28-SEP-2001 BSDS ~g~~0~agPA
`ALCOHOL AHD ALCOHOLISM -LOHDOH- PERGAMON PR
`:-J
`ESS-
`•E,OC
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`0786.754800
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`VOL 36 PART S
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`AMN1028
`IPR of Patent No. 7,919,499
`
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`ALCOHOL AND ALCOHOLISM
`The International Journal of the Medical Council on Alcohol
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`AMN1028
`IPR of Patent No. 7,919,499
`
`

`

`Alcolml & Alcoholism Vol. 36. No.5. pp. 419-425. 2001
`
`NALTREXONE VERSUS ACAMPROSATE: ONE YEAR FOLLOW-UP OF ALCOHOL
`DEPENDENCE TREATMENT
`G. RUB IO*. M. A. JIMENEZ-ARRIERO. G. PONCE and T. PALOMO
`Psychiatric Service, ' 12 de OciUbrc' University Hospital. Madrid, Spai n
`
`CRP<·ei••ed 29 Decembu 2000: in revised form 16 Marr:h 2001: accepted 2 Apri/200 1)
`
`Abstract - Naltrexone and acamprosate reduce relapse in alcohol dependence. They have not yet been companed in a published trial.
`The aim of this study wa• to compare the efficacy of these compounds in conditions similar to those in routine clinical practice. Random
`allocation to a year of trcatment with naltrexone (50 mg./day) or acamprosate (1665-1998 mglday) was made in 157 recently detoxified
`alcohol-dependent men with moderate dependence (evaluated u•ing the Addictions Severity Index and Severity of Alcohol Dependence
`Scale). All were patient• whom a member of the family would accompany regularly to appointments. Alcohol consumption. craving
`and adverse event• 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 rcpons from patients' families. Serum gamma-glutamyltransferase
`(GGT) was also measured. Efforts were made to sustain the blindness of the investigators. The •arne 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 dri nks in a day) was 63 days (naltrexone) versu.<
`42 days (acamprosate) (P = 0.02). At the end of I year. 4 1% receiving naltrexone and 17% receiving acamprosate had not relapsed
`(P = 0.0009). The cumulative number of days of abstinence was signilicantly greater, and the number of drinks consumed at one time and
`severity of craving were sib'lliliciUltly 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 se.-ions. though this could not explain their bener outcome. There
`were non-significant trend' 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.
`
`fNTRODUCTION
`
`Alcoholism is an important and difficult problem from several
`public health perspectives. For a long time. pharmacological
`treatments have been limited mainly 10 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-dependent or -misusing individuals (Volpicell i
`eta/., 1992, 1995a,b, 1997; O'Malley eta/., 1992; Anton eta/,
`1999; Chick eta/., 2000b). These actions seem to be media led
`by the property to block opiate receptors (Ulm eta/., 1995).
`not least in forebrai n area •. This antagonism appears to inhibit
`the actions of e.ndogenous opioids. released because of alcohol
`intake, upon the mesolimbic pathway, which would otherwise
`produce a rise in dopamine (DAl in the accumbens nuclei
`(Benjami n et al., 1993; Valenzuela and Harris, 1997: Catafau
`et a/., 1999). Naltrexone efficacy has been demonstrated in
`short-term double-blind studies (6- 12 weeks) (O'Malley eta/.,
`1992; Volpicelli eta/., 1992, 1995a, 1997; Anton et a/., 1999:
`Chick et a/ .. 200Gb). However, from the available evidence.
`naltrexone efficacy has not yel been verified in long-term
`studies.
`Long-tenn 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 shou ld be addressed at: Servido de
`Psiquiatrfa. Hospital Univcrsitario 12 de Octubre. Avda, C6rdoba sin. 28041.
`Madrid, Spain.
`
`the ti me to relapse. to reduce the number of days of con-
`sumption and to augment the abstinence period (Pelc er al ..
`1992: Ladewig et al .. 1993; Paille et al., 1995; Sass et at .•
`1996; Geerlings eta/., 1997; Poldrugo, 1997; Besson eta/., 1998:
`Tempesta et a/ .. 2000). However. not all the studies confirm
`its efficacy compared 10 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-methyi-D-aspartate) receptors.
`Hypotheses have been drawn up concerning its actions on
`calcium channels as well as on the NMDA receptors 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
`randomized trial has been chosen for two reasons: ( I ) this is
`the experimental situation most similar 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-tenn. 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 dai ly clinical practice.
`
`4 19
`
`© 2001 Medical Council on Alcohol
`
`Supplied by the British Library 18 Apr 2018, 14:45 (BST)
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`AMN1028
`IPR of Patent No. 7,919,499
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`4:!0
`
`G. RUBIO eta/.
`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 pharmacological treat-
`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 hydrolly-
`zine, an H1 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 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 I 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 about the study objectives.
`They were informed about the two phannacological 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 out of the trial 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-Ill-R (SCID) (Spitzer et al.. 1992); the
`Addiction Severity Index (ASI) (McLellan et al .. 1980).
`Severity of Alcohol Dependence Scale (SADS) (Rubio et at..
`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 mglday) divided into three doses
`following the manufacturer's recommendation. Patients
`visited their psychiatrists every 7 days (± 3 days) over the first
`3 months, after which they visited every 15 days, till the end
`of the study. In the event of relapse. the frequency of visits 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
`
`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: (I) the
`patient himself, who was asked not to talk about the type of
`medication he was receiving; (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
`who provided 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 same patient at 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 not to tell the investigator
`the name of the treatment they were taking, its appearance. or
`how often per day they were taking it. Inforn1ation 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 days to first relapse (relapse is defined as the
`consumption of more than five drinks or 40 g ethanol per day).
`Additional outcome variables were number of drinks consumed
`per week. number of drinks consumed at a time. craving.
`abandonment of pharmacological treatment. drop-out from the
`study and 3-monthly serum GGT.
`Statistical a11alysis
`Pairwise x}- and t-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 time to first drink were analysed by Kaplan-Meier
`
`Supplied by the British Library 18 Apr 2018, 14:45 (BST)
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`

`NALTREXONE VERSUS ACAMPROSATE IN ALCOHOLISM
`
`421
`
`survival analysh. The difference in variables. such as number
`of drink consumed per day. drinks consumed at one time or
`percentage of days abstinent. were analysed by analysis of
`covariance (ANCOVA). taking baseline levels as covariants.
`and for drop-outs using the last observation carried forward.
`The biological drinking markers, COT and GOT levels, were
`evaluated by both repeated measures and end-point ANCOVA
`with baseline levels a~ covariants. A composite craving severity
`score was created. as the average of the three scale scores
`(intensity. duration and frequency). Group differences were
`analysed by repeated measures ANCOVA with baseline values
`on the respective scales used as covariants.
`
`RESULTS
`
`Recruitmem and rr!lention
`The total number of patients from the different health centres
`considered for inclusion in the study was 356. of whom 197
`were examined at the start of the study (Fig. I). Of these. some
`were not selected: 30% refused to participate: in 30% the
`family could not commit themselves to accompany the patient
`to the Centre throughout the follow-up period: 27% had been
`treated previously with naltrexone or acamprosate; 25% pre-
`sented co morbidity of another disorder; and in 15% naltrexone
`was contra-indicated because of impaired liver function. Of
`160 subjects selected, three then refused to participate, so
`!57 were submitted to the pre-treatment analysis.
`Randomization gave 77 (naltrexone) and 80 (acarnprosate).
`Sociodemographic variables respectively were: age (mean ± SD
`= 43 ± 10; and mean= 44 ± 12 years). married (95 and 92%).
`employed full
`time (75 and 75%), secondary education
`(84 and 85%). There was no significant difference between
`the groups in any of these variables. There was no significant
`difference between the variables when related to severity of
`dependence; in both groups the severity of dependence meas-
`ured with both the ASI and the SADS was moderate (Table I).
`The average period between the last drink and the start of
`treatment was 16 days (range 10-22).
`A total of 26 patients dropped out during the study (eight
`naltrexone. 18 acamprosate). In the naltrexone group. two
`patients dropped out in the 1st month. four in the 3rd month
`and two in the 4th month. In the acamprosate group. two
`dropped out in the 1st month, five in the 2nd, five in the 3rd.
`
`four in the 4th. one in the 7th and one in the 8th month. The
`reasons for drop-out are shown Fig. I.
`Efficacy
`At the end of the treatment year the number of abstinent
`patients in the naltrexone group was twice that in the acam-
`prosate group and the accumulated abstinence was significantly
`greater in the former (Table 2). The survival until the first
`relapse was longer for naltrexone than acarnprosate patients
`(P = 0.02) (Fig. 2). At the end of the study, 41% of the nal-
`trexone group had not relapsed and 54% were abstinent since
`the last assessment (6 months), compared to I 7 and 27%.
`respectively. in the group treated with acamprosate. Table 2
`shows further alcohol consumption data, including the drinks
`consumed in a session. which was less for patients receiving
`naltrexone than those receiving acamprosate. In the group treated
`with naltrexone fewer patients used disulfiram. If a patient
`drank some alcohol. relapse occurred on average 12 days later
`in the naltrexone group (SD = 16) whereas it occurred in the
`group treated with acamprosate after 6 days (SD = 8).
`A survival curve of time to first alcohol consumption revealed
`no significant differences between the two groups (the mean
`number of days to the first consumption was 44 for the nal-
`trexone group and 39 for the acamprosate group; P = 0.34).
`Regarding the composite score, severity of craving. patients
`receiving naltrexone had significantly lower scores over the
`entire study period.
`TreatmellT compliance
`In the naltrexone group there was a trend towards fewer
`drop-outs. fewer attempts to abandon pharmacological treat-
`ment. more weeks of completed treatment, and greater attend-
`ance at psychotherapy upport sessions. The latter reached
`statistical significance. We considered the hypothesis that the
`number of days of abstinence could be related to attendance at
`therapy sessions, rather than to the use of naltrexone or acam-
`prosate. To test this. we compared the mean number of days of
`abstinence at 3, 6 and 12 months follow-up. taking the number
`of psychotherapy sessions as the covariant (ANCOVA). The
`results showed that. in the naltrexone group the mean number
`of days of abstinence remained constant after the 3rd month.
`whereas in the acamprosate group the mean number of days
`of abstinence decreased over the follow-up period (F = 8.23.
`df = 2. 248. p > 0.05).
`
`Re<:ruited initially n= 197
`Selected n= 160
`
`~
`
`Randomized n=1 57
`Naltrexone : n= 77
`Acamprosate : n=80
`
`r----
`
`1
`
`committing I side effects
`
`\ Withdrawn Withdrawn because
`- Withdrawn
`because or not 1 because of of refusal to continue
`aftet relapse
`themselves to
`attending
`weekly
`
`1
`
`Completed study
`
`Naltrexone
`Acamprosate
`
`n=5
`n=5
`
`n=2
`n=O
`
`n=1
`n=13
`
`-
`
`r-
`
`n=69
`n=62
`
`Fig. I. Retention in the study.
`
`Supplied by the British Library 18 Apr 2018, 14:45 (BST)
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`AMN1028
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`422
`
`G. RUBIO era/.
`
`Table I. Severity of alcoholism. recent ~onsumption panern and
`biological marken. of drinking at study entry
`
`Parameter
`
`Severity of Alcohol Dependence Scale
`Addiction Severity Index
`Composite craving severity score
`Percentage of days drinking in
`past 6 months
`No. of drinks per drinking day
`Gmnma-glutamyltransferase (JU/H
`Aspartate aminotransferase (fUll I
`Alanine aminotransferase ([U/1)
`Carbohydrate-deficient transferrin (U/1)
`Days between last drink and
`start of study medication
`
`Naltrexone Acamprosate
`group
`group
`(11 = 77)
`(11 = 80)
`Mean
`SD Mean
`SD
`
`5
`29
`0.70 0.14
`52
`19
`87
`20
`
`28
`0.71
`51
`87
`
`6
`0.12
`22
`21
`
`12.3
`110
`81
`64
`25
`15
`
`5.0
`98
`21
`30
`17
`3
`
`12.2
`125
`84
`67
`26
`16
`
`5.1
`101
`19
`31
`20
`5
`
`The GGT determinations done at 3. 6 and 12 months were
`compared with baseline levels and ANCOVA showed signifi-
`cant temporal improvements in the whole sample (F = 52.3.
`df = 2, P < 0.000 I). 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 imponant of which were: nausea (25 vs
`4%, X~= 14.1, p = O.OOQJ ), abdominal pain (23% VS 4%,
`x~ = 12.9, p = 0.0003), drowsiness (35 VS 2%, X!= 27.4.
`p = 0.0000), nasal congestion (23 VS I%. x~ = I 2, p = 0.0004 ),
`headache ( 13 vs 6%. X1 = 2.0. P = 0.15). diarrhoea (I 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.
`
`No significant group differences were detected (P > 0.05). All
`comparisons were r-tests with df = 155.
`
`DISCUSSION
`
`Sertraline was prescribed for Jwo patients in whom a
`depressive episode emerged, and hydroxyzine was prescribed
`10 16 patients because of inability to fall asleep. The distribu-
`tion between treatment groups was even, although this was
`nol the case with prescriptions for disulfiram. which was
`prescribed to significantly more patients in the acamprosate
`group than the naltrexone group (Table 2).
`
`Naltrexone was associated 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 of other studies.
`since ours is the first published comparative study of these two
`
`Table 2. Outcome after I year
`
`Nahrexone group
`(II= 77)
`
`Acampro•ate group
`(II= 80)
`
`Parameter
`
`Subject> who completed study
`% subjects abstinent since last assessment (6 months)
`No. of subjects prescribed disulfiram
`No. of subjects who received sertraline to treat depression
`
`No. of subjects receiving hydroxyzine to treat insomnia
`Patients who tried to abandon pharmacological treatment•
`Subjects who relapsed during the >ludy
`
`No. of weeks of study completed
`
`No. of therapy sessions attended
`
`Days to first alcohol consumption
`
`Days to first relapse (2:5 drinks per day)
`
`No. of drinks consumed at one lime
`
`No. of days abstinence (accumulated abstinence)
`
`Composite craving severity score
`
`II
`
`69
`41
`17
`I
`
`7
`28
`32
`
`Mean
`
`.f4
`
`43
`
`Mean
`
`44
`
`63
`
`4
`
`243
`
`11.3
`
`%
`
`90
`54
`22
`I
`
`9
`36
`41
`
`SD
`
`6
`
`5
`
`SD
`
`36
`
`38
`
`6
`
`115
`
`10.1
`
`II
`
`62
`22
`42
`I
`
`9
`37
`14
`
`Mean
`
`35
`
`32
`
`Mean
`
`39
`
`42
`
`9
`
`180
`
`15.3
`
`78
`27
`52
`I
`
`II
`46
`17
`
`SD
`
`6
`
`SD
`
`28
`
`32
`
`7
`
`129
`
`12. 1
`
`Analysis X: tdf = I)
`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 = 0.2 1
`10.89, p = 0.0009
`I (df = 155)
`
`1.92. df = I. 154.
`p = 0.53
`6.8. df= I. 154.
`P=O.O I
`
`F. df. P
`
`2.19.df= I
`p = 0.34"
`6.96, df =I,
`p = 0.02"
`7.01. df = I. 141.
`P=O.O l
`5.76. df = I. 140.
`p = 0.03
`6.2. df = I. 139.
`p =0.01
`
`·'This information was provided by the family member accompanying the patient.
`"Kaplan- Meier survival (log-rank) statistic.
`
`Supplied by the British Library 18 Apr 2018, 14:45 (BST)
`
`AMN1028
`IPR of Patent No. 7,919,499
`
`

`

`NALTREXONE VERSUS ACAMPROSATE IN ALCOHOLISM
`
`423
`
`100
`.. "' c. 70
`.. 80
`90
`.... 60
`...
`:; so
`..: ... -~ 30
`40
`
`01
`
`Q
`
`~
`
`~ 20
`10
`0
`
`~---.....,
`~ -..........._
`P=0.02 -
`"-......
`~ ~ -
`"""
`"'-.....
`
`~
`
`--
`
`~ ....... Naltexone
`-- Acamprosate I
`
`drinking (Anton eta/ .. 1999). Whichever explanation. the higher
`degree of control over their drinking achieved by patients treated
`with naltrexone could explain their lesser use of disulfiram
`and their achieving more days of abstinence and a greater use
`of therapy. In our opinion. this effect could be explained as
`follows: the craving triggered by consumption is slightly less
`with naltrexone than with acamprosate, which enables those
`treated with naltrexone to stop drinking earlier. Since relapses
`are very common in these patients, those treated with naltrexone
`would be more capable of interrupting the relapse or diminishing
`its intensity. This would help to prevent progression in alcohol
`consumption and increase the probability that the patient seeks
`help from a therapist and. therefore. ultimately, curtail relapse.
`This is supported by the fewer absences from therapy in the
`naltrexone-treated group. Since naltrexone reduces the
`intensity of relapse. patients attend more therapy sessions.
`Although this latter effect has not been found by other authors
`(Anton eta/., 1999), this could be due to the shorter duration
`of their studies. Finally. the increased number of attempts to
`abandon treatment with acamprosate may relate to the number
`of doses required daily, and this could contribute to the smaller
`percentage of days of abstinence achieved by these patients.
`Anticraving effects of naltrexone were more important than
`those of acamprosate. although tllis difference could be due
`to their different mechanisms of action and the fact that most
`patients drank alcohol during the study period. Given that
`acamprosate probably exerts its anticraving action by reducing
`the intensity of the symptoms of the conditioned withdrawal
`syndrome and naltrexone probably reduces the reinforcing
`effects of the alcohol. this difference would favour the use of
`naltrexone in patients who are likely to consume some alcohol.
`This would explain why the patients treated with naltrexone
`reported less craving than the acamprosate group over the study
`period (Rubio et al .. 1999). It is also possible that naltrexone
`would be more effective at reducing craving in patients with
`moderate dependence. in whom craving mechanisms related
`to positive reinforcement could be over-represented. Since our
`sample was of patients with moderate dependence. this could
`explain the results obtained.
`With regards to the tolerability of both drugs, although the
`group treated with naltrexone experienced more side-effects,
`these only lasted for the first 2 weeks of the study and there
`was no significant difference in the rate of drop-out due to this.
`Limitations of this stlldy
`This was an open study. and there is the possibility that the
`investigators did not remain blinded. We tried to prevent the
`investigators from gaining direct information about the type of
`
`0
`
`3
`6
`9
`months of follow-up
`
`12
`
`Fig. 2. Survival :malysis to first relapse.
`• . n:tltrexone; • . acamprosate. *Five or more drinks per day.
`
`drugs. With regards to other research on naltrexone, in previous
`studies abstinence rates after 6 weeks were 23-62% (O'Malley
`eta/ .. 1992; Volpicelli eta/., 1992, 1997; Anton eta/ .. 1999; Chick
`eta/.. 2000b). The results of our study, which was four times
`longer than the aforementioned ones. are within this range. The
`levels of abstinence with a~:amprosate in placebo-controlled
`trials with a !-year follow-up are between 18 and 35% (Paille
`eta/ .. 1995; Sass eta/., 1996; Whitworth eta/ .. 1996; Besson eta/.,
`1998). In our study, we recorded a rate of 17%. If we extrapo-
`late these results, it seems that long-term treatment of patients
`with naltrexone is more beneficial than with acamprosate.
`Two hypotheses could explain the benefits of naltrexone
`seen in our study. First. it may be that naltrexone increases the
`period elapsed before the subject takes the first drink. Prolong-
`ing the abstinence period enables the learning of strategies
`taught in the support therapy and increases feelings of self-
`efficacy. Second. it may be that naltrexone has an effect on
`control of alcohol consumption once this has already begun.
`resulting in a delay in relapse. This could also increase the
`patients' faith in the treatment.
`The first of these hypotheses was not confirmed, because
`the survival time to the tirst drink did not differentiate between
`treatments. In contrast, the action of nal