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Assessing the Evidence Base Series   |    
Medication-Assisted Treatment With Buprenorphine: Assessing the Evidence
Cindy Parks Thomas, Ph.D.; Catherine Anne Fullerton, M.D., M.P.H.; Meelee Kim, M.A.; Leslie Montejano, M.A., C.C.R.P.; D. Russell Lyman, Ph.D.; Richard H. Dougherty, Ph.D.; Allen S. Daniels, Ed.D.; Sushmita Shoma Ghose, Ph.D.; Miriam E. Delphin-Rittmon, Ph.D.
Psychiatric Services 2014; doi: 10.1176/appi.ps.201300256
View Author and Article Information

Dr. Thomas and Ms. Kim are with the Heller School for Social Policy and Management, Brandeis University, Waltham, Massachusetts (e-mail: cthomas@brandeis.edu). Dr. Fullerton and Ms. Montejano are with Truven Health Analytics, Cambridge, Massachusetts. Dr. Lyman and Dr. Dougherty are with DMA Health Strategies, Lexington, Massachusetts. Dr. Daniels and Dr. Ghose are with Westat, Rockville, Maryland. Dr. Delphin-Rittmon is with the Office of Policy, Planning, and Innovation, Substance Abuse and Mental Health Services Administration (SAMHSA), Rockville. This article is part of a series of literature reviews that will be published in Psychiatric Services over the next several months. The reviews were commissioned by SAMHSA through a contract with Truven Health Analytics and were conducted by experts in each topic area, who wrote the reviews along with authors from Truven Health Analytics, Westat, DMA Health Strategies, and SAMHSA. Each article in the series was peer reviewed by a special panel of Psychiatric Services reviewers.

Copyright © 2014 by the American Psychiatric Association

Objective  Buprenorphine maintenance treatment (BMT) and methadone maintenance treatment (MMT) are pharmacological treatment programs for individuals with opioid use disorders. MMT is discussed in a companion article. This article describes BMT and reviews available research on its efficacy.

Methods  Authors reviewed meta-analyses, systematic reviews, and individual studies of BMT from 1995 through 2012. Databases surveyed were PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, and Published International Literature on Traumatic Stress. They chose from three levels of evidence (high, moderate, and low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness.

Results  Sixteen adequately designed randomized controlled trials of BMT indicated a high level of evidence for its positive impact on treatment retention and illicit opioid use. Seven reviews or meta-analyses were also included. When the medication was dosed adequately, BMT and MMT showed similar reduction in illicit opioid use, but BMT was associated with less risk of adverse events. Results suggested better treatment retention with MMT. BMT was associated with improved maternal and fetal outcomes in pregnancy, compared with no medication-assisted treatment. Rates of neonatal abstinence syndrome were similar for mothers treated with BMT and MMT during pregnancy, but symptoms were less severe for infants whose mothers were treated with BMT.

Conclusions  BMT is associated with improved outcomes compared with placebo for individuals and pregnant women with opioid use disorders. BMT should be considered for inclusion as a covered benefit.

Abstract Teaser
Figures in this Article

More than two million individuals in the United States are addicted to opioids (1). Two common options for pharmacological maintenance treatment of opioid dependence are the opioid agonists methadone and buprenorphine. Over 300,000 individuals receive methadone through outpatient treatment programs (2). Over half of these programs and thousands of physicians now offer buprenorphine. Such pharmacological treatment is typically provided in combination with psychosocial or other support services.

This article reports the results of a literature review that was undertaken as part of the Assessing the Evidence Base Series (see box on next page). Methadone maintenance treatment (MMT) is reviewed in a companion article in this series (3). As discussed in that review, research has shown that MMT improves treatment outcomes for individuals with opioid dependence (47). However, MMT is associated with serious adverse events, such as respiratory depression and cardiac arrhythmias (810). Because of concern about these adverse events and medication diversion, MMT is restricted to dedicated opioid treatment programs that provide daily medication dosing and offer psychosocial treatment services. In this article, we review buprenorphine maintenance treatment (BMT) as an alternative to MMT for the long-term management of opioid use disorders.

For purposes of this initiative, the Substance Abuse and Mental Health Services Administration describes medication-assisted treatment as a direct service that provides a person who has a substance use or mental disorder with pharmacotherapy in conjunction with behavioral therapies as treatment for associated symptoms or disabilities. BMT is a medication-assisted treatment that uses buprenorphine or buprenorphine-naloxone to treat individuals with an opioid use disorder. A definition of medication-assisted treatment with buprenorphine for opioid use disorders is presented in Table 1.

About the AEB Series 

The Assessing the Evidence Base (AEB) Series presents literature reviews for 14 commonly used, recovery-focused mental health and substance use services. Authors evaluated research articles and reviews specific to each service that were published from 1995 through 2012 or 2013. Each AEB Series article presents ratings of the strength of the evidence for the service, descriptions of service effectiveness, and recommendations for future implementation and research. The target audience includes state mental health and substance use program directors and their senior staff, Medicaid staff, other purchasers of health care services (for example, managed care organizations and commercial insurance), leaders in community health organizations, providers, consumers and family members, and others interested in the empirical evidence base for these services. The research was sponsored by the Substance Abuse and Mental Health Services Administration to help inform decisions about which services should be covered in public and commercially funded plans. Details about the research methodology and bases for the conclusions are included in the introduction to the AEB Series (14).

 
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Table 1Description of medication-assisted treatment with buprenorphine

The objectives of this review were to describe BMT and its primary and secondary treatment goals, rate the level of evidence (methodological quality) of existing studies for this treatment, describe the degree of effectiveness of this service on the basis of the research literature, and compare the relative advantages and disadvantages of BMT and MMT.

Buprenorphine has been available as an injectable medication at low doses to treat pain since the 1980s. In 2000, Congress passed the Drug Abuse Treatment Act (DATA), which allowed physicians to prescribe approved medications for long-term opioid treatment in settings other than opioid treatment clinics, such as in office-based facilities (11). In 2002, the U.S. Food and Drug Administration (FDA) approved high-dose sublingual formulations of buprenorphine and buprenorphine-naloxone for the treatment of opioid use disorders (11,12). Naloxone induces withdrawal symptoms if taken intravenously but not if taken orally. The manufacturer developed the combination buprenorphine-naloxone medication to decrease the potential for abuse and diversion. Buprenorphine and buprenorphine-naloxone became the first medications to be approved under DATA and the first medications available through DATA for office-based treatment of opioid dependence in the United States. Prescribing must be done within the guidelines of DATA, which requires that physicians receive specific training and certification before prescribing buprenorphine and that the number of patients they treat at one time be limited to 100 (originally 30 patients and amended in 2006) (13). In this review, we use buprenorphine in reference to both buprenorphine and buprenorphine-naloxone sublingual tablets. Although buprenorphine can be used to manage withdrawal symptoms during acute detoxification from opioids, BMT refers to the maintenance use of buprenorphine to decrease illicit opioid use.

Because individuals remain dependent on buprenorphine, BMT is not considered an abstinence treatment. The goals of BMT are to reduce or eliminate illicit opioid use and, as a result, to decrease its associated negative outcomes (Table 1). This assessment of the research will help inform behavioral health policy leaders about the merits of BMT as distinct from and in comparison to MMT. A summary of its value as a covered health benefit will also be of use to third-party payers, providers, and people making personal decisions about which medication to use.

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Search strategy

We conducted a literature search of major databases: PubMed (U.S. National Library of Medicine and National Institutes of Health), PsycINFO (American Psychological Association), Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, and Published International Literature on Traumatic Stress.

We identified meta-analyses, research reviews, clinical guidelines, and individual studies about BMT that were published from 1995 through 2012. We found additional literature by examining the bibliographies of major reviews and meta-analyses, major clinical texts, and professional clinical society reviews. We relied on systematic reviews and meta-analyses to summarize relevant findings from earlier years. These review articles were supplemented with individual randomized controlled trails (RCTs) and quasi-experimental observational studies to provide additional information from recent years.

The terms used to search the literature were buprenorphine, buprenorphine/naloxone, opioid maintenance therapy, opioid treatment, addiction pharmacotherapy, medication-assisted maintenance treatment, buprenorphine maintenance therapy, and pregnancy. This review did not compare BMT to naltrexone, another medication used in opioid maintenance treatment, because the literature review uncovered no studies directly comparing the two medications.

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Inclusion and exclusion criteria

The abstracts of identified articles were examined to determine compliance with the review inclusion and exclusion criteria. The following types of articles were included: RCTs, quasi-experimental studies, systematic review articles, meta-analyses, and clinical guidelines; English-language studies conducted in the United States, including international studies that used U.S.-based sites and international reviews encompassing U.S.-based studies; and studies that focused on BMT for individuals with opioid use disorders or the use of BMT during pregnancy.

Excluded were case studies, cross-sectional studies, and those with single-subject designs. Also excluded were studies that focused on buprenorphine use for pain management or for detoxification from opioids. Finally, reviews and meta-analyses that examined only studies that did not meet the inclusion criteria were excluded.

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Strength of the evidence

The methodology used to rate the strength of the evidence is described in detail in the introduction to this series (14). The research designs of the identified studies were examined. Three levels of evidence (high, moderate, and low) were used to indicate the overall research quality of the collection of studies. Ratings were based on predefined benchmarks that considered the number of studies and their methodological quality. If ratings were dissimilar (occurring for 13% of the studies rated), a consensus opinion was reached.

In general, high ratings indicate confidence in the reported outcomes and are based on three or more RCTs with adequate designs or two RCTs plus two quasi-experimental studies with adequate designs. Moderate ratings indicate that there is some adequate research to judge the service, although it is possible that future research could influence reported results. Moderate ratings are based on the following three options: two or more quasi-experimental studies with adequate design; one quasi-experimental study plus one RCT with adequate design; or at least two RCTs with some methodological weaknesses or at least three quasi-experimental studies with some methodological weaknesses. Low ratings indicate that research for this service is not adequate to draw evidence-based conclusions. Low ratings indicate that studies have nonexperimental designs, there are no RCTs, or there is no more than one adequately designed quasi-experimental study.

We accounted for other design factors that could increase or decrease the evidence rating, such as how the service, populations, and interventions were defined; use of statistical methods to account for baseline differences between experimental and comparison groups; identification of moderating or confounding variables with appropriate statistical controls; examination of attrition and follow-up; use of psychometrically sound measures; and indications of potential research bias.

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Effectiveness of the service

We described the effectiveness of the service—that is, how well the outcomes of the studies met the service goals. We compiled the findings for separate outcome measures and study populations, summarized the results, and noted differences across investigations. We considered the quality of the research design in our conclusions about the strength of the evidence and the ffectiveness of the service.

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Level of evidence

The literature search revealed 16 RCTs (1530), a randomized cross-over study (31), a study using a self-administered survey (32), and a retrospective descriptive study (33). Summaries of these studies are provided in Table 2. RCTs used either buprenorphine alone or buprenorphine-naloxone, as noted in the table. The search also found seven reviews or meta-analyses (10,3439), and summaries of these are provided in Table 3.

 
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Table 2Individual studies of buprenorphine maintenance treatment (BMT) included in the reviewa
Table Footer Note

a Studies are listed in chronological order. Abbreviations: MMT, methadone maintenance treatment; NAS, neonatal abstinence syndrome; RCT, randomized controlled trial

 
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Table 3Review articles about buprenorphine maintenance treatment (BMT) included in the reviewa
Table Footer Note

a Studies are listed in chronological order. Abbreviations: MMT, methadone maintenance treatment; RCT, randomized controlled trial

Because of the large number of trials, the overall evidence for BMT was rated as high. Thus the level of research evidence is similar for BMT and MMT (3). In addition, multiple meta-analyses, reviews, and more than three independent RCTs have compared BMT with MMT on the primary outcomes stated above, and these results are also based on a high level of evidence in RCTs (19,20) or reviews (34,36). Secondary outcomes, such as use of other illicit drugs, criminal behaviors, and other measures of addiction severity or psychosocial functioning varied among studies; as a result, the evidence for these secondary outcomes is not as strong.

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Effectiveness of BMT

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Buprenorphine versus placebo.

Studies since 1995 have found buprenorphine to be a safe and effective treatment for opioid dependence. Compared with placebo, buprenorphine significantly improved treatment retention at low (2–6 mg), medium (7–15 mg), and high (≥16 mg) doses (1517,34). In one meta-analysis, buprenorphine showed an improvement in treatment retention over placebo at low doses (relative risk [RR]=1.50, p<.05), medium doses (RR=1.74, p<.05), and high doses (RR=1.74, p<.05) (34). Higher dose ranges (16–32 mg) have been associated with better retention in treatment, compared with the lower dose (69% versus 51%, p=.006) (35). At medium- and high-dose ranges, buprenorphine significantly reduced illicit opioid use compared with placebo or with buprenorphine at a very low dose, as measured by urine drug tests (1518,34). For example, one RCT reported that for the group receiving 16 mg of buprenorphine, 38% of urine samples were negative for opioids, compared with 18% of samples for the group receiving 1 mg (p<.001) (16); another study found 21% opioid-negative urine samples with buprenorphine alone versus 6% with placebo (p<.001) (17). Studies have shown inconsistent results regarding reductions in nonopioid illicit drug use (for example, cocaine). However, most studies of buprenorphine have shown no statistically significant impact on reducing nonopioid illicit drug use compared with placebo (15,17,18,34). Although the addition of naloxone to buprenorphine has been shown to decrease abuse potential (31), naloxone has not been found to alter buprenorphine’s efficacy (40).

Although buprenorphine implants were not FDA-approved in the United States at the time of this review, Ling and colleagues (21) examined the effect of six-month buprenorphine implants compared with placebo in a phase III trial. The study compared patients receiving buprenorphine implants (N=108) and those receiving placebo implants (N=55) after induction with sublingual buprenorphine tablets. Both groups had the option of receiving supplemental buprenorphine tablets for withdrawal symptoms or craving. Participants could also receive a supplemental dose upon request, if it was deemed suitable by the treating clinician. Results showed that a significantly higher percentage of those receiving buprenorphine implants completed the six-month study (65.7% versus 30.9%, p<.001). In addition, patients in the buprenorphine implant group had a significantly higher percentage of their urine samples negative for illicit opioids (40.4% versus 28.3%, p=.04). In regard to secondary outcomes, the buprenorphine implant group had significantly reduced withdrawal symptoms on the Clinical Opiate Withdrawal Scale (p<.001), and the Subjective Opiate Withdrawal Scale (p=.004), lower patient ratings of craving on the Visual Analog Scale–opioid craving (p<.001), fewer symptoms on the Clinical Global Impressions–Severity Scale (34.9% versus 19.1% with no symptoms, p<.001), and greater change on the Clinical Global Impressions–Improvement Scale (56.0% versus 23.4% reporting very much improvement at week 24, p<.001).

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Illicit use of buprenorphine.

Concerns regarding diversion or nonmedical use of buprenorphine have emerged, even with the buprenorphine-naloxone combination (31,32,41). Comer and colleagues (31) confirmed that buprenorphine-naloxone retains some potential for abuse intravenously, but the combination has less abuse potential as measured by self-administration than buprenorphine alone or heroin. Surveys of individuals with opioid use disorders suggest that up to half of clients who use opioid drugs and seek treatment have used illicit buprenorphine. The clients typically stated that they used opioids for management of withdrawal symptoms and in attempts to decrease other opioid use (32,41,42). Individuals addicted to prescription opioids were more likely than those addicted to intravenous heroin to use buprenorphine to “get high” (32).

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Prescription opioid dependence.

A recent study examined the use of buprenorphine to treat patients with prescription opioid dependence. Weiss and colleagues (22) conducted the Prescription Opioid Addiction Treatment Study multiphase clinical trial in community treatment settings, reporting outcomes compared with baseline. The first phase examined brief treatment with buprenorphine and provided a two-week buprenorphine stabilization, two-week taper, and eight-week postmedication follow-up. Patients entered the second phase if they had relapsed (opioid-positive urine sample) during the initial phase. The second phase consisted of a 12-week buprenorphine treatment, four-week taper, and eight-week postmedication follow-up. In both phases, patients were randomly assigned to receive standard medical management (15-minute medical visits) or enhanced management (standard medical management plus opioid dependence counseling in 45-minute visits). Results showed that all urine samples were negative for only 6.6% of patients after the first phase (note that all participants received buprenorphine). During extended treatment with buprenorphine, 49.2% of patients had successful outcomes (all urine samples were opioid negative), but this percentage fell to 8.6% at the eight-week follow-up after buprenorphine was discontinued. Opioid dependence counseling had no effect in either phase. The authors concluded that patients dependent on prescription opioids have good outcomes with improved abstinence while taking buprenorphine, but if they are tapered off of this drug, the likelihood of successful outcomes in terms of no opioid use is low.

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Psychosocial interventions and support services

The addition of structured psychotherapy to standard treatment—which may include peer support services, 12-step programs, and other psychosocial treatment provided at the facility or office—has not been shown to improve outcomes for patients on opioid maintenance therapy. A meta-analysis examined the impact of adding a more structured psychotherapy to standard treatment that included three types of opioid agonist therapy: levomethadyl acetate (LAAM; now off the U.S. market) (one study), methadone (28 studies), or buprenorphine (six studies) (37). The authors found no improvements in treatment retention or abstinence from illicit opioids and no effect on other outcomes, compliance, or psychiatric symptoms. It is important to note that in this meta-analysis, standard treatment may have included peer support, psychosocial treatment and counseling sessions, and referrals for additional support, but the meta-analysis examined only the effects of structured treatment in addition to support services already provided. A more recent study investigated the impact of directly observed therapy plus cognitive-behavioral therapy compared with regular medical management of BMT (23). Results showed no improvement in retention or drug use. It has been noted that the literature on psychosocial treatments is heterogeneous, and there is a lack of sufficient, high-quality studies to assess which psychosocial interventions have the most success in various populations (43).

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BMT versus MMT.

Several studies and meta-analyses have examined the use of BMT compared with MMT. Dose levels have been shown to be important for efficacy of both drugs. In this discussion, we define methadone dose ranges as high (≥60 mg), medium (40–59 mg), and low (<40 mg). We define buprenorphine dose ranges as high (16–32 mg), medium (7–15 mg), and low (2–6 mg).

Barnett and colleagues (36) performed a meta-analysis of data from five RCTs conducted between 1992 and 1997. The authors compared the efficacy of methadone at medium-high doses (50–80 mg) and low doses (20–35 mg) and buprenorphine at medium doses (6–12 mg). Results showed that patients on medium doses of buprenorphine had 1.26 times the relative risk of discontinuing treatment (p=.019), and the number of positive urine samples was 8.3% higher than the number for patients on medium-high doses of methadone (p=.002). However, compared with lower doses of methadone (20–30 mg per day), buprenorphine was more effective in treatment retention (RR for discontinuing treatment=.86, not significant) and in reduction of positive urine drug tests (8.4% fewer positive urine samples per patient, p<.05). Ling and colleagues (19) found similar results. High-dose methadone (80 mg) was superior to medium-dose buprenorphine (8 mg) and low-dose methadone (30 mg) for treatment retention and opioid use.

A more recent meta-analysis comparing BMT and MMT was based on 25 RCTs and 4,497 participants (34). The authors found results that were similar to the study by Barnett and colleagues (36). Specifically, this meta-analysis found mixed results for medium-dose buprenorphine versus medium- and low-dose methadone in retaining patients. Three studies suggested that MMT was superior, whereas seven found no difference between the groups, although results differed by dose. Medium-dose buprenorphine was less likely to suppress illicit opioid use than medium-dose methadone (standard mean difference [SMD]=.27, p<.05), but it was more likely to suppress illicit opioid use than low-dose methadone (SMD=–.23, p<.05). Treatment retention was worse for low-dose buprenorphine than for medium- and low-dose methadone (RR for both comparisons=.67, p<.05). Low-dose buprenorphine showed no difference in illicit opioid use compared with low-dose methadone, but low-dose buprenorphine was inferior to medium-dose methadone in terms of illicit opioid use (SMD=.88, p<.05). In the meta-analysis, flexible-dose buprenorphine and methadone had similar results for illicit opioid use, and methadone had a slight (but statistically significant) edge for retention in treatment—despite the fact that most studies found no difference. Of note, several of the studies used buprenorphine in low- or medium-dose ranges, and the flexible-dose ranges were not higher than 16 mg. No statistically significant differences were found between methadone and buprenorphine at any dose comparison for use of other illicit drugs (primarily cocaine) or criminal activity.

Johnson and colleagues (20) conducted a 17-week RCT (N=220) to compare the effects of LAAM (75–115 mg), high-dose buprenorphine (16–32 mg), high-dose methadone (60–100 mg), and low-dose methadone (20 mg). Although LAAM is no longer marketed in the United States, the comparison of high-dose buprenorphine, high-dose methadone, and low-dose methadone is still important. The results supported the value of high-dose buprenorphine; no difference was found between high-dose buprenorphine and high-dose methadone in the mean number of days in treatment (96 and 105 days, respectively) or in the percentage of participants with 12 or more consecutive urine samples that were negative for illicit opioids (26% and 28%). High-dose buprenorphine was superior to low-dose methadone in terms of the mean number of days in treatment (96 versus 70, respectively, p<.001) and percentage of participants with consecutive negative urine samples (26% versus 8%, p=.005).

Kakko and colleagues (24) tested the efficacy of a stepped-care strategy that used buprenorphine in increasing doses. The researchers compared a flexible-dose MMT group (n=48) and a stepped-care BMT group (N=48). In the stepped-treatment group that used a flexible-dose algorithm, buprenorphine could be increased up to 32 mg. If participants required additional medication, they were switched (stepped) to high-dose methadone. The study found no differences between the stepped-care BMT and MMT groups in treatment retention (76% for both at six months) or in the proportion of urine samples that were free of illicit opioids (80% for both groups). In the buprenorphine stepped-care group, 17 participants who completed treatment did not switch to methadone and finished with a mean buprenorphine dose of 29.6 mg, and 20 participants who completed treatment switched to methadone and finished with a mean methadone dose of 111.0 mg. Those in the methadone group ended with a mean dose of 110.0 mg.

The pharmacology of buprenorphine affords it a better safety profile than methadone, which is important considering that methadone is associated with one-third of opioid-related overdose deaths annually (44). Because it is a partial agonist at the mu opiate receptor, it has a ceiling effect that limits its potential to cause respiratory depression compared with methadone (45). However, this risk still exists, especially if buprenorphine is used in combination with other central nervous system depressants such as benzodiazepines or alcohol (8) or is used in higher doses. In addition, unlike methadone, buprenorphine at standard doses does not affect cardiac electrophysiology by lengthening the cardiac QT interval—a mechanism that can lead to serious cardiac arrhythmias (10). Buprenorphine also has fewer drug interactions than methadone, especially with HIV medications (38).

Taken together, the articles reviewed suggest that the efficacy of BMT is dose dependent, and dose is important to take into account when comparing medications. For comparisons at medium-dose ranges, evidence is mixed—some studies show similar effects of MMT and BMT and some studies suggest that MMT improves treatment retention or reduces illicit opioid use. Only one study reviewed compared high doses of buprenorphine and methadone, and it showed similar outcomes (20). Finally, the stepped-care approach—in which individuals begin with buprenorphine and switch to methadone if buprenorphine doses above 32 mg are required—suggests that MMT may be needed for patients who require high doses of opioid agonist treatment (24).

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Treatment setting.

We reviewed two studies examining the receipt of BMT in an office-based setting compared with treatment in a traditional drug treatment program. In an early RCT (1998), O’Connor and colleagues (25) compared patients randomly assigned to receive BMT in a primary care setting (N=23) or a traditional drug treatment program (N=23). During the 12-week study, retention showed a trend toward being higher in the primary care setting, compared with the traditional setting (78% versus 52%, respectively, p=.06). Patients in the primary care setting had significantly lower rates of illicit opioid use on the basis of urine drug tests (63% versus 85%, p<.01), but they showed no difference in rates of cocaine use. Lucas and colleagues (26) compared outcomes of HIV-positive patients randomly assigned to receive BMT in an HIV clinic (N=46) or an opioid treatment program in which they received either buprenorphine or methadone (N=47). A significantly higher proportion of the patients in the HIV clinic were receiving agonist therapy at 12 months (74% versus 41%, p<.001). Illicit opioid use, as measured by urine drug tests, was less in the clinic-based group (44% versus 65% of patients; p=.015). In addition, the study showed that patients treated in the HIV clinic had significantly fewer cocaine-positive urine drug tests and attended more HIV primary care visits. The groups did not differ in use of antiretroviral therapy or in improvements in tests used to monitor HIV. The authors speculated that streamlined access to treatment in the clinic group was a major reason for the improved results.

None of the RCTs reviewed were implemented in incarcerated populations. A recent survey of criminal justice agencies indicated that medication-assisted treatment of incarcerated individuals is generally limited to pregnant women and detoxification (46).

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Buprenorphine use in pregnancy.

MMT has been used to treat opioid dependence during pregnancy to improve maternal and fetal outcomes (47,48). However, as discussed in the companion article (3), MMT puts newborn infants at risk for neonatal abstinence syndrome (NAS). NAS often requires detoxification treatment in the hospital with a morphine taper (4953). As a result, clinicians and researchers have studied BMT as an alternative to MMT during pregnancy. RCTs were conducted with buprenorphine alone, to avoid prenatal exposure to naloxone.

Three RCTs and observational studies (2729,39) have compared use of buprenorphine with use of methadone by pregnant women. Authors concluded that buprenorphine has similar efficacy to methadone in reducing illicit opioid use among pregnant women, and buprenorphine may lead to less severe NAS. With both MMT and BMT, dose increases may be necessary during pregnancy (39). Although the two smaller RCTs did not find a difference in treatment retention between BMT and MMT (28,29), the largest RCT—the Maternal Opioid Treatment: Human Experimental Research study (27)—found that a higher percentage of patients in the BMT group discontinued treatment before delivery (33% versus 18%, p=.02). Mothers were more likely to discontinue treatment in both groups if they had higher cumulative lifetime months and recent days of heroin use (27). Two RCTs showed no difference in illicit opioid use between the two medications (27,28), whereas one RCT suggested that methadone may be superior in reducing illicit opioid use (29). Infants born to mothers maintained with buprenorphine versus methadone had similar rates of NAS, but the manifestation of NAS was less severe. Infants whose mothers took buprenorphine required significantly lower doses of morphine to treat NAS and needed fewer hospital days (27,30,33).

Overall, a high level of evidence was found for the effectiveness of BMT in improving treatment retention and decreasing illicit opioid use (see box on this page). Research regarding the impact of BMT on nonopioid illicit drug use is less conclusive but suggests positive trends. The addition of any type of psychosocial regimen to BMT or MMT has not been shown to improve outcomes, but the heterogeneity of interventions across trials limits the ability to make strong conclusions. As with MMT, there is growing evidence that higher doses of buprenorphine (16–32 mg) are more efficacious than lower doses; however, because of the pharmacology of buprenorphine, doses above 32 mg do not provide additional efficacy. Research suggests that buprenorphine may be as effective for patients with prescription opioid dependence as it is for patients with heroin dependence. When the medications are dosed similarly, BMT appears to be as effective as MMT in reducing illicit opioid use. Results are mixed regarding treatment retention, but several studies suggest that MMT might confer some advantage. The advantage may be due, in part, to the supportive services or social reinforcement in outpatient MMT programs. However, buprenorphine has a better safety profile than methadone, and the ability to prescribe buprenorphine in office facilities as opposed to only in opioid treatment programs improves access to care and earlier initiation of treatment. A key advantage of buprenorphine is its availability. The number of clinicians approved to prescribe buprenorphine is growing, although many areas of the country do not have access to methadone programs (2).

Evidence for the effectiveness of BMT: high 

Evidence clearly shows that BMT has a positive impact compared with placebo on:

• Retention in treatment

• Illicit opioid use

Evidence is mixed for its impact on:

• Nonopioid illicit drug use

Both BMT and MMT improve pregnancy-related outcomes by reducing illicit drug use during pregnancy. Infants of mothers treated with buprenorphine during pregnancy may be born with NAS, although NAS appears to be less severe in infants of mothers treated with buprenorphine than of those treated with methadone.

Potential areas for future research include increased focus on the impact of BMT on secondary outcomes, additional investigation of appropriate dosing to enhance treatment outcomes, confirmation of the results of the stepped-care protocol, improved induction protocols to minimize initial problems with treatment retention (and thus potentially enhance adoption rates by providers), and examination of the differential effectiveness of BMT in specific subpopulations, such as patients dependent on prescription opioids versus heroin. Differential effects and access to BMT across racial and ethnic groups and geographic areas should also be studied.

Ongoing research needs do not diminish the strong evidence for this treatment approach. Given the poor success rates of abstinence-based treatments for opioid use disorders and the limited access to and more restrictive safety profile of MMT, BMT is an important treatment for opioid dependence. Policy makers have reason to promote access to BMT for patients in substance use treatment who may wish to choose BMT as a potentially safer alternative to MMT. Administrators of substance use treatment programs, community health centers, and managed care organizations and other purchasers of health care services, such as Medicare, Medicaid, and commercial insurance carriers, should give careful consideration to BMT as a covered benefit.

Development of the Assessing the Evidence Base Series was supported by contracts HHSS283200700029I/HHSS28342002T, HHSS283200700006I/HHSS28342003T, and HHSS2832007000171/HHSS28300001T from 2010 through 2013 from the Substance Abuse and Mental Health Services Administration (SAMHSA). The authors acknowledge the contributions of Robert Lubran, M.S., M.P.A., Kevin Malone, B.A., and Suzanne Fields, M.S.W., from SAMHSA; John O’Brien, M.A., from the Centers for Medicare & Medicaid Services; John Easterday, Ph.D., Linda Lee, Ph.D., Rosanna Coffey, Ph.D., and Tami Mark, Ph.D., from Truven Health Analytics; and Sandrine Pirard, M.D., Ph.D., from National Institute on Drug Abuse. The views expressed in this article are those of the authors and do not necessarily represent the views of SAMHSA.

The authors report no competing interests.

Topics in Brief: Medication-Assisted Treatment for Opioid Addiction. Bethesda, Md, National Institute on Drug Abuse, April 2012. Available at www.drugabuse.gov/publications/topics-in-brief/medication-assisted-treatment-opioid-addiction. Accessed Sept 14, 2013
 
 The N-SSATS Report: Trends in the Use of Methadone and Buprenorphine at Substance Abuse Treatment Facilities: 2003 to 2011 .  Rockville, Md,  Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2013
 
Fullerton CA, Kim M, Thomas CP, et al: Medication-assisted treatment with methadone: assessing the evidence. Psychiatric Services, 2013; doi 10.1176/appi.ps.201300235
 
Connock  M;  Juarez-Garcia  A;  Jowett  S  et al:  Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.  Health Technology Assessment 11(9):1–171, 2007
[PubMed]
 
Fletcher  BW;  Battjes  RJ:  Introduction to the special issue: treatment process in DATOS.  Drug and Alcohol Dependence 57:81–87, 1999
[CrossRef] | [PubMed]
 
Hall  W;  Ward  J;  Mattick  R:  The Effectiveness of Methadone Maintenance Treatment 1: Heroin Use and Crime .  Utrecht, Netherlands,  Harwood Academic Publishers, 1998
 
Mattick  RP;  Breen  C;  Kimber  J  et al:  Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.  Cochrane Database of Systematic Reviews 3:CD002209, 2009
[PubMed]
 
Webster  LR;  Cochella  S;  Dasgupta  N  et al:  An analysis of the root causes for opioid-related overdose deaths in the United States.  Pain Medicine 12(suppl 2):S26–S35, 2011
[CrossRef] | [PubMed]
 
Modesto-Lowe  V;  Brooks  D;  Petry  N:  Methadone deaths: risk factors in pain and addicted populations.  Journal of General Internal Medicine 25:305–309, 2010
[CrossRef] | [PubMed]
 
Martin  JA;  Campbell  A;  Killip  T  et al:  QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel.  Journal of Addictive Diseases 30:283–306, 2011
[CrossRef] | [PubMed]
 
Fiellin  DA;  O’Connor  PG:  New federal initiatives to enhance the medical treatment of opioid dependence.  Annals of Internal Medicine 137:688–692, 2002
[CrossRef] | [PubMed]
 
Subutex and Suboxone Approved to Treat Opiate Dependence. T02-38. Silver Spring, Md, US Food and Drug Administration, 2002. Available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm191521.htm
 
Frequently Asked Questions About Buprenorphine and the Drug Addiction Treatment Act of 2000 (DATA 2000). Rockville, Md, Substance Abuse and Mental Health Services Administration. Available at buprenorphine.samhsa.gov/faq.html#A11. Accessed Sept 19, 2013
 
Dougherty RH, Lyman DR, George P, et al: Assessing the evidence base for behavioral health services: introduction to the series. Psychiatric Services, 2013; doi 10.1176/appi.ps.201300214
 
Kakko  J;  Svanborg  KD;  Kreek  MJ  et al:  1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial.  Lancet 361:662–668, 2003
[CrossRef] | [PubMed]
 
Ling  W;  Charuvastra  C;  Collins  JF  et al:  Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.  Addiction 93:475–486, 1998
[CrossRef] | [PubMed]
 
Fudala  PJ;  Bridge  TP;  Herbert  S  et al:  Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.  New England Journal of Medicine 349:949–958, 2003
[CrossRef] | [PubMed]
 
Johnson  RE;  Eissenberg  T;  Stitzer  ML  et al:  A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence.  Drug and Alcohol Dependence 40:17–25, 1995
[CrossRef] | [PubMed]
 
Ling  W;  Wesson  DR;  Charuvastra  C  et al:  A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence.  Archives of General Psychiatry 53:401–407, 1996
[CrossRef] | [PubMed]
 
Johnson  RE;  Chutuape  MA;  Strain  EC  et al:  A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.  New England Journal of Medicine 343:1290–1297, 2000
[CrossRef] | [PubMed]
 
Ling  W;  Casadonte  P;  Bigelow  G  et al:  Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial.  JAMA 304:1576–1583, 2010
[CrossRef] | [PubMed]
 
Weiss  RD;  Potter  JS;  Fiellin  DA  et al:  Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial.  Archives of General Psychiatry 68:1238–1246, 2011
[CrossRef] | [PubMed]
 
Moore  BA;  Barry  DT;  Sullivan  LE  et al:  Counseling and directly observed medication for primary care buprenorphine maintenance: a pilot study.  Journal of Addiction Medicine 6:205–211, 2012
[CrossRef] | [PubMed]
 
Kakko  J;  Grönbladh  L;  Svanborg  KD  et al:  A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.  American Journal of Psychiatry 164:797–803, 2007
[CrossRef] | [PubMed]
 
O’Connor  PG;  Oliveto  AH;  Shi  JM  et al:  A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic.  American Journal of Medicine 105:100–105, 1998
[CrossRef] | [PubMed]
 
Lucas  GM;  Chaudhry  A;  Hsu  J  et al:  Clinic-based treatment of opioid-dependent HIV-infected patients versus referral to an opioid treatment program: a randomized trial.  Annals of Internal Medicine 152:704–711, 2010
[CrossRef] | [PubMed]
 
Jones  HE;  Kaltenbach  K;  Heil  SH  et al:  Neonatal abstinence syndrome after methadone or buprenorphine exposure.  New England Journal of Medicine 363:2320–2331, 2010
[CrossRef] | [PubMed]
 
Jones  HE;  Johnson  RE;  Jasinski  DR  et al:  Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome.  Drug and Alcohol Dependence 79:1–10, 2005
[CrossRef] | [PubMed]
 
Fischer  G;  Ortner  R;  Rohrmeister  K  et al:  Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study.  Addiction 101:275–281, 2006
[CrossRef] | [PubMed]
 
Coyle  MG;  Salisbury  AL;  Lester  BM  et al:  Neonatal neurobehavior effects following buprenorphine versus methadone exposure.  Addiction  107(suppl 1):63–73, 2012
[CrossRef] | [PubMed]
 
Comer  SD;  Sullivan  MA;  Vosburg  SK  et al:  Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers.  Addiction  105:709–718, 2010
[CrossRef] | [PubMed]
 
Bazazi  AR;  Yokell  M;  Fu  JJ  et al:  Illicit use of buprenorphine/naloxone among injecting and noninjecting opioid users.  Journal of Addiction Medicine 5:175–180, 2011
[CrossRef] | [PubMed]
 
Pritham  UA;  Paul  JA;  Hayes  MJ:  Opioid dependency in pregnancy and length of stay for neonatal abstinence syndrome.  Journal of Obstetric, Gynecologic, and Neonatal Nursing 41:180–190, 2012
[CrossRef]
 
Mattick  RP;  Kimber  J;  Breen  C  et al:  Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.  Cochrane Database of Systematic Reviews 2:CD002207, 2008
[PubMed]
 
Fareed  A;  Vayalapalli  S;  Casarella  J  et al:  Effect of buprenorphine dose on treatment outcome.  Journal of Addictive Diseases 31:8–18, 2012
[CrossRef] | [PubMed]
 
Barnett  PG;  Rodgers  JH;  Bloch  DA:  A meta-analysis comparing buprenorphine to methadone for treatment of opiate dependence.  Addiction 96:683–690, 2001
[CrossRef] | [PubMed]
 
Amato  L;  Minozzi  S;  Davoli  M  et al:  Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence.  Cochrane Database of Systematic Reviews 10:CD004147, 2011
[PubMed]
 
McCance-Katz  EF;  Sullivan  LE;  Nallani  S:  Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review.  American Journal on Addictions 19:4–16, 2010
[CrossRef] | [PubMed]
 
Jones  HE;  Heil  SH;  Baewert  A  et al:  Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.  Addiction  107(suppl 1):5–27, 2012
[CrossRef] | [PubMed]
 
Chiang  CN;  Hawks  RL:  Pharmacokinetics of the combination tablet of buprenorphine and naloxone.  Drug and Alcohol Dependence 70(suppl):S39–S47, 2003
[CrossRef] | [PubMed]
 
Monte  AA;  Mandell  T;  Wilford  BB  et al:  Diversion of buprenorphine/naloxone coformulated tablets in a region with high prescribing prevalence.  Journal of Addictive Diseases 28:226–231, 2009
[CrossRef] | [PubMed]
 
Schuman-Olivier  Z;  Albanese  M;  Nelson  SE  et al:  Self-treatment: illicit buprenorphine use by opioid-dependent treatment seekers.  Journal of Substance Abuse Treatment 39:41–50, 2010
[CrossRef] | [PubMed]
 
Drummond  DC;  Perryman  K:  Psychosocial Interventions in Pharmacotherapy of Opioid Dependence: A Literature Review .  London,  St George's University of London, Division of Mental Health, Section of Addictive Behaviour, 2007
 
 Vital signs: risk for overdose from methadone used for pain relief - United States, 1999–2010.  Morbidity and Mortality Weekly Report 61:493–497, 2012
[PubMed]
 
Fareed  A;  Vayalapalli  S;  Byrd-Sellers  J  et al:  Safety and efficacy of long-term buprenorphine maintenance treatment.  Addictive Disorders and Their Treatment 10:123–130, 2011
[CrossRef]
 
Friedmann  PD;  Hoskinson  R;  Gordon  M  et al:  Medication-assisted treatment in criminal justice agencies affiliated with the criminal justice-drug abuse treatment studies (CJ-DATS): availability, barriers, and intentions.  Substance Abuse 33:9–18, 2012
[CrossRef] | [PubMed]
 
Kandall  SR;  Doberczak  TM;  Jantunen  M  et al:  The methadone-maintained pregnancy.  Clinics in Perinatology 26:173–183, 1999
[PubMed]
 
Hulse  GK;  Milne  E;  English  DR  et al:  The relationship between maternal use of heroin and methadone and infant birth weight.  Addiction  92:1571–1579, 1997
[CrossRef] | [PubMed]
 
Kaltenbach  K;  Berghella  V;  Finnegan  L:  Opioid dependence during pregnancy: effects and management.  Obstetrics and Gynecological Clinics of North America 25:139–151, 1998
[CrossRef]
 
Finnegan L, Kaltenbach K: Neonatal abstinence syndrome; in Primary Pediatric Care. Edited by Hoekelman RA, Friedman SB, Nelson NM, et al. St Louis, Mo, Mosby–Year Book, 1992
 
Ebner  N;  Rohrmeister  K;  Winklbaur  B  et al:  Management of neonatal abstinence syndrome in neonates born to opioid maintained women.  Drug and Alcohol Dependence 87:131–138, 2007
[CrossRef] | [PubMed]
 
Dashe  JS;  Sheffield  JS;  Olscher  DA  et al:  Relationship between maternal methadone dosage and neonatal withdrawal.  Obstetrics and Gynecology 100:1244–1249, 2002
[CrossRef] | [PubMed]
 
McCarthy  JJ;  Leamon  MH;  Parr  MS  et al:  High-dose methadone maintenance in pregnancy: maternal and neonatal outcomes.  American Journal of Obstetrics and Gynecology 193:606–610, 2005
[CrossRef] | [PubMed]
 
References Container
Anchor for Jump
Table 1Description of medication-assisted treatment with buprenorphine
Anchor for Jump
Table 2Individual studies of buprenorphine maintenance treatment (BMT) included in the reviewa
Table Footer Note

a Studies are listed in chronological order. Abbreviations: MMT, methadone maintenance treatment; NAS, neonatal abstinence syndrome; RCT, randomized controlled trial

Anchor for Jump
Table 3Review articles about buprenorphine maintenance treatment (BMT) included in the reviewa
Table Footer Note

a Studies are listed in chronological order. Abbreviations: MMT, methadone maintenance treatment; RCT, randomized controlled trial

+

References

Topics in Brief: Medication-Assisted Treatment for Opioid Addiction. Bethesda, Md, National Institute on Drug Abuse, April 2012. Available at www.drugabuse.gov/publications/topics-in-brief/medication-assisted-treatment-opioid-addiction. Accessed Sept 14, 2013
 
 The N-SSATS Report: Trends in the Use of Methadone and Buprenorphine at Substance Abuse Treatment Facilities: 2003 to 2011 .  Rockville, Md,  Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2013
 
Fullerton CA, Kim M, Thomas CP, et al: Medication-assisted treatment with methadone: assessing the evidence. Psychiatric Services, 2013; doi 10.1176/appi.ps.201300235
 
Connock  M;  Juarez-Garcia  A;  Jowett  S  et al:  Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.  Health Technology Assessment 11(9):1–171, 2007
[PubMed]
 
Fletcher  BW;  Battjes  RJ:  Introduction to the special issue: treatment process in DATOS.  Drug and Alcohol Dependence 57:81–87, 1999
[CrossRef] | [PubMed]
 
Hall  W;  Ward  J;  Mattick  R:  The Effectiveness of Methadone Maintenance Treatment 1: Heroin Use and Crime .  Utrecht, Netherlands,  Harwood Academic Publishers, 1998
 
Mattick  RP;  Breen  C;  Kimber  J  et al:  Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.  Cochrane Database of Systematic Reviews 3:CD002209, 2009
[PubMed]
 
Webster  LR;  Cochella  S;  Dasgupta  N  et al:  An analysis of the root causes for opioid-related overdose deaths in the United States.  Pain Medicine 12(suppl 2):S26–S35, 2011
[CrossRef] | [PubMed]
 
Modesto-Lowe  V;  Brooks  D;  Petry  N:  Methadone deaths: risk factors in pain and addicted populations.  Journal of General Internal Medicine 25:305–309, 2010
[CrossRef] | [PubMed]
 
Martin  JA;  Campbell  A;  Killip  T  et al:  QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel.  Journal of Addictive Diseases 30:283–306, 2011
[CrossRef] | [PubMed]
 
Fiellin  DA;  O’Connor  PG:  New federal initiatives to enhance the medical treatment of opioid dependence.  Annals of Internal Medicine 137:688–692, 2002
[CrossRef] | [PubMed]
 
Subutex and Suboxone Approved to Treat Opiate Dependence. T02-38. Silver Spring, Md, US Food and Drug Administration, 2002. Available at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm191521.htm
 
Frequently Asked Questions About Buprenorphine and the Drug Addiction Treatment Act of 2000 (DATA 2000). Rockville, Md, Substance Abuse and Mental Health Services Administration. Available at buprenorphine.samhsa.gov/faq.html#A11. Accessed Sept 19, 2013
 
Dougherty RH, Lyman DR, George P, et al: Assessing the evidence base for behavioral health services: introduction to the series. Psychiatric Services, 2013; doi 10.1176/appi.ps.201300214
 
Kakko  J;  Svanborg  KD;  Kreek  MJ  et al:  1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial.  Lancet 361:662–668, 2003
[CrossRef] | [PubMed]
 
Ling  W;  Charuvastra  C;  Collins  JF  et al:  Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.  Addiction 93:475–486, 1998
[CrossRef] | [PubMed]
 
Fudala  PJ;  Bridge  TP;  Herbert  S  et al:  Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.  New England Journal of Medicine 349:949–958, 2003
[CrossRef] | [PubMed]
 
Johnson  RE;  Eissenberg  T;  Stitzer  ML  et al:  A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence.  Drug and Alcohol Dependence 40:17–25, 1995
[CrossRef] | [PubMed]
 
Ling  W;  Wesson  DR;  Charuvastra  C  et al:  A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence.  Archives of General Psychiatry 53:401–407, 1996
[CrossRef] | [PubMed]
 
Johnson  RE;  Chutuape  MA;  Strain  EC  et al:  A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.  New England Journal of Medicine 343:1290–1297, 2000
[CrossRef] | [PubMed]
 
Ling  W;  Casadonte  P;  Bigelow  G  et al:  Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial.  JAMA 304:1576–1583, 2010
[CrossRef] | [PubMed]
 
Weiss  RD;  Potter  JS;  Fiellin  DA  et al:  Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial.  Archives of General Psychiatry 68:1238–1246, 2011
[CrossRef] | [PubMed]
 
Moore  BA;  Barry  DT;  Sullivan  LE  et al:  Counseling and directly observed medication for primary care buprenorphine maintenance: a pilot study.  Journal of Addiction Medicine 6:205–211, 2012
[CrossRef] | [PubMed]
 
Kakko  J;  Grönbladh  L;  Svanborg  KD  et al:  A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.  American Journal of Psychiatry 164:797–803, 2007
[CrossRef] | [PubMed]
 
O’Connor  PG;  Oliveto  AH;  Shi  JM  et al:  A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic.  American Journal of Medicine 105:100–105, 1998
[CrossRef] | [PubMed]
 
Lucas  GM;  Chaudhry  A;  Hsu  J  et al:  Clinic-based treatment of opioid-dependent HIV-infected patients versus referral to an opioid treatment program: a randomized trial.  Annals of Internal Medicine 152:704–711, 2010
[CrossRef] | [PubMed]
 
Jones  HE;  Kaltenbach  K;  Heil  SH  et al:  Neonatal abstinence syndrome after methadone or buprenorphine exposure.  New England Journal of Medicine 363:2320–2331, 2010
[CrossRef] | [PubMed]
 
Jones  HE;  Johnson  RE;  Jasinski  DR  et al:  Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome.  Drug and Alcohol Dependence 79:1–10, 2005
[CrossRef] | [PubMed]
 
Fischer  G;  Ortner  R;  Rohrmeister  K  et al:  Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study.  Addiction 101:275–281, 2006
[CrossRef] | [PubMed]
 
Coyle  MG;  Salisbury  AL;  Lester  BM  et al:  Neonatal neurobehavior effects following buprenorphine versus methadone exposure.  Addiction  107(suppl 1):63–73, 2012
[CrossRef] | [PubMed]
 
Comer  SD;  Sullivan  MA;  Vosburg  SK  et al:  Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers.  Addiction  105:709–718, 2010
[CrossRef] | [PubMed]
 
Bazazi  AR;  Yokell  M;  Fu  JJ  et al:  Illicit use of buprenorphine/naloxone among injecting and noninjecting opioid users.  Journal of Addiction Medicine 5:175–180, 2011
[CrossRef] | [PubMed]
 
Pritham  UA;  Paul  JA;  Hayes  MJ:  Opioid dependency in pregnancy and length of stay for neonatal abstinence syndrome.  Journal of Obstetric, Gynecologic, and Neonatal Nursing 41:180–190, 2012
[CrossRef]
 
Mattick  RP;  Kimber  J;  Breen  C  et al:  Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.  Cochrane Database of Systematic Reviews 2:CD002207, 2008
[PubMed]
 
Fareed  A;  Vayalapalli  S;  Casarella  J  et al:  Effect of buprenorphine dose on treatment outcome.  Journal of Addictive Diseases 31:8–18, 2012
[CrossRef] | [PubMed]
 
Barnett  PG;  Rodgers  JH;  Bloch  DA:  A meta-analysis comparing buprenorphine to methadone for treatment of opiate dependence.  Addiction 96:683–690, 2001
[CrossRef] | [PubMed]
 
Amato  L;  Minozzi  S;  Davoli  M  et al:  Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence.  Cochrane Database of Systematic Reviews 10:CD004147, 2011
[PubMed]
 
McCance-Katz  EF;  Sullivan  LE;  Nallani  S:  Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review.  American Journal on Addictions 19:4–16, 2010
[CrossRef] | [PubMed]
 
Jones  HE;  Heil  SH;  Baewert  A  et al:  Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.  Addiction  107(suppl 1):5–27, 2012
[CrossRef] | [PubMed]
 
Chiang  CN;  Hawks  RL:  Pharmacokinetics of the combination tablet of buprenorphine and naloxone.  Drug and Alcohol Dependence 70(suppl):S39–S47, 2003
[CrossRef] | [PubMed]
 
Monte  AA;  Mandell  T;  Wilford  BB  et al:  Diversion of buprenorphine/naloxone coformulated tablets in a region with high prescribing prevalence.  Journal of Addictive Diseases 28:226–231, 2009
[CrossRef] | [PubMed]
 
Schuman-Olivier  Z;  Albanese  M;  Nelson  SE  et al:  Self-treatment: illicit buprenorphine use by opioid-dependent treatment seekers.  Journal of Substance Abuse Treatment 39:41–50, 2010
[CrossRef] | [PubMed]
 
Drummond  DC;  Perryman  K:  Psychosocial Interventions in Pharmacotherapy of Opioid Dependence: A Literature Review .  London,  St George's University of London, Division of Mental Health, Section of Addictive Behaviour, 2007
 
 Vital signs: risk for overdose from methadone used for pain relief - United States, 1999–2010.  Morbidity and Mortality Weekly Report 61:493–497, 2012
[PubMed]
 
Fareed  A;  Vayalapalli  S;  Byrd-Sellers  J  et al:  Safety and efficacy of long-term buprenorphine maintenance treatment.  Addictive Disorders and Their Treatment 10:123–130, 2011
[CrossRef]
 
Friedmann  PD;  Hoskinson  R;  Gordon  M  et al:  Medication-assisted treatment in criminal justice agencies affiliated with the criminal justice-drug abuse treatment studies (CJ-DATS): availability, barriers, and intentions.  Substance Abuse 33:9–18, 2012
[CrossRef] | [PubMed]
 
Kandall  SR;  Doberczak  TM;  Jantunen  M  et al:  The methadone-maintained pregnancy.  Clinics in Perinatology 26:173–183, 1999
[PubMed]
 
Hulse  GK;  Milne  E;  English  DR  et al:  The relationship between maternal use of heroin and methadone and infant birth weight.  Addiction  92:1571–1579, 1997
[CrossRef] | [PubMed]
 
Kaltenbach  K;  Berghella  V;  Finnegan  L:  Opioid dependence during pregnancy: effects and management.  Obstetrics and Gynecological Clinics of North America 25:139–151, 1998
[CrossRef]
 
Finnegan L, Kaltenbach K: Neonatal abstinence syndrome; in Primary Pediatric Care. Edited by Hoekelman RA, Friedman SB, Nelson NM, et al. St Louis, Mo, Mosby–Year Book, 1992
 
Ebner  N;  Rohrmeister  K;  Winklbaur  B  et al:  Management of neonatal abstinence syndrome in neonates born to opioid maintained women.  Drug and Alcohol Dependence 87:131–138, 2007
[CrossRef] | [PubMed]
 
Dashe  JS;  Sheffield  JS;  Olscher  DA  et al:  Relationship between maternal methadone dosage and neonatal withdrawal.  Obstetrics and Gynecology 100:1244–1249, 2002
[CrossRef] | [PubMed]
 
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