Mady Chalk, PhD

 To evaluate the healthcare costs associated with treatment of opioid-dependence disorder with medications versus no medication, and with the 4 agents approved by the US Food and Drug Administration (FDA).

 Eligible adults with opioid dependence were identified from a large US health plan and the PharMetrics Integrated Database. Data included all medical and pharmacy claims at all available healthcare sites. Case-mix adjustment was applied using baseline demographic, clinical, and healthcare utilization variables for 13,316 patients; half of these patients used an FDA-approved medication for opioid dependence. A similar comparison was performed among 10,513 patients treated with extended-release naltrexone (NTX-XR) (n = 156) prior to FDA approval for opioid dependence or with a medication approved at the time: oral naltrexone (NTX) (n = 845), buprenorphine (n = 7596), or methadone (n = 1916). Analyses calculated 6-month persistence, utilization, and paid claims for opioid-dependence medications, detoxification and rehabilitation, opioid-related and non-related inpatient admissions, outpatient services, and total costs.

 Medication was associated with fewer inpatient admissions of all types. Despite higher costs for medications, total healthcare costs, including inpatient, outpatient, and pharmacy costs, were 29% lower for patients who received a medication for opioid dependence versus patients treated without medication. Patients given XR-NTX had fewer opioid-related and non—opioid-related hospitalizations than patients receiving oral medications. Despite higher costs for XR-NTX, total healthcare costs were not significantly different from those for oral NTX or buprenorphine, and were 49% lower than those for methadone.

 Patients with opioid dependence who received medication for this disorder had lower hospital utilization and total costs than patients who did not receive pharmacologic therapy. Patients who received XR-NTX had lower inpatient healthcare utilization at comparable or lower total costs than those receiving oral medications.

	Opioid-dependence disorder, or addiction, is a complex brain disease characterized by “uncontrollable drug craving, along with compulsive drug seeking and use that persist even in the face of devastating consequences.”

 In 2009, there were over 2 million opioid-dependent adults in the United States

 and prescription opioid dependence has been increasing over the last 20 years due to growth in prescribing of high potency opioids for the treatment of pain. Drug overdose deaths now surpass gunshot deaths; in 16 states overdose deaths are more common than lethal car crashes, and drugged driving occurs at higher levels than alcohol-impaired driving.

 Among those dependent upon heroin, it is estimated that more than 18 years of potential life are lost by age 65, with the leading causes of death being overdose, chronic liver disease, and accidents.

 The cost of heroin dependence in the United States was estimated at $21 billion in 2000.

	There are 3 main classes of oral pharmacologic treatments for opioid dependence: opioid receptor agonists (methadone),

 partial agonists (buprenorphine, buprenorphine/naloxone),

 and antagonists (oral naltrexone [NTX]).

 Agonist therapy is effective for a broad range of dependence consequences and outcomes, although diversion and abuse can be problematic.

 Antagonist therapy (ie, oral NTX) is not abused; however, its clinical effectiveness has been limited by poor patient compliance with daily dosing,

 leading the National Institute on Drug Abuse to call for a sustained-release antagonist preparation.

 was approved by the US Food and Drug Administration (FDA) in October 2010 for the treatment of alcohol dependence and the prevention of relapse to opioid dependence following detoxification.

	Much of the population with opioid dependence remains untreated, due to obstacles including denial about the disease, poor motivation, stigma, limited insurance coverage, and limited access to care; factors that have been proposed to improve this situation include expanded access to opioid agonist treatment, treatment with a nonreinforcing “blocker,” treatment in a conventional medical setting, and an approach that conforms to the abstinence model.

	Given the growing health and social burdens of opioid dependence and new formulations and approaches to treatment introduced in the past 10 years, the present study was designed to examine a comprehensive range of real-world healthcare costs and utilization with available treatments, including treatment with no medication, treatment with any of the currently approved medications, and among the currently approved medications, treatment with each of the 4 agents.

	Health Insurance Portability and Accountability Act-compliant pharmacy and medical administrative claims data from a proprietary US health plan and the PharMetrics Integrated Database for calendar years 2005 through 2009 were used for this retrospective, longitudinal study. For the first source, data for approximately 14 million individuals was available in 2008. The PharMetrics Integrated Database includes 85 US health plans providing healthcare coverage to more than 10 million persons annually throughout the United States. These data sources are well validated and were chosen because they cover large numbers of patients across all parts of the United States.

	The end points of the study were healthcare cost and utilization. Two different comparisons were conducted: (1) between treated patients with any medication versus no medication, and (2) among patients treated with medication, comparison of patients treated with (a) XR-NTX; (b) oral NTX; (c) buprenorphine (with or without naloxone); and (d) methadone. Patients treated with XR-NTX were identified on the basis of an outpatient drug claim from the National Drug Code (NDC) or medical claims from the Healthcare Common Procedure Coding System code (because it is the 1 agent administered with a procedure). The other medications were identified using outpatient drug claims based on NDCs.

	For patients in the no medication group, the index date was defined as the first medical claim for a nonpharmacologic treatment, such as a detoxification facility claim, a substance abuse treatment facility claim, or a substance abuse counseling claim. The index date for the group with medication use was determined as the earliest pharmacy claim for opioid medication.

	The database’s study population included patients continuously enrolled in a commercial health plan for at least 1 year (6 months pre—index date and 6 months post–index date). Patients were required to have at least 1 claim for opioid dependence or opioid-use disorder (

International Classification of Diseases, 9th Revision, Clinical Modification

] codes 304.0x, 304.7x) in the 6 months prior to the index date or on the index date. Patients were excluded from the analysis if they (1) had claims for pharmacologic treatment for opioid dependence in the 1 month prior to the index date for patients with claims for oral NTX, buprenorphine, methadone, or nonpharmacologic treatment on the index date; or (2) had claims with a diagnosis of acute hepatitis or liver failure in the 6 months pre-index. This later restriction was applied due to the varying hepatic safety profiles of the medications.

	Patients’ age, sex, and geographic region were determined from the claims record. Using a previously validated formula for socioeconomic status,20 we constructed a summary measure of socioeconomic status for each US Zone Improvement Plan (ZIP) code using data on income, education, and occupation from the 2000 US Census, and then linked this information to the patients’ ZIP code of residence in the analytic files.

 Comorbid conditions were measured during the 6-month period before the index date and defined using the methods of Elixhauser

 to produce a single score for use in multivariate models. The Deyo-Charlson comorbidity score is an 

 code adaption of the Charlson index, which assigns a range of weights, from 1 to 6 according to disease severity, for 19 conditions. The Elixhauser score is also a claims-based comorbidity index which sums a patient’s comorbid conditions from among 30 

 comorbidity flags, differentiating secondary diagnoses from comorbidities by using diagnosis-related groups.

	Costs were calculated using the actual patient claims for healthcare use in the matched cohort. They are measured during both the pre- and post-index periods. In addition to the overall costs, the costs of detoxification and/or rehabilitation visits, opioid- and non—opioid-related inpatient and outpatient visits and emergency department (ED) visits, opioid-related physician visits, and opioid and substance abuse psychosocial provider visits were calculated.

	Healthcare utilizations are represented per 1000 patients and detailed similar to healthcare costs. Adherence and persistence were measured using medication possession ratio (MPR) and time from the index date until time of discontinuation. MPR was calculated as the ratio of days’ supply of the index medication to total days in the observation period and it was corrected for inpatient events under the assumption that during hospitalization, medication is supplied by the facility. The date of discontinuation was defined by the run-out days supply of the last prescription filled prior to the gap in therapy.

	Baseline characteristics were compared between patient cohorts and descriptive statistics were calculated as mean (standard deviation) and percentages. Differences between the cohorts were analyzed using the 

-test, Mann-Whitney U tests, and chi-square tests.

	A challenge to retrospective cohort studies in general—and to this study in particular&mdash;is the question of comparability of patient groups at the time of treatment initiation (ie, is the physician equally likely to choose between the treatment options, or rather is the choice of treatment based on patient profile?). Differences in patient and provider characteristics that influence choice of treatment can confound healthcare utilization and costs, especially when one of the treatments is used off label. One method to adjust for differences in patient profiles is propensity-score analysis.

 Heckman et al argued convincingly that if patients are matched using the propensity score, up to 85% of the bias resulting from unequal distributions in patient characteristics can be removed.

	Propensity-score analysis can be implemented in a variety of ways. For medication and nonmedication cohorts we used a logistic regression model to predict the probability that patients belong in each group on the basis of their observed characteristics. The model covariates consisted of age, sex, region, and socioeconomic status variables, baseline healthcare comorbidities, utilization, and costs.

	Once each patient was assigned a propensity score, patients in the medication cohort were matched with the pool of patients in the nonmedication cohort. Matching was undertaken using nearest neighbor 1:1 matching and the resulting matched cohort was compared to determine whether balanced cohorts were created.

 Statistical analyses were performed using SAS v9.2 (SAS Institute, Cary, North Carolina) and STATA v10 (Stata Corp, College Station, Texas).

	For treatment types in the medication cohort, to further control for unobserved biases, the instrumental variable (IV) approach was used. One of the limitations of propensity-score matching analyses is that they control for observed bias (ie, selection from observed and measured factors) but not for unobserved bias. The IV approach is a technique that can be used to control for both observed and unobserved sources of bias, and to ascertain whether the results from the more standard approaches (propensity-score matching or multivariate regression) diverge from the IV results.

	An instrument is a variable that does not belong in the explanatory equation and is correlated with the endogenous explanatory variables, conditional on the other covariates. In this study, because XR-NTX was not yet approved for the opioid dependence treatment indication (and was therefore being utilized off label), its use often required unique physician considerations and reimbursement processes resulting in unique cohort characteristics. Therefore, due to a high probability that unobserved bias would play a role in the use of this agent, copayment and physician/provider prescribing patterns derived from the claims and provider-level data served as instruments. The variables were tested to determine whether they were strong or weak instruments. From prior experience, it is known that physicians’ prescribing patterns are very strong instruments because they are strongly related to treatment choices.

 reports the baseline demographic and clinical characteristics of the sample, stratified by the any medication and no medication groups. Patients were similar in terms of age (36.2 years vs 36.2, respectively; 

 = NS) and sex (61.5% male vs 60.3%, respectively; 

 = NS). Patients in the any medication cohort were less likely to be from the South (18.5%) than patients in the no medication cohort (33.4%; 

 <.0001), and a smaller percentage had socioeconomic status scores in the bottom third (27.6%) relative to patients in the no medication cohort (39.8%; 

	As expected, given the possibilities for adverse selection, patients in the any medication cohort appeared to be sicker than those in the no medication cohort, both medically, with more having an Elixhauser comorbidity score of 3 or greater (22.9% vs 18.4%, respectively; 

 <.0001), and psychiatrically, with more having psychiatric diagnoses and taking psychiatric medications (

	In terms of healthcare utilization, the 6 month pre-index utilization was higher in the any medication group, including number of detoxification facility days, detoxification and/or rehabilitation admissions, opioid-related and non-opioid-related inpatient and outpatient admissions, ED visits, and opioid-related provider visits.

	This greater utilization in the any medication group translated into higher healthcare costs relative to the no medication group. Compared with patients not receiving medication, all of the inpatient and outpatient costs were significantly higher in those receiving medication. The 6-month total cost including inpatient, outpatient, and pharmacy costs was $10,710 per patient in the any medication group compared with $6791 per patient in the no medication group.

	Using propensity-score matching, 6658 patients from each group were matched. 

 presents the risk-adjusted 6-month outcomes following the index treatment for patients in the any medication and no medication groups. Patients in the any medication group had fewer psychiatric diagnoses (3.01 vs 3.81), but more frequent use of distinct psychiatric medications (2.49 vs 1.91) relative to patients in the no medication group. Compared with patients in the no medication group, the number of detoxification facility days was significantly lower for patients in the any medication group (4758 vs 447 per 1000 patients). Post-index detoxification and/or rehabilitation admissions (74 vs 770) and opioid-related (111 vs 677) and non—opioid-related (292 vs 731) admissions were significantly lower per 1000 patients in the any medication group compared with the no medication group. Fewer inpatient admissions translated into lower inpatient costs in the any medication group. In particular, the 6-month costs per patient among those receiving medication for detoxification and/or rehabilitation admissions ($205 vs $2083) and opioid-related ($381 vs $1823) and non-opioid-related ($2928 vs $4184) admissions were significantly lower compared with those not receiving medication.

	The pattern of healthcare utilization and cost for outpatient services was more mixed, with significantly higher use and cost associated with some categories of outpatient services in the any medication group. Overall healthcare cost savings, however, were $4161 per patient treated with medication relative to those not receiving medication ($10,192 vs $14,353).

	Out of 10,513 patients who were given medication, 156 (1.5%) patients were treated with XR-NTX, 845 (8.3%) with oral NTX, 7596 (72%) with buprenorphine, and 1916

	(18.2%) with methadone. Patients in the XR-NTX group were more likely to be male (75% vs 58.7%, 64.1%, and 51.4%, respectively; all 

 <.01) and tended to reside in the eastern part of the United States relative to the other groups (37.8% vs 30.2%, 

 <.0001, respectively). They were older (36.9 years) compared with patients who received oral NTX (34.2; 

 = .06), but younger relative to methadone users (42.3%; 

 <.0001). The XR-NTX group had significantly fewer patients with the lowest socioeconomic score relative to all 3 oral medication groups (18.6% vs 31.7%, 26.0%, and 32.9%, respectively; all 

	Patient pre-index clinical characteristics in the 4 opioid medication groups are presented in 

. Although the distribution was similar among the other groups, patients given buprenorphine appeared to be healthier at the baseline, with significantly fewer patients with an Elixhauser index score of 3 or greater, and fewer distinct psychiatric diagnoses and medications.

	Patients in the XR-NTX cohort spent significantly more days in a detoxification facility (2391 per 1000 patients) relative to those in the buprenorphine (1188) and methadone (301) cohorts. Similarly, the number of patients admitted to detoxification and/or rehabilitation centers at baseline was greater for those given XR-NTX (353) versus those given buprenorphine (212) and methadone (53). This translated into a higher cost for detoxification and rehabilitation at baseline in patients receiving XR-NTX. Outpatient resource use and cost were similar among the groups at baseline, excepting significantly greater opioid-related outpatient physician visits and costs and significantly less non-opioid-related outpatient visits and costs in the XR-NTX group compared with the methadone group.

	Total healthcare cost during the 6-month pre-index period for patients in the XR-NTX group was significantly higher versus the buprenorphine group, but lower versus the methadone group. Among opioid-dependent patients at baseline, there were no significant differences in costs between the XR-NTX and oral NTX groups.

	Overall, the XR-NTX group showed notable cohort differences, including a greater percentage of patients who were male, were from the eastern United States, had higher socioeconomic status, and had higher utilization rates for physician services and detoxification. This pattern indicated a substantial degree of prescribing bias, consistent with the fact that XR-NTX was not yet approved by the FDA for the prevention of relapse to opioid dependence following detoxification. Baseline differences among the opioid treatment groups were controlled using the instrumental variable approach; risk-adjusted outcomes are presented in 

	Compared with patients given oral NTX, those given XR-NTX had a greater number of refill persistence days (55 vs 61 days, respectively), fewer distinct psychiatric medications (2.34 vs 1.99, respectively), fewer detoxification days (71 vs 62 per 1000 patients, respectively), fewer detoxification or rehabilitation admissions (84 vs 69, respectively), fewer ED visits (767 vs 608, respectively), and significantly fewer opioid-related inpatient admission rates (145 vs 93, respectively) and non—opioid-related inpatient admission rates (387 vs 234, respectively) (

	The overall healthcare costs for patients given XR-NTX were not different from those given buprenorphine, despite significantly greater costs for the FDA-approved opioid-dependence medication ($2842 vs $1297, respectively)(

). Patients receiving buprenorphine had greater refill persistence than those receiving XR-NTX (69 vs 61 days, respectively), but had significantly more opioid-related inpatient admissions (249 vs 93 per 1000 patients, respectively) (

), more non—opioid-related inpatient admissions (397 vs 234, respectively) (

), and more ED visits (1092 vs 608, respectively).

	Given these overall utilization differences and their related costs, the overall healthcare costs per patient in the group treated with methadone were significantly greater than those with XR-NTX ($16,752 vs $8582, respectively) (

), despite the significantly lower cost for the opioid dependence pharmacotherapy ($211 vs $2842, respectively) (Figure 2C). Patients given methadone or XR-NTX showed similar prescription persistence. Compared with patients given XR-NTX, those given methadone had a significantly greater number of distinct psychiatric diagnoses, but lower use of distinct psychiatric medications. Also, patients receiving methadone spent more days in detoxification (82 vs 62 per 1000 patients, respectively), had more detoxification or rehabilitation admissions (101 vs 69, respectively) (

), had more opioid-related inpatient admissions (198 vs 93, respectively) (

), had significantly more ED visits (1590 vs 608, respectively), and had significantly more non—opioid-related outpatient visits (22,054 vs 16,654, respectively) compared with those receiving XR-NTX.

	The combined data from these 2 large insurance data sets made possible the first study to date examining healthcare costs and utilization for the full set of currently available opioid-dependence treatments. This risk-adjusted analysis compared outcomes in 13,316 patients who received any versus no medication for opioid-dependence disorder and 10,513 patients who received 1 of the 4 FDA-approved pharmacologic therapies. Thus, this study was one of the largest health economic studies in this disorder to date, and the first such study to analyze treatment with XR-NTX. The study was a comprehensive analysis of total healthcare costs paid and corresponding healthcare service utilization. Compared with opioid-dependence treatment that did not include medication, medication-assisted treatment was associated with significantly fewer admissions for detoxification and/or rehabilitation, opioid-related inpatient medical care, and non—opioid-related inpatient medical care. In all of these inpatient service categories, costs were significantly lower in patients who received a medication, and total healthcare costs, including inpatient, outpatient, and pharmacy costs, were 29% lower for patients who received a medication for their opioid dependence, despite significantly higher costs for medications. Patients given XR-NTX had significantly fewer opioid-related and non–opioid-related hospitalizations than those given any of the 3 oral agents, fewer ED visits than patients who received methadone, and an overall pattern of the lowest use in all categories of inpatient utilization (

). Despite significantly higher costs for XR-NTX, total healthcare costs, including inpatient, outpatient, and pharmacy costs, were not significantly greater than total costs with oral NTX or buprenorphine, and were 49% lower than with methadone (

	This retrospective claims analysis lacked clinical variables such as drug use, severity, and overdose; however, the rate of hospital admissions is an intensive utilization variable that may also represent a proxy for morbidity, which has importance in addition to cost implications. In this study, medication was associated with 29% lower costs than nonpharmacologic treatment, whereas the relative risk reduction associated with medication was 84% for opioid-related hospitalization and 60% for non—opioid-related admission. Of the 4 FDA-approved medications, the total cost associated with XR-NTX was not significantly different from oral NTX and buprenorphine, and it was 49% lower than that with methadone. However, 

 shows that the risk of an opioid-related hospitalization in patients given XR-NTX was 36% lower than that with oral NTX, 63% less than with buprenorphine, and 53% less than with methadone; the risk for non-opioid-related hospitalization with XR-NTX was 40%, 41%, and 58% lower than that with oral NTX, buprenorphine, and methadone, respectively. Similar results have been reported in the treatment of alcohol dependence, with 3 large retrospective claims analyses showing that medication-assisted treatment was associated with lower total healthcare costs than nonmedication treatment.

 Also, XR-NTX treatment cohorts demonstrated utilization and/or cost benefits in relation to approved oral agents for alcohol dependence.

	These overall healthcare cost results highlight the problem of healthcare budget segmentation. The any medication group had total medication costs that were several times greater than those with no anti-opioid medications; however, overall healthcare costs were 29% less in those receiving opioid-dependence medication. Likewise, the cost of XR-NTX itself was more than 10-fold that of methadone, but total healthcare costs associated with methadone were nearly double those of XR-NTX. While many other factors must be taken into account, these findings suggest that stand-alone budgeting based on pharmacy costs may be counterproductive in addiction treatment—the cost offsets of a “carve out” arrangement may not accrue to medical cost centers.

	Refill persistence and outcomes showed an inverse relationship among once-monthly XR-NTX and daily oral NTX. Once XR-NTX is administered by a healthcare professional, the active ingredient, NTX, is present for a month and cannot be removed from the system. Daily oral NTX, however, was found to be ineffective due to poor treatment adherence.

 In the present study, 21% of patients receiving XR-NTX possessed the injection at least 80% of the study days, a percentage which was 2.6 times that with oral NTX (8%). The XR-NTX group had significantly fewer opioid-related and non-opioid-related hospitalizations. Compared with patients given XR-NTX, those given methadone or buprenorphine had similar refill persistence, and a greater percentage of these patients possessed their medication for at least 80% of the duration. This may reflect patient satisfaction, treatment effectiveness, and/or the fact that both agents have agonist properties that maintain opioid physical dependence and result in symptoms of withdrawal upon cessation.

	Limitations of retrospective claims analyses include the absence of randomized controls. Therefore, treatment assignment resulted in imbalances in important clinical variables. There were substantial differences between the cohorts at baseline, some of which may have been unobserved (eg, differential patient motivation or provider characteristics). Possible reasons for these differences include regional differences in access to methadone and buprenorphine, differential reimbursement, and provider and community attitudes toward opioid-maintenance therapy and patient self-selection (eg, orientation toward an opioid-free recovery). These differences were particularly salient because at the time of data collection, XR-NTX was not yet approved by the FDA for opioid-dependence treatment, resulting in a notably smaller cohort receiving this medication. Patients who were seeking XR-NTX and prescribers offering it were possibly quite different from patients and providers utilizing other agents. The statistical methods we used, while designed to adjust for observed and unobserved differences and bias, may have been imperfect in this respect, and thus the observed findings may reflect unadjusted confounding.

Articles

Cost and Utilization Outcomes of Opioid-Dependence Treatments

 To determine the healthcare costs associated with treatment of alcohol dependence with medications versus no medication and across the 4 medications approved by the US Food and Drug Administration (FDA).

 Eligible adults with alcohol dependence were identified from a large US health plan and the IMS PharMetrics Integrated Database. Data included all medical and pharmacy claims at all available healthcare sites. Propensity score—based matching and inverse probability weighting were applied to baseline demographic, clinical, and healthcare utilization variables for 20,752 patients, half of whom used an FDA-approved medication for alcohol dependence. A similar comparison was performed among 15,502 patients treated with an FDA-approved medication: oral acamprosate calcium (n = 8958), oral disulfiram (n = 3492), oral naltrexone (NTX) hydrochloride (n = 2391), or extended-release injectable naltrexone (XR-NTX; n = 661). Analyses calculated 6-month treatment persistence, utilization, and paid claims for: alcoholism medications, detoxification and rehabilitation, alcohol-related and nonrelated inpatient admissions, outpatient services, and total costs.

 Medication was associated with fewer admissions of all types. Despite higher costs for medications, total healthcare costs, including inpatient, outpatient, and pharmacy costs, were 30% lower for patients who received a medication for their alcohol dependence. XR-NTX was associated with greater refill persistence and fewer hospitalizations for any reason and lower hospital costs than any of the oral medications. Despite higher costs for XR-NTX itself, total healthcare costs were not significantly different from oral NTX or disulfiram, and were 34% lower than with acamprosate.

 In this largest cost study to date of alcohol pharmacotherapy, patients who received medication had lower healthcare utilization and total costs than patients who did not. XR-NTX showed an advantage over oral medications in treatment persistence and healthcare utilization, at comparable or lower total cost.

	Alcohol consumption is the third leading actual cause of death in the United States

; however, among the top 25 diseases, patients with alcohol-use disorders are least likely to receive care that is based upon evidence-based practice.

 The overall cost to the United States for alcohol-related illness was estimated at $184 billion in 1998

; payers spend an estimated $9.7 billion annually on direct treatment of these disorders.

 Historically, over 70% of these costs has been spent by public systems

; however, this proportion is expected to increasingly shift to the private pay sector in coming years as a result of federal parity and health care legislative reform. With a national prevalence of alcohol dependence of 3.8%, or 7.9 million adults,

 these morbidity, mortality, and cost burdens are driving efforts to develop the most clinically effective and resource-efficient evidence-based treatments possible.

	The dominant mode of treatment of alcohol dependence is psychosocial treatment or counseling, and several models have shown evidence for effectiveness.

 Although 4 medications have been approved by the US Food and Drug Administration (FDA) for the treatment of alcohol dependence, there is little adoption of these agents.

 Survey results published in 2007 reported that pharmacotherapies for substance-use disorders (SUDs) were offered in less than 25% of public and private specialty treatment programs

 and a 2007 study reported that SUD medications comprised less than 1% of all SUD treatment costs.

 Nevertheless, the National Institute on Alcohol Abuse and Alcoholism has issued recommendations stating that medications are “helpful to patients in reducing drinking, reducing relapse to heavy drinking, achieving and maintaining abstinence, or a combination of these effects” and clinicians should “consider adding medication whenever [they] are treating someone with active alcohol dependence.”

	There are multiple reasons why medication-assisted treatment (MAT) for alcohol dependence is not widely used, including long-standing traditions rooted in the mutual help movement, but adoption of MAT is also predicated on concerns about poor patient adherence to medication, modest efficacy, and poor costeffectiveness.

 Retrospective insurance database studies of oral medications have reported that 50% of patients fail to obtain their first refill,

 and refill rates are worse for alcoholism medications than for statins and psychiatric medications.

 Clinical trials have found that medication adherence is crucial to efficacy.

	Medication adherence in substance-dependence treatment has been a priority concern of the National Institutes of Health for over 3 decades.

 In 2006, the FDA approved the first extended-release formulation for the treatment of alcohol dependence, extended-release naltrexone (XR-NTX), which was designed to address the challenge of adherence through a once-monthly injection.

 Of the 4 agents FDA-approved for the treatment of alcohol dependence studied in a retrospective claims analysis of commercial insureds, XR-NTX was associated with reduced estimated charges and utilization of inpatient detoxification days and alcoholism-related inpatient days, compared with all 3 oral agents (ie, oral naltrexone, disulfiram, and acamprosate calcium).

 Given the importance of alcohol dependence treatment for public health and healthcare cost containment, the present study was designed to extend current knowledge of real-world effectiveness with alcohol dependence treatments, including treatment with no medication, any approved medication, and among the approved medications, treatment with each specific agent. This study sought to examine a larger cohort of insured patients treated with XR-NTX than previously studied, and to determine a comprehensive range of healthcare utilization and actual expended healthcare costs for each treatment category.

	This was a retrospective database analysis conducted using commercial enrollees from a large US health plan affiliated with i3 Innovus and the PharMetrics Integrated Database from 2005 to 2009. These databases included medical and pharmacy claims from all available healthcare sites (inpatient, hospital outpatient, emergency department [ED], physician’s office, and surgery center) for virtually all types of provided services, including specialty, preventive office-based treatments, and retail and mail order pharmacy claims.

	For the comparison of the “no medication” group to the “any medication” group, patients were required have at least 1 claim for alcohol dependence (

Diagnostic and Statistical Manual of Mental Disorders, 4th Edition

, code 303.xx) during the pre- or post-index period, have an alcohol use disorder diagnosis pre-index, and have at least 6 months of continuous enrollment pre-index and 6 months post-index. The earliest pharmacy claim for alcohol medication was set as the index date for the any medication group. The index date was defined as the first medical claim for a nonpharmacologic treatment such as a detoxification facility claim, a substance abuse treatment facility claim, or a substance abuse counseling claim. Patients in the nonpharmacologic substance group had no prescription fills for alcoholism medication while patients in the any medication group had at least 1 fill for any of the 4 alcoholism medications. Patients with liver failure during the pre-index period were excluded. Furthermore, patients were excluded if they had claims for pharmacological treatment in the month prior to the index date (with the exception of the XR-NTX group, because this group was occasionally required to demonstrate prior oral medication failure). These inclusion/exclusion criteria led to a final sample of 20,670 patients in the no medication group and 15,502 patients in the any medication group. 

 presents the sample sizes after applying the inclusion/exclusion criteria.

	Similar criteria were required for patients in the comparison of the 4 alcoholism medications. Patients treated with XR-NTX were identified on the basis of an outpatient drug claim using the National Drug Code (NDC) or medical claims with the Healthcare Common Procedure Coding System code. The other medications, such as oral naltrexone, disulfiram, or acamprosate were identified using outpatient drug claims based on NDCs. The final sample of 661 patients in the XR-NTX group, 2391 patients in the oral NTX group, 8958 patients in the disulfiram group, and 3492 patients in the acamprosate group, was identified after applying the inclusion/exclusion criteria.

	We derived demographic and clinical characteristics of the study populations at baseline. In particular, age, sex, and geographic location were measured at the index date. Deyo-Charlson comorbidity score,

 and the number of distinct psychiatric diagnoses and medications were calculated during the pre-index period. The Deyo-Charlson comorbidity score is an 

) code adaption of the Charlson index, which assigns a range of weights, from 1 to 6 according to disease severity, for 19 conditions. The Elixhauser score is also a claims-based comorbidity index which sums a patient’s comorbid conditions from among 30 

	For socioeconomic status (SES), we constructed a summary measure for each US Zone Improvement Plan (ZIP) code using data on income, education, and occupation from the 2000 US Census and then linked this information to the patient’s ZIP code of residence in the analytic files.

 Factor analysis was used to identify 6 census variables that could be meaningfully combined into a summary socioeconomic status score. These variables included 3 measures of wealth/income (median household income, median value of housing units, and proportion of households with interest, dividend, or rental income), 2 measures of education (proportion of adult residents completing high school and college), and 1 measure of occupation/employment (proportion of employed residents with management, professional, and related occupations).

	Healthcare utilization and costs were calculated during both the pre-index and post-index periods. In terms of inpatient utilization, the number of detoxification facility days, and the number of detoxification and/or rehabilitation (admissions with an 

 procedure for detoxification or rehabilitation), alcohol (admission with a principal diagnosis), and non-related inpatient admissions were measured. ED visits, alcohol-related physician visits, alcohol and substance abuse psychosocial provider visits, and non-alcohol-related outpatient visits were calculated. Utilization measures were presented per 1000 patients. Associated costs related to these measures and total costs were also calculated.

	In addition to healthcare utilization and costs, we evaluated adherence by analyzing medication possession ratio and days of persistence with index medication refills post-index date.

	Baseline characteristics were compared between the patient cohorts, and descriptive statistics were calculated as percentages and standard deviations. Differences between the cohorts were analyzed using the 

-test, Mann-Whitney U test, and chi-square test, and standardized differences were calculated. It has been demonstrated that standardized differences 10% and higher between the baseline variables are significant, and need to be adjusted to compare the outcome measures among the groups.

	Propensity-score matching was applied to compare the risk-adjusted outcomes between the no medication group and the any medication group. Propensity-score matching is a technique that aims at adjusting for selection bias in nonexperimental, nonrandomized, and retrospective studies like the present one.

 By using propensity-score matching, each patient in the any medication group was “mirrored” by a patient with similar predefined characteristics in the no medication group. The following characteristics were used to match: age, sex, region, comorbid scores, SES, baseline healthcare utilization, and costs. Logistic regression was used to estimate propensity scores. Several interaction variables were constructed, but they were not determined to be significant. Estimation power of the logistic regression was determined by C statistics. Following the guidelines set forth by Baser, it was determined that one-to-one matching created the best balance among the groups.

	Following Imbens and Lechner, we applied propensity-score matching that accounts for multilevel treatments when comparing the 4 alcoholism medication groups.

 Several applications of this method are presented in the medical literature.

 The first step uses multinomial logistic regression to estimate conditional probabilities of being in the particular treatment group. The second and final step estimates conditional expectation of outcome given the treatment level. Adjusted Wald tests were performed to test for the difference in weighted characteristics across the treatment cohorts.

	Statistical analyses were performed using SAS v9.2 (SAS Institute, Cary, North Carolina) and STATA v10 (Stata Corp, College Station, Texas).

	The risk-adjusted pre-index characteristics of 10,376 patients matched between each of the 2 groups (any medication and no medication, respectively) showed the following similarities: age, (44.4 vs 44.5 years; 

 = not significant [NS]); sex (male, 61.8% vs 61.9%; 

 = NS); geographic region (Eastern, 18.4% vs 18.0%; 

 = NS); SES score (high SES, 29.2% vs 29.2%; 

 = NS); and pre-index severity (proxied by having a >3 Elixhauser Index score, 25.2% vs 25.1%; 

 = .06). Differences in the Deyo-Charlson comorbidity score (0.34 vs 0.38; 

 =.0002) and Elixhauser Comorbid conditions (1.63 vs 1.57; 

 = .0034) were significant, but in opposite directions. During the pre-index period, the number of distinct psychiatric diagnoses and medications were higher in patients in the any medication group compared with the no medication group (2.71 vs 2.32 and 1.68 vs 1.29, respectively; both 

 shows that, on average, detoxification admissions per 1000 patients in the any medication and no medication groups were similar (15 vs 14, respectively). Outpatient visits were significantly higher for patients in the any medication group. In particular, per 1000 patients, alcohol-related physician provider visits (774 vs 487) and non—alcohol-related outpatient visits (10,602 vs 9846) were significantly higher for the any medication group than the no medication group. The largest driver of pre-index treatment costs, however, was the cost of non–alcohol-related inpatient admission ($2059 vs $2545 per patient). After risk adjustment, the baseline costs in the any medication group were $5922 per patient versus $6174 per patient in the no medication group.

 presents the risk-adjusted outcome results. Patients in the no medication group stayed more days in detoxification facilities post-index relative to patients in the any medication group (3497 vs 483 days per 1000 patients). They had significantly more psychiatric diagnoses during the post-index period (3.19 vs 3.07). Post-index detoxification and/or rehabilitation admissions (563 vs 85), alcohol (660 vs 202), and nonalcohol (407 vs 257) admissions were significantly higher per 1000 patients in the no medication group. Higher admission days for the no medication group in detoxification and/or rehabilitation translated to a cost burden of $1350 versus $209 per patient in the any medication group. Costs for alcohol-related admissions were $2464 versus $801, and $2751 versus $2336 for non-alcohol-related inpatient admissions, respectively.

	The pattern of greater utilization and costs also existed among patients in the no medication group for outpatient visits. This group was more likely to have physician provider visits (1970 vs 1454), psychosocial provider visits (1740 vs 991), and non—alcohol-related outpatient visits (14,101 vs 13,349) per 1000 patients. This translated into a greater cost burden of $106 per patient due to more physician provider visits and $61 due to more psychosocial provider visits. The 6-month total healthcare cost for a patient in the no medication group was $11,677 versus $8134 in the any medication group.

	Among 15,502 patients who used any pharmacologic drug, 661 patients were treated with XR-NTX, 2391 with oral NTX, 3492 with disulfiram, and 8958 with acamprosate. Patients in the XR-NTX group were slightly older (45.91 years vs 44.24, 

 = NS, respectively). There were no differences in the percentages of males in the groups (60% vs 58%, 62%, 59%; all 

 = NS). However, patients given XR-NTX resided more commonly in the East (34.0% vs 26%, 16%, 18%; all 

 <.0001) and South (31% vs 19%, 16%, 26%; all 

 <.01) compared with the Midwest and West. There was no clear pattern of SES differences among the 4 groups.

 presents the pre-index clinical, utilization, and cost characteristics of the 4 alcohol medication groups. In terms of severity (proxied by percentage with a >3 Elixhauser score) the XR-NTX group (31.0%) did not differ in high comorbidity rates relative to oral NTX (34.5%) or disulfiram (28.4%), but it was significantly lower compared with those given acamprosate (37.9%, 

 = .0004). However, patients in the XR-NTX group had a higher use of distinct psychiatric medication relative to the other groups. Compared with patients in the XR-NTX cohort, during the pre-index period, those receiving acamprosate had significantly more detoxification facility days, and those given disulfiram had significantly fewer. Also, the acamprosate group had more detoxification and/or rehabilitation admissions and alcohol- and non—alcohol-related admissions compared with those in the XR-NTX group. During the pre-index period, the number of non–alcohol-related outpatient visits was significantly higher in the XR-NTX group relative to others.

	The total healthcare costs were significantly higher for patients in the XR-NTX group compared with those in the oral NTX and the disulfiram groups, but there were no differences in pretreatment costs between XR-NTX and acamprosate.

	After adjusting for these baseline differences, the risk-adjusted outcome results for the 4 groups are presented in 

. Patients receiving XR-NTX had significantly higher refill adherence rates than patients in the other groups (21% vs 11% for oral NTX, 9% for disulfiram, and 6% for acamprosate). The number of persistence days was also significantly higher (61.6 days vs 49.8 days with oral naltrexone, 45.8 days with disulfiram, and 42.6 days with acamprosate) (

). Patients receiving XR-NTX had a significantly lower number of distinct diagnoses relative to those given acamprosate (3.05 vs 3.30), and a lower number of psychiatric medications relative to those given disulfiram (1.96 vs 2.80).

	Inpatient healthcare utilization in the XR-NTX group was significantly lower than that in the other groups. Patients given XR-NTX spent significantly fewer days in a detoxification facility relative to those given disulfiram or acamprosate (227 days vs 429 days vs 741 days per 1000 patients, respectively). Detoxification and/or rehabilitation admission and alcohol- and non—alcohol-related admission were significantly lower in the XR-NTX group relative to the other groups (

 <.01) (Figure 2B). This translated to lower inpatient costs per patient for detoxification and rehabilitation (XR-NTX: $105 vs $192 with oral NTX, $203 with disulfiram, and $288 with acamprosate), alcohol-related inpatient admission (XR-NTX: $474 vs $618 with oral NTX, $874 with disulfiram, and $1166 with acamprosate), and non—alcohol-related admission (XR-NTX: $730 vs $1091 with oral naltrexone, $1498 with disulfiram, and $3885 with acamprosate).

	Although outpatient healthcare utilization was similar across the groups, the average patient receiving XR-NTX had higher 6-month costs for ED visits ($272) vs oral agents ($227 with oral naltrexone, $227 with disulfiram, and $20 with acamprosate), and lower costs for alcohol-related physician provider visits (XR-NTX: $67 vs $107 oral NTX, $118 with disulfiram, and $291 with acamprosate) and alcohol and substance abuse outpatient visits (XR-NTX: $46 vs $76 with oral NTX, $114 with disulfiram, and $82 with acamprosate). XR-NTX was associated with higher costs for non-alcohol-related outpatient visits (NXT-XR: $4510 vs $3444 with oral NTX, $3194 with disulfiram, and $3589 with acamprosate).

	Post-index pharmacy costs were higher for the XR-NTX group; cost savings from inpatient and outpatient admissions, however, resulted in total costs that were significantly lower in patients given XR-NTX compared with those given acamprosate ($6757 vs $10,345 per patient). Significant differences in overall costs were not observed among the NXT-XR group and other groups.

	Access to the combined data from these 2 large insurance data sets allowed for the examination of clinical outcomes and costs/benefits associated with available types of alcoholism treatments (as employed in the US healthcare system), resulting in the largest health economic evaluation of alcoholism treatments reported to date in the literature.

	This risk-adjusted analysis compared 20,752 patients who received any versus no medication, and 15,502 patients who received 1 of the 4 FDA-approved medications. A total of 661 patients received treatment with XR-NTX, making this the largest sample studied to date with this particular treatment. In addition, the study involved a comprehensive analysis of actual total healthcare costs paid and healthcare service utilization. Results showed that, compared with alcohol dependence treatment that did not include medication, medication-assisted treatment was associated with significantly fewer admissions for detoxification and/or rehabilitation, alcohol-related inpatient medical care, and non-alcohol-related inpatient medical care. Costs for services in all of these inpatient categories were significantly lower in patients who received a medication, and (despite significantly higher costs for medications) total healthcare costs, including inpatient, outpatient, and pharmacy costs, were 30% lower for patients who received a medication for their alcohol dependence. With XR-NTX, cost data associated with hospital admissions and stays reflected a similar picture. Hospital costs for patients receiving XR-NTX were significantly and substantially lower than those for patients receiving 1 of the 3 oral medications. Patients given XR-NTX used fewer days in detoxification and had fewer admissions to the hospital for any reason than patients given 1 of the 3 oral medications.

	Costs for services in all of these inpatient categories were significantly lower for patients who received XR-NTX, and despite significantly higher costs for XR-NTX, total healthcare costs, including inpatient, outpatient, and pharmacy costs, were not significantly different from total costs with oral NTX or disulfiram, and were 34% lower than with acamprosate.

	The frequency of hospital admission is an intensive utilization and cost-related variable and may also represent a proxy for morbidity, in the absence of direct clinical data (which is lacking with retrospective claims data such as these). As such, reduced hospitalization, which is obviously important in cost reduction, is also an important objective in its own right. For example, medication was associated with 30% lower costs than no medication treatment; compared with no medication treatment, the relative risk reduction associated with medication was 85% for admission to detoxification or rehabilitation, and 69% for alcohol-related admission. Among the 4 medications, total costs with XR-NTX were not significantly different from oral NTX and disulfiram, and they were 34% lower than those with acamprosate. XR-NTX was associated with relative risk reductions for admission to detoxification/rehabilitation of 43% versus oral NTX, 56% versus disulfiram, and 64% versus acamprosate, and reductions for admission to alcohol-related hospitalization of 55% versus oral NTX, 69% versus disulfiram, and 74% versus acamprosate.

	These reductions showed an inverse association with refill persistence (

). One of the most important challenges in the use of alcohol pharmacotherapies is retaining patients in treatment (on medication) for clinically adequate durations. In the 2 measures of treatment duration, participants receiving XR-NTX were retained significantly longer and more continuously on medication than participants receiving oral medications. Of the 4 agents, the 2 compliance parameters, persistence (days with index medication) and continuous mean possession ratio greater than 80% of days, both showed a similar pattern (in increasing order of persistence): acamprosate, disulfiram, oral NTX, and XR-NTX. This pattern closely follows the burden of medication administration: acamprosate, 2 tablets 3 times daily; disulfiram and oral NTX, 1 tablet once daily (oral NTX is sometimes given in higher doses every other day); and XR-NTX, 1 injection per month. Also, the pattern of persistence is opposite the rate of admissions with the 4 medications (

	The cost differences found in these comparisons are revealing, because the group treated with any medication had overall medication costs that were more than double the medication costs (ie, nonalcoholism medications) of those with no alcoholism medications. Yet, their total healthcare costs were less. Similarly, the cost of XR-NTX alone was up to 10-fold higher than that for the oral alcohol dependence agents (some of which are available as generic products). Total healthcare costs, however, were either associated with no difference or lower expense. This finding suggests that the cost of a particular treatment should not be confused with the overall cost of care and that the overall objective of quality and efficient healthcare needs to transcend the compartmentalization of costs within pharmacy benefit management versus overall healthcare management.

	These patients, in general, also had psychiatric and other medical comorbidities. The reasons for the higher cost of psychiatric and other medication are not clear. Physicians who use alcoholism pharmacotherapies may be more familiar with appropriate diagnosis and treatment of concurrent psychiatric and medical conditions. Also, because the any medication group spent less time in the hospital, effective outpatient management may have necessitated more aggressive use of outpatient medications.

	Retrospective claims analyses such as these have a number of limitations. Because the study design did not include random assignment to the any versus no medication conditions, nor to specific medication conditions, the findings represent associations, but not necessarily causality. The cohorts may have had unobserved differences in baseline characteristics; for example, patient motivation or healthcare service quality (eg, physician knowledge and training, psychosocial treatment methods used), so that the precise contribution of medication or type of medication cannot be definitively determined. Because there were no quantitative measures of baseline alcohol use, comparability of the participants’ alcohol-use disorder severity across treatment conditions could not be ensured. Similarly, the absence of these baseline data make it impossible to compare reduction in alcohol quantity or frequency across conditions, a commonly used outcome measure in treatment outcome research. No data are available regarding adverse events, which are important considerations, given that medications are known to have side effects, some of which are associated with boxed warnings on the prescribing information, and these differ between the oral and the injectable agents. Also, the time frame for outcomes was limited to 6 months and the samples consisted of commercial insureds as opposed to Medicaid or uninsured patients. Furthermore, the XR-NTX sample was smaller than the others (because it is the most recently introduced agent), subject inclusion was limited to patients with 1 year of continuous enrollment (which could omit those who lost insurance due to job loss), no information was available as to the recommended or adequate duration of treatment, and oral medication adherence was only indirectly measured through prescription refills (therefore no information was available to confirm that patients took their oral medications).

	Despite these limitations, the study has some relevant strengths. Baseline data (

), with propensity-score matching and inverse probability weighting across a number of demographic, clinical, and utilization variables, demonstrated good comparability between the any versus no medication cohorts. The analysis showed robust findings in healthcare cost and utilization domains, a major strength that mitigates the limitation of not having alcohol consumption data. Although the average treatment duration was 2 to 3 months, meaningful outcomes were detected over a 6-month time frame, indicating that treatment benefits may outlast the active treatment phase. The patterns observed with medication adherence, hospital utilization, and costs demonstrated a high degree of internal consistency. External validity was also strong, given the relatively large sample sizes composed of real-world patients treated by community providers and given conventional treatment.

	These findings are compatible with real-world evaluations of alcohol pharmacotherapy refill persistence.

 Three prior analyses of pharmacy claims for oral NTX refills have shown that as few as half of patients obtain the first refill, and most do not complete a reasonable course of treatment.

 One of these studies found significantly lower refill rates for oral alcohol pharmacotherapies than for statins, antidepressants, and antipsychotics,

 and another found that refill failure was associated with significantly more detoxifications and hospital admissions.

	More recently, a retrospective claims analysis in NJ Blue Cross Blue Shield insureds found that although medication persistence remains an issue, XR-NTX was associated with significant reductions in cost due to alcohol-related hospitalizations, total medical costs, and total pharmacy costs (

see the article by Jan et al in this supplement

 A study of AETNA beneficiaries showed that patients given XR-NTX persisted with treatment longer than those given oral medications, and XR-NTX was associated with decreased inpatient and emergency healthcare costs and utilization to a greater extent than patients receiving 1 of the 3 oral agents (see the article by Bryson et al in this supplement).

	Mark et al also analyzed retrospective commercial claims between any versus no medication, and among the 4 FDA-approved alcoholism medications. They determined that medication was associated with less detoxification and alcoholism-related inpatient care. That study also showed a similar pattern among the 4 medications; increased burden of medication administration (acamprosate >oral NTX or disulfiram >XR-NTX) was associated with decreased refill persistence. The XR-NTX cohort used 224 detoxification days per 1000 patients (vs 227 in the present study) and was associated with the fewest days for detoxification or alcohol-related hospitalizations among the 4 agents.

 The present study replicates those findings and extends them, because the earlier study consisted of a single data source (examining 5954 matched cases in the any vs no medication comparison and 295 patients given XR-NTX) and used estimated charges and calculated these for only detoxification and alcohol-related inpatient admissions, whereas the present study combined 2 large data sources (examining 20,752 overall cases and 661 patients given XR-NTX) and calculated actual expended dollars for all healthcare costs, including the costs of the agents.

Alcohol Dependence Treatments: Comprehensive Healthcare Costs, Utilization Outcomes, and Pharmacotherapy Persistence

To determine in a large claims database the healthcare utilization and costs associated with treatment of alcohol dependence with medications vs no medication and across 4 US Food and Drug Administration (FDA)-approved medications.

Eligible adults with alcohol dependence claims (n = 27,135) were identified in a commercial database (MarketScan; Thomson Reuters Inc, Chicago, Illinois). Following propensity score-based matching and inverse probability weighting on demographic, clinical, and healthcare utilization variables, patients who had used an FDA-approved medication for alcohol dependence (n = 2977) were compared with patients who had not (n =2977). Patients treated with oral naltrexone hydrochloride (n = 2064), oral disulfiram (n = 2076), oral acamprosate calcium (n = 5068), or extended-release injectable naltrexone (naltrexone XR) (n = 295) were also compared for 6-month utilization rates of alcoholism medication, inpatient detoxification days, alcoholism-related inpatient days, and outpatient services, as well as inpatient charges. 

Patients who received alcoholism medications had fewer inpatient detoxification days (706 vs 1163 days per 1000 patients, 

 <.001), alcoholism-related inpatient days (650 vs 1086 days, 

 <.001), and alcoholism-related emergency department visits (127 vs 171, 

 = .005). Among 4 medications, the use of naltrexone XR was associated with fewer inpatient detoxification days (224 days per 1000 patients) than the use of oral naltrexone (552 days, 

 <.001). The group receiving naltrexone XR also had fewer alcoholism-related inpatient days than the groups receiving disulfiram or acamprosate. More patients in the naltrexone XR group had an outpatient substance abuse visit compared with patients in the oral alcoholism medication groups.

 Patients who received an alcoholism medication had lower healthcare utilization than patients who did not. Naltrexone XR showed an advantage over oral medications in healthcare utilization and costs.

Retrospective comparisons among similar patients taking any alcoholism medication vs no alcoholism medication and among similar patients taking 1 of 4 alcoholism medications found the following:

Filling a prescription for alcoholism medication was associated with fewer inpatient detoxification days, alcoholism-related inpatient days, and alcoholism-related emergency department visits. 

Using extended-release naltrexone hydrochloride was associated with fewer inpatient detoxification days and fewer alcoholism-related inpatient days compared with using oral naltrexone, disulfiram, or acamprosate calcium.

Alcohol use disorders (AUDs), including alcohol abuse and dependence, occur commonly in the general population, with an estimated 12-month prevalence of 8.46%.

 Alcohol abuse and dependence are associated with a range of adverse medical, psychiatric, family, legal, and work-related problems. Although alcoholism is a leading cause of preventable death in the United States,

 evidence-based treatment of AUDs is not commonly used.

 Since 2005, the National Institute on Alcohol Abuse and Alcoholism

 has recommended that medication should be considered for every patient with alcohol dependence. In practice, few patients with alcohol dependence are prescribed medications approved by the US Food and Drug Administration (FDA) to treat the disorder.

 Moreover, among patients who are prescribed such medication, adherence is low, which significantly reduces efficacy.

 In part, the reluctance of physicians to prescribe alcoholism medications and of patients to take the medications stems from  skepticism about their efficacy.

 Comparative effectiveness investigations, particularly comparing alcoholism medication treatment with standard care, are needed to address this information gap. Efficacy studies

 using randomized controlled trial (RCT) designs have found that pharmacotherapy is superior to psychosocial treatment alone. However, there are inconsistencies in results across studies, with large multisite RCTs failing to meet their specified end points for disulfiram,

 Furthermore, where efficacy trials have shown positive findings, results have demonstrated only modest effects.

 Information is also needed to compare the relative efficacy of existing alcoholism medications, particularly their ability to address the problem of poor adherence. There are 4 FDA-approved medications for the treatment of alcohol dependence. Disulfiram, an aversive agent, acts as a deterrent to drinking.

 Naltrexone is an opioid antagonist and is thought to reduce the rewarding effects of alcohol.

 Acamprosate is believed to reduce the risk of relapse by stabilizing glutamatergic pathways in individuals during the postwithdrawal phase.

 First approved as an oral treatment, naltrexone was subsequently approved also as an extended-release injectable suspension (naltrexone XR). In contrast to oral naltrexone, disulfiram, and acamprosate, which require daily dosing, naltrexone XR is administered as a monthly injection. Because naltrexone XR was designed to enhance patient adherence, comparison of the effect of that formulation vs oral medications on treatment outcomes is of considerable interest.

Treatment of alcohol dependence with medications offered advantages in reduced healthcare utilization and costs compared with usual treatment without medications.

Mady Chalk, PhD

Articles

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