Efficacy of Medications Approved for the Treatment of Alcohol Dependence and Alcohol Withdrawal Syndrome in Female Patients: A Descriptive Review

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1 Addictio Europea Res ear c h Review Published olie: August 29, 2015 Efficacy of Medicatios Approved for the Treatmet of Alcohol Depedece ad Alcohol Withdrawal Sydrome i Female Patiets: A Descriptive Review Roberta Agabio a Pier Paolo Pai b Atoio Preti c Gia Luigi Gessa a, d Flavia Fracoi e a Departmet of Biomedical Scieces, Sectio of Neurosciece ad Cliical Pharmacology, Uiversity of Cagliari, b Social-Health Services, Cagliari Health Public Trust (ASL Cagliari), c Uit of Psychosomatics ad Cliical Psychiatry, Uiversity Hospital, Uiversity of Cagliari, d Neurosciece Istitute, Natioal Research Coucil of Italy, Sectio of Cagliari, Cagliari, ad e Departmet of Biomedical Scieces, Uiversity of Sassari, Sassari, Italy Key Words Alcohol depedece Alcohol withdrawal sydrome Wome Pharmacotherapy Geder differeces Abstract The aim of this study was to evaluate whether the umber of wome recruited for studies to establish the efficacy of medicatios approved for treatmet of alcohol depedece (AD) ad of alcohol withdrawal sydrome (AWS) is sufficiet to reveal possible geder differeces i the respose to these medicatios ad i suggestig the use of differet doses i female patiets. Our results show that the rates of wome recruited for studies evaluatig the efficacy of disulfiram (1%), bezodiazepies (3%), ad aticovulsats (13%) were too low to establish possible geder differeces. The rates of wome recruited for studies evaluatig the efficacy of acamprosate (22%), altrexoe (23%), ad almefee (30%) were higher ad allowed evaluatio of data obtaied for female patiets. Wome receive medicatios for treatmet of AD ad/or AWS for which efficacy has bee demostrated i studies i which me were more largely represeted S. Karger AG, Basel Itroductio Pharmacotherapy is emergig as a valuable tool for the treatmet of alcohol depedece (AD), but oly a few medicatios are available to date. Curretly, medicatios approved i the Uited Kigdom ad/or i the Uited States for AD treatmet to help patiets achieve abstiece, or at least to reduce alcohol cosumptio, comprise disulfiram, altrexoe, acamprosate, almefee ad gamma-hydroxybutyrate (GHB) [1 3]. Briefly, disulfiram is the oldest medicatio for the treatmet of AD, approved by the FDA sice 1948 [3]. Its mechaism of actio ivolves ihibitio of aldehyde dehydrogease (ALDH), the ezyme resposible for covertig acetaldehyde to acetate durig alcohol metabolism, which leads to the accumulatio of acetaldehyde after alcohol itake [4]. Accumulatio of acetaldehyde causes a cosequet aversive reactio that deters further alcohol use [5]. Accordigly, disulfiram is idicated for the prevetio of relapse i abstiet patiets. G.L.G. ad F.F. cotributed equally to this work. karger@karger.com S. Karger AG, Basel /15/ $39.50/0 Roberta Agabio, MD Departmet of Biomedical Scieces, Sectio of Neurosciece ad Cliical Pharmacology Uiversity of Cagliari, Cittadella Uiversitaria S.S. 554, km , IT 09042, Moserrato CA (Italy) uica.it

2 Naltrexoe is a competitive atagoist of μ-opioid receptors, approved by the FDA i 1994 for the treatmet of AD [2, 3]. Its mechaism of actio is ot fully uderstood [2]. As the rewardig effects of alcohol are partly mediated through the opioid receptors, blockig of these receptors could explai the reductio i reward effects iduced by alcohol cosumptio ad subsequetly the reductios i itake ad cravigs for alcohol [6]. Cocers about low adherece for oral formulatios led to the developmet of slow-release formulatios of altrexoe [6]. Nalmefee is a μ-opioid atagoist, like altrexoe, but, compared to altrexoe, almefee has a loger plasma half-life, higher bioavailability, ad lower liver toxicity [7]. This medicatio has bee recetly approved by the Europea Committee for Medicial Products for Huma Use for the treatmet of AD [8]. I the Uited States, acamprosate is curretly the most widely prescribed medicatio to prevet AD relapse [9, 10]. The mechaism of actio of acamprosate is ot completely kow. It shares similarities with several amio acids, such as glutamate, gamma-amiobutyric acid, aspartate, glycie, ad taurie [11]. Covergig evidece idicates that acamprosate ormalises a hyper-glutamatergic state caused by extesive alcohol exposure ad repeated phases of alcohol withdrawal, restorig the balace betwee ihibitory ad excitatory eurotrasmitters, ad atteuatig alcohol cravig [12]. GHB is a edogeous eurochemical curretly marketed i some Europea coutries for the treatmet of AD [13]. The mechaism of actio of GHB i the treatmet of AD is substitutive [1]. While substitutio therapy carriers a lower risk tha the use of the substace of abuse, the substitute also has a potetial for abuse, ad cases of GHB itoxicatio have bee reported [14, 15]. For this reaso, i the Uited States, GHB has ot bee approved for the treatmet of AD [13]. Fially, medicatios approved i the Europe ad/or the Uited States for the treatmet of alcohol withdrawal sydrome (AWS) comprise bezodiazepies (e.g. diazepam, chlordiazepoxide, ad lorazepam), aticovulsats (e.g. carbamazepie, valproic acid, ad pheytoi), ad GHB [16 18]. Ufortuately, AD medicatios are ot effective i all ad the magitude of the respose to these medicatios is geerally modest [3]. To improve the efficacy of AD medicatios, there is growig iterest i ivestigatig possible factors that mediate the respose to pharmacotherapy, such as differet patiet characteristics ad geetic factors [19, 20]. It is otable that wome ad me vary largely i terms of biological ad psychosocial-cultural factors ivolved i the respose to medical treatmets, ad sex differeces i respose to medicatios have bee described for several treatmet methods [21 25]. For istace, it has bee observed that wome elimiate the hypotic medicatio zolpidem more slowly tha me do, ad lower doses of this medicatio have bee recommeded for wome compared to me [26, 27]. Similarly, wome could differ from me i the respose to medicatios approved for treatmet of AD ad/or AWS. Wome differ from me with regard to several AD aspects [28 34]. This metal disorder is twice as prevalet i me as i wome [35], although wome suffer serious egative cosequeces of alcohol cosumptio much early i life ad to a greater degree tha me. I additio, wome also experiece specific alcohol-related problems, such as the risk of foetal alcohol sydrome if alcohol is cosumed durig pregacy [36, 37]. The higher vulerability to the developmet of alcohol-related cosequeces i wome is, at least i part, due to sex differeces i alcohol pharmacokietics. The risk of medical cosequeces is related to blood alcohol cocetratio, ad after drikig equivalet amouts of alcohol, wome achieve higher blood alcohol cocetratio tha me of similar body weight [38 40]. This occurs because wome have a smaller volume of distributio (due to a higher proportio of body fat ad lower body water tha me) ad a lower first-pass metabolism of alcohol tha me (because of lower levels of the gastric ezyme that metabolises alcohol: alcohol dehydrogease) [38]. For these reasos, wome are advised to cosume lower amouts of alcohol tha me do. Geder differece has also bee described as a importat factor i determiig alcohol cosumptio, as well as the respose to alcohol at comparable blood alcohol cocetratio. For istace, i humas ad o-huma adult primates, males cosume higher amouts of alcohol tha females [33, 41] do, while i rodets, females cosume higher amouts of alcohol tha males [42, 43]. Moreover, aggressive behaviour after alcohol cosumptio is less evidet i wome tha i me [44], ad female rats are more sesitive tha males to alcohol-iduced hypothermia [45]. Both aimal ad cliical studies have foud that females ted to develop less severe AWS tha males [31, 46]. Complex iteractios betwee itrisic sex differeces i brai orgaizatio ad the activatioal effects of circulatig goadal steroids, euroactive steroids (steroids sythesised i the brai, adreals, ad goads that affect euroal excitability), ad stress hormoes have bee proposed to explai these fidigs [47, 48]. For istace, as allopregaoloe, a metabolite of 2 Agabio/Pai/Preti/Gessa/Fracoi

3 progesteroe, has show a aticovulsat effect i some precliical models, the curret hypothesis is that females ad males might have differet sesitivity to AWS owig to the effects of eurosteroids [47, 49]. Some of the sex differeces observed i alcohol cosumptio ad/or i resposes to alcohol have bee attributed to differeces i levels of oestroges ad adroges betwee wome ad me. Ideed, it has bee observed that oestroge ad adroge levels modulate the mesocorticolimbic reward dopamiergic system [50], ad that wome release less amouts of dopamie i the vetral striatum compared to me after acute alcohol cosumptio [51]. Huma ad precliical studies have also show that the patter of alcohol cosumptio varies throughout the differet phases of the mestrual cycle, ad these differeces have bee attributed, at least i part, to differet levels of oestroges ad progesteroe [50]. I view of all these sex differeces, it ca be hypothesised that wome ad me might also differ i their respose to medicatios approved for treatmet of AD ad/or AWS, ad might require differet doses of these medicatios. To test this hypothesis, we performed a descriptive review of studies o the efficacy of these medicatios to evaluate: (a) whether a sufficiet umber of wome were recruited to evaluate possible sex differeces i the respose; (b) if the umber of wome was sufficiet, whether sex differeces i the respose were observed; ad (c) the doses admiistered i these studies. To this ed, recet meta-aalyses evaluatig the efficacy of AD ad/or AWS medicatios were selected. From these meta-aalyses, data o female patiets ad medicatio doses admiistered were collected. Whe this iformatio was ot available i the selected meta-aalyses, the primary cliical trials were examied. Methods Search Methods for Idetificatio of Reviews A systematic search was coducted o PubMed/Medlie ad the Cochrae database of Systematic Reviews to idetify metaaalyses o the efficacy of medicatios approved for AD ad AWS treatmet. A first systematic search was coducted usig the keywords pharmacological treatmet (mesh) AND alcohol depedece (mesh), ad a secod systematic search usig the keywords pharmacological treatmet (mesh) AND alcohol withdrawal sydrome. I both searches, the filters meta-aalysis, Humas, ad Eglish laguage were activated. The search was performed i August Whe o meta-aalysis was foud for a medicatio, a maual search throughout the readig of the other selected metaaalyses was coducted. Whe more tha oe eligible meta-aalysis was available for the same medicatio, the more recet oe was selected. Criteria for Cosiderig Reviews for Iclusio Oly meta-aalyses o the efficacy of medicatios already approved for AD ad/or AWS treatmet were icluded. Other iclusio criteria were (1) use of rigorous methods to miimise bias, (2) diagosis of AD ad/or AWS accordig to appropriate stadard criteria (e.g. the criteria of Diagostic ad Statistical Maual of Metal Disorders), ad (3) compariso betwee the results obtaied by patiets treated with the pharmacological itervetio ad those obtaied by patiets treated with placebo. Recet primary cliical trials ot yet part of the selected meta-aalyses were ot icluded. I the first search, oly meta-aalyses o oe of the followig medicatios were icluded: (1) altrexoe, (2) acamprosate, (3) almefee, (4) disulfiram, ad (5) GHB. I the secod search, oly meta-aalyses o oe of the followig medicatios approved for AWS treatmet were icluded: (1) bezodiazepies, (2) aticovulsats, ad (3) GHB. Assessmet of the Methodological Quality of Icluded Reviews The quality of the icluded reviews was ot evaluated, as it was assured by selectig meta-aalyses. Data Extractio ad Maagemet From each selected meta-aalysis, the followig iformatio was collected: (1) umber of radomised cotrolled trials (RCTs) evaluated; (2) umber of patiets recruited by these RCTs; (3) umber of RCTs i which oly male patiets were recruited; (4) umber of RCTs i which the sex of patiets was ot idicated; (5) umber of RCTs i which female ad male patiets were recruited; (6) umber of RCTs i which oly female patiets were recruited; (7) medicatio doses admiistered (whe this iformatio was ot specified by the meta-aalysis, it was obtaied from the origial article o the RCT); ad (8) levels of medicatio efficacy assiged by the meta-aalysis, regardless of patiet sex. From this iformatio, the followig data were calculated: (1) the rate of female patiets amog patiets for whom sex was kow; (2) the highest ad lowest doses used i ay RCTs. Sufficiet Number of Female Patiets Recruited for RCTs Cosiderig that the lifetime prevalece of AD is twice as high i me as i wome [35], female patiets should costitute approximately oe-third of the sample of patiets recruited i studies evaluatig the efficacy of medicatios for this disorder (33% of patiets). Assessmet of Efficacy For each medicatio (or class of medicatios), the efficacy, regardless of the sex of the patiet, evaluated by the selected metaaalysis was expressed i levels ( table 1 ) [52 54]. Whe a metaaalysis showed superiority of a medicatio to placebo, level A1 was assiged; whe a meta-aalysis did ot show superiority of a medicatio to placebo, level C was assiged. The efficacy of each medicatio i female patiets was assiged accordig to the criteria provided i table 1, cosiderig the source of the evidece ad possible egative results. Results The first search for meta-aalyses of medicatios approved for AD treatmet idetified 79 articles. Amog these, 75 were excluded (see olie suppl. refereces; Medicatios for AD Wome 3

4 Table 1. Levels of efficacy Level Source of the evidece If egative RCTs do exist A1 A2 Oe meta-aalysis shows superiority to placebo (with a arrow cofidece iterval i at least 3 RCTs, at least oe of which was large) At least 2 positive RCTs show superiority to placebo (with a arrow cofidece iterval i at least 1 large RCT) They have already bee evaluated by the meta-aalysis They are outweighed by: (1) a meta-aalysis o all available studies showig o-iferiority to a established comparator treatmet, or (2) at least 2 more positive studies showig superiority to placebo B Oe or more RCTs shows superiority to placebo They are outweighed by: (1) a meta-aalysis of all available studies showig o-iferiority to a established comparator treatmet, or (2) at least 1 more positive study showig superiority to placebo C Icosistet evidece from ay umber of RCTs They are ot outweighed by positive RCTs This table summarises how the level of efficacy was established, cosiderig the source of the evidece ad possible egative results. RCTs = Radomised, cotrolled trials based o a double-blid, parallel-group desig. Large = Number of patiets recruited 100 subjects. for all olie suppl. material, see / ) ad 4 were selected [55 58] (table 2 ). Aother article was added after a maual search [59]. Oe meta-aalysis specifically ivestigated the efficacy of acamprosate i AD wome [57]. Reasos for exclusio of meta-aalyses are listed i olie supplemetary table S1. Iformatio collected from the selected meta-aalyses is summarised i table 2. Briefly, the meta-aalysis selected for disulfiram evaluated the results obtaied by 11 RCTs i which 1,521 patiets were recruited ad did ot fid a sigificat effect of this medicatio o abstiece, regardless of patiet sex [59]. Accordigly, the level C of efficacy was assiged to this medicatio ( table 2 ). The rates of wome recruited i these 11 RCTs are show by table 3. Globally, (a) 7 RCTs recruited oly male patiets ( = 1,133 me), (b) 1 study did ot idicate the geder of subjects ( = 39 patiets), whereas (c) 3 RCTs recruited both male ad female patiets (92 wome i a total sample of 349 patiets (26.4%)). Amog the 1,482 patiets for whom the sex was kow, 92 were wome (6.2%). Oly 3 RCTs compared disulfiram to placebo, ad the rate of wome recruited i these RCTs was too low (9 wome i a sample of 759 patiets (1.2%)) to allow a geder aalysis ( tables 2 ad 3 ; fig. 1 ). The dose of disulfiram raged from 100 mg per day to 800 mg twice a week [59]. Oly oe study icluded i the meta-aalysis adjusted the daily dose of disulfiram accordig to body weight [60]. I this study, the dose of disulfiram was 100 or 200 mg oce a day, or 400 mg twice a week, but it was ot specified whether wome received lower doses of disulfiram tha me did [60]. The meta-aalysis selected for acamprosate evaluated the results obtaied by 24 RCTs ad foud that this medicatio sigificatly reduced the risk of ay drikig after detoxificatio (14% lower risk), ad icreased the cumulative duratio of abstiece (3 additioal days a moth) [56]. Accordig to these results, the level A1 of efficacy for AD treatmet was assiged to acamprosate, regardless of sex ( table 2 ). The rates of wome recruited i these 24 RCTs are show by table 4. Globally, (a) 2 RCTs recruited oly male patiets ( = 85 me), whereas (b) the other 22 RCTs recruited both female ad male patiets (1,326 wome i a sample of 6,062 patiets (21.9%)). All the RCTs compared acamprosate to placebo. Amog the total sample of patiets ( = 6,147 patiets), 1,326 were wome (21.9%). The rate of wome recruited for RCTs evaluatig the efficacy of acamprosate was close to the real frequecy of female patiets with AD ad allowed a geder aalysis ( tables 2 ad 4 ; fig. 1 ). Specifically, the secod meta-aalysis selected foud o sex differeces i all the outcomes evaluated [57]. Accordig to these results, the level A1 of efficacy for AD treatmet was assiged to acamprosate for AD female patiets ( table 2 ). The daily dose of acamprosate raged from 1,332 to 3,000 mg; i most studies, the dose was adjusted accordig to body weight (1,332 mg for body weight <60 kg; 1,998 mg for 60 kg) [56]. It was ot specified whether wome received lower doses of acamprosate tha me did. 4 Agabio/Pai/Preti/Gessa/Fracoi

5 Table 2. Iformatio collected by selected meta-aalyses o medicatios approved for the treatmet of alcohol depedece Medicatio Disulfiram Acamprosate Naltrexoe NalmefeeGHB Selected meta-aalyses Jørgese et al., 2011 [59] Röser et al., 2010 [56] Röser et al., 2010 [55] Röser et al., 2010 [55] Le oe et al., 2010 [58] Characteristics of RCTs evaluated by the selected meta-aalyses Total umber, Total patiets recruited i these RCTs, 1,521 6,147 6, RCTs i which oly male patiets were recruited, RCTs i which the sex of patiets was ot idicated, RCTs i which male ad female patiets were recruited, RCTs i which oly female patiets were recruited, Patiets for whom sex was kow, 1,482 6,147 6, Wome, 92 1,326 1, Wome, % of patiets for whom sex was kow Characteristics of RCTs evaluated by the selected meta-aalyses i which medicatios were compared to placebo Total umber, Total patiets recruited i these RCTs, 759 6,147 6, Wome, 9 1,326 1, Wome, % of patiets for whom sex was kow Lower dose used by some RCTs orally, 100 mg, oce a day Higher dose used by some RCTs orally, 800 mg, twice a week orally, 333 mg, 3 times a day orally, 1,500 mg, twice a day orally, 25 mg, oce a day; i.m., 150 mg, every 4 weeks orally, 100 mg, oce a day; i.m., 400 mg, every 4 weeks orally, 5 mg, oce a day orally, 80 mg, 2 times a day Level of efficacy regardless of patiet sex C A1 A1 C C Level of efficacy i female patiets? A1 ot clear?? orally, 50 mg/kg, divided ito 6 daily admiistratios orally, 150 mg/kg, divided ito 3 daily admiistratios This table summarises iformatio collected by selected meta-aalyses o the efficacy of medicatios approved for the treatmet of alcohol depedece. i.m. = Itramuscularly. Levels of efficacy rage from A1 (the best) to C (the worst). Medicatios for AD Wome 5

6 Rates of patiets (%) Me ad wome recruited i the RCTs coducted to evaluate the efficacy of medicatios approved for the treatmet of alcohol depedece Me Wome Color versio available olie Fig. 1. Rates of male ad female patiets recruited i radomised, placebo-cotrolled trials coducted to evaluate the efficacy of AD medicatios Disulfiram 3 RCTs 759 patiets Acamprosate 24 RCTs 6,147 patiets Naltrexoe 46 RCTs 6,380 patiets Nalmefee 3 RCTs 396 patiets GHB 2 RCTs 88 patiets Table 3. Number of female patiets recruited i the RCTs evaluated by the meta-aalysis etitled The efficacy of disulfiram for the treatmet of alcohol use disorder by Jørgese et al., 2011 [59] Study Wome Total 1 De Sousa ad De Sousa, De Sousa ad De Sousa, De Sousa ad De Sousa, De Sousa et al., Fuller ad Roth, Fuller et al., Laaksoe et al., 2008 [60] Nava et al., Niederhofer ad Staffe, Toese et al., Ulrichse et al., 2010.a..a. 39.a. = Data ot available. I bold: studies i which disulfiram was compared to placebo. Refereces are listed i olie supplemetary refereces. The meta-aalysis selected for altrexoe revealed that both oral ad ijectable log-actig formulatios of this medicatio are superior to placebo primarily i reducig the risk of heavy drikig [55]. This meta-aalysis evaluated the results of 50 RCTs: (a) 43 RCTs, i which patiets received the oral formulatio of altrexoe, (b) 4 RCTs i which patiets received the ijectable logactig formulatio of altrexoe, ad (c) 3 RCTs i which patiets received almefee (see below). The rates of wome recruited i the 50 RCTs evaluated by this metaaalysis for altrexoe are show by table 5. Naltrexoe was admiistered at fixed doses, regardless of body weight [55]. The daily dose of oral altrexoe raged from 25 to 150 mg; most trials used 50 mg per day. Ijectable altrexoe was admiistered at 4-week itervals at doses betwee 150 ad 400 mg. Accordig to the results obtaied by the meta-aalysis selected, the level A1 of efficacy for AD treatmet was assiged to altrexoe, regardless of sex ( table 2 ). Amog the 47 RCTs for altrexoe (icludig 6,437 patiets), globally, (a) 1 study did ot idicate the umber ad geder of patiets recruited, (b) 10 RCTs recruited oly male patiets ( = 721), (c) 35 RCTs recruited both male ad female patiets (1,376 wome i a sample of 5,613 subjects (24.5%)), ad, iterestigly, (d) 1 recruited oly female patiets ( = 103). Amog the 6,437 patiets for whom the sex was kow, 1,479 were wome (23.0%). Forty-six RCTs compared altrexoe to placebo recruitig 1,468 wome, i a sample of 6,380 patiets (23.0%). The rate of wome recruited for evaluatig the efficacy of altrexoe may allow compariso of results betwee female ad male patiets. However, this meta-aalysis did ot coduct a geder aalysis [55]. Moreover, the majority of the studies evaluated by the meta-aalysis did ot report the results obtaied by female patiets i detail, while the few studies i which this iformatio was reported foud cotrastig results. Namely, the RCT i which oly female patiets were recruited failed to demostrate a sigificat effect of altrexoe [61]. I this RCT, altrexoe did ot improve drikig outcomes, although altrexoe delayed the o- 6 Agabio/Pai/Preti/Gessa/Fracoi

7 Table 4. Number of female patiets recruited i the RCTs evaluated by the meta-aalysis etitled acamprosate for alcohol depedece by Röser et al., 2010 [56] StudyWome Total 1 Ato et al., Baltieri ad Adrade, Barrias et al., Besso et al., Borg, Chick et al., Geerligs et al., Gual ad Lehert, Kiefer et al., Ladewig et al., Lhuitre et al., Lhuitre et al., Maso et al., StudyWome Total 14 Morley et al., Namkoog et al., Niederhofer ad Staffe, Paille et al., Pelc et al., Pelc et al., Poldrugo F, Roussaux et al., Sass et al., Tempesta et al., Whitworth et al., Refereces are listed i olie supplemetary refereces. Table 5. Number of female patiets recruited i the RCTs evaluated by the meta-aalysis etitled opioid atagoists for alcohol depedece by Röser et al., 2010 [55] Study Wome Total 1 Ahmadi ad Ahmadi, Ato et al., Ato et al., 2004 [68] Ato et al., Ato et al., 2006 [65] Auriacombe et al., 2000.a..a..a. 7 Balldi et al., Baltieri et al., Brow et al., Chick et al., de Goes ad Castro, Galarza et al., Garbutt et al., 2005 [63] Gastpar et al., Guardia et al., Heiala et al., Hersh et al., Huag et al., Johso et al., Johso et al., Kiefer et al., Killee et al., Krazler et al., Krazler et al., Krazler et al., Krystal et al., Latt et al., Study Wome Total 28 Lee et al., Martiotti et al., Maso et al., 1994 [66] Maso et al., 1999 [67] Moterosso et al., Moti et al., Morley et al., Morris et al., O Malley et al., O Malley et al., 2007 [61] O Malley et al., Osli et al., Osli, Osli et al., Petrakis et al., Petrakis et al., Pettiati et al., 2008a Pettiati et al., 2008b [62] Schmitz et al., Schmitz et al., Volpicelli et al., Volpicelli et al., Ziólkowski, a. = Data ot available. I bold: studies for almefee. I italic: studies i which altrexoe was ot compared to placebo. Refereces are listed i olie supplemetary refereces. Medicatios for AD Wome 7

8 Table 6. Number of female patiets recruited i the RCTs evaluated by the meta-aalysis etitled Gamma-hydroxybutyrate (GHB) for treatmet of alcohol withdrawal ad prevetio of relapses by Leoe et al., 2010 [58] StudyWome Total 1 Addolorato et al., 1999 [72] Caputo et al., Caputo et al., Ceccati et al., Di Bello et al., Elsig et al., Ferri et al., 1991.a..a Gallimberti et al., Gallimberti et al., Nava et al., Nava et al., 2007 [74].a..a Nimmerrichter et al., Stella et al., a. = Data ot available; I bold: studies i which GHB was compared to placebo. I italic: studies i which GHB was admiistered to reduce the severity of AWS. Refereces are listed i olie supplemetary refereces. set of subsequet drikig days amog wome who lapsed. This RCT also foud a higher proportio of adverse effects amog wome treated with altrexoe (77%) tha amog those who received placebo (52%). Aother RCT evaluated the efficacy of a higher dose of altrexoe compared to the typical oe (150 mg istead of 50 mg per day) i 164 patiets (48 wome) with co-occurrig cocaie ad AD [62]. The results showed that me treated with altrexoe had reductios i cocaie ad alcohol use ad drug severity, whereas wome did ot beefit from this treatmet. I fact, wome who received altrexoe used more cocaie ad had higher rates of drikig tha wome treated with placebo. Aother RCT foud that admiistratio of ijectable formulatios of altrexoe yielded sigificat results i me (423 patiets) but ot i wome (201 patiets) [63]. I the latter RCT, wome were more likely to report ausea tha me. Coversely, a post-hoc aalysis of aother RCT evaluated by the meta-aalysis (160 patiets; 42 wome) foud that AD wome treated with 50 mg of altrexoe per day abstaied from alcohol for a loger period tha AD me did [64]. Fially, the COMBINE study foud that altrexoe iduced similar beefits i both me ad wome [65]. Accordig to these results, it is ot clear if wome respod differetly to altrexoe ( tables 2 ad 5 ). The meta-aalysis selected for almefee evaluated the results obtaied by 3 RCTs ad foud o sigificat differeces betwee patiets who received this medicatio ad those who received placebo [55]. Accordigly, the level C of efficacy was assiged to this medicatio, regardless of patiet sex ( table 2 ). Globally, the 3 RCTs recruited 117 wome i a total sample of 396 subjects (29.5%), ad all RCTs compared almefee to placebo ( table 5 ). The rate of wome recruited for RCTs evaluatig the efficacy of almefee was close to the real frequecy of female patiets with AD. However, the meta-aalysis did ot coduct a geder aalysis, ad the studies did ot report the results obtaied by female patiets i detail [55, 66 68]. Accordig to these results, it is ot clear if wome may respod differetly to almefee. The doses of almefee raged from 5 to 80 mg [55]. The meta-aalysis selected for GHB foud that patiets who received this medicatio achieved better results tha patiets who received placebo i treatmet of both AD ad AWS [58]. This meta-aalysis evaluated the results obtaied by 7 RCTs (icludig 345 patiets) i which GHB was admiistered to reduce the risk of relapses, ad 6 RCTs (icludig 286 patiets) i which GHB was admiistered to reduce the severity of AWS. The rates of wome recruited i these 13 RCTs are show by table 6. Globally, amog the 7 RCTs for the prevetio of relapses (a) 1 study did ot idicate the geder of patiets ( = 40), whereas (b) the other 6 RCTs recruited both male ad female patiets for a total of 74 wome i a sample of 305 patiets (24.3%). Amog the 305 patiets for whom the sex was kow, 74 were wome (24.3%). Oly 2 RCTs compared GHB to placebo (28 wome i a sample 88 subjects (31.8%)). Amog the 6 RCTs for AWS treatmet (a) 2 studies did ot idicate the geder of patiets ( = 63), (b) 1 RCT recruited oly male patiets ( = 42), whereas (c) 3 RCTs recruited both male ad female patiets for a total of 25 wome i a sample of 181 patiets (13.8%). Amog the 223 patiets for whom the sex was kow, 25 were wome (11.2%). Oly 1 RCT compared GHB to placebo (7 wome i a sample of 23 patiets (30.4%)). Cosiderig the low umber of patiets recruited by RCTs, the level C of efficacy was assiged to GHB both for AD ad AWS, regardless of sex ( tables 2 ad 7 ). The daily dose of GHB was always adjusted accordig to body weight (50 mg/kg body weight, divided ito 3 daily doses) [58]. It was ot specified whether wome received lower doses of GHB tha me did. Globally, the 4 meta-aalyses selected reviewed 92 RCTs for AD treatmet, i which almost 15,000 patiets were recruited ( table 2 ). Amog these 92 RCTs, 19 (approximately 21%) recruited oly male 3 studies 8 Agabio/Pai/Preti/Gessa/Fracoi

9 Table 7. Iformatio collected by selected meta-aalyses o medicatios approved for the treatmet of alcohol withdrawal sydrome Medicatio Bezodiazepies Aticovulsats GHB Selected me ta-aalyses Amato et al., Miozzi et al., Leoe et al., 2010 [69] 2010 [70] 2010 [58] Characteristics of the RCTs evaluated by the selected meta-aalyses Total umber of RCTs evaluated, Total patiets recruited i these RCTs, 4,612 4, RCTs i which oly male patiets were recruited, RCTs i which the sex of patiets was ot idicated, RCTs i which male ad female patiets were recruited, RCTs i which oly female patiets were recruited, Patiets for whom sex was kow, 4,025 3, Wome, Wome, % of patiets for whom sex was kow Characteristics of the studies evaluated by the selected meta-aalyses i which medicatios were compared to placebo Total umber of these RCTs, Total patiets recruited i these RCTs, 1,301 1, Wome, Wome, % of patiets for whom sex was kow Level of efficacy regardless of patiet sex A1 C C Levels of efficacy i female patiets??? This table summarizes iformatio collected by selected meta-aalyses o the efficacy of medicatios approved for the treatmet of alcohol withdrawal sydrome. Levels of efficacy rage from A1 (the best) to C (the worst). (3%) did ot specify the sex of 1 RCT recruited oly female ad the other 69 RCTs (75%) recruited both female ad male patiets. The rate of wome (amog patiets of whom sex was kow) recruited by the RCTs i which the efficacy of medicatios was compared to that of placebo varied from 1.2% for disulfiram to 31.8% for GHB. Noe of the RCTs evaluated by selected meta-aalyses reported the use of differet doses of medicatios for female patiets. The secod search for meta-aalyses for AWS medicatios idetified 21 articles: of these, 17 were excluded (see olie suppl. refereces) ad 4 were selected [58, 69 71]. A meta-aalysis ivestigated the efficacy of GHB for the treatmet of both AD ad AWS [58]. Fially, 1 article was a overview of meta-aalyses that compared the efficacy of differet AWS medicatios [71]. Reasos for exclusio of meta-aalyses are listed i olie supplemetary table S2. Iformatio collected from the selected meta-aalyses is summarised i table 7. The meta-aalysis selected for bezodiazepies evaluated the results obtaied by 65 RCTs, i which 4,612 patiets were icluded, ad demostrated a sigificat effect of this class of drugs compared to placebo i treatmet of AWS [69]. Accordigly, the level A1 of efficacy was assiged to bezodiazepies, regardless of patiet sex. The rates of wome recruited i these 65 RCTs are show by table 8. Globally, (a) 21 RCTs recruited oly me ( = 1,726), (b) 9 studies did ot idicate the geder of patiets ( = 587 patiets), ad (c) 35 RCTs recruited both male ad female patiets (414 wome i a sample of 2,249 subjects (18.4%)). Amog the 4,025 patiets for whom the sex was kow, 414 were wome (10.3%). Twelve RCTs compared bezodiazepies to placebo ( table 8 ). Amog them, (a) 7 RCTs recruited oly male patiets ( = 1,035 patiets), (b) 1 study did ot idicate the geder of subjects ( = 91 patiets), ad (c) 4 RCTs recruited both male ad female patiets (42 wome i a sample of 175 subjects (24%)). Amog the 1,210 patiets for whom the sex was kow, 42 were wome (3.5%). I the evaluatio of the efficacy of bezodiazepies compared to that of placebo, the meta-aalysis icluded oly 3 of these 12 RCTs: amog them, 1 recruited oly male patiets ( = 537 patiets), ad the other 2 recruited 13 wome ad 78 me. Globally, these 3 RCTs recruited 13 wome i a sample of 628 patiets (equal to 2.1%). The low umber of wome recruited i these RCTs did ot allow the evaluatio of possible geder differeces i the respose to these medicatios ( fig. 2 ; tables 7 ad 8 ). Amog all 65 RCTs evaluated by the meta-aalysis, oly 3 Medicatios for AD Wome 9

10 Table 8. Number of female patiets recruited i the RCTs evaluated by the meta-aalysis etitled bezodiazepies for alcohol withdrawal by Amato et al., 2010 [69] Study Wome Total 1 Addolorato et al., 1999 [72] Addolorato et al., 2006 [73] Adioff, Asoms et al., Ato et al., Bailly et al., Baumgarter ad Rowe, Baumgarter ad Rowe, Borg et al., Brow et al., 1972.a..a Burroughs et al., 1985a Burroughs et al., 1985b Choi et al., Daeppe et al., Day et al., Dio et al., Favre et al., Fuderburk et al., Gillma ad Lichtigfeld, 2004.a..a Gillmer, Golbert et al., Jauhar et al., 2000.a..a Kaim et al., Kaim ad Klett, Kalyocu et al., Koli ad Liet, Kramp ad Rafaelse, Krupitsky et al., Kumar et al., Lapierre et al., Lezehuber et al., Lepola et al., Logo et al., Lucht et al., Malcolm et al., Malcolm et al., Study Wome Total 37 Malcolm et al., Marti, McGrath, 1975.a..a McLedo ad Fabre, Medels et al., Mielke et al., 1976.a..a Miller ad McCurdy, Mukherjee, 1983.a..a Narajo et al., Nava et al., 2007 [74] O Brie et al., Overall et al., 1973.a..a Palestie ad Alatorre, Pea-Ramos, 1977.a..a Pea-Ramos ad Horberger, Radouco-Thomas et al., Ritso ad Chick, Ruio ad Fowler, 1978.a..a Saitz et al., Saletu et al., Sellers et al., Sellers et al., Solomo et al., Spies et al., Spies et al., Stuppaeck et al., Tubridy, Wilso ad Vulcao, Worer, a. = Data ot available. I bold: studies i which a BDZ was compared to placebo. I italic: studies aalysed by the metaaalysis for the evaluatio of the efficacy of bezodiazepies compared to placebo. Refereces are listed i olie supplemetary refereces. studies adjusted bezodiazepie doses accordig to body weight [72 74]. I these studies, a daily oral dose of diazepam of mg/kg body weight was admiistered for 6 days; the the dose was tapered off by 25% daily util day 10 i 139 comprisig 24 wome. However, iformatio o female patiets was ot provided. The meta-aalysis selected for aticovulsats evaluated the results obtaied by 58 RCTs, icludig 4,218 ad failed to demostrate a sigificat effect of aticovulsats compared to placebo i treatmet of AWS [70]. Accordigly, the level C of efficacy was assiged to aticovulsats, regardless of patiet sex. The rates of wome recruited i these 58 RCTs are show by table 9. Globally, (a) 11 RCTs recruited oly me ( = 905), (b) 8 studies did ot idicate the geder of patiets ( = 599 patiets), ad (c) 39 RCTs recruited both male ad female patiets (460 wome i a sample of 2,714 subjects (16.9%)). Amog the 3,619 patiets for whom the sex was kow, 460 were wome (12.7%). Sevetee RCTs compared aticovulsats to placebo; amog them, (a) 4 RCTs recruited oly male patiets ( = 489 patiets), (b) 1 study did ot idicate the geder of subjects ( = 157 patiets), ad (c) 10 Agabio/Pai/Preti/Gessa/Fracoi

11 Fig. 2. Rates of male ad female patiets recruited i radomised, placebo-cotrolled trials coducted to evaluate the efficacy of AWS medicatios. Rates of patiets (%) Me ad wome recruited i the RCTs coducted to evaluate the efficacy of medicatios alcohol withdrawal sydrome Bezodiazepies 12 RCTs 1,301 patiets Aticovulsats 17 RCTs 1,602 patiets GHB 1 RCT 23 patiets Me Wome Color versio available olie 12 RCTs recruited both male ad female patiets (182 wome i a sample of 956 subjects (19.0%)). Amog the 1,445 patiets for whom the sex was kow, 182 were wome (12.6%). I the evaluatio of the efficacy of aticovulsats compared to that of placebo, the meta-aalysis icluded oly 9 of these 17 RCTs. These 9 RCTs recruited 933 icludig 106 wome (13.7%). The majority of the studies evaluated by the meta-aalysis did ot report the results obtaied by female patiets i details. Moreover, amog these RCTs, some recruited a umber of wome too small to ivestigate possible geder differeces ( fig. 2 ; tables 7 ad 9 ). Accordig to these results, it is ot clear if wome may respod differetly to aticovulsats. Globally, table 7 shows that, the 3 selected meta-aalyses reviewed 129 studies for AWS medicatios, i which more tha 9,000 subjects were recruited. Thirty-three out of 129 studies (approximately 26%) recruited oly male 19 studies (15%) did ot specify the sex of o study recruited oly female ad the other 77 studies (60%) recruited both female ad male patiets. The rate of wome (amog patiets of whom sex was kow) recruited by the studies i which the efficacy of medicatios was compared to that of placebo varied from 3.2% for bezodiazepies to 30.4% for GHB. Noe of the selected meta-aalyses reported the use of differet doses of medicatios for female patiets. Discussio The results of this study showed that the rates of wome recruited by studies evaluatig the efficacy of disulfiram (1%) for AD treatmet ad of bezodiazepies (3%) ad aticovulsats (13%) for AWS treatmet were too low to establish possible sex differeces i the respose to these medicatios ( fig. 1 ad 2 ). The rate of wome recruited for GHB was higher (32%), but the total umber of patiets was too small (88 subjects) to reach ay sigificat coclusio regardig its efficacy for the treatmet of both AD ad AWS. Fially, the rates of wome recruited for acamprosate (22%), altrexoe (23%), ad almefee (30%) for AD treatmet were sufficiet to permit geder aalysis, but the results of these comparisos are cotrastig ad ot coclusive. Acamprosate was the oly medicatio that could achieve the best level of efficacy for AD treatmet i female patiets [56, 57]. However, i the COMBINE study, acamprosate failed to reduce alcohol cosumptio, regardless of patiet sex [65]. Although these egative results were already evaluated i the selected meta-aalysis [56], they deserve further explaatio because of the large umber of patiets recruited [65]. Moreover, a geder aalysis (ot icluded i the meta-aalysis we selected) of the results obtaied by the COMBINE study specifically showed that acamprosate failed to reduce alcohol cosumptio i wome as well as i me [75]. Naltrexoe achieved the best level of efficacy regardless of the sex of but it is ot clear if wome respod differetly to this medicatio. Ideed, amog the studies icluded i the selected meta-aalysis, some foud that altrexoe is ot effective i female patiets [61] or is more effective i me tha i wome [62, 63], whereas others foud that altrexoe is more effective i wome tha i me [64]. The geder aalysis o the results obtaied by the COMBINE study foud that altrexoe iduced similar beefits i both me ad wom- Medicatios for AD Wome 11

12 Table 9. Number of female patiets recruited i the RCTs evaluated by the meta-aalysis etitled aticovulsats for alcohol withdrawal by Miozzi et al., 2010 [70] Studies Wome Total 1 Agricola et al., Alldredge et., Balldi ad Bokstrom, 1986.a..a Bjorkqvist et al., Blachard, Boet et al., Boet et al., 2007.a..a..a. 8 Borg et al., Burroughs et al., 1985a Burroughs et al., 1985b Chace, Choi et al., Croissat et al., Decker et al., Elsig et al., Elsig et al., Flygerig et al., Ga et al., Glatt et al., Golbert et al., Kaim ad Klett, Kalyocu et al., Koethe et al., Koppi et al., Kramp ad Rafaelse, Krupitsky et al., Lambie et al., Lapierre et al., Logo et al., Lucht et al., Madde et al., Malcolm et al., Studies Wome Total 33 Malcolm et al., Malcolm et al., Mahem et al., Mariai et al., McGrath, 1975.a..a Murphy et al., Myrick et al., 2000.a..a Nimmerrichter et al., Radouco-Thomas et al., Rathlev et al., Reoux et al., Ritola ad Malie, Robiso et al., Rosethal et al., Rothstei, 1973.a..a Samplier ad Iber, 1974.a..a Sato Domigo Carrasco et al., Schik et al., Seifert et al., Spies et al., Stahope, Stuppaeck et al., Stuppaeck et al., 1998.a..a Teijeiro, 1975.a..a Thompso et al., Tubridy, a. = Data ot available. I bold: studies i which aticovulsats were compared to placebo. I italic: Studies aalysed by the meta-aalysis for the evaluatio of the efficacy of aticovulsats compared to placebo. Refereces are listed i olie supplemetary refereces. e, as well as aother study ot icluded i the selected meta-aalysis [75, 76]. It is importat to ote that i the COMBINE study, patiets treated with altrexoe achieved better results tha patiets treated with placebo, while the results obtaied did ot differ betwee patiets treated with acamprosate ad patiets treated with placebo [65]. Globally wome reported more adverse effects tha me with altrexoe treatmet [61, 63]. The lack of iformatio o the results obtaied by female patiets recruited by primary trials of the selected meta-aalysis for almefee did ot allow the possibility of coductig a geder-aalysis [55]. Subsequet multicetre RCTs (ot icluded i the meta-aalysis we selected) i which a total of 1,322 AD patiets (394 wome) were recruited foud that almefee sigificatly reduced the umber of heavy drikig days compared to placebo, with the same efficacy i both sexes [77, 78]. This umber of patiets was three times higher tha that i the RCTs evaluated by the meta-aalysis we selected. Cosiderig the results obtaied by these recet studies, almefee may achieve the best level of efficacy both i female ad i male AD patiets. Nevertheless, the efficacy of almefee has recetly bee severely criticised [79]. It was calculated that almefee reduced alcohol cosumptio by approximately 1 2 uits of alcohol per day i people who cosumed a average of 13.5 uits per day. The magitude of this effect raises the questio whether statistically sigificat beefits may be margial i cliical practice [80]. 12 Agabio/Pai/Preti/Gessa/Fracoi

13 Theoretically, disulfiram could acts differetly i the two sexes. Ideed, oe study (ot icluded i the metaaalysis we selected) foud that disulfiram was effective i me with cocaie ad AD but ot i wome with the same disorders [81]. The use of disulfiram for the treatmet of cocaie depedece is motivated by a mechaism of actio other tha ALDH ihibitio. I details, the primary metabolite of disulfiram, S-methyl N,N-diethyldithiocarbamate sulphoxide, chelates copper ad ihibits the fuctio of ezymes that require copper as a cofactor [82]. Oe of these ezymes is dopamie β-hydroxylase (DβH), which coverts dopamie to oradrealie i the fial step of oradrealie sythesis i oradreergic euros [83]. Through DβH ihibitio, it has bee foud that disulfiram depletes oradrealie ad icreases dopamie cocetratios i rodets ad humas, a mechaism proposed to explai the efficacy of disulfiram for cocaie depedece [83]. The sex differece i the respose to disulfiram observed i patiets with cocaie ad AD may be due to the sex differeces i DβH activity, as oestroges ad oral cotraceptives stimulate the activity of this ezyme [84, 85]. Accordigly, i wome, the ihibitio of DβH activity due to disulfiram admiistratio may be atteuated by the stimulatig effect of DβH activity iduced by oestroges ad/or oral cotraceptives. Aother study, ot icluded i the meta-aalysis we selected, recetly foud a iverse relatioship betwee the efficacy of disulfiram ad DβH activity i patiets with cocaie depedece [86]. Sex differeces have already bee described for bezodiazepies i studies coducted for reasos other tha AWS treatmet, ad ot icluded i the meta-aalysis we selected. These studies observed that wome metabolise diazepam faster tha me do [87, 88]. This differece may be because diazepam is metabolised by the cytochrome ezymes CYP3A4 ad CYP2C19, ad CYP3A4 is more highly expressed i wome tha i me [21]. It is therefore possible that wome ad me may require differet doses of bezodiazepies for AWS treatmet, as already observed for zolpidem [26]. Wome appear to be at higher risk tha me to develop brai damage followig chroic alcohol cosumptio [89, 90]. For istace, it has bee foud that AD wome have smaller gray ad white matter volumes ad greater CSF volumes tha healthy wome, ad that these differeces are cosiderably larger tha those foud betwee alcoholic ad healthy me, despite the fact that AD wome have cosumed large amouts of alcohol for fewer years tha AD me [91]. The higher vulerability to the eurotoxic effects of alcohol, ad the subsequet icreased severity of brai damage i AD wome compared to AD me, might costitute a further cause of possible geder differeces i respose to AD medicatios. However, the complete lack of iformatio o female patiets does ot allow the possibility of ivestigatig the possible differeces ad potetial explaatios i respose to pharmacotherapy. I additio, the selected meta-aalyses did ot report the use of differet doses of medicatios for male ad female patiets. The doses of some medicatios (e.g. acamprosate ad GHB) were adjusted accordig to body weight. As wome usually have a lower body weight tha me, it is possible that female patiets received lower doses of these medicatios tha male patiets did. However, it was ot specified. Fially, the specific hormoal phases of wome life (e.g. pregacy) were ot cosidered, eve if may medicatios for AD ad AWS beloged to FDA class C pregacy risk [92]. Coversely, female patiets should receive doses adjusted accordig to body weight, at least at the start of treatmet ad female AD patiets of childbearig age should also be tested for pregacy before startig pharmacological treatmet. I coclusio, wome receive medicatios for treatmet of AD ad/or AWS for which efficacy has bee demostrated i studies i which me were more largely represeted. The scarce erolmet of wome strogly suggests that it is time to perform further studies to evaluate the efficacy ad safety of AD ad/or AWS medicatios i wome cosiderig differet subgroups of the female populatio, such as adolescets, adults, ad the elderly, to reveal geder differeces i respose to these medicatios ad improve the quality of medical assistace for AD wome. It is importat to bear i mid that the majority of subjects with AD ever receive treatmet [35, 93]. Wome are more likely tha me to meet umerous barriers to accessig treatmet, ad pregat wome are less likely to receive AD therapy tha o-pregat wome [94, 95]. Improvig kowledge of the efficacy ad safety of medicatios for treatig AD ad/or AWS may cotribute to the amelioratio of the quality of medical assistace for AD wome ad icrease the umber of female patiets who seek ad receive medical treatmet for this disorder. Disclosure Statemet Noe declared. This study was partially supported by a grat from the Regioe Sardega Progetti di farmacovigilaza attiva, fiaziabili attraverso i fodi fv 2008/09. We are grateful to the Major of Osilo ad all Muicipal Hall for the laboratory space that they dedicated to the Natioal Laboratory i Geder Medicie of INBB. Medicatios for AD Wome 13