Extended-release naltrexone plus medical management alcohol treatment in primary care: findings at 15 months

Journal of Substance Abuse Treatment 43 (2012) 458–462

Contents lists available at SciVerse ScienceDirect

Journal of Substance Abuse Treatment

Extended-release naltrexone plus medical management alcohol treatment in primary care: findings at 15 months Joshua D. Lee (M.D., M.Sc.) a,⁎, Ellie Grossman (M.D. M.P.H.) a, Laura Huben (M.P.H.) a, Marc Manseau (M.D. M.P.H.) a, Jennifer McNeely (M.D. M.Sc.) a, John Rotrosen (M.D.) a, David Stevens (M.D.) a, b, Marc N. Gourevitch (M.D. M.P.H.) a a b

New York University School of Medicine, New York, NY, USA New York City Health and Hospitals Corporation

a r t i c l e

i n f o

Article history: Received 1 March 2012 Received in revised form 31 July 2012 Accepted 9 August 2012 Keywords: Alcohol treatment Extended-release naltrexone Primary care Alcohol pharmacotherapy Alcohol medical management

a b s t r a c t The feasibility of long-term extended-release naltrexone (XR-NTX) alcohol treatment is unknown. Following an initial 12-week, single-arm, observational trial of XR-NTX plus medical management (MM) in primary care, we offered 48 additional weeks of XR-NTX treatment (12 additional monthly injections) in two public primary care clinics as a naturalistic extension study. Of 65 alcohol dependent adults initiating XR-NTX treatment, 40 (62%) completed the initial 12-week XR-NTX observational trial, and 19 (29%) continued treatment for a median of 38 weeks total (range, 16–72 weeks; median 8 total XR-NTX injections). Among active extension phase participants, self-reported rates of drinking days (vs. last 30 days pre-treatment baseline) were low: median 0.2 vs. 6.0 drinks per day; 82 vs. 38% days abstinent; 11 vs. 61% heavy drinking days. Long-term XR-NTX treatment in a primary care MM model was feasible and may promote lasting drinking reductions or alcohol abstinence (clinical trial: NCT00620750). © 2012 Elsevier Inc. All rights reserved.

1. Introduction National health reform and current addiction treatment priorities align around the expansion of addiction and alcohol medications within primary care settings, including the patient-centered medical home (PCMH) and accountable care organizations (Buck 2011; Mechanic 2011). Within the PCMH, preventive services, disease management, and addiction and mental health care will be coordinated by teams of generalist and specialty providers (Kim et al. 2011). Effective alcohol medications and non-specialized counseling approaches surrounding decreased drinking and medication adherence clearly fit into primary care and PCMH models, yet widespread adoption of these interventions has not occurred (CSAT, 2009). This may be due in part to a lack of data on the routine and long-term use of alcohol medications in primary care settings. Extended-release naltrexone (XR-NTX) is the newest FDA-approved pharmacotherapy for alcohol dependence in the United States. The medication's long-acting depot formulation produces a 4–5 week period of therapeutic plasma naltrexone levels, equivalent or superior to that seen with daily adherence to oral naltrexone (Garbutt 2009). The extended release formulation confers a potential advantage in effectiveness in treating alcohol dependence over the oral formula⁎ Corresponding author. Division of General Internal Medicine, VZ30 622, New York, NY 10016, USA. Tel.:+ 1 212 263 4242; fax: +1 646 501 2706. E-mail address: [email protected] (J.D. Lee). 0740-5472/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jsat.2012.08.012

tion, which is compromised by low rates of daily medication adherence as observed in clinical trials and commercial pharmacy data (Kranzler, Stephenson, Montejano, Wang, & Gastfriend 2008; Krystal, Cramer, Krol, Kirk, & Rosenheck 2001). Medical management (MM) of alcohol use disorders, as adapted from the NIAAA-supported COMBINE and other addiction pharmacotherapy trials, consists of a provider–patient partnership surrounding the alcohol dependence diagnosis and effective medication treatment. In this model, the clinician provides brief counseling to reinforce the goals of abstinence or reduced alcohol use, encourages 12-step or other psychosocial treatment involvement, prescribes pharmacotherapies, and supports medication adherence (Anton et al. 2006). Previously, we have investigated and reported on the feasibility of an initial 12 weeks of XR-NTX for alcohol dependence in a primary care medical management model in a single-arm, open-label, observational treatment study (Lee et al. 2010). In this initial study, 92% of adult alcohol dependent participants eligible for XR-NTX initiated monthly injections, and 56% (40 of 72) of the total sample completed three consecutive injections. Self-reported drinking outcomes in-treatment demonstrated robust improvements from baseline levels, mirroring the pivotal 24-week efficacy study of XR-NTX for alcohol dependence (Garbutt et al. 2005). Beyond 12 weeks the feasibility, acceptability, and effectiveness of alcohol treatment with XR-NTX are not well described in the ‘real world’ of primary care. Most naltrexone clinical trials have involved a 12–24 weeks of treatment, including the pivotal efficacy trial. Longer-

J.D. Lee et al. / Journal of Substance Abuse Treatment 43 (2012) 458–462

term treatment data are important given the chronically relapsing nature of alcohol dependence. In addition, 12–24 week treatment phases may not adequately stabilize patients in terms of maintaining abstinence, avoiding heavy drinking, and consolidating the complex behavioral changes required for optimal treatment outcomes. We therefore conducted a naturalistic observational study of prolonged primary care-based alcohol treatment with XR-NTX for up to 48 additional weeks of active treatment (12 additional injections) among participants completing the initial 12-week trial. Outcomes of interest were rates of treatment retention, the quantity and frequency of selfreported alcohol use, engagement in other addiction related care including 12-step participation, and rates of adverse events. 2. Materials and methods An open-label extended treatment phase followed an initial 12week study evaluating the use of XR-NTX with MM among alcohol dependent adults in the primary care clinics of two public hospital facilities in lower Manhattan (Bellevue Hospital Center and Gouverneur Diagnostic and Treatment Center). Seventy-two participants provided written informed consent and were enrolled in the initial 12-week trial, the methods and results of which we have reported previously (Lee et al. 2010). Briefly, eligible participants were English- or Spanish-speaking adults (age ≥18 years) meeting DSMIV criteria for alcohol dependence and stating a willingness to initiate XR-NTX treatment. Exclusion criteria were (a) pregnancy; (b) liver function tests (LFTs) greater than three times upper normal limits; (c) opioid dependence or an anticipated need for opioid analgesia, (d) record of recent missed visits in primary care (≥2 or last 3 scheduled visits) or no working phone number, and, (e) any serious uncontrolled medical or psychiatric disorders judged by the study physician to compromise the subject's ability to participate in the study (i.e., active psychosis, dementia). Monthly treatment visits consisted of physician-delivered medical management and XR-NTX intramuscular administration. MM consisted of counseling in support of alcohol abstinence or reduction, medication adherence, developing sober behaviors, and accessing available 12-step programs (e.g. Alcoholics Anonymous) or specialized addiction treatment. MM clinicians also managed any adverse events or medical issues surrounding treatment (i.e., monitoring LFTs). A research coordinator led recruitment, conducted telephone prescreens, and coordinated all visits and study assessments. Physicians and the research coordinator assisted interested patients in locating and evaluating 12-step and specialty addiction treatment services, but did not directly refer to or mandate the use of such resources. In the extension phase study, up to 12 additional XR-NTX (with MM) visits were scheduled every 4 weeks (28 days), with telephone reminders of upcoming visits. Time in treatment varied due to missed visits and rescheduled injections in keeping with a naturalistic study: patients generally in contact with study staff and intending to continue treatment were allowed to complete the 15 injections over a total time in treatment of greater than 60 weeks; patients who dropped in and out of active treatment were discontinued from the study at 60 weeks (i.e., prior to completing the 15 possible injections). Patients received medication free of charge but were otherwise not offered compensation or visit incentives. The Institutional Review Board of the New York University School of Medicine approved both the initial 12-week study and the extension phase. 2.1. Assessments A diagnostic interview and a written DSM-IV alcohol dependency checklist were completed by study physicians to document a diagnosis of alcohol dependence at baseline. A baseline survey measured demographics and medical, psychiatric, alcohol and substance misuse, and current (last 30 days) and lifetime alcohol

459

and addiction treatment histories. A baseline 30-day timeline follow back (TLFB) followed by monthly serial TLFB (covering all days since the last visit) documented self-reported alcohol use over time (Sobell LC, Sobell MB, 1995). Participation in 12-step and specialty services were tracked at each visit. Adverse events (AEs) and serious adverse events (SAEs) were characterized by the study clinician as medication- or non-medication related. LFTs were monitored bi-monthly; urine pregnancy and urine drug screens were performed at each visit. A final exit interview was conducted in person at study close, or, the event of early drop-out, by telephone. In the event of drop-out the research coordinator asked open-ended questions concerning reasons for early drop-out, drinking status, AEs, and further treatment plans. All data were collected in writing by the research coordinator and physician during the MM visit. 2.2. Analysis Analysis was primarily descriptive. Differences in baseline characteristics between extension study participants and those enrolling in the initial 12-week study and not participating in the extension study were analyzed using the Fischer's exact test or analysis of variance. The primary outcome was the median number of total XRNTX injections completed during an observed time in treatment. Secondary outcomes of interest were rates of self-reported drinking from the TLFB and AEs. We did not perform regression analysis of baseline in-treatment factors associated with longer XR-NTX treatment given the small sample size. Analysis was performed in STATA/ SE 10.0 (Stata Corp LP, College Station, TX). 3. Results The initial 12-week study began in August, 2007. Regulatory approval and study drug supply were obtained for the extension phase by January 1, 2008. Twenty-two subjects completed the initial 12week study before January 1, 2008; 10 of these received all three injections, and of these, 3 enrolled in the extension study following a lapse of 2 to 8 months between study phases. Fifty subjects completed the initial 12-week study after January 1, 2008; of these, 30 received all three injections, and 16 of these enrolled in the extension study (with no lapse in treatment) (Fig. 1). Among 72 participants consented, 65 initiated XR-NTX, 40 of 65 (62%) completed the 12-week study and 19 of 65 (29%) entered the extension phase. Of the 21 of 65 (32%) eligible participants not enrolling in the extension phase, 5 continued XR-NTX treatment with other providers, 3 switched to oral naltrexone, 1 declined further treatment while planning conception, 5 declined further medication treatment, and 7 were lost to follow-up. In total, 24 of 65 (37%) of those initiating treatment continued or intended to seek XR-NTX treatment beyond an initial 12 weeks. We have previously reported detailed baseline characteristics and drinking histories for the initial 12-week study cohort (N=72; Lee et al. 2010). Extension phase participants were largely similar to the remaining sample, while better educated (Table 1). Extension phase participants reported higher rates of 12-step and outpatient specialty addiction treatment involvement at baseline, possibly an importance difference that was not statistically significant. Extension phase participants self-reported common alcohol dependence comorbidities, including a history of hepatitis C (1 of 19, 5%), HIV (1, 5%), any lifetime mental health problem (12, 63%), and current active mental health treatment (6, 31%). None reported a history of cirrhosis or liver failure. Regarding the primary outcome of the number of total monthly injections over time, extension phase participants completed a median eight XR-NTX injections (range, 4–15) over a median observed time in treatment of 38 weeks (range, 16–72) (Fig. 2). MM injection visits were scheduled every 28 days; the median interval between doses was 32 days (range, 28–125 days).

460

J.D. Lee et al. / Journal of Substance Abuse Treatment 43 (2012) 458–462

Prescreened, n=116 Consented and screened, n=76 Initial 12-week study enrollment, N=72

Extension phase launch prior to initial 12-week study completion, n=50

Extension phase launch after initial 12-week study completion, n=22

Eligible for extension phase, n=30

Eligible for extension phase, n=10

Enrolled in extension phase, n=16

Enrolled in extension phase, n=3

Enrolled in extension phase, n=19: •Completed 60 weeks of active treatment (15 monthly XR-NTX injections): n=7 •Median time in treatment, n=19: 38 weeks (range, 16-72 weeks) •Discontinued XR-NTX due to reported medication-related side effects: n=0 Fig. 1. Study enrollment and flow.

Drinking outcomes reported during treatment demonstrated high rates of alcohol abstinent days and low rates of heavy drinking. Participants reported alcohol abstinence 82% of days, drinking 18% of days, heavy drinking 11% of days (11 of 18 drinking days were heavy drinking days), and a median 0.2 drinks per day (range, 0–15). This contrasted with baseline (last 30-days) drinking rates of alcohol abstinence of 38% of days, drinking 62% of days, heavy drinking 61% of

Table 1 XR-NTX plus MM extension phase: participant characteristics at baseline. Extension phase participants

Initial 12-week participants, no extension phase

n=19

n=53

n (%) Male Age in years, mean (range) Race/ethnicity African American Hispanic White, non-Hispanic Other Education ≤12th grade Some college Post-graduate degree Formal employment No active health insurance Homelessness (living in street or shelter) Alcohol history, last 30 days % drinking days, median (range) % heavy drinking days (range) Drinks per day, median (range) Drinks per drinking day, median (range) Any alcohol withdrawal seizure, lifetime Alcohol abstinence, 7 days prior to Initial XR-NTX injection Alcohol specialty outpatient treatment 12-Step involvement Any alcohol medication, lifetime ⁎ pb0.05.

n (%)

14 (74) 47 (36–59)

35 (66) 45 (29–61)

4 (21) 3 (16) 12 (63) 0 (0)

7 (13) 13 (25) 31 (58) 2 (3)

2 (10) 14 (74) 3 (16) 9 (47) 5 (26) 0 (0)

23 (43)⁎ 25 (47) 5 (9) 31 (58) 14 (26) 3 (6)

62 61 6 10 2 3

66 (0–100) 57 (0–100) 4.5 (0–40) 8 (0–40) 4 (8) 9 (17)

(0–98) (0–98) (0–17) (0–37) (10) (17)

8 (42) 11 (56) 7 (37)

9 (17) 13 (25) 14 (26)

days (61 of 62 drinking days were heavy drinking days), and a median of 6 drinks per day (range, 0–17). Four of 19 participants (21%) reported 100% days abstinent throughout the extension phase and over a median 14 weeks (range, 8–54 weeks). The seven participants completing all 12 additional injections reported non-significantly lower rates of drinking compared to those completing b12 additional injections: 85 vs. 77% days abstinent, 4 vs. 15% heavy drinking days, and 0.2 vs. 0.6 drinks per day. Across all 19 extension phase participants, alcohol craving measured on a 10 point Likert scale decreased from baseline (group mean of 3.5 during treatment vs. 8.0 at baseline). Importantly, post-drop-out reports of drinking rates and alcohol cravings were not available among the 12 participants ending study involvement prior to completing the 12 possible additional injections. No study-related serious adverse events (SAEs; defined as death, new disability, or hospitalization) were observed during the extension phase. No severe injection site reactions were observed among 113 total XR-NTX injections administered during the extension phase, as compared to 1 severe injection site reaction observed during the initial 12-week observational trial (154 total injections among 65 participants). The most common medication-related adverse events reported at any time during the extension phase were injection site pain (8 of 19, 42%, of participants reported at least one occasion of injection site pain), a non-painful injection site nodule (5, 26%), fatigue (4, 21%), nausea (3, 16%), musculoskeletal pain (2, 11%) or flulike symptoms (2, 11%). No cases of pregnancy or LFTs elevated ≥3× normal were observed. Participants ending treatment prior to the maximum 15 injections cited various reasons for stopping, including ‘wanting to do it myself (without medication),’ ‘tired of the shot,’ and an attitude of having achieved success thus far in the recovery process and feeling they no longer needed active medical management. Of the 12 participants ending the extension phase early, 6 dropped out and were out of contact, 3 continued alcohol specialty treatment involvement and declined further XR-NTX, 1 pursued XR-NTX through a provider closer to her residence, and 2 re-located elsewhere. Specific medication side effects were not reported as reasons for stopping injections, though it is possible that patients missing a next visit and subsequently remaining out-of-contact dropped out due to adverse events.

461

60

15

56

14

52

13

48

12

44

11

40

10

36

9

32

8

28

7

24

6

20

5

16

4

12

3

8

2

4

1

Cumulative additional XR-NTX injections (range, 1-12)

Observed time in treatment (weeks, 4-60)

J.D. Lee et al. / Journal of Substance Abuse Treatment 43 (2012) 458–462

0

0 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

Individual participants Fig. 2. Observed time in treatment and cumulative XR-NTX injections. While MM injection visits were scheduled every 4 weeks (28 days), participants commonly presented for follow-up at longer intervals, and the observed time in treatment was usually greater than the total time of ‘active’ naltrexone treatment (4 weeks multiplied by the total number of injections received).

Generally, participants endorsed an attitude that the medication treatment was helping them avoid or control alcohol use, and reported diminished alcohol cravings, as above. Of the seven participants completing all 15 possible injections, three planned to continue XR-NTX treatment through outside physicians, two were interested in continued XR-NTX but switched to oral naltrexone due to insurance benefits, and two intended to stop medication treatment. Community 12-step (AA) or ancillary alcohol and behavioral health treatment service involvement at any point during treatment was reported by 11 of 19 (58%) participants: 9 (47%) participated in 12-step meetings, 6 (32%) reported intensive outpatient program (IOP) attendance, 7 (37%) reported individual behavioral counseling, and the remaining 9 (47%) participants reported no 12-step or other community treatment involvement.

4. Discussion An XR-NTX and medical management long-term alcohol treatment model appeared feasible and acceptable to a substantial proportion of alcohol dependent patients in an urban primary care setting. Alcohol dependence is a chronic relapsing disorder, and successful recovery and sustained decreased drinking require lasting behavior change and maintenance (McLellan, Lewis, O'Brien, & Kleber 2000). XR-NTX may greatly assist in reducing total alcohol use and the frequency of heavy drinking episodes beyond an initial 12-week therapeutic trial, including in the ‘real world’ of nonspecialty general care and outside of a randomized control trial design. Findings from this feasibility study are similar to open-label safety data from the manufacturer of XR-NTX, in which a small number of participants were maintained on XR-NTX for alcohol or

opioid dependence for up to 80 weeks with good tolerability/ acceptability and low rates of AEs (FDA, 2010). Alcohol treatment effects associated with XR-NTX and MM were similar to those observed in previous XR-NTX and oral naltrexone trials. XR-NTX appears to promote reduced alcohol cravings, diminished total alcohol intake, and reduced heavy drinking and increased rates of abstinence in the majority of patients in treatment. Of course, persons leaving treatment may return to baseline rates of heavy drinking, and this modestly budgeted observational study was unable to track these drop-outs. As a public health intervention, XR-NTX and MM in primary care alcohol dependent populations likely has merit, based on substantial drinking reductions in the 62% of participants completing the 12week initial study (Lee et al. 2010), which yielded 37% either entering the extension phase or continuing XR-NTX elsewhere, and 11% completing 60 weeks of active treatment. While the proportion of patients retained in treatment over time could certainly be improved, it is quite similar to our experience with buprenorphine treatment for opioid dependence in these same primary care clinics as well as published rates of retention in alcohol specialty treatment settings (Lee, Grossman, DiRocco, & Gourevitch 2009; SAMHSA, 2010; SAMHSA, 2008). Clearly more research is needed to track drinking and health service outcomes among the 63% of persons ending XR-NTX treatment after 12 weeks or less, and to estimate the overall cost-effectiveness of XR-NTX and primary care MM. This extension study population was majority Caucasian, with some college or higher level of education and active health insurance (32% Medicaid, 42% commercial insurance or Medicare, 26% uninsured), already active in AA at baseline, and with substantial proportions also engaging in specialty outpatient alcohol treatment at baseline (42%) and reporting lifetime experience with alcohol

462

J.D. Lee et al. / Journal of Substance Abuse Treatment 43 (2012) 458–462

medications (37%). In this sense, the extension phase and the preceding 12-week study may have attracted a more treatmentand medication-oriented cohort than is typically seen in urban alcohol dependent populations. Our sample was less ethnically heterogeneous and reported higher rates of health insurance and current employment than the general population of one of the same primary care clinics (Lee, Delbanco, Wu, & Gourevitch 2011). Conversely, the sample more closely resembled national samples of alcohol dependent patients with commercial insurance and fewer barriers to obtaining XR-NTX in everyday care (Bryson, McConnell, Korthuis, & McCarty 2011). Also affecting generalizability, this naturalistic observational trial was not tied to any program of Screening, Brief Intervention and Referral to Treatment (SBIRT): most participants were enrolled through exogenous recruitment rather than through the systematic screening of existing clinic populations. SBIRT models have not focused on engaging patients in alcohol pharmacotherapy, but a model of primary care ‘SBIT,’ where screening, brief intervention, and on-site treatment take place in a continuous manner, may be a worthwhile strategy for the expansion of evidence-based alcohol treatment. In this study, the bulk of participants in the initial 12-week study and the extension phase were community-dwelling adults who were new to our primary care clinics, demonstrating the feasibility of recruiting alcohol dependent patients into medical care (a ‘recruit-in’ strategy). Both ‘SBIT’ and ‘recruit-in’ approaches are highly relevant in the era of the PCMH, in which a robust combination of psychiatric, behavioral, and addiction treatments will be delivered by provider teams in primary care settings (Kim et al. 2011; Saitz, Larson, Labelle, Richardson, & Samet 2008). The psychosocial foundation of this trial was primary care medical management, an easily adapted approach to alcohol treatment versus more specialized counseling strategy. Medical management models, which are based on health-care provider support of patient adherence to effective medications, are common among care for patients with hypertension, diabetes, HIV, and depression, and are now proven interventions in conjunction with addiction pharmacotherapies (Anton et al. 2006). This is critically important, as few adults with current alcohol dependence are engaged in any addiction treatment, and fewer still are ever offered medications (SAMHSA, 2010; SAMHSA, 2008). MM counseling includes encouragement to pursue 12-step and other appropriate alcohol treatment services, and these recommendations were made to all patients in this trial at each MM visit. Within the small sample of the extension phase, ancillary treatment trends were difficult to interpret: any 12-step involvement decreased non-significantly from 56% (baseline) to 47% during the extension phase, while intensive outpatient program attendance similarly decreased from 42 to 32%. Nonetheless, a greater proportion of participants active in AA or specialty treatment modality at baseline were generally more likely to participate in the extension-phase. Associations between primary care XR-NTX and ancillary treatment are likely multi-directional: some patients appear to find XR-NTX and MM sufficient or optimal monotherapy, others already involved in fairly comprehensive behavioral treatment are attracted to the additional treatment effect offered by pharmacotherapies in an office-based setting, while a third cohort accesses treatment for the first time through the MM model and then later pursues more comprehensive behavioral support. Limitations to this XR-NTX open-label observational extension trial included a single arm (no placebo or comparison condition), a modest sample size, and a limited ability to track drinking outcomes and safety data among participants who dropped out of treatment. It is possible that rates of AEs and SAEs were higher than reported if patients discontinued treatment and did not inform staff of these events following their last injection. Reported rates of AEs were otherwise in keeping with prior XR-NTX studies and post-marketing safety data reported by the manufacturer (FDA, 2010). Further, this

was not a continuous 15-month treatment trial for its entirety, as a first wave of 22 participants were not initially offered extension study participation due to a lag in regulatory approval, which likely suppressed enrollment and retention from the initial 12-week study into the extension phase. In this observational extension study, XR-NTX appeared feasible and acceptable as a long-term, primary care-based medical management strategy for the treatment of alcohol dependence. Randomized trials, comparative effectiveness, and cost-effectiveness research should evaluate similar alcohol treatment strategies in an effort to further expand evidence-based alcohol treatment.

Acknowledgments Grant support and study drug product was provided by Alkermes, Inc., through an Investigator Sponsored Study mechanism. We would like to acknowledge the efforts in support of and involvement in this study by Les Chuang MD, Kathleen Hanley MD, Valerie Perel MD, Andrea Truncali MD, and Andrew Wallach MD.

References Anton, R. F., O'Malley, S. S., Ciraulo, D. A., Cisler, R. A., Couper, D., Donovan, D. M., et al. (2006). Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial. JAMA : The Journal of the American Medical Association, 295, 2003–2017. Bryson, W. C., McConnell, J., Korthuis, P. T., & McCarty, D. (2011). Extended-release naltrexone for alcohol dependence: Persistence and healthcare costs and utilization. American Journal of Managed Care, 17(Suppl 8), S222–S234. Buck, J. A. (2011). The looming expansion and transformation of public substance abuse treatment under the Affordable Care Act. Health Affairs, 30(1), 1402–1410. Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration (2009). Alcohol Pharmacotherapies Into Medical Practice. Treatment Improvement Protocol (TIP) Series 49, HHS Publication No. SMA 09–4380. (Rockville, MD). Food and Drug Administration (2010). Meeting of the Psychopharmacologic Drugs Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/ ucm225655.pdf (accessed Dec. 10, 2011) Garbutt, J. C. (2009). The state of pharmacotherapy for the treatment of alcohol dependence. Journal of Substance Abuse Treatment, 36(1), S15–S23. Garbutt, J. C., Kranzler, H. R., O'Malley, S. S., Gastfriend, D. R., Pettinati, H. M., Silverman, B. L., Loewy, J. W., & Ehrich, E. W.Vivitrex Study Group. (2005). Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial. JAMA : The Journal of the American Medical Association, 293(13), 1617–1625. Kim, T. W., Saitz, R., Cheng, D. M., Winter, M. R., Witas, J., & Samet, J. H. (2011). Initiation and engagement in chronic disease management care for substance dependence. Drug and Alcohol Dependence, 115(1–2), 80–86. Kranzler, H. R., Stephenson, J. J., Montejano, L., Wang, S., & Gastfriend, D. R. (2008). Persistence with oral naltrexone for alcohol treatment: Implications for health-care utilization. Addiction, 103, 1801–1808. Krystal, J. H., Cramer, J. A., Krol, W. F., Kirk, G. F., & Rosenheck, R. A. (2001). Naltrexone in the treatment of alcohol dependence. NEJM, 345, 1734–1739. Lee, J. D., Delbanco, B., Wu, E., & Gourevitch, M. N. (2011). Substance use prevalence and screening instrument comparisons in urban primary care. Substance Abuse, 32(3), 128–134. Lee, J. D., Grossman, E., DiRocco, D., & Gourevitch, M. N. (2009). Home buprenorphine/naloxone induction in primary care. Journal of General Internal Medicine, 24(2), 226–232. Lee, J. D., Grossman, E., DiRocco, D., Truncali, A., Hanley, K., Stevens, D., Rotrosen, J., & Gourevitch, M. N. (2010). Extended-release naltrexone for treatment of alcohol dependence in primary care. Journal of Substance Abuse Treatment, 39(1), 14–21. McLellan, A. T., Lewis, D. C., O'Brien, C. P., & Kleber, H. D. (2000). Drug dependence, a chronic medical illness: Implications for treatment, insurance, and outcomes evaluation. JAMA : The Journal of the American Medical Association, 284, 1689–1695. Mechanic, D. (2011). Seizing opportunities under the Affordable Care Act for transforming the mental and behavioral health system. Health Affairs, 31(2), 376–382. Saitz, R., Larson, M. J., Labelle, C., Richardson, J., & Samet, J. H. (2008). The case for chronic disease management for addiction. Journal of Addiction Medicine, 2, 55–65. Substance Abuse and Mental Health Services Administration, National Survey on Drug Use and Health (2010). http://www.samhsa.gov/data/NSDUH/2k10NSDUH/ 2k10Results.htm (retrieved Feb 15, 2012). Substance Abuse and Mental Health Services Administration, Office of Applied Studies (2008). Treatment Episode Data Set (TEDS): 2005. Discharges from Substance Abuse Treatment Services. DHHS. (Rockville, MD).