information from the family. It would have
`Rockville, MD.
`been moreaccurate to use a urinary marker such asriboflavin.
`Moncrieff, J. and Drummond, D. C. (1997) New drug treatments for
`A difficulty in extrapolating the results of this study to other
`alcohol problems: a critical appraisal. Addiction 92, 939-947.
`O’Malley, S. S., Jaffe, A. J., Chang, G., Schottenfeld, R S., Meyer, R. E.
`treatmentsettings could bethat, in our study, there was a high
`and Rounsaville, B. (1992) Naltrexone and coping skills therapy
`level of family support available to patients. If this had
`for alcohol dependence. Archives of General Psychiatry 49,
`not been available, the retention levels, and compliance with
`881-887.
`medication, might have been lower for both treatments, and
`O’Malley, S. S., Jaffe, A. J., Rode, S. and Rounsaville, B. (1996a)
`there would possibly have been no measurable difference
`Experience of a ‘slip’ among alcoholics treated with naltrexone or
`placebo. American Journal ofPsychiatry 153, 281-283.
`between them. In our opinion, further studies comparing the
`O’Malley, S. S., Jaffe, A. J., Chang, G., Rode, S., Schottenfeld, R.S.,
`efficacy of these two drugs are required in varying therapeutic
`Meyer, R. E. and Rounsaville, B. (19965) Six-month follow-up of
`contexts in patients with different severity profiles.
`naltrexone and psychotherapy for alcohol dependence. Archives of
`General Psychiatry 53, 217-224.
`Paille, F. M., Guelfi, J. D., Perkins, A. C., Royer, R. J., Steru, L. and
`Parot, P. (1995) Randomised multicentre trial of acamprosate in a
`maintenance programme ofabstinence after alcohol detoxification.
`Alcohol and Alcoholism 30, 239-247.
`Pelc, Y., Le Bon, O., Verbanck, P., Lehert, P. H. and Opsomer, L.
`(1992) Calcium acetyl homotaurinate for maintaining abstinence in
`weanedalcoholic patients; a placebo controlled double-blind multi-
`centre study. In Novel Pharmacological Interventionsfor Alcoholism,
`Naranjo, C. and Sellers, E. M. (eds), pp. 348-352. Springer-Verlag,
`New York.
`Poldrugo, F. (1997) Acamprosate treatmentin a long-term community
`based alcohol rehabilitation programme. Addiction 92, 1537-1547.
`Rubio, G., Urosa, B. and Santo-Domingo, J. (1998) Validacién de
`la escala de la intensidad de la dependencia alcohdlica (EIDA).
`Psiquiatria Biolégica 10 (Suppl. 1), 44-47.
`Rubio, G., Ponce, G., Jiménez-Arriero, M. A. and Santo-Domingo,J.
`(1999) La pérdida de control en la dependencia alcohdlica:
`conceptualizacion. Adicciones 11, 143-158.
`Sass, H., Soyka, M., Mann, K. and Zieglgansberger, W. (1996) Relapse
`prevention by acamprosate: results from a placebo controlled study
`on alcohol dependence. Archives ofGeneral Psychiatry 53, 673-680.
`Spitzer, R. L., Williams, J. B. W., Gibbon, M. and First, M. B. (1992)
`The Structures Clinical Interview for DSM-III-R (SCID), I: History,
`rationale, and description. Archives of General Psychiatry 49,
`624-629.
`Tempesta, E., Janiri, L., Bignamini, A., Chabac, S. and Potgieter, A.
`(2000) Acamprosate and relapse prevention in the treatment
`of alcohol dependence: a placebo-controlled study. Alcohol and
`Alcoholism 35, 202-209.
`
`American Psychiatric Association (1987) Diagnostic and Statistical
`ManualofMental Disorders, 3rd edn, revised. American Psychiatric
`Association, Washington, DC.
`Anton, R. F., Moak, D. H., Waid, L. R., Latham, P. K., Malcolm,R. J.
`and Dias, J. K. (1999) Naltrexone and cognitive behavioral therapy for
`the treatmentof outpatient alcoholics: results of a placebo-controlled
`trial. American Journal ofPsychiatry 156, 1758-1764.
`Benjamin, D., Grant, E. R. and Phorecky, L. (1993) Naltrexone reverses
`ethanol-induced dopamine release in the nucleus accumbens in
`awake, freely moving rats. Brain Research 621, 137-140.
`Besson, J., Aeby, F., Kasas, A., Lehert, P. and Potgieter, A. (1998)
`Combinedefficacy of acamprosate and disulfiram in the treatment of
`alcoholism: a controlled study. Alcoholism: Clinical andExperimental
`Research 22, 573-579.
`
`Acknowledgements — We thank the Fundacion Cerebro y Mente for funding
`this research. This foundation is dedicated to neuroscience research. The
`funding received from this institution was used to remunerate the investigators
`whoreceived no other funding for this work from any other institution or
`pharmaceutical laboratory. Since this was an open study, the patients were
`prescribed their pharmacological
`treatments on National Health Service
`prescriptions from their psychiatrists. We would also like to thank the doctors
`Roberto Rodriguez, Jesus Pascual and Jose Ramon Lopez-Trabada forcollab-
`orating in the study and Luis Miguel Molinero for his advice on the statistical
`treatment ofdata.
`
`REFERENCES
`
`

`

`NALTREXONE VERSUS ACAMPROSATEIN ALCOHOLISM
`
`425
`
`Ulm, R. R., Volpicelli, J. R. and Volpicelli, L. A. (1995) Opiates
`and alcohol self-administration in animals. Journal of Clinical
`Psychiatry 56 (Suppl. 7), 5-14.
`In
`(1997) Alcohol: neurobiology.
`Valenzuela, F. and Harris, A.
`Substance Abuse. A Comprehensive Textbook, 3rd edn, Lowinson,
`J. H., Ruiz, P., Millman, R. B., Langrod, J. G. eds, pp. 119-142.
`Williams and Wilkins, Baltimore.
`Volpicelli, J. R., Alterman, A. I., Hayashida, M. and O’Brien, C. P.
`(1992) Naltrexone in the treatment of alcohol dependence. Archives
`of General Psychiatry 49, 876-880.
`Volpicelli, J. P., Clay, K. L., Watson, N. T. and O’Brien, C. P. (1995a)
`Naltrexone in the treatment of alcoholism: predicting response to
`naltrexone. Journal of Clinical Psychiatry 56, 39-44.
`
`Volpicelli, J. R., Watson, N. T., King, A. C., Sherman, C. E.
`and O’Brien, C. P. (1995) Effect of naltrexone on alcohol
`‘high’
`in alcoholics. American Journal of Psychiatry 152,
`613-615.
`Volpicelli, J. R., Rhines, K. C., Rhines, J. §., Volpicelli, L. A.,
`Alterman, A. I. and O’Brien, C. P. (1997) Naltrexone and alcohol
`dependence. Role of subject compliance. Archives of General
`Psychiatry 54, 737-742.
`Whitworth, A. B., Fisher, F., Lesch, O., Nimmerrichter, A.,
`Oberauer, H., Platz, T., Potgieter, A., Walter, H. and Fleischhacker,
`W. W.
`(1996) Comparison of acamprosate and placebo in
`long-term treatment of alcohol dependence. Lancet 347,
`1438-1442.
`
`