Several medications have been approved by the U.S.

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1 Article Gbpentin Combined With Nltrexone for the Tretment of Alcohol Dependence Rymond F. Anton, M.D. Hugh Myrick, M.D. Tr M. Wright, M.D. Ptrici K. Lthm, Ph.D. Alici M. Bros, Ph.D. L. Rndolph Wid, Ph.D. Ptrick K. Rndll, Ph.D. Objective: Nltrexone, n efficcious m ediction for lcohol dependence, does not work for everyone. Sym ptom s such s insom ni nd m ood instbility tht re m ost evident during erly bstinence m ight respond better to different phrm cotherpy. Gbpentin m y reduce these sym ptom s nd help prevent erly relpse. This clinicl tril evluted whether the com bintion of nltrexone nd gbpentin ws better thn nltrexone lone nd/or plcebo during the erly drinking cesstion phse (first weeks), nd if so, whether this effect persisted. Method: A totl of 15 lcohol-dependent individuls were rndom ly ssigned to -week course of nltrexone lone (5 m g/dy [N=5]), nltrexone (5 m g/ dy) with gbpentin (up to 1, m g/ dy [N=5]) dded for the first weeks, or double plcebo (N=5). All prticipnts received m edicl m ngem ent. Results: During the first weeks, the nltrexone-gbpentin group hd longer intervl to hevy drinking thn the nltrexone-lone group, which hd n intervl similr to tht of the plcebo group; hd fewer hevy drinking dys thn the nltrexone-lone group, which in turn hd more thn the plcebo group; nd hd fewer drinks per drinking dy thn the nltrexonelone group nd the plcebo group. These differences fded over the remining weeks of the study. Poor sleep ws ssocited with more drinking in the nltrexone-lone group but not in the nltrexone-gbpentin group, while history of lcohol withdrwl ws ssocited with better response in the nltrexone-gbpentin group. Conclusions: The ddition of gbpentin to nltrexone im proved drinking outcom es over nltrexone lone during the first weeks fter cesstion of drinking. This effect did not endure fter gbpentin ws discontinued. (Am J Psychitry 11; :79 717) Severl medictions hve been pproved by the U.S. Food nd Drug Administrtion for the tretment of lcohol dependence disulfirm, nltrexone (both orl nd long-cting injectble), nd cmproste nd few other medictions, such s topirmte, hve been shown to be effective in treting lcohol dependence. However, mny individuls respond only prtilly or not t ll to these gents. There is need for new mediction tretments, especilly ones using gents tht trget different spects of lcohol dependence, rnging from individul phenomenologicl to genetic differences. One such phenomenologicl difference my be defined by set of signs nd symptoms tht might chnge over time s individuls ttempt to stop drinking. For instnce, it is well known tht the period immeditely fter cesstion of lcohol consumption is high-risk time for relpse drinking. This erly bstinence period might be defined by certin phenomen tht re likely to meliorte over time with continued bstinence. These signs nd symptoms could rnge from esily observed lcohol withdrwl symptoms to more subtle but still meningful constelltion of problems, including sleep difficulty, irritbility, concentrtion problems, nxiety, nd dysphori. Some hve lbeled this constelltion of lingering symptoms tht occur fter the initil cesstion period s protrcted lcohol withdrwl (1). While this symptom constelltion is not well defined, it is likely tht some of these symptoms re experienced by those who do not show florid lcohol withdrwl symptoms on cesstion of drinking. Nevertheless, this constelltion of symptoms, nd the ssocited crving tht could mnifest secondry to them, might not be prticulrly responsive to medictions tht reduce lcohol reinforcement or cue-induced crving, such s nltrexone ( ). Since clinicins often cnnot predict, priori, wht sort of symptoms n individul will exhibit or wht sort of crving (withdrwl bsed versus rewrd bsed) will be the most slient, it might be wise to ttempt to reduce both in order to improve tretment efficcy. We nd others hve shown tht nticonvulsnts in generl (5 7) nd gbpentin in prticulr (1,, 9) cn meliorte cute lcohol withdrwl symptoms nd could ctully be useful in preventing relpse (1), especilly in ptients with previous lcohol withdrwl symptoms (11). Gbpentin, which works by modulting both γ-minobutyric cid (GABA) nd glutmte tone, is n especilly ppeling drug since it hypotheticlly cn normlize the known GABA deficits nd glutmte excess tht re thought to underlie lcohol withdrwl (1) nd perhps prts of the This rticle is fetured in this m onth s AJP Audio, is discussed in n editoril by Dr. O Brien (p. 7), is the subject of CME course (p. 757), nd is n rticle tht provides Clinicl Guidnce (p. 717) Am J Psychitry :7, July 11 jp.psychitryonline.org 79

2 Gbpentin With Nltrexone for Alcohol Dependence erly bstinence or protrcted withdrwl syndrome (13). It is lso sfe to use in lcoholics, s it ppers to hve limited or no dverse interction with lcohol (9, 1) nd is excreted by the kidneys rther thn the liver, which is known to be compromised in mny lcoholics. The primry gol of this study ws to evlute whether gbpentin, when dded for the first weeks of -week course of nltrexone, would be well tolerted nd improve the efficcy of nltrexone. Secondry gols were to evlute the effects of the nltrexone-gbpentin combintion on prmeters such s sleep (15) nd mood tht hve been thought to predict poor tretment outcome. In ddition, we explored whether history of lcohol withdrwl symptoms would be predictive of response to this combintion of medictions. Method This ws rndomized controlled clinicl tril pproved by the institutionl review bord of the Medicl University of South Crolin. Prticipnts provided written informed consent fter receiving complete description of the study. After initil screening nd ssessment, lcoholdependent ptients were rndomly ssigned to receive nltrexone plus ctive gbpentin (N=5), nltrexone plus plcebo gbpentin (N=5), or plcebo nltrexone nd plcebo gbpentin (N=5), using double dummy plcebo-controlled mediction design. Nltrexone or its mtching plcebo ws given s 5 mg for dys nd then 5 mg/dy for up to weeks. Gbpentin (3-mg cpsules) or its mtching plcebo ws given s one cpsule t night (3 mg/dy) on dy 1; one cpsule in the morning nd t night ( mg) on dy ; one cpsule morning, noon, nd night (9 mg/dy) on dys 3 nd ; nd one cpsule in the morning, one t noon, nd two t night (1, mg/dy) on dys 5 through ( weeks). All prticipnts met DSM-IV criteri for lcohol dependence, consumed on verge five or more stndrd drinks per dy for men or four or more per dy for women, were ble to mintin sobriety for dys prior to rndomiztion, nd lived within 5 miles of our study site in stble living sitution. Ptients were excluded if they met DSM-IV criteri for other substnce dependence (except nicotine); used illicit drugs in the pst 3 dys or hd positive urine drug screen; met DSM-IV criteri for n xis I disorder; hd current suicidl or homicidl idetion; needed mintennce with psychotropic or nticonvulsnt mediction; hd unstble medicl conditions; hd liver enzyme (ALT nd AST) levels more thn three times norml; used disulfirm, cmproste, or either of the study medictions within the pst 3 dys; took n opioid mediction on routine bsis; hd legl chrges pending; nd hd undergone more thn one previous inptient medicl detoxifiction tretment. Prticipnts hd to bstin from lcohol for t lest consecutive dys before rndomiztion to study medic- tion. During the ssessment period, the following instruments were dministered: the Structured Clinicl Interview for DSM-IV, the Alcohol Dependence Scle (), the Obsessive Compulsive Drinking Scle (17), the Form 9 ( modified timeline follow-bck method for documenting lcohol consumption) (1), the Profile of Mood Sttes (19), the Beck Depression Inventory (), the Epworth Sleepiness Scle (1), the Insomni Severity Index (), nd the Clinicl Institute Withdrwl Assessment for Alcohol Scle Revised (3). Lb tests included helth screen, liver function tests, pregnncy test for femles, nd lcohol use mrkers γ-glutmyltrnsferse nd crbohydrtedeficient trnsferrin (CDT) (). Mediction ws dispensed in identiclly pckged blister crds. Ech cpsule of nltrexone, gbpentin, or plcebo lso contined 1 mg of riboflvin. Prticipnts were provided up to sessions of combined behviorl intervention therpy using the Combining Medictions nd Behviorl Interventions (COMBINE) study s combined behviorl intervention tretment mnul (5), which combined cognitive-behviorl therpy, motivtion interviewing, nd 1-step fcilittion techniques in client needs-bsed pproch. A physicin or nurse evluted physicl complints nd encourged mediction dherence. Procedures Prticipnts were seen by helth cre provider nd therpist providing combined behviorl intervention t weeks 1,, 3,,,, 1, 1, nd of tretment. Similr to procedures used in the COMBINE study, reserch ssistnt used the timeline follow-bck clendr method to ssess lcohol intke nd the Obsessive Compulsive Drinking Scle to ssess crving nd dministered symptom checklist nd the Profile of Mood Sttes in ll groups. Liver function tests nd %CDT were mesured t weeks 3,, 1, nd. Resons for erly termintion were recorded, nd full -week drinking dt were collected where possible. Sttisticl Anlysis Group differences in bseline vribles, study retention, therpy dherence, nd mediction complince were nlyzed with nlysis of vrince or chi-squre tests using SAS, version. (SAS Institute, Cry, N.C.). Prticipnts with t lest one postrndomiztion outcome mesurement were included in the efficcy nlyses. Two prticipnts in the plcebo group, two in the nltrexone-lone group, nd two in the nltrexone-gbpentin group did not return for t lest one postrndomiztion evlution. Time to the first hevy drinking dy ws nlyzed using Cox regression nlysis with percent hevy drinking dys t bseline s covrite nd missing dt due to dropout censored. A preplnned two-step nlysis ws conducted evluting the overll survivl curve from study entry through week nd the survivl curve for the first weeks, when nltrexone nd gbpentin were tken together. To evlute ny differentil response between 71 jp.psychitryonline.org Am J Psychitry :7, July 11

3 Anton, Myrick, Wright, et l. FIGURE 1. Prticipnt Flow in Plcebo-Controlled Tril of Nltrexone Alone or Nltrexone Plus Gbpentin for the Tretment of Alcohol Dependence Assessed for eligibility (N=195) Rndomly ssigned to tretment group (N=15) Did not meet inclusion criteri (N=1) Declined to prticipte (N=5) Lost to ssessment (N=) Plcebo (N=5) Nltrexone (N=5) Nltrexone + gbpentin (N=5) Missed visits or chose to discontinue (N=1) Elevted liver function tests (N=1) Moved (N=1) Medicl problem (N=1) More intensive tretment (N=) Incrcertion (N=1) Missed visits or chose to discontinue (N=11) Elevted liver function tests (N=1) Side effects (N=1) Psychitric problem (N=1) Incrcertion (N=1) Missed visits or chose to discontinue (N=17) Moved (N=1) Side effects (N=1) Incrcertion (N=1) Completed tretment (N=3) Completed tretment (N=35) Completed tretment (N=3) Anlysis Anlysis Anlysis No drinking dt (N=1) No drinking dt (N=1) No drinking dt (N=) Evluble subjects (N=9) Evluble subjects (N=9) Evluble subjects (N=) Completed tretment=hd combined behviorl intervention session t week. those who hd history of lcohol withdrwl symptoms or tretments (those who either experienced lcohol withdrwl symptoms t study entry or hd pst inptient detoxifiction tretment) nd those who did not, this vrible ws entered into the Cox regression nlysis long with mediction group to evlute interctions. Percent hevy drinking dys per week nd drinks per drinking dy were nlyzed first over the whole tril nd secondrily in the first six weeks (the gbpentin phse) nd lst 1 weeks (the nltrexone lone phse). If significnt overll effect ws found, between-group comprisons were undertken. Score on the Obsessive Compulsive Drinking Scle nd sleep qulity were similrly nlyzed. The nlytic pln used ws liner mixed model evluting min effects of group, time, nd group-by-time interctions (using SAS PROC MIXED). Alcohol consumption mrkers (%CDT nd γ-glutmyltrnsferse) were nlyzed using the generlized estimt- ing eqution pproch (PROC GENMOD) cross mesurements t bseline nd t weeks 3,, 1, nd s binry outcome vribles with positive result indicting hevy drinking. An unstructured covrince mtrix ws employed. Results Prticipnts Figure 1 illustrtes the process of prticipnt recruitment nd rndomiztion. Prticipnt chrcteristics re summrized in Tble 1. Prticipnts verge ge ws in the mid-s, nd most were mle nd Cucsin. On verge they drnk 1 13 drinks per drinking dy on bout three-qurters of the dys in the 9 dys prior to rndomiztion. Of note, 1% of prticipnts were mediclly detoxified prior to prticiption in the tretment study (lmost exclusively s outptients by study physicins). Am J Psychitry :7, July 11 jp.psychitryonline.org 711

4 Gbpentin With Nltrexone for Alcohol Dependence TABLE 1. Demogrphic nd Clinicl Chrcteristics of Alcohol-Dependent Ptients Treted With Plcebo, Nltrexone, or Nltrexone Plus Gbpentin Chrcteristic Plcebo (N=9) Nltrexone (N=9) Nltrexone Plus Gbpentin (N=) N % N % N % Mle 39 3 Rce Cucsin 3 Africn Americn Other 1 Detoxifiction prior to study Smoking in pst 3 dys Men SD Men SD Men SD Age (yers) Drinks per drinking dy Drinks per dy Percent hevy drinking dys Obsessive Compulsive Drinking Scle score Beck Depression Inventory score Insomni Severity Index score There were no significnt between-group differences on ny vrible. There were no differences between mediction groups on ny demogrphic or drinking vrible. Retention nd Adherence On verge, prticipnts received 1 11 combined behviorl intervention therpy sessions, nd the proportion of prticipnts who provided drinking dt for ll weeks rnged from % to % in the three groups. Prticipnts took bout the sme number of mediction cpsules cross ll tretment groups (rnge=9% 9% of prescribed mediction). There were no between-group differences. Drinking Outcomes Time to first hevy drinking dy is illustrted in Figure. There ws n interction of tretment phse by mediction group (p=.). During the first weeks, the nltrexone-gbpentin group hd longer time to relpse thn the nltrexone-lone group (p=.), whose time to relpse ws not different from tht of the plcebo group. However, over the reminder of the tril, there were no tretment group differences. For percent hevy drinking dys (Figure 3), there ws significnt difference between mediction groups over the -week study (F=.59, df=, 1, p=.). During the first weeks, those treted with nltrexone lone ctully did worse thn those treted with plcebo (t=.35, df=1, p=.), while percent hevy drinking dys for the nltrexone-gbpentin group ws similr to tht of the plcebo group (t=1., df=1, p=.) but significntly lower thn tht of the nltrexone-lone group (t=1., df=1, p<.1). While the nltrexone-gbpentin group ppered to do better, even fter gbpentin ws stopped, this difference did not rech sttisticl significnce. For drinks per drinking dy (Figure ), there ws significnt difference between mediction groups over the -week study (F=.77, df=, 95, p=.1). During the first weeks, the nltrexone-lone group did not do significntly better thn the plcebo group, while the nltrexone-gbpentin group did significntly better thn both the plcebo group (t=.5, df=1, p=.1) nd the nltrexone-lone group (t=.57, df=1, p=.). After gbpentin ws stopped, there were no significnt differences between groups. Crving There were no significnt differences between the groups on the Obsessive Compulsive Drinking Scle score in either phse of the study. On the instrument s resistnce control fctor subscle, which we previously found to be most responsive to nltrexone (17), the mediction groups differed but not significntly (F=.33, df=, 139, p=.1), with significnt differences evident only during the first weeks. There ws no significnt difference between the plcebo nd nltrexone-lone groups, but the nltrexonegbpentin group showed significntly lower score tht is, more control over drinking urges thn the nltrexone-lone group (t=., df=139, p=.) nd lower score thn the plcebo group but with the difference flling short of sttisticl significnce (t=1.9, df=139, p=.9). Biomrkers of Drinking The probbility of hving positive γ-glutmyl trns ferse test showed significnt group-by-time interction (c =., df=, p=.3), with the nltrexone-gbpentin group hving significntly fewer positive γ-glutmyltrnsferse vlues thn the other two mediction groups during the gbpentin phse (c =7., df=, p=.) nd fewer positive vlues fter gbpentin ws stopped, but flling short of sttisticl significnce (c =5.55, df=, p=.). The probbility of hving positive %CDT showed n lmost significnt group-by-time interction (c =1.7, df=, p=.), with the nltrexone-gbpentin group hving sig- 71 jp.psychitryonline.org Am J Psychitry :7, July 11

5 Anton, Myrick, Wright, et l. nificntly fewer positive %CDT vlues thn the other two groups during the gbpentin phse (c =.37, df=1, p=.1 compred with the nltrexone-lone group nd c =5.3, df=1, p=. compred with the plcebo group). There were no significnt differences fter gbpentin ws stopped. Overll, the blood tests indicting hevy lcohol consumption were consistent with the verblly reported drinking, showing similr between-group effects. Sleep Qulity, Mood Stte, nd Tretment Response The difference in sleep qulity between groups over the course of the study pproched significnce (F=., df=, 1, p=.7). During the gbpentin phse, there ws no significnt difference in reported sleep between the plcebo nd nltrexone-lone groups, but the nltrexonegbpentin group reported significntly better sleep thn did either the plcebo group (t=.9, df=1, p=.) or the nltrexone-lone group (t=.9, df=1, p=.3). Poor sleep qulity (high scores on the Insomni Severity Index) ws significntly relted to hevy drinking, but only in the nltrexone-lone group (B=.1; SE=.1, t=.13, df=139,.35) tht is, in the nltrexone-lone group, but not in the other two groups, prticipnts were more likely to drink hevily during periods in which they reported poor sleep. Profile of Mood Sttes scores or fctors were not significntly different between mediction groups nd did not differentilly predict tretment outcomes. History of Alcohol Withdrwl nd Tretment Response Figure 5 illustrtes n overll lcohol withdrwl history-by-mediction group interction (p=.3). Among prticipnts with history of lcohol withdrwl, those in the nltrexone-gbpentin group hd significntly less relpse to hevy drinking thn those in the plcebo group (p=.3), while mong prticipnts with no lcohol withdrwl history, there ws no difference between these mediction groups. An nlysis of hevy drinking dys during the gbpentin phse essentilly found the sme reltionship. Alcohol withdrwl history hd no effect on the comprison between the nltrexone-lone nd plcebo groups. Side Effects Both ctive mediction groups reported more dizziness thn did the plcebo group (p=.). The nltrexonegb pentin group reported more dytime somnolence thn the other two groups (p=.) nd more blurred vision (p=.) nd more premture ejcultion (p=.) thn the plcebo group. All these side effects were mild to moderte in severity. Discussion As hypothesized, gbpentin, when combined with nltrexone, ppered to be well tolerted nd to improve FIGURE. Cumultive Survivl to First Hevy Drinking Dy Among Alcohol-Dependent Ptients Treted With Plcebo, Nltrexone, or Nltrexone Plus Gbpentin Cumultive Survivl Plcebo Nltrexone Nltrexone nd Gbpentin Study Week During the first weeks, the nltrexone-gbpentin group hd more time to first hevy drinking dy thn the nltrexone-lone group (p=.), which in turn ws not significntly different from the plcebo group. There were no significnt differences during the period fter gbpentin ws stopped. overll efficcy bove tht noted for nltrexone lone nd for plcebo. Perhps surprisingly, nltrexone lone ws not superior to plcebo in this study, nd in fct on some mesures it ws worse. This is consistent with the results from the COMBINE study (), which found tht nltrexone dded nothing to the efficcy of the combined behviorl intervention. In the present study, combined behviorl intervention ws employed s the stndrd psychosocil intervention nd ws delivered primrily by the sme therpists who delivered it in the COMBINE study t our site. In the COMBINE Study, nltrexone showed superiority over plcebo only for those who received medicl mngement without combined behviorl intervention. Since tht study ws completed fter the present one ws initited, we were unwre of this finding nd chose to use combined behviorl intervention s n ncillry tretment. Nevertheless, the results of the present study re exctly wht would hve been predicted by the COMBINE study, tht is, tht the combined behviorl intervention might msk nltrexone s phrmcologicl effects. Despite this, it ppered tht the nltrexone-gbpentin combintion ws better thn nltrexone lone or plcebo on severl drinking, crving, nd blood-mrker outcome vribles, especilly during the first weeks while prticipnts were ctully tking gbpentin. While some of the positive effects of combining gbpentin nd nltrexone during the first weeks could still be observed over the next 1 weeks, for the most prt these effects were no longer significnt, which implies tht gbpentin exerted its effects only while prticipnts were ctully tking it. We hd hypothesized priori tht gbpentin might work best during the initil phses of bstinence, when cute lcohol withdrwl effects might be the most pronounced. The hope ws tht by using gbpentin to meliorte symptoms Am J Psychitry :7, July 11 jp.psychitryonline.org 713

6 Gbpentin With Nltrexone for Alcohol Dependence FIGURE 3. Percent Hevy Drinking Dys per Week During the Tril nd for the Pre- nd Post-s Among Alcohol-Dependent Ptients Treted With Plcebo, Nltrexone, or Nltrexone Plus Gbpentin Percent Hevy Drinking Dys Plcebo (N=9) Nltrexone (N=9) Nltrexone nd Gbpentin (N=) Study Week Percent Hevy Drinking Dys Plcebo Nltrexone Nltrexone nd Gbpentin Post- Plcebo Nltrexone Nltrexone nd Gbpentin During the first weeks, those receiving nltrexone nd gbpentin hd fewer hevy drinking dys thn those receiving nltrexone lone (p=.) but similr number to those receiving plcebo (p=.). These effects fded fter gbpentin ws stopped. Error brs indicte stndrd errors. Percent Hevy Drinking Dys such s insomni, irritbility, nd withdrwl crving during this period, nltrexone might hve better chnce to work nd would continue to work once gbpentin ws stopped. This hypothesis could not be vlidly confirmed. While we did find n dditive response of gbpentin nd nltrexone in ptients with history of pst or current lcohol withdrwl s well s some fvorble effects on sleep while individuls were tking gbpentin, the importnce of these findings is not cler. Other reserchers found tht gbpentin worked better thn plcebo in preventing relpse in ptients who hd undergone benzodizepine detoxifiction (1), but they did not compre these ptients with ptients who hd not undergone detoxifiction. Our group recently reported (11) tht gbpentin worked significntly better thn plcebo only in those who hd cliniclly significnt lcohol withdrwl t study entry. In tht study, gbpentin ws djunctive to n initil tretment with intrvenous flumzenil, so the direct effect of gbpentin could not be vlidly confirmed. Group specificity (it worked only in those who hd lcohol withdrwl symptoms) nd gbpentin s longer-term dosing period (over bout 7 weeks, similr to the present tril) compred with flumzenil (over dys) do imply tht gbpentin might hve been the primry component of the effective tretment. Of note, in tht study, those without current lcohol withdrwl ctully did significntly worse on gbpentin compred with plcebo, finding consistent with reports in niml studies (). This effect ws not observed in the present study. However, the group size of our post hoc explortory nlysis ws smll, nd the definition of lcohol withdrwl history ws defined post hoc, limiting the vlidity of this finding nd requiring repliction. Nevertheless, the confluence of results suggests tht more evlution of gbpentin by itself is necessry, especilly in lcoholics who hve current, or possibly pst, lcohol withdrwl symptoms nd those who do not. Interestingly, when gbpentin ws stopped, there ppered to be some increse in drinking, with worsening in sleep qulity (dt not shown); the sme chnges, however, were lso noticeble to some degree in the plcebo group. It is difficult to determine whether this ws physiologicl response to discontinuing gbpentin or just n effect of tking fewer pills, especilly those t bedtime. In controlled sleep study, gbpentin improved lcoholdisrupted sleep (7) nd normlized sleep in non-tretment-seeking lcoholics (). Our group reported (9) tht gbpentin normlized sleep during lcohol withdrwl better thn did lorzepm, but only in ptients with history of multiple detoxifictions. Krm-Hge nd Brower (3) originlly proposed tht gbpentin might work to reduce relpse drinking by normlizing sleep, prticulrly in those who might drink to help with sleep. However, in 71 jp.psychitryonline.org Am J Psychitry :7, July 11

7 Anton, Myrick, Wright, et l. FIGURE. Averge Drinks per Drinking Dy Ech Week During the Tril for the Pre- nd Post-s Among Alcohol-Dependent Ptients Treted With Plcebo, Nltrexone, or Nltrexone Plus Gbpentin Drinks per Drinking Dy 1 Plcebo (N=9) Nltrexone (N=9) Nltrexone nd Gbpentin (N=) Study Week Number of Drinks Number of Drinks Plcebo Plcebo Nltrexone Post- Nltrexone Nltrexone nd Gbpentin Nltrexone nd Gbpentin During the first weeks, those receiving nltrexone nd gbpentin hd fewer drinks per drinking dy thn those receiving nltrexone lone (p=.) nd plcebo (p=.1). There were no significnt differences during the period fter gbpentin ws stopped. Error brs indicte stndrd errors. more recent study in lcoholic insomnics (15), Brower et l. found tht while gbpentin delyed onset of hevy drinking fter initil bstinence, its efficcy ws not ttributble to improved sleep. There ws initil concern bout the sfety of gbpentin, especilly when ingested with lcohol. Severl controlled studies conducted by us (31) nd others (1) hve lrgely ssuged tht concern. In the present tril, while some low-grde symptoms, such s dizziness, were reported more frequently in the nltrexone-gbpentin group, in generl the mediction ws well tolerted, which is consistent with dt from other relpse prevention trils with gbpentin lone (1, 11). Of note, since gbpentin is excreted in the urine, there would not be ny expected interction with nltrexone on liver metbolism or toxicity, nd none ws noted in this tril. Since gbpentin nd nltrexone work on different neurophysiologicl systems, this combintion hs some ppel. Nltrexone, s n opioid receptor ntgonist, ppers to reduce the reinforcing spects of lcohol cues nd consumption (3, 3) while reducing crving nd slip drinking (33). Gbpentin, working to normlize GABA nd glutmte blnce, might work best t restoring norml overll brin ctivity nd tone nd be most useful in individuls who hve imblnces in these systems, such s those experiencing cute or protrcted lcohol with- drwl symptoms. Hence, this mediction combintion mkes phrmcologicl sense nd is consistent with wht is known bout the neuroscience of ddiction in generl nd of the effects of lcohol on the brin. It is possible, however, since the GABA nd glutmte systems lso ply role in reinforcement, extinction, nd cue-induced lerning (3), tht gbpentin plys primry role in preventing lcohol relpse nd reducing drinking, similr to other nticonvulsnts, such s topirmte (35), tht hve similr bsic phrmcologicl nd brin effects. It should be noted, however, tht in some pilot work done by our group in lbortory prdigm designed to test the lcohol ntireinforcement effects of mediction, gbpentin did not pper to block crving nd drinking behvior (3) in the sme wy tht nltrexone hd done previously (3, 37). However, others hve found some effects of gbpentin on lcohol cue-induced crving (). This study hd some limittions. It ws single-site study with limited number of prticipnts. Moreover, prticipnts did not hve significnt psychitric conditions other thn lcohol dependence, were not on psychitric medictions, were mediclly stble, nd were, for the most prt, motivted towrd bstinence. Prticipnts received n efficcious psychosocil intervention long with mediction nd were encourged to dhere to their mediction regimen nd the study protocol. In ddition, since this study Am J Psychitry :7, July 11 jp.psychitryonline.org 715

8 Gbpentin With Nltrexone for Alcohol Dependence FIGURE 5. Cumultive Survivl to First Hevy Drinking Dy Among Alcohol-Dependent Ptients With nd Without History of Alcohol Withdrwl Treted With Plcebo or Nl trexone Plus Gbpentin Cumultive Survivl History of Alcohol Withdrwl Nltrexone nd Gbpentin (N=) Plcebo (N=15) No History of Alcohol Withdrwl Nltrexone nd Gbpentin (N=31) Plcebo (N=33) Study Week Those with history of lcohol withdrwl who were treted with nltrexone nd gbpentin hd more time to first hevy drinking dy thn those receiving plcebo (p=.3). For those without history of lcohol withdrwl, there ws no difference between mediction groups. 1. Bonnet U, Bnger M, Leweke FM, Mschke M, Kowlski T, Gstpr M: Tretm ent of lcohol withdrwl syndrom e with gbpentin. Phrm copsychitry 1999; 3: Volpicelli JR, Wtson NT, King AC, Sherm n CE, O Brien CP: Effect of nltrexone on lcohol high in lcoholics. Am J Psychitry 1995; 15: O Mlley SS, Krishnn-Srin S, Frren C, Sinh R, Kreek MJ: Nltrexone decreses crving nd lcohol self-dm inistrtion in lcohol-dependent subjects nd ctivtes the hypothlm o- pituitry-drenocorticl xis. Psychophrm cology (Berl) ; :19 9. Anton RF, O Mlley SS, Cirulo DA, Cisler RA, Couper D, Donovn DM, Gstfriend DR, Hosking JD, Johnson BA, LoCstro JS, Longbugh R, Mson BJ, Mttson ME, Miller W R, Pettinti HM, Rndll CL, Swift R, Weiss RD, W illim s LD, Zweben A; COMBINE Study Reserch Group: Com bined Phrm cotherpies nd Behviorl Interventions for Alcohol Dependence: the COMBINE study: rndom ized controlled tril. JAMA ; 95: Mlcolm R, Myrick H, Brdy KT, Bllenger JC: Updte on nticonvulsnts for the tretm ent of lcohol withdrwl. Am J Addict 1; 1: 3. Leggio L, Kenn G, Swift R: New developm ents for the phrm - cologicl tretm ent of lcohol withdrwl syndrom e: focus on non-benzodizepine GABAergic m edictions. Prog Neuropsychophrm col Biol Psychitry ; 3: Book SW, Myrick H: Novel nticonvulsnts in the tretm ent of lcoholism. Expert Opin Investig Drugs 5; 1: Mrini JJ, Rosenthl RN, Tross S, Singh P, Annd OP: A rndom ized, open-lbel, controlled tril of gbpentin nd phenobrbitl in the tretm ent of lcohol withdrwl. Am J Addict ; 15:7 9. Myrick H, Mlcolm R, Rndll PK, Boyle E, Anton RF, Becker HC, Rndll CL: A double-blind tril of gbpentin versus lorzepm in the tretm ent of lcohol withdrwl. Alcohol Clin Exp Res 9; 33: Furieri FA, Nkm ur-plcios EM: Gbpentin reduces lcohol consum ption nd crving: rndom ized, double-blind, plcebo-controlled tril. J Clin Psychitry 7; : Anton RF, Myrick H, Bros AM, Lthm PK, Rndll PK, Wright TM, Stewrt SH, Wid R, Mlcolm R: Efficcy of com bintion of flum zenil nd gbpentin in the tretm ent of lcohol dependence: reltionship to lcohol withdrwl sym ptom s. J Clin Psychophrm col 9; 9: Littleton J: Neurochem icl m echnism s underlying lcohol withdrwl. Alcohol Helth Res World 199; : Gss JT, Olive MF: Glutm tergic substrtes of drug ddiction nd lcoholism. Biochem Phrm col ; 75: Bisg A, Evns SM: The cute effects of gbpentin in com bintion with lcohol in hevy drinkers. Drug Alcohol Depend ; 3: Brower KJ, Myr Kim H, Strobbe S, Krm -Hge MA, Consens F, Zucker RA: A rndom ized double-blind pilot tril of gbpenws strted prior to knowledge of the potentil prediction of nltrexone response by μ-opioid receptor genetic polymorphism (3), we could not ccount for this potentil confound. Finlly, the independent effect of gb pentin lone could not be evluted in this study design. In sum, the ddition of gbpentin to nltrexone for the tretment of lcohol dependence seems efficcious nd well tolerted. While there re hints tht this combintion might work best in those who hve previously experienced lcohol withdrwl symptoms, further study is needed to confirm this specultion. The dt from this study combined with those of others suggest tht future studies should explore the use of gbpentin lone while tking into ccount current or pst cute nd protrcted lcohol withdrwl signs nd symptoms, including sleep difficulties nd lcohol crving. A better understnding of the role of gbpentin nd other nticonvulsnts on reinforcement nd extinction issues is needed. Presented in prt t the 1 nd nnul meeting of the Americn Psychitric Assocition, Sn Frncisco, My 1 1, 9. Received Oct., 1 ; revision received Jn. 5, 1 1 ; ccepted Feb., 1 1 (doi: /ppi.jp ). From the Medicl U niversity of South Crolin, Institute of Psychitry. Address correspondence nd reprint requests to Dr. Anton, Center for Drug nd Alcohol Progrms, Medicl U niversity of South Crolin, 7 President St., MSC 1, Chrleston, SC 95; [email protected] (e-mil). Dr. Anton hs received grnt support or served s consultnt or on scientific dvisory bords for Abbott Lbortories, Alkermes, Eli Lilly, GlxoSmithKline, Hythim, Johnson & Johnson, Lundbeck, Merck, Novrtis, Orgnon, nd Schering-Plough. Dr. Myrick hs served on spekers bureus for Bristol-Myers Squibb nd Alkermes. The other uthors report no finncil reltionships w ith commercil interests. Supported by Ntionl Institute on Alcohol Abuse nd Alcoholism grnts RO1 AA95 nd K5 AA1735. The follow ing individuls ssisted in the collection of dt: Allison Hrdy, Shron Kntl, Dnielle Lrson Moore, Steven LRow e, Srh Miles, Amnd Mountford, Srh Jckson, Abrhm Tiffny, nd Glenn W orshm. Clinicltrils.gov registry number NCT1319. References 7 jp.psychitryonline.org Am J Psychitry :7, July 11

9 ANToN, MyriCk, WriGhT, ET Al. tin versus plcebo to tret lcohol dependence nd com orbid insom ni. Alcohol Clin Exp Res ; 3: Skinner HA, Allen BA: Alcohol dependence syndrom e: m esurem ent nd vlidtion. J Abnorm Psychol 19; 91: Roberts JS, Anton RF, Lthm PK, Mok DH: Fctor structure nd predictive vlidity of the Obsessive Com pulsive Drinking Scle. Alcohol Clin Exp Res 1999; 3: Miller W R: Form 9: A Structured Assessm ent Interview for Drinking nd Relted Behviors: Test Mnul (pub no NIH 9- ). Bethesd, Md, US Deprtm ent of Helth nd Hum n Services, Ntionl Institutes of Helth, McNir DM, Lorr M, Dropplem n LF: Mnul for the Profi le of Mood Sttes. Sn Diego, Eductionl nd Industril Testing Service, Beck AT, Wrd CH, Mendelson M, Mock J, Erbugh J: An inventory for m esuring depression. Arch Gen Psychitry 191; : Johns MW: A new m ethod for m esuring dytim e sleepiness: the Epworth Sleepiness Scle. Sleep 1991; 1:5 55. Bstien CH, Vllieres A, Morin CM: Vlidtion of the Insom ni Severity Index s n outcom e m esure for insom ni reserch. Sleep Med 1; : Sullivn JT, Sykor K, Schneiderm n J, Nrnjo CA, Sellers EM: Assessm ent of lcohol withdrwl: the revised Clinicl Institute W ithdrwl Assessm ent for Alcohol Scle (CIWA-Ar). Br J Addict 199; : Anton RF, Dom inick C, Bigelow M, Westby C; CDTect Reserch Group: Com prison of Bio-Rd % CDT TIA nd CDTect s lbortory m rkers of hevy lcohol use nd their reltionship with γ-glutm yltrnsferse. Clin Chem 1; 7: Miller WR: Com bined Behviorl Intervention Mnul: A Clinicl Reserch Guide for Therpists Treting People W ith Alcohol Abuse nd Dependence (pub no NIH -5). Edited by Mttson ME. Bethesd, Md, US Deprtm ent of Helth nd Hum n Services,. Roberto M, Gilpin NW, O Dell LE, Cruz MT, Morse AC, Siggins GR, Koob GF: Cellulr nd behviorl interctions of gbpentin with lcohol dependence. J Neurosci ; : Bzil CW, Bttist J, Bsner RC: Gbpentin im proves sleep in the presence of lcohol. J Clin Sleep Med 5; 1: 7. Mson BJ, Light JM, W illim s LD, Drobes DJ: Proof-of-concept hum n lbortory study for protrcted bstinence in lcohol dependence: effects of gbpentin. Addict Biol 9; 1: Mlcolm R, Myrick LH, Vetch LM, Boyle E, Rndll PK: Selfreported sleep, sleepiness, nd repeted lcohol withdrwls: rndom ized, double blind, controlled com prison of lorzepm vs gbpentin. J Clin Sleep Med 7; 3: 3 3. Krm -Hge M, Brower KJ: Open pilot study of gbpentin versus trzodone to tret insom ni in lcoholic outptients. Psychitry Clin Neurosci 3; 57: Myrick H, Anton R, Voronin K, Wng W, Henderson S: A doubleblind evlution of gbpentin on lcohol effects nd drinking in clinicl lbortory prdigm. Alcohol Clin Exp Res 7; 31: Drobes DJ, Anton RF, Thom s SE, Voronin K: A clinicl lbortory prdigm for evluting m ediction effects on lcohol consum ption: nltrexone nd nlm efene. Neuropsychophrm cology 3; : O Mlley SS, Jffe AJ, Rode S, Rounsville BJ: Experience of slip m ong lcoholics treted with nltrexone or plcebo. Am J Psychitry 199; 153: Klivs PW, Volkow ND: The neurl bsis of ddiction: pthology of motivtion nd choice. Am J Psychitry 5; : Johnson BA, Rosenthl N, Cpece JA, Wiegnd F, Mo L, Beyers K, McKy A, Ait-Doud N, Anton RF, Cirulo DA, Krnzler HR, Mnn K, O Mlley SS, Swift RM, for the Topirm te for Alcoholism Advisory Bord nd the Topirm te for Alcoholism Study Group: Topirm te for treting lcohol dependence: rndom ized controlled tril. JAMA 7; 9: Myrick H, Anton R, Voronin K, Wng W, Henderson S: A doubleblind evlution of gbpentin on lcohol effects nd drinking in clinicl lbortory prdigm. Alcohol Clin Exp Res 7; 31: Anton RF, Drobes DJ, Voronin K, Durzo-Avizu R, Mok D: Nltrexone effects on lcohol consum ption in clinicl lbortory prdigm : tem porl effects of drinking. Psychophrm cology (Berl) ; 173:3 3. Anton RF: Genetic bsis for predicting response to nltrexone in the tretm ent of lcohol dependence. Phrm cogenom ics ; 9:55 5 Clinicl Guidnce: Gbpentin Combined With Nltrexone for Tretment of Alcohol Dependence Gbpentin nd nltrexone hve both been proposed s tretments to diminish relpse in recently bstinent ptients with lcoholism. In -week tril of nltrexone (5 mg/dy), nltrexone combined with gbpentin (up to 1, mg/dy) for the first weeks, or double plcebo, the combined tretment outperformed both nltrexone lone nd plcebo, but the effect did not persist beyond weeks. The -week period ws chosen becuse Anton et l. believed tht initil co-tretment with gbpentin would help by diminishing the insomni nd mood instbility experienced by ptients in their first weeks of bstinence. O Brien points out in n editoril (p. 7) tht the combintion is sfe nd tht the study is good exmple of the rigorous evlution of rtionl combintion designed to ddress the rnge of symptoms nd difficulties presented by ptients with lcoholism who seek to mintin bstinence. Am J Psychitry :7, July 11 jp.psychitryonline.org 717