`A
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`
`VOLUME 99 • NUMBER 7 • JULY 2004
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`Addiction
`
`Volume 99 Number 7 July 2004
`
`Blackwell
`Publishing
`
`This material was co,pcied
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`AMN1034
`IPR of Patent No. 7,919,499
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`ADDICTION
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`l( J 2£Hl·t Society fort he Study of Addict ion
`
`This materia t was <O·pi.ed
`at the NLM an<l may be
`5ubje;:t U5CoJ:>yright Laws
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`REVIEW
`
`Efficacy and safety of naltrexone and acamprosate
`in the treatment of alcohol dependence:
`a systematic review
`
`Bouza Carmen, Magro Angeles, Munoz Ana & Amate Jose Maria
`Agency for- Health Technology Assessment M.!clt·td, Sp.1i11
`
`('orrespondi'IICl' to:
`Carmen Bouza
`Agency for Ilealth Teclt!I(JI<Jgy Assessmcttf
`lnstituto de Salud Carlos Ill
`Sine~io Delgado 4
`2H112'! Madrid
`Srain
`Fax:+ H<JI lH77H41
`I·>mail: cbouza(a;isciii.es
`
`Submitted 11 ,\ugust 200 l:
`initial review completed IS October 21111l:
`final version accepted 1 ~ March 2011·l
`
`ABSTRACT
`
`Aims To ascertain the efficacy and safety of naltrcxonc and acamprosatc in
`the treatment of alcohol dependence.
`Methods Systematic review of the literature (I ':)90-2002) and meta-analysis
`of full published randomized and controlled clinical trials assessing acampro-
`satc or naltrcxonc therapy in alcohol dependence. Estimates of effect were cal-
`culated according to the fixcd-c!Tccts model.
`Measurements Relapse and abstinence rates, cumulative abstinence duration
`and treatment compliance were considered as primary outcomes.
`Findings Thirty-three studies met the inclusion criteria. Acamprosatc was
`associated with a signi!lcant improvement in abstinence rate [odds ratio (01{):
`J.SS (I. 57, 2.2 5), l' < 0.0011 and days of cumulative abstinence JWMD: 2(, 'i 5
`(I 7. 56, 36. 54[. Short-term administration of naltrcxonc reduced the relapse
`rate significantly [OJ{: 0.62 (0.52, 0.75), 1'<0.001], but was not associated
`with a significant modification in the <tbstinencc rate [OJ{: 1.26 (0.':)7, 1.64),
`l' = O.OS J, There were insufficient data to ascertain naltrcxone's dlicacy over
`more prolonged periods. 1\camprosate had a good sal'cty pattern and was asso-
`ciated with a significant improvement in treatment compliance JOR: 1.2':)
`(I. I 3, 1.4 7), I'< 0.00 IJ. Naltrcxonc's side effects were more numerous. yet the
`drug was nevertheless tolcmted acceptably without being associated with a
`lower adherence to treatment (OR: 0.':)4 (O,SO, 1.1 ). I'= 0. 'i). llowcver. overall
`compliance was relatively low with both medications.
`Conclusions
`Jloth acamprosatc and naltrcxonc arc ciTectivc as adjuvant ther-
`apies for alcohol dependence in adults. Acamprosate appears to be especially
`useful in a therapeutic approach targeted at achieving abstinence. whereas nal-
`trcxone seems more indicated in programmes geared to controlled consump-
`tion. Jloth drugs arc safe and acceptably tolerated but issues of compliance need
`to be addressed adequately to assure their usdulncss in clinical practice.
`
`KEYWORDS 1\cmnprosatc. alcohol dependence. alcoholism treatment.
`meta-analysis. naltrexone.
`
`I NTRO D UCTI 0 N
`
`At present. alcohol dependence constitutes one of the
`most serious public health problems, not only because of
`its high prevalence and impact on the personal. family.
`occupational and social spheres. but also because of its
`
`economic and medical consequences JI-S J. Treatment of
`alcohol dependence, the favourable effects of which have
`been demonstrated clearly in terms of related morbidity
`and mortality 141 and health-care costs IBJ, has made
`substantial progress in recent decades. Indeed. drugs arc
`now available that seemingly improve on the results
`
`o 2004 Society l'or the Study of Addiction
`
`This material was co-pied
`doi: I 11.1 I I I /j, I l~Y~~l;~Jd.I/IJ."t,·Jf\lJ~'yli:i\,
`~u bject US Co-·p'lright Laws
`
`t1ddiction, 99, HI I ~S2S
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`812
`
`Bouza Carmen cl al.
`
`yielded by standard techniques employed to dale in the
`management of such patients r 4-7].
`fn the forefront of the pharmacological options cur-
`rently available arc nallrcxone and acamprosalc. Nallr-
`cxonc is a pure opioid antagonist, whose favourable
`effects were first noticed in I he early 1 990s 17,9-1 J 1.
`Although its mechanism of action is not known fully, nal-
`trcxonc exerts a competitive antagonism with respect to
`the opioid receptors: this, in tum, blocks the release of
`alcohol-induced dopamine. thereby reducing the stimu-
`lus and reinforcing effects of ethanol. and with il the
`ensuing craving to drink and loss of conlrolll 11. !\cam-
`prosaic (calcium acclylhomolaurinalc) is a simple deriv-
`ative of the essential taurine amino acid and displays a
`structural resemblance to gamma-amino butyric acid
`(C;ABA). !\cam prosaic enhances CAB!\ reception and the
`transmission of the Ci\Bi\crgic system, reduced by
`chronic exposure
`to alcohol, and
`interferes with
`glutamate action in diiTcrcnl pathways, such as the
`N-mclhyi-D-aspartate (NMDA) receptors 112]. 1\campro-
`salc also acts on the calcium channels and reduces cen-
`tral nervous system hyperexcitability
`induced by
`suppression of alcohol II 31.
`llowcvcr. experience with both drugs in the field or
`dependency is still limited. While some countries have
`officially approved acamprosalc for treatment of alcohol
`dependence, others arc still engaged in gathering evi-
`dence on its efficacy and safety. Nallrcxonc has been
`approved since 1994 for the treatment of alcohol depen-
`dence but the record shows that its usc is less than might
`h<IVC been expected and that such undcrusc is clue to the
`existence of considerable uncertainty surrounding its
`activity and possible toxicity lSI.
`The aim of this study was lo analyse the collected body
`of evidence regarding
`the efficacy and safely of
`naltrcxone and acamprosalc for lrcalmcnl of alcohol
`dependence.
`
`METHODS
`
`This review confined itself to full published. randomized
`and controlled clinical trials in peer review journals,
`which compared naltrcxonc or acamprosalc with pla-
`cebo or a reference group without medication, in adults
`with alcohol clcpcndcncc. We excluded studies thai had
`fewer than I 0 participants. duration of less than 2 weeks,
`proceedings of meetings or congresses and publications
`that contained no relevant primary clinical data or failed
`to report results quantitatively. Studies were identified by
`means of a systematic search of the MEDLINE (Silvcrl'lal-
`tcr WcbSI'IRS), CINAIIL (WcbSI'IRS) and EMBASE (l'ol-
`lution and Toxicology, WcbSI'IRS) electronic databases,
`with no language restriction, covering the period January
`
`1 990-Scplcmbcr 2002 and employing the following
`terms:
`alcolwl-rclatcd-disorders.
`therapy,
`opioid-
`anlagonists. narcotic-antagonists/therapeutic usc, nallr-
`acamprosatc,
`randomized-controlled-trial.
`cxonc.
`clinical-trial. Similarly, the Cochrane Controlled Trials
`lkgistcr was examined, and bibliographies of relevant
`articles were examined manually for additional studies.
`Two reviewers evaluated and extracted the data inde-
`pendently. To extract data. we designed a specific form
`thai included the following: study design and scope:
`duration of treatment and f(Jllow-up period: inclusion
`and exclusion criteria: sample size and method employed
`for the calculation of same: interventions: type of ran-
`domization: baseline population characteristics: clinical
`outcomes and compliance with treatment. Duplic<lle
`articles were removed. During the trial selection and data
`extraction we were not masked to authors. institutions,
`journal or interventions assessed.
`
`Quality assessment
`
`Metlwdological quality and grade of scientific evidence
`was evaluated f(Jr each selected paper using the Jadml
`scale 114] and l-ladorn's guidelines II 51. respectively.
`
`Data analysis
`
`IZcvMan 4.1 software (Cochrane Collaboration 2000)
`was used to obtain a quantitative overall measure of the
`cfTect of naltrcxone and acamprosate on the outcomes of
`interest. The studies were combined, by analogy. in terms
`of type of intervention, scope, treatment period and out-
`comes. Only those studies in which the analysis and the
`form of presentation of results was comparable and
`showed no statistically significant heterogeneity were
`the Q statistic
`included. This was evaluated with
`(I'> 0.0 5) and potential reasons for hl'lerogcneity were
`explored. The mcta-<m<ilysis was conducted using a fixed-
`cfTccl model with dichotomous outcomes being analysed
`by means of l'cto's odds ratio (OR) (9 'i')(, confidence inter-
`val) and continuous outcomes using wcighll'd mean dif-
`ference 19 5% confidence interval (Cl) 1. Scores obtained in
`the assessment of methodological quality allocated no
`weight to the meta-analysis. Sensitivity analyses were
`pcrf(mned lo assess the influence of methodological
`issues such as study selling, inclusion criteria-particu-
`larly the presence or absence of another dependence and
`the existence of a prior phase of detoxification or absti-
`nence, study size and study quality on the ciTed estima-
`tion. In accordance with some recent literature we have
`not used funnel plots to examine the possibility of publi-
`cation bias, given the limitations and potential mislead-
`ing results of these graphs II6I.llclcrogcneous data were
`analysed individually. ]{csults were drawn largely from
`
`'0 2004 Society for the Study of Addiction
`
`This material was co-pcied
`at the N LM and may b,e
`~ubject USCopcyright Laws
`
`,\ddiction. 99. HI I ~S2N
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`intention-to-treat analysis and deemed signilicant at a
`value of I'< O.OS. The number needed to treat (NNT) was
`calculated using the internet-accessible Visual Rx pro-
`gram (http:/ /www.nntonlinc.nct).
`
`RESULTS
`
`Figure I summarizes the search for relevant studies.
`showing those that met the inclusion criteria. those that
`were excluded due to duplication in the publication of
`results II 0. I 7-1 ()I and I hose that were lin ally included
`[9.20-511 after eliminating redundancies arising from
`the usc of several databases.
`
`Acamprosatc versus placebo
`
`Thirteen single or double-blind randomized clinical trials
`j20-l2l (Table l) evaluated the eflicacy and safety of
`<rcamprosatc versus placebo in a total of 4000 <rdult men
`and women, who had DSM-lll or DSM-111-R (Diagnostic
`and Statistical Manual of Mental Disorders. lrd edition,
`revised: American Psychiatric Association l 9H7) alcohol
`dependence and had undergone a previous detoxification
`process. All patients presented with no unstable medical
`pathology. i\11. except the study by l{oussaux cia/. j29j,
`were conducted
`in an ambulatory setting and all
`included some type of psychosocial intervention. In some
`studies. standard adjustnwnt of acamprosatc dosage was
`made for patients' body weight. while the more recent
`
`Elficac!Jalld sa./l'I!J of rwltrc.\'Oill' mrd acanrprosalc
`
`X 13
`
`studies relied on a fixed dose. Eleven were multicentre
`studies. The duration of the studies ranged from 3 to
`24 months and they generally displayed good method-
`ological qwrlity and scicntilic evidence. i\11 studies speci-
`fied
`the withdrawals. seven
`reported
`the method
`employed I{Jr randomization j20-22.2H. 30-321. and all
`but one l2 S I report that the analysis of results was on an
`intention to treat basis. Eighty per cent of trials scored
`greater than or equal to "land 20% scored 3 on the ]adad
`scale, indicating good methodological quality. !!adorn's
`criteria showed 92'Y., of studies as having grade i\ I
`evidence.
`Outcomes considered of primary interest were: absti-
`nence rate, defined as the percentage of patients that
`complete the study without ingesting alcohol: cumula-
`tive abstinence duration (Ci\D), delined as the sum of the
`periods of abstinence during the study: and the rate of
`compliance with treatment. These outcomes proved sub-
`stantially homogeneous.
`
`Elfictll'!f
`
`lkgarding the abstinence rate, given that Roussaux's
`study 129 I entailed the institutionalization of patients
`during treatment it was considered inappropriate its
`inclusion in meta-analysis al'ter pcrl{mning a sensitivity
`analysis. The said study showed no difl<-·•-em·es between
`patients treated with acamprosate (11 = 6 3) and those
`who received placebo (II= 64) in respect to the absti-
`nence rate jl'cto's OR (95% Cl): O.X2 (0. 3l), 1.74).
`
`Trials identified as potentially relevant
`and screened for retrieval: 427
`Naltrexone: 29:1
`Acamprosate: 1:14
`
`l l:~llldomi!.ed co.ntroll~d trials: 51
`
`Controlled cl!mcal tnals: 2
`
`I
`
`Potentially appropriate trials: 37
`
`I
`...
`I Trials included: :1:1
`
`l
`
`Excluded due to total or partial
`duplication in publication of
`results: 4Hl.l?-IY
`
`I
`
`Comparisons:
`-Acamprosate versus placebo: 1:1 trials
`-Naltrexone versus placebo or reference group: I 9 trials
`-Naltrexonc versus Acamprosatc: I trial
`
`Til is mate ria I was copiied
`at th€ N LM and may be
`5ui:J.j€ct US Copyright Laws
`
`:\ddiction. 99, X I 1-XlX
`
`Figure I Process of inclusion of studies
`ilnd useable infor·m,llion
`
`'C1 2004- Society for the Study of Addiction
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`~
`I i\
`
`:-
`s.
`
`Q
`~
`
`.j:.
`X
`
`Not available
`
`Merck Lipha. Spain
`
`Lrpha. Belgium
`
`Abstinence rate, CAD
`crav1ng. compl1ance
`trial (SRD). GGT. CD1
`last dnnk and the end of the
`abstinent days between the
`Abstinence rate, CAD, no. of
`
`GG1 AS1 .AL1 CDT
`fwst dnnk. compliance, MCV.
`Abstinence rate. CAD. time to
`
`Pharmaceutrcals
`
`Lipha
`
`compliance, MCV. GGT, AST
`Abstinence rate. CAD. crav1ng.
`
`compliance. GG1 MCV.
`
`Lipha. Inc.
`
`Abstinence rate. CAD, craving.
`
`(n = 14 7); psychosocial support
`
`a = 1998 mg/day (n = 141 ), placebo:
`
`(n = 134): psychosocial support
`1332 mg/day (n = 128): placebo:
`
`a = 260 kg: 1998 mg/day, <60 kg:
`
`Anonymous
`social skills training. Alcoholics
`educational groups. manta! therapy,
`therapy. out-patient support groups,
`(n = 292); cognitive-behavioral group
`
`a = 1998 mg/day (n = 289): placebo
`P:(n = 22): psychosocial support
`(n = 55): disulfiram: a (n = 24)
`<60 kg: 1300 mg/day (n = I 0), placebo
`
`a = 260 kg: 1998 mg/day (n = 45).
`
`consumpt1on in the previous 7 days
`of DSM-111 dependence, with alcohol
`18-65 years of age. 12-month history
`
`at least 5 days
`for alcohol dependence. abstinent for
`
`18-65 years of age. DSM-111 critena
`
`least 5 days
`preceding 5 weeks, abstinent for at
`withdrawal from alcohol during the
`12-month histor-y of DSM-111 dependence,
`
`18-65 rears of age, > 60 kg.
`GGT 22 ULN. MCV >95 fl
`minimum of 5 days of abstinence
`history of DSM-111 dependence,
`
`18-65 1ears of age. 12-month
`
`Fundrng sources
`
`Outcomes
`
`lnten entrons
`
`l.r]dus;on criteiiC
`
`MCV
`compliance, GGT. AST, AL T,
`~rst drink, craving,
`
`Lipha, France
`
`Abstinence rate, CAD. time to
`
`MCV. complrance
`~rst drink, GGT. ALT. AST
`
`Lrpha. Belgium
`
`Abstinence rate, CAD. time to
`
`MCVcraving. compliance
`~rst drink. GGT. AL1 AST.
`
`Not availab'e
`
`Abstinence rate. CAD. time to
`
`rehabilitation programme
`(n = 124); community-based
`1300 mgiday (n = 122): placebo
`
`a = 260 kg 1998 mgida;: <60 kg:
`
`and social support
`(n = 63); placebo:(n = 62); counsellrng
`a = 1332 mg/day (n = 63); 1998 mg/day
`
`supportive psychotherapy
`(n = 173): placebo: (n = 177):
`a = 1.3 g/day (n = 188): 2.0 g/day
`
`(n = 290); psychotherapy
`
`Not ava1lable
`
`Compliance. GG1 AS1 MCV
`
`a = 1332 mg/day (n = 279), placebo:
`
`(n = 32)
`1332 mg/day (n = 29): placebo
`a= 260 kg: 1998 mgiday, <60 kg:
`
`history of DSM-111-R dependence
`
`7-28 days
`DSM-111-R, abstinent from alcohol for
`
`value or MCV >98 fl
`alcohol dependence, GGT 22 nonmal
`18-65 years of age, at least one sign of
`
`at least 5 days of abst1nence
`
`>95 J.l0
`abstinence, GGT 22 ULN, MCV
`DSM-111. minimum of 5 days of
`18-65 1ears of age. dependence
`
`18-65 yea~s of age. 260 kg. 12-month
`
`18-65 years of age. dependence
`
`DSM-111-R criteria for alcohol dependence.
`
`6-month post-treatment follow-up
`placebo-controlled, 6-month treatment.
`
`Multi-centre, randomized, double-blind.
`
`1997 [28]
`
`Po!drugo
`
`placebo-controlled. 3-month study
`
`Multi-centre, randomized. double-blind.
`
`1997 [27]
`
`Pelc
`
`6-month post-treatment follow-up
`placebo-controlled. 12-month treatment.
`
`Multi-centre. randomized, double-blind.
`
`1995 [26]
`
`Paille
`
`placebo-controlled. 3-month study
`
`1990 [25]
`
`Multi-centre, randomized. double-blind.
`
`Lhu1ntre
`
`post-treatment follow-up
`controlled. 6-month treatment. 6-month
`
`Randomized, double-bl1nd, placebo-
`
`1993 [24]
`
`Ladewig
`
`placebo-controlled. 6-month study
`
`2001 [23]
`
`Multi-centre, randomized. double-blind,
`
`6-month post-treatment follow-up
`placebo-controlled. 6-month treatment.
`
`Multi-centre. randomized, double-bl1nd.
`
`Gual
`
`1997 [22]
`
`Geerlings
`
`·~ z
`I z
`
`:z
`-:; :c
`
`~
`~
`
`"'
`iii
`fl.
`~ g~.
`""''""
`:::r"""
`::::!. 3
`ill
`lli
`14:_
`.g ~ ~
`iii'
`Cl
`'"
`"' ;:: '
`c:rill
`:::.z~
`ill 3
`ill
`..5! g. v;·
`I.': rl :::r
`l,o"] w -t
`
`post-treatment follow-up
`controlled. 6-month treatment. I month
`
`Multi-centre, randomized placebo-
`
`2000 [21]
`
`Chick
`
`12-month post-treatment follow-up
`placebo-controlled. 12-month treatment.
`
`1998 [20]
`
`Multi-centre, randomized. double-blind.
`
`Besson
`
`Methods
`
`Study
`
`Table I Acamprosate: characteristiCS of included studies.
`
`;:::·
`1:
`;:-
`
`~
`
`~
`;:
`
`" :i
`~
`:r:
`~
`
`'<
`
`1
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`"'
`
`X
`
`~ ,.,
`2
`s
`
`~
`;::;
`
`·~
`
`·~
`~
`
`:::::
`:~
`
`'
`~ §.
`r.
`
`2
`
`'
`n
`-· r::
`C/c r.
`~ ~ g·
`r. z
`X u ..,
`r.
`
`_-a
`?. ~ r.
`
`r. -g
`
`c.. ~
`r-::
`
`(;
`
`::;.· ~
`.:z
`
`:/0
`
`--::
`
`..,
`
`r::
`
`_
`
`z
`
`..,
`
`__
`
`...:;
`
`,....,
`
`~
`
`:r. <
`
`· ·
`
`-
`
`.... 2 n
`
`r.:
`
`""::
`
`-
`
`I+ :;:
`
`II
`
`::;
`
`:_ r. c
`
`:::-'-!" 0
`..,
`
`r. r:
`§
`
`~ -
`
`~
`
`~·
`v
`
`"B ::::!. -<
`
`~
`
`Lipha. France
`
`Lipha, France
`
`Lipha. Essen. Germany
`
`compliance
`first drink, crav1ng.
`
`Abstinence rate, CAD. time to
`compliance, COT GGT MCV
`first drink. craving.
`
`Abstinence rate, CAD. time to
`
`Not available
`
`Abstinence rate. GGT MCV.
`
`craving. compl1ance
`
`day (n = 224); placebo: (n = 224)
`a = ?60 kg: 1998 mglday, <60 kg: 1300 mg/ Abstinence rate. CAD. time to
`
`GGT
`first drink. MCV. AST ALT
`
`Alcoholics Anonymous attendance
`orientated supportive counselling and
`(n = 166). Individual behavior~
`a = 1998 mg/day (n = 164); placebo:
`(n = 136); supportive therapy
`1300 mg/day (n = 136); placebo:
`a = ?60 kg: 1998 mg/day. <60 kg:
`family counselling
`(n = 64); group. individualized and
`a = 1998 mg/day (n = 63); placebo:
`
`:::
`
`...., - 2
`
`..::;,
`
`r.
`
`~
`
`notransferase: COT: carbohy:drate-def1C1ent transferrn: MCV: rf'ean corpuscular volume: fl: femtol1tre = ~m-': ULN: upper l1m1t of normal: CAD: cumulat1ve abst1nence durat1on: SRD: sta~!e recovery Curat;on
`DSM-111. DSM-11-R D1agnost1c a:td Stat1st1cal Manual of Menta! D1sorders. 3rd edit1on~rev1sed: .Amencan Psychiatnc Assooat1on; a: acamprosa:e: p: placebo: GGT: gamma-glutamyl tra:ts•erase; AST: asoar"Late 3'1llno:ransferase: ALT: alanine ami-
`
`?2 ULN and/or MCV ?93 fL
`minimum of 5 days of abstinence. GGT
`18-65 years of age. dependence DSM~III.
`
`12~month post~treatment follow~up
`placebo~controlled. 12~month treatment,
`Multi~centre, randomized. double~blind,
`
`1996 [32]
`Whitworth
`
`?2 ULN and/or MCV ?95 fl
`dependence, 5 days of abstinence, GGT
`dependence, 2~month h1story of alcohol
`
`18-65 years of age. DSM~III~R
`
`abstinence 14-28 days
`
`3~month post~treatment follow~up
`placebo~controlled, 6~month treatment
`
`Multi~centre, randomized. double~bllnd,
`12~month post~treatment follow~up
`placebo-controlled, 12~month treatment
`
`DSM~III~R criteria for dependence.
`
`Multi~centre. random1zed. double~blind,
`
`2000 [31]
`
`Tempesta
`
`1996 [30]
`
`Sass
`
`minimum of 14 days of abst1nence
`
`controlled, 3~month study
`
`1996 [29]
`
`DSM~III critena for dependence,
`
`Random1zed. double~blind. placebo~
`
`Roussaux
`
`"titil;t~ilff~!i~
`~~~~f!I~!if!~lil~![!~ c..
`a:i!illl!liit!lll!~t!
`
`f --
`r. ,..
`~
`r.
`r.
`8_ ~ ; .g .g E 5 I+ :; 8 ;. -=-3 g ; ; s;
`r: ..,
`
`:::... ~ :r;
`c=;
`
`......
`? ~-~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 2 § ~ ~ ~ ~
`~ ;:::-S ~ i'S ~ c.. S i'S
`r.
`
`;2.
`
`-
`
`t-....1
`
`~~riHtHHH~
`
`:::-
`
`z-C/c_..,~n~----r.
`B..
`
`~
`~ ~
`
`:?
`
`::;
`
`~
`.~
`
`.., :-
`
`~j!HHHHHI
`:::"' * ~ Q 3 n r.
`~ - Vl
`
`. !21"!2cc'"':::..if.u:-::r.nc
`
`-5
`~
`r.
`~
`~
`n r.
`:l
`2 .., r.
`::; .., r:
`~ r; r. g-
`~ z
`-<: r. ..,
`:l r.
`~
`
`~ .., r.
`
`r-
`:::...
`§ ~
`~~
`
`a_ ~·
`B.. ~
`- =· ~
`~~
`~ ~ E ~·
`._.
`:J.
`~ 2
`r.
`=-
`("; -~
`:::; s
`;: §
`=· =
`~ :::
`2-c..
`~ ::
`r.
`?.
`
`~ ,......_
`
`:r;
`
`I I
`
`I "' ·~ :r.
`"'
`"' ~
`i
`§:
`
`"'
`""
`d.
`:;;-ifil
`~"'< Q
`(!'Q w r'1
`:::!. 3
`itJ
`~ fL ~
`b1 ~ ~
`~~~
`a~~
`..!:!. g. v;·
`ri ::r
`c
`l,ci] w -t
`
`5.'
`~
`
`~
`~
`
`'"' §;
`"' §"
`'£-
`:;::
`!.:::
`
`,..
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`Sl6
`
`Bouza Carll!rll et al.
`
`Comparison: 03 Acamprosate vs Placebo
`Outcome:
`01 Abstinence rate
`Treatment
`n.•ll
`
`Study
`
`Besson 1998
`Chick 2000
`Geerf1ngs 1997
`Gual 2001
`Ladewig 1993
`Paille 1995
`Pelc 1997
`Poldrugo 1997
`Sass 1996
`Tempesta 2000
`VIJ!·,itworth 1996
`
`14155
`351289
`141128
`49/141
`12129
`451361
`521126
`531122
`541136
`621164
`27 I 224
`
`Control
`n.•ll
`
`3155
`321292
`71134
`381147
`7132
`161177
`9162
`371124
`231136
`481166
`111224
`
`Peto OR
`(95%CI Fixed)
`
`Weight
`%
`
`Peto OR
`(95%CI Fixed)
`
`3.1
`12.6
`4.1
`12.9
`2.8
`101
`7.7
`12.1
`11.7
`15.5
`7.4
`
`4.56[1 63,12.76]
`1.12[0 67,1 .86]
`2 .16[0.89,5.27]
`1.52[0.92,2.52]
`2.45[083,7.18]
`1.41[0.80,2.48]
`3.37[176,644]
`1 .79[1 07,3.01 I
`3 06[1 .81 ,5 1 8]
`1 49[0 .94 ,2 .35]
`2.50[1.29,4.87]
`
`100.0
`
`1 88[157 ,2.25]
`
`T otai(95%CI)
`231 11549
`41711775
`Test for heterogeneity chi-square=17 .00 df=1 0 p=O 07 4
`Test for overall effect z=6 .87 p<O 00001
`
`•
`
`.2
`.1
`Favours placebo
`
`10
`Favours acamprosate
`
`Figure 2 Acamprosate versus placebo: results of the meta-analysis on abstinence rate. Fixed-effects model. OR: odds r·atio; Cl: conDdence
`interval.
`
`Comparison: 03 Acamprosate vs Placebo
`Outcome:
`02 Cumulative abstinence duration (CAD)
`Treatment
`Control
`n
`n
`
`mean(sd)
`
`mean(sd)
`
`Study
`
`Besson 1998
`Geerlings 1997
`Gua\2001
`Paille 1995
`Poldrugo 1997
`Tempeda 2000
`\IWJitWOtth 1996
`
`137 .00( 14 700)
`55
`128
`61.00(70.00)
`141
`9300(7500)
`361
`21 0.00(134.00)
`122 168.00(151 00)
`164 15500(11400)
`224
`230 00(259 .00)
`
`55
`75.00(1 08.00)
`134
`43.00(58.00)
`147
`74.00(75.00)
`177 17300(13700)
`124 120.00(147 .00)
`166 12700(115.00)
`224 183.00(235 .00)
`
`11 95
`T otai(95%CI)
`Test tor heterogeneity chi-square=6.71 dt=6 p=0.35
`Test tor overall effect z=5.79 p<0.00001
`
`1 027
`
`WMD
`(95%CI Fixed)
`
`Weight WMD
`(95%CI Fixed)
`%
`
`-£l-
`
`--
`--
`•
`
`3.5
`332
`269
`13.5
`5.8
`13.2
`39
`
`6200[13.79,11021]
`18 00[240,3%0]
`1900[1.67,36.33]
`3700[12.54,6146]
`4800[10.75,8525]
`28 00[329,52.71]
`47 00[120,92.80]
`
`1000
`
`2655[17 .56,35.54]
`
`-50
`·100
`Favours placebo
`
`50
`100
`Favours acamprosate
`
`Figure 3 Acamprosate versus placebo: results of the meta-analysis on cumuldtive abslinence duration (days). Fixed-effects model. WMD
`weighted mean difference
`
`was controlled without randomized allocation 136], one
`had an open-label design 14 31 and the remainder were
`single- or double-blind randomized clinical trials. or
`these, liJUr 13 5,44,45, 50 I specified the method employed
`for randomization; eight I'>.)S-42.45.461 made express
`reference to masking in the assessment of resulls: and all
`but two 141.50 I reported the withdrawals. Five 13 5-
`37.42.441 were mulli-centre
`studies. Ten
`trials
`I'>. 3 5, 3S-40,42,44-46, 511
`scored greater
`than or
`equal to 3 on the Jadad scale, indicating good quality,
`
`while Jladorn's criteria showed 65% as having grade 1\ I
`evidence.
`There was a total of 3205 participants. made up of
`adult men and women with DSM-IIl-R or DSM-IV
`(Diagnostic and Statistical Manual of Mental Disorders;
`American Psychiatric Association I ')')4) alcohol depen-
`dence. In general, with the exception of lilllr studies
`I33,34,3S,3'>1. the inclusion criteria resulled in a popu-
`lation comprising individuals who had undergone a
`phase of alcohol dctoxilication and presented with no
`
`'<) 2004 Society for the Study of Addiction
`
`This material was co-pcied
`at th-e N LM and may b-e
`~ubject USCopcyright Laws
`
`tlddirtion, '-J<J, HI I-X2X
`
`AMN1034
`IPR of Patent No. 7,919,499
`
`
`
`Table 2 Effects of acamprosatc as an adjunct to psychosocial interventions compared with placebo: overall results of the r·eview for· dichot-
`omous outcome measur·es.
`
`E.lficac!J and sa}i'l!J of wrltrexone and acamprosate
`
`81 7
`
`Placebo
`Total
`Mean effect srze,
`AcomprosCJte
`no. of
`Peto's OR
`Test for
`(cosesltotal of
`No. of sludies
`(cases/toto/
`of patients)
`heterogeneity
`polients
`patients)
`(95% C/), P-value
`contrrbuting data
`---~~------~ -----------~--------~-- -~---- - - - - - - -
`: 14.83; P = 0.19
`884/1871
`3959
`1.29 ( 1.13, 1.47), <0.00 I
`c1
`12 [20-23,25-32]
`I I 00/2088
`c2: 9.90; P = 0.36
`c2: 9.16; P = 0.31
`
`I 0 [20-23,25-27.30-32]
`
`3125
`
`314/1832
`
`178/1593
`
`1.69 ( 1.38, 2.07), <0.00 I
`
`9 [20-23,27,28.30-32]
`
`2697
`
`38/1357
`
`29/1340
`
`1.29 (0.79, 2.1 I). 0.3
`
`Outcome
`
`~~~-----
`
`Compliance with
`treatment
`Gastrointestinal side
`effects
`Discontrnuation due
`to adverse effects
`
`Fixed-effects model. OR: odds ratio; Cl: confidence rnter·val.
`
`unstable medical pathology. Only Morris 146] included
`patients with psychiatric pathology and all, except Hersh
`139]. excluded patients with active non-nicotine drug
`addiction. Apart from Knox [401. all studies were con-
`ducted in an ambulatory setting. and some type of psy-
`chosocial therapy was provided in all cases. Standard
`dosage was usually 50 mg/day. Only
`in
`two cases
`142.431 was naltrexone administered in a llxed dose for
`more than 3 months. lleinala's study r 381 had a partic-
`ular design with naltrexone being administered in a
`fixed dose for 12 weeks and in a targeted mode. only
`when craving was high. for 20 weeks. To maintain clini-
`cal homogeneity. this latter phase of the study was not
`included in the meta-analysis. Two studies 134.471 con-
`sisted of the li>llow-up phase of previously treated
`patients 19.3 31.
`Outcomes deemed to be of primary interest were
`mainly relapse and abstinence rates. lklapse was defined
`variously as: intake of~ 5 standard drinks per day for men
`and ~4 for women [9. 3 3-3 5. 3 7- 39.41]; intake of ~(,
`dr