Medication-enhanced behavior therapy for alcohol use disorder: Naltrexone, Alcoholics Anonymous Facilitation, and OPRM1 genetic variation

Journal of Substance Abuse Treatment 104 (2019) 7–14

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Medication-enhanced behavior therapy for alcohol use disorder: Naltrexone, Alcoholics Anonymous Facilitation, and OPRM1 genetic variation

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Scott H. Stewarta, , Kimberly S. Walitzerb, Javier Blancoc, Denise Swiatekd, Linda Paine Hughese, Adolfo Quiñones-Lombrañac, Kathleen Shyhallab a

Section on Addiction Medicine, Department of Family Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA c Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA d Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA e School of Nursing, University at Buffalo, Buffalo, NY, USA b

A R T I C LE I N FO

A B S T R A C T

Keywords: Alcohol use disorder Naltrexone Alcoholics Anonymous OPRM1 Treatment outcomes

Medication-assisted behavior treatment for alcohol use disorder (AUD) holds promise to enhance the efficacy of medication and of behavior therapy when administered individually. The present study examines the treatment benefit of combined outpatient naltrexone (NTX) treatment with Alcoholics Anonymous Facilitation (AAF) behavior therapy, in the context of OPRM1 genotype. The minor OPRM1 Asp40 G-allele has been associated with greater positive reinforcing effects of alcohol consumption and greater alcohol craving, suggesting that individuals carrying the OPRM1 G allele may have an improved naltrexone response. Twenty patients, including 7 G-allele carriers, received 90 days of naltrexone with medication support and dispensing sessions, and ten AAF behavior therapy sessions. During treatment and the eight-week posttreatment follow-up, an overall increase in percent days abstinent was observed for the sample as a whole, but G-allele carriers reported relatively heavier drinking relative to other subjects. These findings suggest that this enhanced medication-assisted behavior treatment is a promising therapeutic combination, and mirror other recent findings that G-allele carriers may require more intensive treatment.

1. Introduction The development of AUD is hypothesized to proceed through several phases, which can ultimately co-exist in fully developed disease (Koob & Volkow, 2016). These include an initial “binge-intoxication” state characterized by alcohol use to obtain pleasurable effects, a subsequent “withdrawal-negative affect’ stage characterized by drinking to relieve negative symptoms, and a “preoccupation-anticipation” stage, characterized by compulsive drinking to the detriment of other activities and despite often severe consequences. This framework has both clinical and research relevance, and can guide efforts to improve treatment for AUD (e.g., by selecting medications and behavioral interventions targeting different phases and the corresponding neurocircuitry). Naltrexone (NTX) was approved in 1994 for the treatment of alcohol dependence. This mu-opioid receptor antagonist is believed to decrease the rewarding effects of alcohol intake through opioid effects on dopamine release, and can thus be thought of as targeting the

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reward-seeking component of AUD. Naltrexone does not appear to increase abstinence, but has a robustly-demonstrated, albeit modest, efficacy on heavy drinking days (Del Re, Maisel, Blodgett, & Finney, 2013; Donoghue et al., 2015; Gueorguieva et al., 2007; Pettinati et al., 2006; Rosner et al., 2010; Swift, Oslin, Alexander, & Forman, 2011). This modest benefit may reflect that only a subset of patients respond to this medication. While many factors may influence response to medications, genetic variation is of great interest. The less-common OPRM1 “G-allele” (SNP rs1799971), resulting in substitution of an aspartate residue for an asparagine residue at position 40 in the receptor amino acid sequence (Chamorro et al., 2012; Jonas et al., 2014; Setiawan, Pihl, Benkelfat, & Leyton, 2012), has received the most attention in AUD treatment. Particularly relevant to the binge-intoxication component of AUD, the minor G-allele has been associated with greater positive reinforcing effects of alcohol consumption (Ray et al., 2013; Ray, Bujarski, Squeglia, Ashenhurst, & Anton, 2014), as well as greater alcohol craving (Bach et al., 2015; Kranzler, Armeli, Covault, & Tennen, 2013),

Corresponding author at: Primary Care Research Institute, UB Gateway Building, 77 Goodell Street, Suite 220, Buffalo, NY 14203, USA. E-mail address: ss243@buffalo.edu (S.H. Stewart).

https://doi.org/10.1016/j.jsat.2019.05.004 Received 5 October 2018; Received in revised form 3 May 2019; Accepted 3 May 2019 0740-5472/ © 2019 Elsevier Inc. All rights reserved.

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improvements in drinking involvement through eight weeks posttreatment, and 2) enhanced outcome in G-allele carriers due to complementary pairing of medication addressing rewarding alcohol effects with behavioral therapy that is strongly abstinence-oriented.

which suggests the potential for a greater response to naltrexone. However, reported associations of OPRM1 polymorphism on response to naltrexone for AUD treatment are mixed, with potentially improved treatment outcomes reported in meta-analytic reviews (Chamorro et al., 2012; Jonas et al., 2014) despite negative findings in individual studies (Arias, Gelernter, Gueorguieva, Ralevski, & Petrakis, 2014; Coller et al., 2011; Foulds et al., 2015; Gelernter et al., 2007). The Chamorro metaanalysis included 6 studies (total n = 453 from 4 placebo-controlled randomized trials of naltrexone and 2 prospective cohorts of naltrexone treated subjects) with some measure of relapse/return to heavy drinking. The authors concluded that relapse risk in naltrexone-treated subjects was lower in G-allele carriers relative to non-G-allele carriers. The Jonas analysis included 8 studies (total n = 1365 from 5 placebocontrolled randomized trials of naltrexone and 3 prospective cohorts of naltrexone treated subjects), including 5 of the 6 studies in the Chamorro analysis, and found a not quite statistically significant but lower return to heavy drinking in naltrexone-treated G-allele carriers relative to naltrexone-treated non-carriers. Both meta-analytic groups noted that none of the controlled studies had specifically randomized subjects by genotype. However, two subsequent placebo-controlled naltrexone trials that included randomization stratified by genotype and over-recruitment of G allele carriers did not support improved outcomes for Gallele carriers (Oslin et al., 2015; Schacht et al., 2017). Oslin et al. evaluated naltrexone effects in n = 139 A allele homozygotes and n = 82 G allele carriers, all of whom received relatively brief medical management counseling, and found no significant naltrexone-byOPRM1 effects on alcohol outcome measures. However, point estimates suggested a lesser rather than greater response in G-allele carriers. The study by Schacht and colleagues (n = 75 with G allele and n = 77 without) evaluated the effects of naltrexone on percent heavy drinking days, again with concurrent medical management counseling, and also did not find that naltrexone response depended on OPRM1 genotype. However, G-allele carriers increased their percent heavy drinking days as treatment progressed (both naltrexone and placebo groups), whereas AA subjects did not. Given the accepted mechanism for naltrexone benefits, these reports are difficult to reconcile with potentially greater alcohol craving and alcohol rewarding effects in G-allele carriers, but could be related to addiction that has extended well beyond the bingeintoxication phase in individuals with established AUD. Pharmacotherapy for AUD should be provided along with a complementary behavioral therapy, although an optimal combination with naltrexone has not yet been determined (Agosti, Nunes, & O'Shea, 2012). Alcoholics Anonymous Facilitation (AAF) behavioral therapy is a manualized approach aimed at promoting abstinence via increasing attendance and participation in 12-step groups, and can thus be thought of as targeting the preoccupation-anticipation phase of AUD. Unlike CBT therapy, AAF specifically focuses on Twelve Step goals of sobriety and recovery and has a strong emphasis on achieving and maintaining abstinence. A clinical trial demonstrated that AAF was associated with increased abstinence outcomes, but not reduction of heavy drinking days, in the year following treatment (Walitzer, Dermen, & Barrick, 2009). Naltrexone treatment (i.e., reduction of heavy drinking by targeting rewarding effects of drinking) and AAF therapy (i.e., efforts to increase abstinence targeting alcohol preoccupation) may be additive and improve outcomes for individuals with moderate to severe AUD.

2. Method All methods, procedures, and assessment materials were reviewed and approved by the University at Buffalo's Institutional Review Board. 2.1. Subjects Individuals were required to meet diagnostic criteria for current Alcohol Use Disorder based on a checklist for DSM-V (Diagnostic and Statistical Manual of Mental Disorders, revised 5th edition). Eligible individuals were required to be between 21 and 72 years of age; exclusion criteria included other primary substance use disorder (other than tobacco or caffeine), taking any opioid drug (illicit or prescribed) or alcohol-modifying treatment drug, a legal mandate to treatment, history of hepatitis or liver disease, significant elevations of liver function tests, current treatment for alcohol or drug problems and, if female, pregnancy or breastfeeding. We aimed to recruit 20 subjects as a preliminary evaluation of treatment effects and potential differences by OPRM1 genotype. Subject flow is presented in Fig. 1. Eligible individuals based on the telephone screening interview participated in an initial appointment (N = 37) with authors KSW, SHS, DS, or LPH at the University at Buffalo's Clinical and Research Institute on Addictions' Alcohol Treatment Services to assess for DSM-V Alcohol Use Disorder. A review of alcohol use and medical history, a blood draw (for the OPRM1 genotyping, hepatic panel) and urine toxicology screen (to exclude those with positive opioid screen) occurred. Individuals were remunerated with a $10 gift card. From this group of 37 individuals, 23 subjects were selected to participate in the study; during the first month of participation, one individual withdrew and two were lost to contact. OPRM1 G-allele carriers were over sampled such that the intent-to-treat sample (n = 20) was comprised of seven G-allele carriers and 13 A-allele carriers. 2.2. Genetic assay The OPRM1 polymorphism (rs1799971) was investigated by allelic discrimination by authors JB and AQL with TaqMan genotyping assay C___8950074_1_ (Thermo-Fisher Scientific, Walthan, MA) following the manufacturer's instructions. DNA genotyping reactions were assembled in Labconco PCR workstations by using dedicated consumables to prevent carry-over contamination. Adequate negative (no DNA) and positive controls (DNA samples with known OPRM1 A118G genotypes) were routinely included in each round of analysis. Other than authors JB and AQL, who had no patient contact, the other investigators, therapists, and research interviewers were blind to OPRM1 polymorphism. 2.3. Treatment 2.3.1. NTX medication As recommended by the FDA-approved prescribing information, 25 mg/day of naltrexone was administered for eight days, then 50 mg daily, for a total of 90 days. Medication was dispensed, and adherence and potential side effects were reviewed during four 20-minute Medical Management sessions (Anton et al., 2003) during the 90-day treatment.

1.1. Summary and hypotheses The present study examines the treatment benefit of combined outpatient NTX treatment with AAF counseling, in the context of OPRM1 genotype. All patients received, during a 90-day period, daily naltrexone, four 20-minute medication support and dispensing sessions, and 10 sixty-minute individual AAF counseling sessions. Patients were followed for eight weeks posttreatment, at which time they completed a final research assessment. We hypothesized that this medication-assisted behavior therapy would be associated with 1) sustained

2.3.2. AAF counseling This manualized 10-session outpatient weekly behavior therapy familiarizes and encourages clients to attend mutual help meetings, such as Alcoholics Anonymous (AA) or Secular Organization for 8

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60

48

24 11

37

14

23

17% 20

1 Withdrew

Fig. 1.. Study sample recruitment

Sobriety (SOS), and become involved in activities and fellowship. This protocol includes a client contract to attend an agreed upon number of meetings per week, weekly AA readings, discussion of the first three AA Steps, and a variety of behaviorally-based sobriety skills (including problem solving, drink refusal, relapse prevention). Our previous work with this treatment protocol (Walitzer et al., 2009) has demonstrated increased AA attendance, posttreatment abstinence and treatment satisfaction relative to a control group. This treatment was delivered by a MSW addictions therapist and a PhD addictions psychologist.

AA meeting attendance were collected during the interview. At baseline, the TLFB covered a six-month retrospective window in order to obtain a stable picture of recent behavior for these domains. At the endof-treatment and the eight-week follow up, this interview was again administered to cover the time between the previous interview and the day before the current interview in order to capture a complete sequence of data. For analysis, data were collapsed for pretreatment (six 30-day periods), treatment (three 30-day periods); and posttreatment (eight seven-day periods).

2.3.3. Remuneration In order to enhance attendance at counseling sessions, compliance with the end-of-treatment blood draw, and participation in the end-oftreatment and the eight-week follow-up assessments, subjects received cash remuneration. The total amount potentially received was $250 for completion of all aspects of the study.

2.4.1. Alcohol involvement Percent days abstinent (PDA, arc sine) and drinks per drinking day (DDD, log distribution) were calculated from the TLFB interview. Alcohol consequences were assessed with the Short Inventory of Problems - Revised (SIP; Kiluk, Dreifuss, Weiss, Morgenstern, & Carroll, 2013). The Desire for Alcohol Questionnaire (DAQ; Mo, Deane, Lyons, & Kelly, 2013) was completed to assess craving for alcohol.

2.4. Assessments 2.4.2. Treatment compliance The TLFB interview was used to assess self-report of compliance with naltrexone as well as mutual help group attendance (MHG; almost entirely AA).

Research assessments were conducted at pretreatment, end of treatment, and eight weeks posttreatment. The interview portion of each assessment included the Time Line Follow Back (TLFB) interview. The TLFB is a well-established and valid specialized interview method used to gather retrospective information on daily behavior. As described below, daily alcohol consumption, naltrexone compliance and

2.4.3. Treatment satisfaction The Client Satisfaction Questionnaire (CSQ; Larsen, Attkisson, 9

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indicate that G-allele carriers reported a greater DDD relative to A-allele carriers throughout the study, and DDD increased over the course of the 8-week follow up for the sample as a whole. The interaction indicated that among those who reported heavier DDD at pretreatment, those with the G-allele fared worse than those with A-allele. However, among those who reported lower DDD at pretreatment, those with the G-allele fared similarly to those with the A-allele. With regard to the RCI, 40% of the sample evidenced reliable change at posttreatment, including 46.2% of A-allele carriers and 28.6% of G-allele carriers (p = .444). These figures were the same for DDD from pre- to eight-week follow up.

Hargreaves, & Nguyen, 1979) was used to assess client's general satisfaction (6 items), satisfaction with counseling (2 items) and medication satisfaction (2 items). Mean scores were calculated for each domain, ranging from 0.0 to 3.0. 2.5. Primary data analytic strategies Outcome variables (PDA, DDD, SIP, and DAQ) were analyzed via hierarchical random effects models (SAS 9.4) to evaluate whether: (a) drinking involvement changed over time, (b) drinking involvement differed as a function of genotype, and (c) change over time, if it occurred, differed as a function of genotype. Clients served as random factors and repeated measures were nested within clients. Time was modeled piece-wise so that the three-month treatment period and the eight-week follow-up period effects could be assessed separately. Models accommodated for pre-treatment drinking behaviors, and for the possibility that effects from pretreatment values might be different as a function of genotype. Corresponding analyses were performed on treatment compliance measures (NTX compliance, MHG attendance). The Reliable Change Index (RCI) (Jacobson & Truax, 1991) assesses the magnitude of client change for any given client and whether this change for any given client is statistically reliable. RCI was calculated for the four alcohol involvement measures: PDA, DDD, SIP, and DAQ. Two RCIs were calculated – the first describing change from pretreatment to immediately posttreatment and the second describing change from pretreatment to the eight-week follow up. The denominator of the index is the standard error of the difference between the two assessment scores. Chi-square analyses were performed to evaluate the relationship between genotype with RCI at posttreatment and at eight-week follow up. 3. Results

3.2.2. Secondary outcomes Negative drinking consequences (SIP) and craving (DAQ) reports at pretreatment were compared with reports during treatment and during follow-up. Models showed that SIP and DAQ scores were significantly lower during treatment than prior to treatment, and those scores were also lower at follow up than they were prior to treatment. Additional analyses showed that scores reported at follow up were not significantly different than scores reported during treatment. No main effects or interactions with genotype were significant in these analyses. For the SIP pre- to posttreatment, 80% of the sample had a positive RCI for reduction of negative consequences from drinking. By genotype, 76.9% of A-allele carriers and 85.7% of G-allele carriers evidenced reliable change (p = .639). For pre- to eight-week follow-up, 55% of the sample demonstrated reliable change, of whom 45.5% were A-allele carriers and 54.5% were G-allele carriers (X2[1] = 4.105, p = .043). For the DAQ, 80% of the sample had a positive RCI for craving, including 76.9% of A-allele carriers and 85.7% of G-allele carriers (p = .639). For pre- to eight-week follow-up, 80% of the sample demonstrated reliable change, including 69.2% of A-allele carriers and 100% of G-allele carriers (X2[1] = 2.692, p = .101).

3.1. Patient characteristics

3.3. Treatment compliance

The sample (n = 20) was primarily non-Hispanic white (90%) and comprised of males (65%) and females (35%). Subjects were, on average, 51.0 (SD = 12.2) years of age and reported 14.8 (SD = 2.1) years of education. They reported drinking an average of 5.8 (SD = 1.5) days per week and 9.2 (SD = 4.3) standard drinks per day. There were no significant differences on these variables as a function of genotype.

Treatment compliance was assessed in three domains: daily NTX compliance, AAF counseling sessions attended, and MHG involvement. 3.3.1. Naltrexone treatment Operationalizing naltrexone compliance at 80% or greater during the 90-day treatment period, 61.5% of A-allele carriers were compliant during the 90-day treatment, and 100% of G-allele patients were compliant (X2 = 3.59, p = .058). A hierarchical random effect model evaluated the self-report of daily naltrexone compliance as a function of time (three successive 30day periods), OPRM1 genetic status and their interaction. Results indicated a significant time effect (F (1, 38) = 12.36, p = .001), and timeby-gene interaction (F(1, 38) = 13.09, p = .001). For the sample as a whole, daily naltrexone use declined during the 90-day course of treatment, and this decline differed as a function of genetic status. Specifically, A-allele carriers evidenced a decline from the first month of NTX treatment to the third month of NTX treatment (lsm = 96.1% [se = 5.5] to lsm = 62.7% [se = 5.5]), whereas G-allele carriers did not evidence this decline (lsm = 93.7% [se = 7.5] to lsm = 94.2% [se = 7.5]).

3.2. Treatment outcomes 3.2.1. Primary outcomes Fig. 2A illustrates changes in PDA for each subject during treatment stratified by OPRM1 genotype. For PDA (arc sine transformed), the hierarchical random effects model yielded no significant main effects or interactions; during-treatment and post-treatment PDA was stable with no genotype differences. Table 1 displays pre-, during-, and posttreatment reports of PDA (mean values), as a function of genotype, captured in nine monthly (six baseline and three during-treatment periods) and the eight weekly posttreatment periods. With regard to the RCI for PDA, 90% of the sample evidenced reliable change at pre- to posttreatment, including 92.3% of A-allele carriers and 85.7% of G-allele carriers (p = .639). At pre- to eight-week follow up, 80% demonstrated reliable change, including 84.6% of Aallele carriers and 71.4% G-allele carriers (p = .482). Fig. 2B provides individual trajectories for DDD during treatment stratified by OPRM1 genotype. The hierarchical random effects model for this outcome (logarithmic transformation) indicated significant main effects for pretreatment DDD covariate (F[1, 16] = 8.13, p = .012), genetic status (F[1, 16] = 8.23, p = .011), and marginally for posttreatment time (F[1, 191] = 2.86, p = .092); these main effects were moderated by a significant Pretreatment DDD X Genotype interaction (F[1, 16] = 10.34, p = .005. These data, presented in Table 1

3.3.2. AAF counseling sessions Counseling session attendance was positive for the sample as a whole. Over the course of the 90-day treatment period, eighteen patients attended all 10 counseling sessions; one patient attended six and one patient attended seven sessions. 3.3.3. Mutual-help group attendance MHG meeting attendance, primarily Alcoholics Anonymous, was assessed over the course of the study via the TLFB interview (percent days AA attended; PAA). For the PAA, the hierarchical random effects 10

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Fig. 2. Change in A) percent days abstinent and B) average drinks per drinking day for each subject during the 12 weeks of active treatment, stratified by OPRM1 genotype.

3.4. Treatment satisfaction

model (without the baseline PAA covariate due to minimal variability) yielded no significant main effects or interactions. Thus, the frequency of AA meeting attendance did not differ as a function of genotype, time, or their interaction. During treatment, 45% of the sample reported attending one or more MHG meetings during the 90 treatment days, and 40% of the sample reported attending at least one meeting during the eight-week follow-up period.

Assessed at the end of treatment, treatment satisfaction was positive for the program overall (M = 2.76 [SD = 0.30]), the medication component (M = 2.60 [SD = 0.45]) and the counseling component (M = 2.72 [SD = 0.34]). There were no differences in treatment satisfaction as a function of genotype (all p's > .15).

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Table 1 Baseline, treatment, and follow-up drinking measures stratified by OPRM1 genotype. Baseline

Treatment month

Follow-up week

1

2

3

1

2

3

4

5

6

7

8

A-allele homozygotes (n = 13) PDA Mean 17.9% SD 21.8% DDD Mean 8.0 SD 6.7

86.4% 24.1% 2.2 4.8

89.5% 16.4% 1.7 3.5

85.1% 22.1% 2.0 4.3

81.3% 28.8% 0.7 1.2

82.4% 28.0% 1.6 3.2

84.6% 27.6% 1.0 1.7

85.7% 24.0% 0.9 1.6

83.5% 23.9% 1.0 1.4

90.1% 17.9% 1.8 4.2

84.5% 24.0% 1.9 4.0

88.9% 17.2% 2.2 4.6

G-allele carriers (n = 7) PDA Mean 23.6% SD 24.4% DDD Mean 7.8 SD 2.2

74.8% 29.8% 3.9 2.9

75.2% 32.1% 4.8 3.6

81.4% 35.1% 3.4 3.1

83.7% 37.3% 2.3 4.1

81.6% 36.7% 2.7 3.9

79.6% 36.8% 3.8 4.5

77.6% 37.7% 3.1 4.1

83.7% 37.3% 2.3 4.1

79.6% 35.8% 3.6 4.3

75.5% 35.7% 3.4 4.0

76.5% 38.4% 3.7 4.8

Notes. See text for statistical significance. PDA = percent days abstinent. DDD = drinks per drinking day. Baseline Average – arithmetic mean and standard deviation for the six-month baseline period. Treatment = three one-month periods representing the 90-day treatment window. Follow up = eight one-week periods representing the eight-week follow-up window.

full 90-day treatment period were 62% for A-allele carriers and 100% for G-allele carriers. This is in contrast to 73% for A-allele carriers and 50% for G-allele carriers in the Oslin et al. (2015) sample based on pill counts and interviews and between 79% to 89% in the Schacht et al. study (2017) for the full sample, based on urine samples and pill counts. Self-report of NTX treatment satisfaction was strongly positive and similar across genotype. Thus, with regard to medication compliance, AAF with monthly medical visits seems to compare favorably with other treatment approaches.

3.5. Unwanted effects and adverse events Early in naltrexone therapy (at approximately 14 days), patients reported fatigue (55%), dizziness and sleepiness (each at 45%) and headache (40%). Later in therapy (at approximately 80 days), report of these side effects dropped (25%, 5%, 20% and 5%, respectively). The severity of these unwanted effects was, on average, rated as mild. One adverse event was experienced in the sample; a patient reported mild aphasia during the second week of naltrexone therapy and discontinued the medication at that time. Two patients reported alternating between a 25 mg and 50 mg dose to manage unwanted side effects.

4.4. Future research The present findings encourage future research to enhance the modest efficacy of NTX treatment via adjunct behavior therapies targeting other phases of AUD, such as the preoccupation-anticipation stage. Our implementation of a 10-session, empirically-based, standardized and manualized treatment approach to both teach behavioral abstinence skills as well as to encourage, educate, and facilitate involvement in AA shows initial promise in combination with NTX treatment. The therapeutic combination of addressing increased abstinence (via AAF) and decreased drinking (via NTX) has a strong rationale and appeal. Future studies of AAF with NTX will benefit from larger sample sizes, greater racial diversity, gender representation, and a broader range of AUD severity. Research should focus on demonstrating the efficacy of this medication-enhanced treatment combination, identifying possible mediators of treatment effects (i.e., participation in AA-related behaviors, medication compliance, medication expectancies), evaluating the effects of added treatments such as complementary medications targeting other neurocircuitry, and enhancing external validity for translation into clinical practice. The trials conducted by Oslin et al. and to some extent Schacht et al. (see Section 1) suggest that G-allele carriers with AUD may surprisingly have a lesser response to naltrexone, consistent with the results in our pilot trial. As G-allele carriers may have a greater rewarding effect of alcohol consumption, a decreased or similar response to naltrexone in this group is surprising. This may reflect the development of predominant stressinduced mechanisms in advanced AUD, leading to greater urges to drink to relieve negative symptoms (Becker, 2017), or other drivers of habitual drinking patterns that may be independent of alcohol's specific rewarding effects (Barker et al., 2015). Such mechanisms may vary by earlier reward-mediated drinking effects and OPRM1 genotype, and may be less responsive to counseling strategies that predominantly address the preoccupation-anticipation phase of AUD. Our finding that G-allele carriers with heavier drinking at baseline had the least treatment benefit is consistent with this hypothesis. In addition, prior studies have suggested an enhanced response to naltrexone in smokers (Fridberg, Cao, Grant, & King, 2014; Fucito et al., 2012; Schacht et al.,

4. Discussion 4.1. Summary of drinking outcomes This pilot study estimated the combined effects of naltrexone, a medication known to reduce heavy drinking but not increase abstinence, with AAF, an abstinence-focused counseling strategy. We also evaluated if OPRM1 genotype influenced treatment outcomes. An overall increase in percent days abstinent, and decreases in alcoholrelated consequences and craving were observed and did not differ by genotype. Relative to pre-treatment, the average number of drinks per drinking day decreased during and after treatment, but, inconsistent with our hypothesis, less so in G-allele carriers. 4.2. AAF and mutual help group involvement Slightly less than half of our subjects reported attending any mutual help group meetings, which is substantially lower for example, than Twelve Step Facilitation (TSF) yielded in the multicenter Project MATCH (Project MATCH Research Group, 1997). However, while not specifically tested relative to other approaches in our pilot study, AAF with naltrexone was associated with favorable results in our sample, and AA involvement in Project MATCH did not fully explain the benefits of this behavioral counseling strategy (Project MATCH Research Group, 1998). Based on the content of AAF treatment sessions, interventions relevant to the preoccupation-anticipation stage of addiction that may provide benefit include review of the first 3 steps, AA-based readings and the serenity prayer with the therapist, and development of sobriety-focused skills such as drink refusal. 4.3. Compliance and satisfaction with treatment As in other recent work (Oslin et al., 2015; Schacht et al., 2017), we operationalized adherence to NTX as 80% compliant, in our case, based on self-report on the daily TLFB interview. Our adherence rates for the 12

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2017) and it is possible that nicotine moderates compensatory antireward mechanisms or alleviates negative symptoms that otherwise promote continued alcohol use. Testing such hypotheses to improve treatment outcomes is particularly important. Although beyond the scope of the present research, a multivariate approach for AUD genetic variants and biomarkers will be critical to more deeply illuminate associations between brain functioning, AUD symptoms and severities, and treatment outcomes. Over 300 genetic biomarkers, including OPRM1, have been identified as empirically and biologically relevant to AUD and addictions (e.g., Manzardo, McGuire, & Butler, 2015; Wang et al., 2011). Rather than a single candidate gene, a multiple gene approach will better facilitate identification of AUD subtypes (Hu et al., 2013; Ray, Mackillop, & Monti, 2010) and potential differential treatment outcomes. Limitations of the present study include the small sample size, relatively short follow-up period and the absence of control groups necessary to directly evaluate the addition of AAF to NTX. Given a modest increase in drinking quantity during the eight-week follow up, assessment of longer posttreatment periods, particularly for G-allele carriers who did not reduce their drinking as much, is clearly warranted.

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4.5. Conclusion This study examined treatment and early posttreatment alcohol outcomes for twenty patients with severe AUD receiving a 90-day course of NTX with ten AAF behavior therapy sessions. Patients reported benefits including improvement in alcohol use (that was less substantial in G-allele carriers), negative drinking consequences and craving. A randomized trial comparing the efficacy of the combined treatment approach is warranted to evaluate whether the strongly abstinence-focused AAF enhances the robust, but modest, therapeutic effect of NTX treatment in decreasing heavy alcohol use. Future trials should also evaluate more intensive medication-enhanced treatment strategies for OPRM1 G-allele carriers, which this study and recent findings suggest is a less responsive treatment population. Declarations of interest None. Acknowledgements The authors acknowledge the tremendous work efforts of the staff on The Next Step alcohol treatment and research program: Molly Rath, Paulette Giarratano, Diane Augustino, Florence Leong, Dorothy Sterlace, Lara Balawejder, Ayla Stafford, Arianna Slotnick, and Robert Kelly. Funding This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 to the University at Buffalo. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. References Agosti, V., Nunes, E. V., & O'Shea, D. (2012). Do manualized psychosocial interventions help reduce relapse among alcohol-dependent adults treated with naltrexone or placebo? A meta-analysis. The American Journal on Addictions, 21(6), 501–507. https://doi.org/10.1111/j.1521-0391.2012.00270.x. Anton, R., Randall, C., Latham, P., Ciraulo, D., LoCastro, J., Donovan, D., ... Grp, C. S. R. (2003). Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: Rationale and methods. Alcoholism, Clinical and Experimental Research, 27(7), 1107–1122. https://doi.org/10.1097/01.alc.0000086765.46408.64. Arias, A. J., Gelernter, J., Gueorguieva, R., Ralevski, E., & Petrakis, I. L. (2014). Pharmacogenetics of naltrexone and disulfiram in alcohol dependent, dually

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