Him ORIGINAL CONTRIBUTION Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence The COMBINE Study: A Randomized Controlled Trial MD ‘O'Malley, PhD David Couper, PAD Dennis M. Donovan, PD. David R. Gantivend, MD. PhD MD, PAD, Mattson, PRD. ren D. Williams, MD Allen Zovehen, DSW Tor the COMBINE Croup OUT SMILLION INDIVIDUALS IN the United States currently meet diagnostic erteriaforal- cohol dependence, a leading preventable cause of morbidity and mor- tality and a major contributor to health care costs In primary cae settings, the prevalence of alcohol use disorders ranges from 20% 9 36% most of those paticntsare never teated and, if ‘See also p 2075 and Patient Page. (©2006 American Medical Assoc ton, Al rights reserved. (Repent) JAMA, ay 3, Context Alcohol dependence treatment may include medications, behavioral thera- pies, orboth, Itis unknown how combining these treatments may impact their effec~ tiveness, especially in the context of primary care and other nonspecialty settings. Objectives To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome. Design, Setting, and Participants Randomized controlled tral conducted Janu- ary 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of ‘Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence. Interventions. Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with cr without a combined behavioral intervention (CB). A ninth group received CB only (no pills). Patients were also evaluated for up to 1 year after treatment. ‘Main Outcome Measures Percent days abstinent from alcohol and time to first, heavy drinking day. Results ll groups showed substantial reduction in érinking. During treatment, pa- tients receiving naltrexone plus medical management (n=302), CBI plus medical man- agement and placebos (n=305), or both naltrexone and CBI plis medical management (1=309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than. the 75.1 in those receiving placebos and medical management only (n=305),asignifi- cant naltrexone x behavioral intervention interaction (P=.009). Naltrexone also re- duced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% Cl, 0.53-0.98; P=.02) cover time, most evident in those receiving medical management but not CBI. Acam- prosate showed no significant effect on drinking vs placebo, either by itself or with any Combination of naltrexone, CB, or both. During treatment, those receiving CBI without pil or medical management (n= 157) had lower percent days abstinent (666) than those receiving placebo plus medical management alone (n= 153) or placebo plus medical man- agement and CBI (n=156) (73.8 and 79.8, respectively; P<.001). One year after treat- ment, these between-group effects were similar but no longer significant. Conclusions Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of ef- ficacy, with or without CBI, No combination produced better efficacy than naltrexone ‘oF CBI alone inthe presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment. ‘Trial Registration clinialtals.gov Identifier: NCTO0006206 JAMA, 20062952002-2017 ww jamacom Author Affllations ae Isted atthe end ofthis Conesponding Author Raymond. Aton MD, Cen ate, terfor Dug aa Aleaal Mogan, Medal Unive. ‘Members fthe COMBINE Study Research Group are yf Sut Carns, 6 resent PO Box 250851 Ined ot he endot te aril (Chaston SC 29825 (atenrdmusc ed). vol 295, No. 17 2008PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE similar to those represented in general population data, do not receive spe- aly care (National Institute on Aleo- hhol Abuse and Alcoholism [NIAAA], unpublished data).* Primary care phy sicians can play a significant role in ad- dressing alcohol use disorders.""* It is of interest whether medications for al- ccoholist are efficacious without spe- alist intervention and whether effi- cacy can be improved by combining different medications with of without specialist care. These questions are par- ticularly important given that most prob- lem drinkers are seen in health care se lungs, rather than in specialist treatment programs. The Combined Pharmaco- therapies and Behavioral Interventions (COMBINE) study was designed toad- dress these issues, Several behavioral treatments” and. at least 2 medications approved by the Usood and Drug Administration, nal- trexone and acamprosate, shown efficacy in the treatment of al- cohol dependence. However, no large- scale randomized controlled study has evaluated whether combined pharma- cotherapy with or without behavioral therapy could improve outcome. For ‘example, itis unclear'® whether com- Dining naltrexone (an opiate receptor antagonist) with acamprosate (a puta- tive glutamate modulator)" is supe- rior to monopharmacotherapy, with or ‘without additional behaviorsl therapy. AL the time of initiation of this stud ‘acamprosate was approved in Europe >but was still an investigational drug in the United States. Although naltrex- ‘one was approved in the United States evidence of its efficacy was primari based on small single-site studies us- ing specialist models of treatment. Mul- liste studies have yielded conflicting re sults.*2! Thus, assessing the efficacy of teach of these medications, alone and combined, ina large multisite trial was of interest. Sponsored by the NIAAA, this multisite, randomized, controlled trial evaluated medical management with naltrexone, acamprosate, or both, with oF without additional specialist treatment (combined behavioral inter- vention [CBI]). * have 2004 JAMA stay 3, 2005Vol 295, No. 17 Reprinted) Inaddition, there is no solid informa- tion on how wellalcohol-dependent in- dividuals will respond solely to the act of pill aking and being counseled by a health eate professional. secondary aim ofthis study was to evaluate whether tak- ing placebo pills and being seen regu- larly by a health eare professional would enhance addiction specialist counsel- ing, A final goal was to evaluate if im- provements observed over 16 weeks of treatment would be maintained for up to 1 year after treatment ended, METHODS: Overview of Study Design The COMBINE Study rationale, design, and methods have been previously de- tailed.*** In brief, after baseline assess- ‘ment and attainment of 4 days of absti- rence, 1383 eligible alcohol-lependent individuals were randomly assigned to of 9 groups for 16 weeks of outpatient treatment (FIGURE 1). Eight of these groups (n=1226) received medical ‘management, a 9-session intervention focused on enhancing medication ad- herence and abstinence using a model that could be adapted by primary care settings. Pour ofthese groups (n=619) also received more intensive counsel ing (CBD delivered by aleoholism treat- ment specialists Patients i all 8 groups received either active/placebo nalirex- one or active/placebo acamprosate, yielding 4 medication conditions (pla- eebo, acamprosate, naltrexone, and acamprosate plus naltrexone) within each level of behavioral counseling (CBI vsno CBI). A ninth group (n=157) re- ceived CBI alone, without pills oF medi- cal management, and was included 10 address the separate question of pla- cebo effects. The protocol specified that all individuals should be assessed 9 limes during the 16 weeks of treat- ‘ment and at 26, 52, and 68 weeks after randomization, ie, up to 1 year alter tweatment ended, Recruitment and Randomization Participants were recruited by adver- Lisements and from clinical referrals at academic sites. Approximately 5000 potential participants were screened by telephone or in person.” All partici. pants seen in person signed an in- formed consent form approved by each site's institutional rev companied by a certificate of confides liality issued by the NIAAA. Baseline drinking histories, psychosocial data, health screens (including laboratory ‘general health panels), and levels ofs cific alcohol biomarkers were ob- tained, totaling about 4.5 hours. Eligibility criteria included (1) aleo- hhol dependence, determined by Diag- nostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) teria, using the Structured Clinical Inte view for DSM-IV"; (2) 4 to 21 days of abstinence; and (3) more than 14 drinks (women) or 21 drinks (men) perweek, ‘with at least 2 heavy drinking days (de Fined as =4 drinks/d for women and =" drinks/d for men) during a consecu- live 30-day period within the 90 days prior to baseline evaluation. Exclu- sion criteria included (1) history of other substance abuse (other than nico- Line or cannabis) by DSM-IV eriteriain the last 90 days (6 months for opiate abuse) orby urine drug screen, (2) ps chiatric disorder requiring medica- tion, or (3) unstable medical condi tions (eg, serum liver enzyme level limes the upper limit of normal). Eli- gible participants were randomly assigned (0 Lrealments using a per- muted block design, using blocks of, strafed by site. The randomization was implemented via a central telephons based interactive voice response sys- tem at the coordinating center. sw board, ac- Assessment Drinking parameters obtained from structured interviews at baseline” and during the 1o-week treatment period” are the main focus ofthis report. A sec- ondary analysis of drinking parameters inthe 1 year after treatment is also pre- sented. Atthe 9 medical management visits (except forthe CBI no pill medi cal management group) during treat- ment (see below), research assistants (not blinded to, oF providing, psycho- social treatment) assessed alcohol consumption and craving. Two- (©2006 American Medical Association, All sights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE hour assessments were performed at andliverand kidney function tests were _Race/ethnicity data were collected in weeks 8 and 16 during treatment and _ performed at baselineand every +weeks. compliance with National Institutes of again at postrandomization weeks 26, Levels of'y-glutamyltransferaseand per- Health guidelinesandself-designated by 52, and 68 (1 year posttreatment) dur- cent carbohydrate-deficient transferrin participants, using an item allowing ing follow-up. Adverse medication ef (9%CDT)"" were measured at baseline _ open-ended responses. For this report, fects were assessed by alealth care pro- and at weeks 8 and 16. For the CBI no responseswere categorized asblack,His- fessional at each appointment using the _pill/no medical management group, as-_ panic, non-Hispanic white, or other. Systematic Assessment for Treatment sessments were made by research assis- Race/ethnicity was not used inanalyses Emergent Effects (SAPTEE) inter- tants at the same postrandomization of outcomes. However, exploratory view." A complete blood cell count time points as for the other 8 groups. analyses will evaluate racial factors, eth- Figure 1. Stoay Profle T T T T T sone 9 orer 7 One Omer paar 3 aaere ‘Oars aaron Faoweuet ftowet || “rooewet ||" Feewriet ||" Faowact |] “Simao |] rae |f “cena |] *na T foot |] fans |] Sarat |] Amat |] Amr |) Soar |] So | toast | Saat (Ginter combined behavioral intention. "A patie coud dscontine 1 orton of eave whe remaining in another parton ei patient was signed to MIM pls CBl and helshedscontaued study ‘meceaton, tha patent coud continue to alend sts and CA st). However, patents Who asconbnled media management dd not eve urther mediation. "Stat coud inate multe reasons for witha 4Patens who didnot hae a dking assesment at he end of eatment were categorized as st to olow-up {Patents with po pestandontzabondrking data were excluded rm the pean days abstinent als. In he anass of relapse to heawy dking, they were sumed to have elapsed of te est coat date (©2006 American Medical Assoc tion. Al rights reserved. (Reprinted) JAMA, ay 3, 2005 Vol 295, No. 17-2008PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE nic factors, or both, as predictorsof reat ment response in the future. All sud site personnel, including investigators, research stall, evaluators, health care (medical management) practtioners,and Bl therapists were blinded tomedica- tion assignment, as were participants, through the end ofthe treatment and the 1-year posttreatmentassessment period. ‘Treatment Conditions Medications. Each participantin the pill- laking groups was assigned a uniquely. numbered medication pack (blister cards) and took up to 8 pills of active medication or placebo daily for 16 weeks. Allnaltrexone and placebo pills, and all acamprosateand placebo pills, wereiden- Licalin appearance. Participantsin each, ‘group took the samenumber of pills per day. Naltrexone or its placebo was given once per day as2 pills (1 placebo and 1 pillcontaining 25 mgorplaceboondays 1 through 4,1 placebo and 1 pill con- laining 50 mg or placebo on days 5 though 7, and two 50-mg pills [100 mg, daily] or placebo on days 8 through 112) Acamprosate orits placebo was adinin- istered as 2 pills (500 mg each ofacam- prosate or placebo) 3 times perday (ie, 3 gdally).Naltrexoneandits placebo dif fered in appearance [rom acamprosate andits placebo. Based on tolerability. the medical management clinician could re duce the acamprosate pillsand then duce thenaltrexone pills Attempts were made to reestablish the full dose. Doses ‘were chosen based on preliminary evi- dence that doses higher than those com- monly prescribed could be more ffica- ious and provide better coverage for missed doses.” Prior to the tral, we confirmed the tolerability of these doses aloneand in combination in 2random- ized, placebo-controlled pilot studies." Medical Management. Medical man- agement” was delivered by alicensed health care professional (14 physicians, 28 nurses, I physician assistant, 1 clink- cal pharmacist) over 9 sessions (weeks 01,2, 4,6,8, 10, 12, and 16) in which pills were dispensed. The inital vist av craged 45 minutes and began with a view of the alcohol dependence diag- nosis and negative consequences of 2006. JAMA stay 3, 2005 Vol 295, No. 17 Reprinted) drinking. The professional recom- mended abstinence, provided educa tion about the medications, and deve oped a medication adherence plan i collaboration with the patient. AUen- dance at support groups available in the community (eg, Alcoholics Anony- mous) was encouraged. Subsequent ses- sions, averaging 20 minutes, included re- view of drinking, overall functioning, medication adherence, and adverse ef fects, Participants who restumed drink- ing were given advice and encouraged to attend support groups, Problems with medication adherence were addressed, Participants who discontinued medica tion because of intolerance continued in medical management sessions to sup- port abstinence. For the CBI no pill group, access to health eate profession- als was available at weeks 4,8, 12, and 16 to assess liver function and provide health care advice ‘Combined Behavioral Intervention The CBI" was delivered by licensed be- havior health specialists all wth atleast master’s degrees in psychology, social work, or counseling) in up torventy50- minute sessions It integrated aspects of cognitive behavioral therapy.” 12-step fa cilitation,** motivational interview- ing" and support system involvement external tthe study*” Pleability was permitted in the numberof sessions and selection of modules oaddess cach par Uicipant’s needs. A motivational inter viewing style was used throughout. Treatment Quality Assurance. All medical management practitioners and CBI counselors had professional de- grees and atleast 2 years of postdegree experience. Treatment professionals were trained by standard protocols and used sntervention manials.”*' Before teat- ing participants, treatment profession- als submitted at least 2 tape-recorded cases and were cerlied by the taining center” Sessions were audiotaped, with 8 (medical management) or 12% (CBI) monitored and corrective action taken to ensure adherence. Statistical Methods The primary goal of the COMBINE Study was to determine if improve ment in treatment outcome could be achieved by combining pharmacothera- pies and behavioral interventions. To evaluate this, 8 of the treatment com- binations were chosen to form a 2 (acamprosate/placebo) X 2 (naltrexone! placebo) X 2 (CBIU/no CBI) factorial design. This allowed estimation and testing of the effects of each of the in- lerventions as monotherapies, as well ‘as comparisons of the effects of each combination of 2of the 3 therapies and of all 3 therapies combined. Thus, as described in detail previously.2=® the primary hypotheses of the COMBINE Study were the testing of the conver ional analysis of variance main ef- fects for naltrexone, acamprosate, oF CBI, as well as interaction effects. The protocol prospectively specified 2 primary intent-to-treat efficacy analy ses, based on the 8 groups that received pills. The coprimary end points wer percent days abstinent and time to first, heavy drinking day (=5 standard drinks per day for men, =4 for women) dur- ing the Loweek treatment period. Astan- dard drink was 0.5 02 of absolute aleo- hhol, equivalent to 10 oz of beer, 4.02 of ‘wine, oF 1.0 02 of 100-proof liquor.” Par- Licipants lost to follow-up (6%) were as- sumed to have resumed heavy drinking ‘on the day after their ast contact. For each dependent variable, a 2 (acamprosate/placebo) X 2 (naltrexone! placebo) X 2 (CBU/no CBI) factorial rodel was fit A mixed-effects general lin- ‘ear model was used for percent days abs nent. The treatments (acamprosate,nal- trexone, and CBD were analyzed as ixed effects and time (month since random- ization) asarepeated-measureseffect. An analogous proportional hazards model ‘was used to analyze the time tothe first heavy drinking. The percentage of total individuals who relapsed (=1 day of heavy drinking) by the end of reatment ‘was derived from this analysis and sented for greater clinical clarity. Ba line percent days abstinent (within 30 days prior tothe participant's last drink) aand research site were covatiates forboth the linear and proportional hazard mod- ls. A Bonferroni-corrected significance level of P=.025 (07 5%confidenceinter- (©2006 American Medical Association, All sights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE val [Cl]) was eta priori toadjust for the 2 coprimary end points. The traditional Factorial analysis of variance approach ‘wasadopted, evaluating interactionsand main effects of the 3 treatments at this 025 level, without furtheradjustment for rmuluplicity, Power lor detecting « 10% main et of each treatment was estimated to be ‘greater than 0.90 foreach copritnary end point. Estimated power for detecting an interaction elfect of half the magnitude ‘of the main effects was estimated to be lower but acceptable (eg, 040-0.50). The steering committee had extended dis- ‘aussion ofthe relative importance of pro- viding definitive evaluations of the main effects of the treatments (eg, the effi- cacy of naltrexone, ignoring acampro- sateand psychotherapy) vs evaluating in- teraction elfects. The only way to have ample power for interactions would have been to use an incomplete factorial d sign that would have made untestable assumptions about main effeets. Ulti- mately, it was decided that it was pref erable to ensure sensitive, reliable as- sessments of the main effects, seling for modest power for interactions. Preplanned interim analyses, ported to a data and safety monitoring board, were performed 18, 24, and 30 onthe after the first participant was ran- domized A Lan-DeMets spending fanc- lion approach was used to monitor the need for early trial termination, Preplanned secondary analyses in- cluded evaluations of site X treatment in- teractions, alternative summary me: sures of drinking, outcome parameters other than drinking, and adjustment for various baseline prognostic factors. We also used a composite secondary out- ‘come measure," in which a good elini- ceal outcome was categorized as absti- ence or moderate drinking without problems. Moderate drinking was de- fined as a maximum of 11 (women) or 14 (men) drinks per week, with no more than 2dayson which more than 3 drinks (women) oF 4 drinks (men) were con- sumed. Problems were defined as en- dorsing 3 oF more items on a standard- ized questionnaire” assessing physical, social, and psychological consequences (©2006 American Medical Assoc 1, All rights reserved. of drinking. Logistic models were used to evaluate the effect of treatment on, clinical outcome. A preplanned secondary analysis was conducted to evaluate the effect of tak- {ing pills and medical management, These analyses compared the CB! only condition with patients receiving placebo plus medical management and with those receiving placebo plus medi- cal management plts CB Similar to the primary analyses described above, these included mixed models for percent days abstinent, proportional hazard mod- els for ime to heavy drinking, and alo- gistic regression model for the com- posite clinical outcome. ‘A preplanned secondary analysis was also conducted to evaluate the persis- tence or emergence of hetween-group drinking differences over the posttreat- ‘ment period (Irom the end of week 16 through up to 1 year afterwards). This analysis used the same variables and analytic strategy used for the analysis ofthe 16-week within-treatment period, Secondary analyses and decomposi- ion of interaction effects are pre- sented here when they facilitate inter- pretation of the primary analyses. Data were organized, archived, and ana- lyzed by the coordinating center. The proportion of patients report- ing adverse events was tabulated and compared using x? or Pisher exact tests asappropriate. SAS version 8.2 (SAS In- stitute Ine, Cary, NC) was used for all analyses. RESULTS Study Population Randomization began in January 2001, and follow-up of the last participant ended in January 2004, A total of 1383, patients (428 women and 955 men) \were enrolled and randomly assigned (Figure and TABLE 1), slightly more than the target of 1375 specified in the protocol, Participants’ median age was 44 years, 71% had at least 12 years of education, and 42% were married. Eth- rile minorities comprised 23% (321) of the sample. In the 30 days prior to ran- domization, 2.3% of patients were medi- cally detoxified and 7.7% received in- patient treatment. The percentage of individuals abstinent for 4, 5 10 7,8 10 14, oF 15 to 21 days at randomization were 42%, 24%, 18%, and 15%, respec- tively (not significantly different across treatment groups). Seventy-six pretreatment character Isties were compared across groups (s2- lent ones are summarized in Table 1) The only nominally significant (P<.05) between-group comparison was the number of DSM-IV alcohol depen- dence symptoms, which were 5.4 (SD, 1.3) for the collapsed medical manage ment plus CBI groupsand 5.6 (SD, 1.3) for the collapsed medical manage- ment without CBI groups. Thus, the {groups were comparable on pretreat- ment characteristics Data Completeness There were no statistically significant dif ferences in research retention between treatment groups: although a number of people did not complete 1 or more as- pects of treatment, 04% (group rang 192%-06%) provided complete within- treatment (weeks 1-16) drinking data, The average l-year posttreatment deink- ing data completion rate was 82.3% (range, 80%-87%), with no significant difference between treatment groups. ‘Medication Adherence/ Dose Reductions Mean medication adherence, com- puted as the ratio of pills taken from returned blister pack counts to those prescribed throughout Lo weeks of treatment, was 85.8% (median, 96.4%). Mean adherence rates were similar for acamprosate (84.2%) and naltrexone (85.4%) and for those who received CBI (85.3%) or not (86.3%). Ongoing or re- ‘current dose reductions were 7.8% for placebo, 11.9% for acamprosate, 12.19% for naltrexone, and 20.9% for acam- prosate plus naltrexone (P<.001).On average, 88 mg of naltrexone and 2537 mig of acamprosate were taken daily. Adherence in Behavioral Interventions The median CBI and medical manage- ment sessions completed were 10 and (Reprinted) JANA, ay 3, 2005 Vol 295, No. 17-2007PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE 9, respectively. Therapists’ adherence Adverse Events limit of normal (P=.02). These re- ratings measured on six 7-pointscales” OF 70 serious adverse events occur- solved following discontinuation of were high, witha median score of 6 for ring during teatment,2 were possibly medication, except for 2 cases (1 pat both medical management and CBtrat- related to study medication (I naltrex- _teipantdid not retur for etesing: the ings (where a ra ceptable protocol adherence). Alcohol- mon serious adverse event was hospi- ies Anonymousattendance ates during llzation for detoxification (n=38). The treatment were similar across Ureal- rales of serious adverse events Were ment groups ranging from 17% 10 35% similar across groups, as Were adverse Time Effects. Overall, percent daysab- (6-15 median meetings attended). events leading to treatment dropout stinent from baseline to end of study (TABLE 2). However, there were sig- ipled from 25.210 73.1 (P<001), and Biological Verification of Drinking nificant dillerences in the percentages drinks per drinking day declined by Level of %CDT, an abnormal serum reporting nausea (P<001), vomiting 44% from 12.610 7.1 (P<03), withthe transferrin proteinalteredbyaleoholeon- (P<.001), diarrhea (P<.001), de- neteffect that alcohol consumption d sumption, was used asa veracity check creased appetite ( and Som- creased by 80%, from 66 to 13 drinks for sel-reported drinking. Parucipants nolence (P=.003) (Table 2). Twelve _ per week reporting complete abstinence over the participants, primarily in the nal Site Effects, It was anticipated, a study (n=212) had a 15% decrease in one groups, had reatment-emergent prior, that there would be diferences ygof 5 indicated ac- one, 1 acamprosate). The most com- other continued heavy drinking). level of CDT, whereas those reporting levels of liver enzymes (aspartate ami- in outcome among sites, based on dif- any drinking (n=694) hada 5% increase notransferase or alanine aminotrans- ferences in patient populations, effec from baseline to week 16 (P<001). _ferase) greater than 5 times the upper tiveness of therapists, and other local ". bneeine Characterscr of Patiopants 22008 JAMA stay 3, 2005 Vol 295, No. 17 Reprinted) (©2006 American Medical Association. All ights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE factors, A significant main effect of site ‘was found in most analyses. No signifi- ‘cant site X treatment interactions wer found inany analysis. Therefore, as pre specified in the protocol, all analyses control for site as a baseline covariate Primary Outcomes. TABLE 3 and TABLE 4 present the estimated effects and associated P values for the protocol- specified main effects and interactions for percent days abstinent and time to first heavy drinking day: FIGURE 2 pre- sents effect sizes and hazard ratios (HRs) for main effects and interaction celfects. TABLE 5 provides the indi- vidual treatment group means, For percent days abstinent, the 3-factor interaction (naltrexone X acamprosate X CBI) was not signifi- cant. The 2-factor interaction (naltrexone X CBI) was significant (P2009) (Table 3). No other interac tions were significant; nor were any of the main effects for acamprosate, nal- trexone, or CBI. However, given the naltrexone X CBI interaction, the main clfect tests for naltrexone and CBIshould be interpreted with caution. Examina- tion of the least-squares means associ- ated with this interaction (Table 3) shows thal the participants receiving neither nal- lrexone nor CBI had the fewest absti- nent days, whereas those participants receiving either naltrexone or CBI showed the most abstinence. Com- bined therapy with naltrexone plus CBL showed no incremental benefit over CBL ‘oF naltrexone alone, The ellect size for the comparison of naltrexone to pla ceebo in the absence of CBI was 0.22 (07.5% Cl, 0.03-040) (Figure 2). No significant main effects oF inter. actions involving acamprosate, with or ‘without CBI, were observed for time to the first heavy drinking day: Howey there wasa significant main effect of nal- trexone (HR, 0.72; 97.5% C1, 0.53- 0.98; P=.02) fortime to first heavy deink- ing day (Table 4). Groups receiving naltrexone had, on average, alower risk of heavy drinking than those receiving placebo. Although the naltrexone X CBI interaction was not significant for this cend point (P=.15), the pattern of re- sults is identical to that found for per (©2006 American Medical Assoc ton, Al rights reserved. cent days abstinent (Table 4: in the con- hose not the group receiving naltrexone without CBI fared best, and the CBI plus pla- ccebo and CBI plus naltrexone groups ext of medical manageme receiving naltrexone of CBI fared worst, ‘Table 2, Adverse Events During Treatment by Medication Group Ne 2) ‘Acamprosate + Placebo Acamprosato Naltrexone Naltrexone | P Event (ozs “isso ies 30) “f= 305) Value” Tame we 7eey torah 125) aT Veta 2507 Hh BOE Ta DoT Dire Taser ozs Tes Gor __—=00T Decreased aepaTS To) cara Sammons BO OT ee __008 AST ALT SG TO Set Te Segue ache ‘Achat etowteaton 31) 11 (a 6a we 58 Ofer Se 72 2) = Witness coat am 38) TSE oH ‘bres events Val Tear a Tater e 2] = Interactions Placebo Acamprosate Natvexone | "Placebo Nalrerr racy) inaso) nan Keampoutex Towa Tezgsay _T/spsay Tos psaN No car t Placebo Acamprosata ' Placebo Acamprossta in=c0q) n= 300) TS psa) TroPeRoo| Tea sea Pao No Cal t Placebo Nalvexone | ' Placebo Nalvexone ineo0o)_in=30g) ins ae) in = ao TaterrexCaTe1 sae) _soweam) 7 Tes. (Repent) JAMA, ay 3, 2009PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE Particpants With = Heavy Drnuing Day During Treatment” were intermediate ‘only the pairwise comparison of naltrexone vs placebo in No. (6) the no-CBI (ie, medical management Gontol only) condition reached statistical sig- Wain Bets nificance; the other 2 comparisons showed trends ina consistent direction (Figure 2 and FIGURE 3). Secondary Outcomes. Analyses of al- lemative summary measures of drink TE _ ing, including drinks per drinking day (P2.03), drinks per day (P=.03), and heavy drinking days per month Rearpneie = TE (P=.006), were consistent with those Interactions for the coprimary end points, all show- Placabo ing a significant naltrexone X CBL Plasto Nalrexone Interaction, freon 300 Abstinence hasbeen the primary end. 2a) BOT aT point for most acamprosate studies.» Cumulative proportion of abstinent days, isanalogous lo percent days abstinent in cour study. Wealso examined time to first drink as. secondary outcome. None of No car Placebo Acamprosata ines in a00 ‘Acamprosate x CBI oe the main effects or interactions were sta- toca signiant bute veel pat temo tats scansstent wh tha or primary end pote 1 The Obsessive Compulsive Drink- SEEMS TOSS TE newer ay smegeoieermteeom mens Ug Seales” showed a math effect SEES Suen Gun vaeS ecm nerumereisorser | (P= in which naltrexone was ax sociated with lower craving than was Figure 2: Eiect Se Ertmates and Para Rat for Primary Outcomes Peco a ant een ety ning tet ae 97) Sen Ore cro 7%) Leesa tr Rk ec sie etrates for percent dys abstinent are reported as Cohen vale. Thee way wlractns anol shown but al were na giant CBindcats com bined behavior intervention Cl confidence tra *Comparéon group fr navexone is placebe, for acamprsate, laceb; and for CB, no CB {Compson toups placebo acangrosate place ralexone Compson ups placebo acarorsae/no CEL Compan fous placebo rltexone/ne CB 2010 JAMA stay 3, 2005 Vol 295, No. 17 Reprinted) (©2006 American Medical Association. All ights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE ‘5 Danking Outcomes Through Ena of Westnet Medical Management No CB CEI Maciel Management Dinkng No. Pacabo Naltrexone Acamprosate Acamprosate Placebo Nalvexone Acamprosate Acamposate No Pils ‘outoomae™ ES Feces Tare TAS PSO SOO PEOH TSR) eLSPEOy TApSaH TAUTPGI TeDesas —TTHBEOH es! aan it Faanioneay STEED OT TTT RT TTT SE TOE TEE EEO ring, No tori Reaane a CL come, No, eri placebo (9.7 [SD, 7-60] vs 10.9 ISD. Figure, Time to Fist Heavy Drinking Day By Nalerone and Combined Behavioral 7.64], respectively; P=.01). This effect, remained significant (P=.02) ifthe ob- sessive factor score, not including the drinking items, was analyzed sepa- rately, A trend for a main elfect favor- ing naltrexone (P=.08) was seen on a measure of alcohol-related conse- quences.” Dilferential treatment ef fects were not seen on levels of y= lamyliransferase oF %CDT. Clinical Significance. Analysis ofthe composite outcome measure at end of treatment (FIGURE + and Table 5) revealed significant interaction between naltrexone and CBI (P=.02), in which naltrexone, CBI, oF both ‘enhanced positive outcomes in the pres- cence of medical management. The pe centages of good clinical outcomes were 58% for the placebomedical manage- ment group, 74% for the naltrexone/ medical management group, 71% for the placebo/CBI plus medical manage- ment group, and 74% forthe naltrexone/ CBI plus medical management group. The numbers needed to treat (I/abso- Jute risk reduction, which is the rate of ‘good composite outcome foreach group tinue that for the placebo plus medi cal management group) toachieve the ‘good composite outcomes are 7 for CB 6 for naltrexone, and 7 for naltrexone plus CBI. There were no other signifi- ‘cant main or interactive effects Sex Effects. Overall, men had a slightly better outcome for percent days (©2006 American Medical Assoc ton, Al rights reserved. Intervention (CB) Interaction abstinent (men, 78.0 [SD, women, 75.4 [SD, 19-44]; ever, sex did not significantly affect re- sponse to any of the treatments. It should be noted, however, that statis- tical power to detect small to moder- ate sex X treatment effects in this study was limited. Within-Treatment Evaluation of CBI Therapy Without Pills (Placebo Effect) To evaluate the effect of taking pills and medical management on CBI, we con- tasted the drinking outcomes (pe cent days abstinent, relapse rates, and clinical outcome) (Table 5) between those taking placebo who only re- (Repent) JAMA, ay 3, ceived medical management (n=153), those taking placebo who received medical management and CBI (n=156) and those taking no pills who ceived only CBI (n=157). Percent Days Abstinent, During the 16 weeks of treatment, there was an overall difference (P<.001) in percent days abstinent between those receiv- ing placebo pills and medical manage ment alone (73.8), placebo pills and medical management plus CBI (79.8), and CBLalone (no pills or medical man- agement) (66.6). Pairwise post hoc tests, corrected for multiple compari- sons, showed a significant difference tween those receiving pills and medi- ceal management compared with those Vol 295, No. 17 2014PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE receiving pills and medical manage- Global Clinical Outcome. The per- ing (11%) or emotional problems ment plis CBI (P=.04) and with those centage of patients receiving CBI only (17%), and detoxification (6%) were receiving CBlalone (P2.03). There was who had a good global clinical out- not significantly different between the a larger difference between those re-_ come (60.6%) was intermediate be- treatment groups (TABLE 6). ceiving pillsand medical management (ween those receiving placebo and Percent Days Abstinent. Overall, pe plus CBl and those receiving CBlalone medical management (58.2%) and cent days abstinent declined across (r<001) those receiving placebo medical man- groups during the year after treatment Relapse to Heavy Drinking. There agementand CBI(71.3%). Overall the ended. was more rapee to heavy drinking in differences amongthese 3 groupe were While the direction ofthe lfeences those receiving CBI alone (no pills or not significant (P-.07). observed during treatment remained in medical management) (79.0%) com- the posttreatment period (TABLE 7), the pared with those receiving pills and Posttreatment Follow-up naltrexone X CBI interaction was 0 medical management plus CB Outcomes longer significant. Those treated with pla (71.2%) (HR, 0.77; 97.5% Cl, 0.60- Initial analyses were performed to ceboand medical management had lower 1,00; P=.05). The relapse rate to evaluate potential confounding vari- _ mean percentdaysabstinent (61.4) com- heavy drinking for the placebo pill ables during the 1-year posttreatment pared with those treated with naltrex- and medical management group follow-up period. Overall, frequency of _oneand medical management (66.2) and (75.2%) was intermediary to the other hospitalization (11%), emergency de- with those treated with CBI with nal- 2 groups and did not differ signifi- partment treatment for alcohol prob-_trexone (67-3) or without (66.6). Ove cantly from them. Jems (6%6), use of medication fordrink- all, there was a trend (P=.08) for CBI- treated individuals to have higher percent ss abstinent than those treated with, Figure 4, Ode: Ratios for Good Componte Cinteal Outcome st End of Treatment Compared "dl uranagearewin recreate of ‘with Placebo Naltrexone/No Combined Behaviaal Intervention (CI) igement, iFresp medication group. The overall percent days abstinent in those who received CBL ener ‘without pills (60.9), those who re- uso : ceived placebo and medical manage- yeas = ment (59.4, and those who received pla- deoavas, Cebu plus medical management and CBI (67.5) were no longer significantly dif- ferent (P=.08). Relapse to Heavy Drinking. Over. _agistcregresion madlof good cial oucoreGee "Matador dsnton)attheendafthekstweas ‘ll, more individuals had at leat 1 heavy of festment war sgnfeant for naluexone = CBinteacten, P= 02. Clindatescondence tea. drinking day during the posttreatment Table 6: Despton of Medel intavertons Dung Yeu Postentmenttn Fartparte To) MecialManagerent fo CB Cal Weil Managemen et choy atresone | Presb Natverone Acamprosste Presb Naterone Acampo Reampecsie Sehavornenenion fai) theta fs) fetes "nei “ety “etn Teticblonsp ang Beas) aay) aah aaa) aaa) eva waa ie Focal ventions Hompmloreber 200131) 10(10) 100 ous 18009 BEN PDR “0 tea a a a a 7 Tiesente TET SS oe En 7 ‘ang a CD TaS = neato Titan 0 TES SHES ao ean 2012 JAMA stay 3, 2005 Vol 295, No. 17 Reprinted) (©2006 American Medical Association. All ights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE period (TABLE 8) than during treat ment. The direction of the ellects ob- served during treatment persisted, with ‘only those receiving naltrexone show- ing nominally les isk (HR, 0.77;97.5% €1,0.58-1.02; P= .04) of returning toat least 1 heavy drinking day over time. No cother medication or medication by be- hhavioral therapy interaction was signifi cant, The CBI-no pills group had a non- significantly greater rate of at least 1 heavy drinking day (86.6%) than the pla- ceebo and medical management group (843%) or the placebo and medical man- agement plus CBI group (80.8%). Global Clinical Outcome. There was no significant overall group difference in global clinical outcome as assessed, cover the last 16 weeks of the 1-year fol- low-up period. It should be noted that the group intially treated with pla echo and medical management had the least number of participants with «4 good clinical response at the end of the 1-year posttreatment follow-up period (TABLE 9), consistent with that ‘observed at the end of the treatment pe- riod. The CBI-no pills group no longer differed significantly [rom the CB placebo or the medical management— placebo groups (Table 9) ‘COMMENT As in prior multisite trials of treatment foralcoholism, all treatment groupsex perienced large increase in percent days, abstinent, from 25 prestudy to 73 dur- ing treatment, Across several deinking measures, patients receiving medical management showed better outcomes when also receiving either CBI oF nal- trexone: in the absence of CBI, naltrex- cone helped; without naltrexone, CBI |helped. The combination of CBI plus nal- trexone did not further improve out ‘comes. With regard to naltrexone, the re- duction in risk fora first heavy drinking day was 0.2 consistent with meta- analyses of other naltrexone trials!2"> that used 50 mg/d and included special- isteare. However, our findings stand in contrast to the negative results of the rmulliste Veterans Affairs Naltrexone Co- ‘operative Study.” Potential reasons for discrepancy between our results and (©2006 American Medical Assoc ton, Al rights reserved. ‘Table 7. Adjustea Mean Percent Days Absinent Through the Era ot Folow-up (80) Control intervention P Value Acamprosate in 63 Tearporaie Saw B50) = Placebo lateae a a eC Interactions Placebo Acamprosate Placebo Nalvexone | ' Placebo Nalvexone 286) in=2e) n= 2at) n= 28a) Teapostax _USEIO —SrOGIan —Gapisy —espI7a a Tc Placsbo _ Acamprosaia (n= 200) 3 Reape CREAT BTS _wIS TAD BTS TAM No Car Placebo Nalvexone "Placebo Nalvexone fne28) n=287) n= 280) Tateoore XC SLa TE 602 was wrey erst those of that study, and possibly those of others, relate to differences in partici- pant characteristics, the use of 12-step facilitation therapy, the high placebo re- sponse rate, lower follow-up rate, and smaller sample s theless, our data suggest that naltre lone ean be ellective within the context of medical management without special- {st behavioral treatment The lack of acamprosate efficacy was surprising, given the positive results of many previous trials." Our study used a higher dosage (3 g/d) than that used in most trials (approximately 2 g/d), although exploratory analyses of 2 US multisite study of acamprosate found efficacy for the 3-#/d dosage, whereas the 2-/d dosage was not ofsig- nificant benefit in the intention-to- that trial. Neve reat analysis.” Neither adverse events nor medication adherence appeared to be especially problematic with the 3-y/d dosage used in our study. One salient difference is that our tial required only (Reprinted) JAMA, May 3, 2005 Vol 295, No 4 days of abstinence, achieved primar- ily onan outpatient basis, whereas most positive studies of acamprosate had a longer pretreatment abstinence pe- riod established during inpatient teat- ment. Also, prior acamprosate trials used less Frequent assessment, non standardized counseling, and patients recruited from clinical (primarily in- patient) seuings Consistent with our pilot stud- fone and acamprosate appeared to be safe and well tolerated. However, con- trary t ourstudy hypothesis and tends observed inasingle-site study, our ccurrent data do not support the com- boned use of these 2 medications Previous tials reported an advan- tage of pairing naltrexone with spectal- ist-delivered behavioral therapy." In the COMBINE Study, however, compa- rable outcomes were produced by CBI the combined use of naltre alone, naltrexone alone, and the com- bination of CBI and naltrexone, if pro- 2013PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE vided in the context of medical man- agement. The lack of additive effect of Bland naltrexone in this study might be attributable to methodological dif- ferences between studies, including the higher naltrexone dosage in this study. Also, all pill-taking participants re- ceived 9 sessions of medical manage ‘ment in addition to medication and CB, pethaps making it difficult to show an added advantage for the combination ‘of CBI plus naltrexone over either alone. te Participants With Control Heavy Drinking Day Over 1 Year Posttreatment™ No) Intervention Value ain Ete Rearpneie = Placabo Reamprocaia x ratrerone earpiece xR, Taree x CEP I Acampeosate a = Natrexore | i= 312) 2s ras) ae 3. One- Yeu Postveatment Dinkng Owcomes Moreover, while CBI in this study in- corporated components of cognitive be havioral therapy, it differs in many ‘ways from standard cognitive beha ioral therapy, including a greater em- phasis on Alcoholics Anonymous lendance. Our results, however, are consistent with those of OMalley etal,” ‘who found that naltexone did not com- tribute to the maintenance of improv ment in patients who initially re- sponded to naltrexone ard CBI but die for those patients who received a pri- mary care model of counseling. Our data support previous r sults suggesting that naltrexone ean bbe a viable medical management option for teatingaleohol-dependentindividu- als, Although our medical management intervention” is more intensive than that provided to alcahol-dependent pa- tients it. most health care settings, tis not too dissimilar to other common get cra medicine patient care activities, sch as iniiating insulin therapy in a patient with diabetes melts, initial manag ment of human immunodeficiency vi- rusmedications, and intensive manag ment of congestive heart failure. For individuals who prefercounseling rather than medication, CBI could be pro- vided bya specialist counseloralong with coordinated medical cre." In this study, the numbers needed to treat to achieve a good clinical out- come in medical management with sther naltzexone oF CBI were similar esa Management No CB Natrexone «| rl NoPile raking No, Placsbo Natuexane Acamprosate Acamprosele Placebo Naloxone Acamprosate Acamyosate Outcomest (N= 1ESHt_ n= 189) _In= 184) = 182) fp) n= 158)_(n= 165 inten _=180) Parent cays THE SOARED BST GTAH COTTA BABII SRE WOGIAT I BTAT CSET OORT arent rraan Sit Faunioneay 13S __TURET OTTER TBI TORE HI TATE 5 aTES aR ‘rng, No.of tori Reaane SES SM RATT a) SET RATE ‘core, No. eri (Bare 2014 JAMA stay 3, 2000—Vol 295, No 7 epriotee) (©2006 American Medical Association, All rights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE (in this ease, approximately 1 in every 6-7 individuals) to those for other chronic conditions, including chronic depression,” chronte obstructive pule monary disease" Crohn disease * ype 2 diabetes," and Alzheimer disease." Although not the main focus of the study, iti notable that the patients re ceiving only CBI had worse outcomes than those receiving CBI and medical management plus placebo pills or medi- cal management pls placcho pills. The “placebo elfet” in this trial may have consisted of a combination of factors: a worse outcome secondary to disap- ointment at not receiving medica- tion in those not receiving pills (nega- live expectancy feet), optimists about the potential benelits of the medica- Ui in those receiving pills (pesitivee pectancy effect), daily pilltaking act ing asa reinforcer of motivation, the nonspecific effect of mecting regu- larly with a medieal professional, and the content of the medical manage- ment visits themselves, Further evalu ation of these issues i anticipated. should be noted that the dilferen- ual treatment elfecis seen during teat- ment, while persisting to some degree, largely dissipated over the year post treatment, consistent with previous ports" While those treated with nal- trexone sil had less relapse to a heavy drinking day over the year postieat- ment, this was only marginally signifi cant. No other significant treatment cllect emerged, although there was some indication that those who had received CB had more abstinent days during the year alter treatment. These results sug- gest that a number of aleobol-depen- dent individuals require either pro- longed or intermittent cae. It has been previously suggested that continued nal- trexone and medical monitoring, con- Uinuation of Ct therapy, or both might bye useful approaches for those who do well during initial treatment.” Theinternal validity ofthis tial ishigh, with excellent balance between groups medication and therapy adherence, complete roaweck drinking data for 94% of the sample, and biological verification of sell (©2006 American Medical Assoc ‘Downloaded From: https:/jamanetwork.com/ on 06/12/2023 1, All rights reserved. report, Potential limits to external gen- cralizabily include the intensive research assessments (upto 12 hours), the recruit- ‘ment and treatment of patients in non primary care academic settings, exclu sion of participants with substantial concurrent psychiatric illness and drug abuse, and the limited time of teatiment (ie weeks) given the chronicity and relapse potential in alcohol-lependent individuals, The resulting sample, how- ever, may represent poptilation of aleo- hol-dependent patients who could be treated withina medical setting in which health care professionals are in aunique position to intervene, given their ongo- {ingrelationships with patients, Posttreat- ment outcomes will be evaluated fur- ther and subsequently reported. In conclusion, within the context of medical management, naltrexone Ided outcomes similar to those ob- tained from specialist behavioral treat- ment (ie, CBI). We found no evidence of efficacy for acamprosate and also no evidence of incremental efficacy for combinations of naltrexone, acampro- sate, and CBI. Somewhat unexpeet- edly, we observed a positive effect of re- ceiving placcbo medication and medical ‘management over and above that seen with specialist-delivered behavioral therapy alone, Medical management of alcohol dependence with naltrexone ap- pears to be feasible and, if imple- ‘mented in primary, and other, health care settings, could greatly extend pa- Lent access to effective treatment. Pu ture studies that evaluate the useful- ness of continued of intermittent care of aleohol-dependent individuals over the longer term should be considered, Author filstions: Centr forO1ug and leah Po (gam Medal Unversity of South Carolina, Chars {en\brs Anton ana Randall Substance Abuse Test ment Un ale Urivrsty School of edre, New Hayen, Conn (1 tal Boson Unversty Scot tM Boston, Mass (Diao, Univers of ‘Wisconsinhwaukee (rs Csr and Zeb) Co laberative sts Coointng Carter, Uversy of North Carina, Chapel Mil (Ds Couper and Hes ting: Addictions Treatment Center, Univrsty of ‘Wastington, Seat (or Donovan) Massachusetts General Hospital Soton (Or Castiend: Unversity ‘of Tens Heath Saence Center at San Aono (Or ‘eansonVelrans Aas teston Heather Sten! feton Univerty Scho! of Men, Boron, Mase {Druacaso ager liars Mace Center Brown Urey, Prolene (Ds Logabaugh and Su nivrsty of Mam school of Meine, Mami Fa (Ors Mason and Was) Natal nite of A (chet Abuse and Accom Benes, Md (Oe Mat Sea} Center on Acchasm, Substance Abus and A Gletor, Univerty of New Mexca, Abuauerque (Or Mate) reatment an Research Centr, Urwesty of Pennsyvania,Piacelpi Dr Peta: and Ha ‘ard Univers /Mtean Hostal mor. Mass Dr ‘Wis Dr casters now afaed with Akermes Ine, Cambridge, Mas: John snow with Un erty of Vela Heath Systems, Chatotie; Dr Mason row with The Sips Resear stu Lz Jala Calf andr 2ueben# pow wh Calbia Un erst Shoo! of Sal or, New York, NY. ‘Author Contributions: Dr Hsing ha fl acces fo [tof the tan the study an takes esponsbatyfor {he mognty of the dead the aecuraey ofthe dts als. Study concept and desig: Anton, ©'Maley, Cal, ier Coupe Donovan Castend, Hosting ltnsn, Locasto, Longabaugh, Mason, Matson, Mile, Petiab, Renal, Swit Wess, weber ‘equlstin a daa: ton, © Maley, Cra, Cis, Donovan, Gastend obser, Loca Langabough, ‘Mas ile Petal Randal Sw Wits, Milas, 2weben ‘nabs and interpretation of dat: to, © Maly ado, Cie, Couper Donovan, Gastinnd Hoskng Johnson, LoCaso, Longabaugh, Mason, Matson, ‘ater, Petit, Randal Swit Wats, eben Daftngottnemanszri Aton, © Mey, Donovan, Hosking, Mile, les, Zneben Citcal revision ofthe manu for important in {elects content Anton, © Madey, Cul, Cie, (Couper Donovan, Castnend, Hastng, Jhon, Locasto, Longabaugh, Mason, Matson, Mile, Petinat, Renal, Swit Wess, Willan Sasa analysis: Coupe, Hosting (Obtained ind Anton, O'My, au, Donovan, Castnend, Hosting fson Lngabaugh, Mason, ier, eta, St Wess, 2weben ‘Aamiistatve tcl oy material support Anton, ‘inate, Cra, Cs, Couper Donan Castrend erlang hnson, LoCasee, Longabaug, Mason, Matson, Miler, ettinat, Randall, Swit, Webs, Wilans,2neben, Sud) sipenson: Aston, Maley, Calo, Cie, Couper Donovan, Castnend, Hastng, Johnson, Locasto, Longabaugh, Mason, Matson, Mile, Petinab, Renal, Swit Wess Willan, Zweber Fanci Discosures: Gr Anton bat ered rece ingeonsufaten fe and honvara am Forest abo. "aloes and Altermes (he maker flog actngiec. {Ble naloxone) consti fes and a grant Tom Bsta-yes Squib and Hy cosatation fees, hovorara nd grarts rom Corral Pharma Pha. acetals andlonson oesor/Ortho MN can “ton es and grant nde rom ze ap eon Salton fees rom asbazenecs Aas Shed, Cepia, Drug Abuse ences and Sana-Avents Dr Maly has ered receiving research support (rant ung Ing or pes) rom Akers, Sel jer Sab, (abort, Foret Ustoratnes, lsaSrihtin, Lips Pharmaceuteas, Malinéoat Ocho MeN, Per, and Sanotavents serving as consultant fot ‘Skemes Foret abraoes, Claret, Jean ‘Blonnson,Orho-MeNl and hae receing travel ‘eimburement rom ales hats annvertor ‘onpatens edb Val Unies petsinngto sak Ing cessation using naesone and elated com Pounds. and may in the future consult for {lacSatitne Dr Ceauohasrepred ccng can sang fees romdtatl-Myets Sau, Cephalon as {vand Oro Mel and cies al contac om Dermes,Aseazenecs stl Myers Squbb, Drug ‘Abscess ipa Pamacetcas Oho Devel and UCB Pharm Ootnsonhsrepardsen. Ings constant or Aller, Pres aba, (Reprinted) JANA, ay 3, 2005 Vol 295, No. 17-2015PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE ClaxoSmithkine, and Johnson & Johnson/Ortho- Mae. Or Masonhastepried recengconsuting es ‘ndhonorararomForet.sbrstanesend ph har maces const es anaresearch support fom ‘Ares and research supa from Drug Abuse S- cer end DuPont Parma ries opertd ee ing author royals fam Cato Press or Mata {anal inerengOrPetinat has reported esting "esearch support rom Armes, AstaPnec, st yer Squbo, Contra Pharma, Drug Abuse cece, Ly, pha Maric KGaA Ortho MeN, and Per Savi aacontant or Abermes, Astazenea Aa: ‘Std Conta Pharma Foret aboratores and Tan ind parbcpating the Forest Laboratovies Speakers bureau Dr Swit has repo esi esearch sup Port om the National rte on Aaa Abuse and ‘Resholsm Fret aboratnes Drug Abuse cence, Prat ard Orto- Wel serving a3 constant fr ‘eres, Fors Labratoren and Paes od pare ating nthe Foret Laborato speaker: bureau, Dr letshastepotedseviigonthe board advisers ‘Akers pricpatg inthe Feet Labtalores peak fs bureay eeting research sppot tom Ortho MeNer and may the fare eecve gat support from Foret Laboratories. No oer dlsues were reported Fnding/ Suppor This study was supper by Na tinal netiute on Alcohol Abuse and Alcoholism (NIAAA) Cooperative Agreements UIOAATI715, 17g 11720 T1727 11756 11768, 11773, 11776, 1977711783, 11787, 14798, and 11773 any cx ‘ee cents awarésKOSAADIA715, KOBARDO!S3, ORORD0326 and K224A00329. he acamproate, Falexone, andthe matching placebos wed ths study were donated by Lpha Pharmaceuticals Role of the Sponsor: Th was conducted under UUphaPharmacescal’Ivesiatona New Druga aon for acres Lipa conducedmantong fete cial ses buf had no vole ne manage ret, aris ae treat of he data nthe Pepaaton or approtale themanuscrpt. Te NABA Clabes he desgnandconducotthestuy.and NAMA sta asstedin the management nas and Inlepretatin of he ta and proved comments fr anaeraton in cai of he ance ‘COMBINE Stdy Research Grp: Raymond A Anton, ‘No: Domenic A cal, Ms Deni Mt Donovan, PHD James, Hosking PID Bankele oho, MD, PAD Baral Mason nD: Margaret Matson PR: ‘iam Rl, PhD, Stephanie 8 Malley. PRD: Helen Mt Petia, PRD; Raber Swit, MD: ger D Wiis, MO: Alen 2eben, DS Naina At-Doud Teuntine MD: Micro Bogenscuta. NO Ron Cie, PHD: Dave Couper, PRD lames Gut, MD: David BR Gasthiend, MD: Shay Geen, MD, MP Kye aroun MO; Dang olahan aD: Som yt, MO: Jowegh §LoCas, Pio: Ricard Longabaug, ED tance Longo, MB; James Mekay PD emene Petras MD Cri Randal Pao. Roache, PhO; Femando svaia, MD, Anew Sexo, MD, Scot Trgan i Lauren ‘lr MD. Stay es sod Boston Univer School of fe, oston Mas D. A. Cral MD princes. {esto Locate PHD Gopmnipalineshgate ‘Aha AD; Achaia BA Cake BS Oa four: ie PROM Buna MD: AM Cra, NX Coveney, BAE Devine PRD elenberg. Ma UAC: BL Feng MMA LW Carvey, PHO;S ‘Good, 85, Greene, MA 5B. Gulver PHD, §. eurgar, B&R Hull BA: Man MD: T Keane, PRD: | Koplow. BA! Larence, MSW: Manoney. A: Mor Tran MDs Nenagoutan, A) eh eek: ucrel, MD, S. Po, BA Resto, MD, 0. Sora Sega MDL Sees ANC Sete, MD: FO. Sart RPM Tramele, BA, MLZ 8. Roger Wi las Media Centr own Unversity, Proven, FER Suit MD, PRO (peel nest R Lor abaughEaD(irvesigato Carty. nD, LICSW, 2016 JAMA stay 3, 2000—vol 295, No. 17 Reprinted) ‘Downloaded From: https:/jamanetwork.com/ on 06/12/2023 "MW. Davison PADD. Dt AN MAD Eek ‘orl Fear: amo PRD; Kenna PRO: Pat, I M Santa res, MA V Solos RN PW, PD: ‘AleeN ebro Harvard Unveny iclean Hoe pital Benen as: RD. Wes MO iia eve Seaton; SF Ceenel, MD, MPH (corvette) tuba: C Coe: A Lower M Kolodag PO: Niner CNS Lat Naas PRD; G Henney, MD: ‘Roda, PnD] Sharpe PRD. MPH A Shs aD; (asachsets Cenc Hosa Bost): O.R Gistnd MO (coprincpal estat | Baath, {ies Le: eee, nO: E Sharon P50. Un vey of Miam’ Sahoo Medine, Mam, FB. Iason, nD cin mest LD Willams, MD (investigate Lozano Mest, MS, LM: 8 ecara Carte for Alco! Prgms Meda! Un: verte South Cana Charen RA Anton, MD (Grn vesigaton C Randal, PRO (ommestea {oor PK Latha PRD, CS: D-H, oak MD, GF ‘Wersha, MED. Geddes, MEd. Mulan, MAR ‘ad Po Wild, MS; Verdin. MDD. Laon Moot 88/5 Kata BSL Rudge, 8 Tiny Keron MD PRO: Westen WA Ceieran co alm, Substance Abuse and Adction Univesity of ‘He Mexico, Albuquerque: W. Rr, PD (i ‘Spalimestgator 1. Tongan, PRD (comes) isopentane N Aa Aro, aD: R Buca) Bel, MS: A Bono, NS; D Bue’ Caro 0. Chapma RP Chaser MAN Dene 1S, ND. erst MS) AM. Plager, CNP A Fore fines, MS: Hendickson, MS) Houck, MAS Johnson Keight s Lope Mazon. Loper its Pad, A Marin A Marines, MS; Manes, ASV McGinley, MAI Mito BAG, Montoya, Bh. Moyers Pro; MC O'Nusa, BBA. Pace, BAN ‘Avett Mac. Rawat MS: C. Roybal A Sa ‘rls ¢ Santer Stee 5 Swart 8 Toren L ATeay:K Verner. PD. ek PRD: Vea 8, Vs. Weserber PRD: is MS LM Wort A Trextment and Research Center, Univers of Pen {yhani Phiadepia: HM. Petts, PaO nea esis) M. Kanpman, MD (enevestigat) Ritekay, PhD (comvesigatn J. ide, CRNP. Mt ute 1 Cage Caperte MEd LPC. Drabl MSW Burdon, PROL Epperson, CRNE, 8 Fa ary, PRO;P antl PRD K Hanes Henao CRW Kae CANP: Masny MOD. Maur ae IM Maly, CRNP-A Rainawex Schwa 5, LPC Shao H Sasa MSD. Sepson M. Wind th, MS LPC, Wortman Southwest Texas Ade ton Research and Tecnology Center, The Unverty Of Texas Healt Scene Centar t San Antonia A Soson DSc, MD, Pa panapalinesiatod NA Daoud Turin, MD (snes 1D. Roache, aD (cmestgaio Mc Avarado, 8D. A Casto, 1 Cepeda ARH. Cormier BE Cru 85M. Diaz RN MSN, ENP. BC: Duaue, BS A Gram SA Guereo, AD. Hargita MPA, EM Jenkin Mendora BS, Mekrigt D. Mote, MBA: Nash, SS Semoroweh AN MSN, FB, BC NV. Sr ‘eer BAT Sa, PRO'S-M Stk PAD. ‘akc Treatment Centar Univesty of Washing fon Seat ©-Mi Donovan, PRD inal vega {od D.Kivahan PRD (caiestatn: A Sakon MD (Ctnvestgaton) Baer, PD, Honduran, MDC (Gehan F DeMarco, PHO; M. Hansen, MSW G Rowe PaO: sulvan MSN. Wil) Walams Univesity of Wisconsin, Miva: Zeben, OS (Grin ivestgatr A. Cir, PD (eomesia {oer Lang, MD eoiesigaton Areca A, Dave MS; L serge, MSW A Beg. Cis ‘arson € Fey, M.BermngS.Hubaen, MGN Jones Peterman, MSW M Keler Kopin B&B {tus Dil, RN Ml RN Nore ‘Ale hb; 8 Pelerson, MSW R Robles. sal ‘laa ASL Serva, PhD, Substance Abuse Tea. ‘ment Unt, Yale Units Shoo of Medicine, Hew ‘Haven, Conn: 5. Maley, PHD (pina ves tof L Peta, MD (coivestiatn 1H. Keys MD (Coes Ande: Rebaluc, PAD Cae ToS BA DLL Kerns, APRN FNP 8. Malnowi D1 ‘Mr, PROB anda. DK Poh RP Re tales LCSW: ERevtetuer, Robinson, PD: Rorano-Daigar. ARO FNP Tapas BA Peed Office Ntonal nat an Aca Abute and Al Patan, Bete, MME Matson PRD aa co labors) RFs, MD erect oficeR Lien, HD (project ofan len PHD) Fe PO. Osta Coo dating Canter: Colabrative Stuer Coordnating ‘Cente Univer of North Crating, Chapa i Hosking PD (pencil vestigate, D. Couper, PRD (convesteatr Carat, MD investiga) ‘roe, PRD: 8 Boon H yan, MSN Can ng IS": barn: KT Mura, Orgen:K Rogge amp, MA, MAT; G. Song MS: Sure, MS, Yernjkove;M. Yourgcod, MA, MPH. Data and Sey Manitoning Boar: ngs, ScD kar, nu ‘1998 Ferury 2008) Kade, PD: M. Maul Pho: C Meier PRD; R Satz MD, MEH! G.Con os, PRD Investigational New Drog Sponsr/site MonitorNedaton Sup: Heche Ache Phar maces ne Medication Supply: Arie rams (atic ne Taningand Criieaton Cente: Unie. St of New Mesco Center on Aol, Substance ‘Aust, and Adactors(CASAA) Medan Padag- ing: Bomedial Research tute af New Meco Os. (alee Pharmacy GRINVLCRP) Labor Ou ties Transnational Corp. CDT Analysts: Mil Une ofa Cin Cnc eathaog ase ‘atoy” Consultan Slut PHD (Beeson Scenes Inst, Peidence. iy Dsciment, PD Unive ‘hy of Manan alimore County Baim, Ster ing Commitee Arto, MDS O'Malley PRD Pub. leans andra Commaite.D R Caner MD: [Hosting PD: WR. Mile, PRD Reseach roel ‘Camis Anton, MD; O'My, PHD". Denovan, PhD: C Randa PRO. Treatment Commi: feer Re Longabaugh, E20; Swit Mi, PhO. RD. Vises, MO:A.Zweben, DSW. Clin Cre Commit tee!) Carb MD. Poet Coordinator Comme: Devine PROS, Hubsten MSN IM, Klocz, PRO: P Latham PhO, RN D1 Man, PAO Rearrent Retention, ComplanceVS Westberg PAD Design fd Analyses! 0 Hosking. PaO. Behavioral ne ‘enton'kLongatsigh £40 Pharmacobepy te ‘enton: 8: Mason, PhO Assessments and Compl tre: Donovan PhO: D-R.Castiend, MD ‘edpowiedgment chr Ful MD, revs with IIAKA. and Raye ite, PHO, NIAAA, contbuted {ea to te mplerentatn of ths sty. We ao {Rank Mark Weng, MD, NAAA, and Pate (O'Connor, MO, Yale Seal of Medicine, for thei ‘hough comments n he reparaon othe ari Wierecogne the corto ofthe may invests ‘os and at (esecaly Marton Yourgobod. MA MP) whose ers were nee to anand feat ts poet (alt ofthese nnd avalabe itp sccune educate EARN 1. Gant BF DaysonDA, Stns Seal The 12-menth Pievlee and wens in DSUV acho abuse and epee Unted Sats 1991-192 an 2001-2002 Drug Ala! Dopod 2004 74223-238 2 Moka AM, Mars JA, Soup OF, Gerberding Detnlenteeot eatin Unted Sates 2000 JAA poo2at iaaaas, 2 ekenna Mi Michaud CM, Mara Cl, Maks ‘Asesng burden ot ass fe United Satesusng bi aay A Pre ed 205,28 Tee 4 Hanson GR, LT Pubcheathimpicaonsof exes Ste akofalcnsupon JAMA 2008281031082 ret DA Red © Comor PG New herpes forall piles A Med 2000 108227257 6 Vilerngi, OsonDH Arancomard le (©2006 American Medical Association, All sights reserved.PHARMACOTHERAPIES AND BEHAVIORAL INTERVENTIONS FOR ALCOHOL DEPENDENCE sin ott ie ei ae setae oe IM et matinee Seti feed urcnct eee Pee ccmeotet Cae ene ee FEE es seaman 2 Resi hers mer isan esse a Se Ne ene urea era aaeanaasarys ieee ee tc a etre eevee sue i SERS Rents Wing « reenter Fines Ses ent aes ears sea Fee inn EB haa heneelo sani 1 IEE cms meets omer EE ee pamaanen eer a ee i Ee eee na ant Bee ows ri Se sed Bee Eee me res esr rca seat hernia Sauer tare rane ‘Tau 3005393617135. _ BEESMEE I ce nse Se eee ree sone satiate serena anak fe ES en pm co Ihe haere ao Be ceric enisedniemcmetttae escort ry eater a ie SPEARS Cai ane Eaten uae aoe Set recent efecto iterates enh ceeiemncciinon ee Sica mc sn erst oeeteete terested ieee Saar ec Latnd eet un ieee ieee tears ersten hone Hache se (©2006 American Medical Association, All rights reserved. ‘Downloaded From: https:/jamanetwork.com/ on 06/12/2023 28, Arto. Mosk DH Latham. Tecbsesvecam faba see (OCDS) Ar Gen Pei 196 Baga 3 Rober), Anton RF, Latham P, Mook DH Fac: ‘orseuce and pedcbevaly fhe Obsesste Cor Bure Ding, Aa inp es. 59523 ao 3. Level Sealer N. SAFTEE 2 achrigue fo the Spiemaicasessmentofseetletsnenica as Py ‘opharmacol Bu 198622348381 SB "anmon BA, Ai-Daoia Roache ID. The COM. Bie SAFTEE: a srocured instrument for colecting ‘vee events adapts for cial tudes nthe ‘gota et St Aa Sp 20509557 3B, Anton, Doric Bsow M Westy Con ran of bee COT Tanda er hen Setelse anderson ‘wthgarma zara Ch Cher 200147 ek 3, foto, ibn COTe Sty Gosp eh dtr basen (CON an ps. {Euanysanee eden na mang Staonal Achol Cin Exp es 2000 2601 om 33 Rian Rates forcambirng sano snd ‘irxne resign epee StS A Te pp 200309) a8 96 52 SOR Ratna Ee Choosing parmacoters Bes fr the COMBINE study pocess and proce: ‘esaninesigaonaprachtoconbnabon phar astray ore este seco epee 130g Atel Supp 30055). 1a7 37. haan, © Maley 8, Creu DA eta Doe ‘ening nets ad behoverl ramsclgy {foo rg sempre, bone ard ced inlet depernt abc) Cn 5yopharmac. fusaaet 3. COMi Sy Co, aig combine a imc nd esas erento seal ‘epedence the COMBINE Sy plot essay $y Abel Cn Exp Res 200827 128-131, 55. Fett Wee A, te, Donon ita Noun) Meat Manageme 4) "stat al Sater Weston bean ‘eco tes ool 200 ‘neti West Banden tl At {ied sproac to meds managenené pena ‘eerie suppor humor neta tarot sesh coc Suc Ao Sp 05 tsinoae See 41, Miler WR. Combined Seavia trveton ‘intl Stes Nstoal ee Aol ‘ie an Aeclry 2004, ‘2 Tergoaen abun Locator WR eh ue nd apne nte sevonment ot he ‘bibcavonlitenenon Steal Sop Stastsr 1B. Kaden Canatk Donovan, tl Cope ‘thane Coping ie Tsp Mansa & Cal ese Terps Meenas iy ‘ist Aegand Dependence Bea Nason Intute on lool an and Aecol199, 12 Novara ter, Carl ee tp Fc {sion Therapy Mana Cina Reseach Cs fr ‘hep a th Abe beard Dapendoce Btn Me tonalite on le tele and Alston 955 1B ie WR eben hs Neier Cea ‘Motnatonal oncom Them Mau A Cn ‘ales Gude Therap reg dials Wor Ase Abuse and Dependence ede Ne Nato! inte on Mechel Noe sc Atsatm 198 46 rin Son BW, Mey, Codey M.A fol teste yd nd sonmunty {reentry eho hard chat 88 Sonn 1, Neyo Sh Clinical Guts lo Tat ae mance apo en se comet ee atte AR et re rahe Bi noe eps i neuer tore: miecolantich cet Sees aa eth He Ry cs Sais ans ah cae sans Fick Soe dinntscrante oe ani Pekan Hiei taeteon nome cette ee eka i deriaee ee Seal AStmocconcncce cats Se Son agente GEE Sa eee ees ieee ie aeetie ssc saeeeee sna Sse green BEE inne mor onion ge erate are Seas SRA AEE nanos Brae eae Fendt Sh umes umn tn ee ces ispecies foc SERS RASS cmp een eens Sn say la % 59. OMaleyS, Rouse Fae etait nd mantenance naltrexone treatment fr seal dependeree usg primary cares seca cre Ach Ink ie, 2003 168 1695-174 60, LANG. Houseman} Wutke E Nate foneindeata dependence ed Aus 2002176530. Sa 1 Blount A. Itegatea Pinay Cae Theatre ‘tla and ental Penh Cotta New Yor, WOW Norton, 1998. (2. Keler Mi, McCutough Kin etal Acom. Dalton cf neszadone. te cognitive behavior [ass stem of poeta. and ther comb on forthe reste of come depress, N Eng) Mad 200,362 140.9470. 5" Newothner DE land MK, Deuce RH ta Bepartment of Vetrane Aare Cooperative Study ‘Goup fect of tee acocriois on exaceba Some’ dencabsruciegumonry dsease. Eng) Tied 1999 380/1981-1907. 64. Thorsen 00, Crt A, evel, ea Items Sonal Gugesonde-Maslanee Stuy Croup. A ea son ofaacsonde and mesaamieleraive Cras (seas Eel Med 1998 39 370-374 15. UX Prospective Diabetes Study (UKPDS) Grove fect of tere loc cose coats wth meter ‘minon comptcatone overweight patents wth ‘ype? dabetes (UKPDS 39) Lancet. 1856352354 a, 66. RogesS, Doody 8, Mah RC Fedo LT: Done el Stuy Group. Donepeal improves corion snd {eal tuncionn etme ease Arh rt Med {ss t361021-1031 67. Oley Carell KM. Pschateapeut cor Sean nphamacsoge! tas. Alco! Cn Bp es 1996207208. 68, Anton, Moa Di Latham P, el Poste ten ests of combing naesone win cogrtve behavior therpy tothe tezmentotakaholsm Cla Pyyhopharmaol 2001217277 (Reprinted) JANA, ay 3, 2005 Vol 295, No. 17-2097