The American Journal on Addictions, 24: 24–29, 2015 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/ajad.12174
Trends in the Use of Buprenorphine by Office-Based Physicians in the United States, 2003–2013 Lydia Turner, MHS,1,2 Stefan P. Kruszewski, MD,3,4,2 G. Caleb Alexander, MD, MS1,2,5 1
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 3 Stefan P. Kruszewski, MD & Associates, Harrisburg, Pennsylvania 4 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 5 Department of Pharmacy Practice, University of Illinois at Chicago School of Pharmacy, Chicago, Illinois 2
Background and objectives: Despite buprenorphine’s promise as a novel therapy for opioid dependence, little is known about its clinical adoption. We characterized trends in ambulatory use of buprenorphine in the United States. Methods: Cross-sectional, descriptive analyses of buprenorphine utilization from 2003 to 2013 using the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory care. The primary unit of analysis was an office visit where buprenorphine was used for opioid dependence (treatment visit). Results: Between 2003 and 2013, there was significant uptake of buprenorphine in ambulatory treatment visits, from 0.16 million [M] (95% confidence interval [CI] 0.10–0.20) visits in 2003 to 2.1M (CI 1.9–2.3M) treatment visits during 2013. Approximately 90% involved the use of brand name combination buprenorphine/naloxone (Suboxone), although this percentage decreased modestly to 80% by the last quarter of 2013. Buprenorphine prescribing increased among all specialties, but the proportion accounted for by primary care physicians increased significantly from 6.0% in 2003 to 63.5% in 2013 and decreased among psychiatrists from 92.2% to 32.8% over the same time period. Conclusions: The use of buprenorphine products to treat opioid dependence has increased significantly in the past 10 years and has shifted to greater use by primary care physicians, indicating a rapidly changing face of opioid maintenance therapy in the United States. (Am J Addict 2015;24:24–29)
Received February 12, 2014; revised September 9, 2014; accepted October 12, 2014. Address Correspondence to Alexander, Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 N. Wolfe Street W6035, Baltimore, MD 21205. E-mail: [email protected] 24
INTRODUCTION Although opioids have been subject to abuse for centuries, during the past two decades, rates of abuse and misuse of these drugs in the United States have been particularly noteworthy.1–3 These changes have been fueled primarily by prescription opioid abuse and dependence, although rates of heroin use have also been increasing in many communities in recent years.4–8 Between 1999 and 2009, the death rate from prescription opioids increased by nearly 300% and was, by 2009, four times higher than the death rate from heroin.9 Pharmacologic management of opioid dependence is a vital component of most treatment strategies. Since the 1960s, methadone hydrochloride, a long-acting opioid, has been a mainstay of such treatment.10 However, because of its high potential for abuse, the production, distribution, and dispensing of methadone are highly regulated;11 only registered physicians and hospitals are permitted to dispense methadone for opioid dependence, and methadone maintenance programs face further regulations by state governments, most of which are more restrictive than federal standards.12 Although to some degree prescribers can circumvent restrictions by writing prescriptions for methadone for pain, existing restrictions have nevertheless substantially limited its adoption in ambulatory clinical practice. In October of 2002, the Food and Drug Administration (FDA) approved the fixed dose combination of buprenorphine/naloxone (Suboxone) and buprenorphine (Subutex) specifically for the treatment of opioid dependence.13 In contrast to methadone, buprenorphine hydrochloride is a partial mu-opioid agonist and Class III controlled substance, resulting in similar physiological results as methadone, but with a “ceiling” of certain effects such as respiratory depression.14 Combination buprenorphine/naloxone has a putative lower potential for abuse as well as a reported enhanced safety profile due to the inclusion of naloxone hydrochloride, an opioid
antagonist used to counteract the depression of the central nervous system and respiratory system caused by opioids.15 These pharmacologic properties, in the context of an increasing public health toll from opioid abuse and dependence, contributed to the passage of the Drug Addiction Treatment Act of 2000 that allowed qualified physicians to treat opioid addiction with Schedule III, IV, and V controlled narcotics that are FDA approved for that indication,16 paving the way for buprenorphine to be used in treatment settings other than traditional opioid treatment programs. Prior studies of buprenorphine adoption have suggested considerable uptake, but have been limited to veteran populations,17 behavioral health care settings,18 and were completed many years ago.19 We sought to update these analyses using a large, nationally representative, annual audit of ambulatory-based physicians. In addition to characterizing trends between 2003 and 2013, we were also interested in examining the effect of market changes on buprenorphine utilization, including the October 2009 patent expiry of buprenorphine for opioid dependence (Subutex), the February 2013 patent expiry of buprenorphine/suboxone (Suboxone) and the September 2013 approval of the newer buprenorphine/naloxone combination (Zubsolv), reformulated to increase the bioavailability of the molecules and improve the taste. Finally, we examined how the ambulatory use of buprenorphine has varied between psychiatrists and other specialists compared with primary care physicians.
METHODS
ambulatory practice conducted by the National Center for Health Statistics, have yielded comparable findings.21–23 Analysis We used descriptive statistics to examine trends in buprenorphine utilization. Our outcome of interest was a physician encounter where buprenorphine was used to treat opioid dependence, heretofore referred to as a treatment visit. To identify these visits, we first identified all buprenorphinecontaining products available during the period of interest, including: buprenorphine (Subutex, Butrans, Buprenex), buprenorphine/naloxone (Suboxone, Zubsolv) and generic formulations of these products. Second, we limited our data to dependence-related diagnoses (ICD-9 Codes 304.00, 304.01, 304.02, 305.50, 305.51, 305.52), and thus, we excluded the small proportion of treatment visits (annual range of 0–11%) where buprenorphine products were identified and used for a primary indication of pain or other non-opioid dependence diagnosis. Third, we aggregated monthly data available from the NDTI into calendar quarter estimates and calculated 95% confidence intervals using tables of relative standard errors that are derived to account for the survey’s complex sampling design. Analyses adjusting for seasonality and the differing length of each calendar quarter yielded virtually identical findings and are not presented herein. Finally, we examined buprenorphine utilization stratified by physician specialty, focusing on psychiatry, internal medicine, osteopathic medicine and family and general practice.
RESULTS
Data We analyzed data derived from the IMS Health National Disease and Therapeutic Index (NDTI) from 2003 through 2013.20 The NDTI provides nationally representative estimates of office-based physicians through a two-stage stratified sampling method by: (1) random selection of physician by specialty and geographic region; and (2) random selection of two consecutive workdays per calendar quarter for recording of all physician encounters. The random sample includes approximately 4800 physicians who participate each calendar quarter and for each patient encounter, physicians complete a patient record form that includes information on each condition that was evaluated or treated, as well as over-thecounter and prescription therapies that may have been recommended or prescribed. Data regarding physicians such as physician age and specialty are derived from the AMA Masterfile, which is the largest physician database in the United States. The Masterfile includes information both on AMA members and non-members. The majority of encounters within the NDTI take place in ambulatory offices; however, we excluded approximately 15% of visits which took place outside of ambulatory care, including long-term care institutions or hospitals. Studies comparing the NDTI with data from the National Ambulatory Medical Care Survey (NAMCS), a similar nationally representative audit of Turner et al.
Figure 1 depicts the quarterly treatment visits where buprenorphine and combination buprenorphine/naloxone products were used to treat dependence in ambulatory practice between 2003 and 2013. Overall, uptake of buprenorphine monotherapy has remained very low; quarterly treatment visits remained below 20,000 (K) (95% confidence intervals [CI] 18–22 K) until 2009, followed by a slight increase through 2013. The initial uptake of combination buprenorphine/naloxone was relatively modest over the first three years it was available, remaining below 100 K (CI 97–103 K) quarterly treatment visits. By the first quarter of 2006, quarterly treatment visits had more than doubled from the prior quarter, and continued to rapidly increase, reaching nearly 400 K (CI 393–497 K) quarterly visits by the end of 2008, where it leveled off around 300 K visits for the next two years. Another increase occurred in Q1 of 2011, with quarterly visits between 400 K and 500 K through 2013, or 1.7 million (M) annual treatment visits. Table 1 quantitatively depicts changes in the number of treatment visits over time, stratified by patient age, physician specialty and physician region. The majority of visits during each year were for individuals 20–39 years of age, although the proportion accounted for by these individuals decreased from 81% (CI 79–83%) in 2003 to 61% (CI 58–64%) in 2013, January 2015
25
FIGURE 1. Trends in ambulatory treatment visits using buprenorphine products for opioid dependency, 1997–2013.
with proportionate increases in the percent of visits accounted for by individuals aged 40–59 years of age. There were also important changes among the physicians treating dependence with buprenorphine. While the overall number of physicians in each specialty increased year after year, there were important shifts in the proportion of treatment visits accounted for by different physician specialties. Nearly all (92%) of the 78,000 treatment visits in 2003 were accounted for by psychiatrists; by 2013, of the more than two million treatment visits where buprenorphine products were used to treat dependence, only 32.8% involved psychiatrists, with the remainder accounted for primarily by internists (32.2%), osteopaths (13.9%) and family physicians (14.2%).
DISCUSSION In this analysis of a nationally representative audit of physician practices, we found rapid adoption of buprenorphine into ambulatory practice. Rates of buprenorphine treatment visits increased steadily over the period examined, and by 2013, there were more than two million annual treatment visits where buprenorphine was used to treat opioid dependence, 26
primarily accounted for by the fixed dose combination of buprenorphine/naloxone and increasingly prescribed by primary care physicians, including internists, osteopaths, family practitioners, and general practitioners. While buprenorphine exists in a fluid clinical and policy environment governing prescription opioids, several significant regulatory and clinical events have facilitated its rapid growth (Table 2). First, stigma associated with methadone maintenance programs has often been a barrier to treatment seeking,24 and thus the passage of the Drug Addiction Treatment Act of 2000 has served an important role in expanding treatment access for individuals with opioid dependence. Many methadone clinics also require daily visits for treatment, so the convenience of buprenorphine’s 30-day supply may also expand access.25 Second, FDA approval of both the fixed dose combination of buprenorphine and naloxone (Suboxone) in October 2002 and buprenorphine (Subutex) in October 2002 have been accompanied by marketing and promotion of these agents which in turn is a powerful driver of drug utilization.26 Third, in January of 2007, the patient limit each qualified physician could treat expanded from 30 to 100, more than tripling the provision of ambulatory treatment with buprenorphine.27 Finally, to some
Buprenorphine Use by Physicians in US, 2003–2013
January 2015
TABLE 1. Ambulatory utilization of buprenorphine products for dependency in the United States, 2003–2012
Patient age, % 10–19 20–39 40–59 60–64 65–74 75–84 Physician specialty, % Psychiatry Internal medicine* Osteopathic medicine* Family practice* General practice* All others Total visits, in thousands**
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
5.2 81.0 6.3 5.7 0.0 0.0
10.1 50.9 37.3 0.0 0.0 0.0
8.2 49.8 35.2 2.3 0.0 0.0
4.1 72.6 21.4 0.8 0.0 0.0
3.1 66.7 24.7 0.7 2.1 1.0
1.6 63.2 29.9 2.3 0.5 0.0
1.7 61.2 31.4 1.1 1.2 0.0
2.4 73.6 21.0 0.5 1.0 0.0
2.0 67.3 27.5 0.7 0.8 0.1
1.3 71.6 22.7 2.7 0.0 0.0
1.9 60.8 28.6 3.1 0.6 0.5
92.2 0.0 0.0 0.0 6.0 1.7 78
68.7 24.1 0.0 0.0 4.1 3.1 123
49.8 33.3 0.0 5.2 0.6 11.2 301
22.2 47.2 0.0 22.1 2.7 5.8 814
39.9 15.6 1.7 29.9 5.4 7.5 664
34.4 25.2 6.1 28.7 3.7 1.9 1,079
40.5 15.3 5.7 27.2 4.6 6.7 1,124
44.2 17.6 11.8 12.4 5.8 8.1 1,210
39.2 20.8 14.4 15.8 4.0 5.8 1,734
43.9 27.2 15.8 8.6 3.7 0.8 1,841
32.8 32.2 13.9 14.2 3.2 3.7 2,012
* Included in primary care physicians; **Values represent ambulatory office visits where buprenorphine mentioned in association with diagnosis of opioid dependency (see Methods); Source: IMS Health National Disease and Therapeutic Index1, 2003–2013, IMS Health Incorporated. All Rights Reserved.
degree buprenorphine itself contributes to opioid abuse as these products are frequently diverted, fueling the demand for them in both treatment settings and illicit markets.28 Many studies have compared the safety and efficacy of buprenorphine and methadone. Despite some reports of overdose, the majority of evidence and clinical opinion indicates the greater safety of buprenorphine.29 By contrast, most investigations suggest that buprenorphine and methadone offer overall comparable efficacy in managing symptoms of opioid dependence.30,31 This is important because although methadone has been the gold standard of opioid dependence treatment for decades, approximately 25% of patients do not respond to methadone treatment,32 and the retention rate for methadone maintenance programs is
relatively low, ranging from 25% to 60% at one year.33 While some studies have found methadone to be superior when the outcome is retention in a treatment program,34,35 evidence shows buprenophine can also effectively retain patients in both short and long term studies.36–38 More research is needed to identify subpopulations that may better respond to or continue either methadone or buprenorphine maintenance therapy. The extent to which buprenorphine use will increase further depends on a number of factors. The recent availability of generic buprenorphine/naloxone and Zubsolv could expand overall utilization of these products. Furthermore, public health and regulatory agencies are mounting numerous interventions to quell the rising prescription opioid abuse epidemic; the relative success of these interventions will
TABLE 2. Significant buprenorphine regulatory events
Date
Event
October 2000
Drug Addiction Treatment Act of 2000 (DATA 2000) granted authority to the Secretary of Health and Human Services to grant a waiver to physicians with certain training to prescriber and administer Schedule III, IV, and V narcotic drugs for the treatment of addiction or detoxification October 2002 DEA scheduled buprenorphine and buprenorphine-containing products under Schedule III of Controlled Substances Act October 2002 Buprenorphine sublingual preparations approved by FDA for management of opioid dependence; physicians limited to treating only 30 patients with buprenorphine in ambulatory setting December 2006 US Congress passed law allowing physicians with at least one year of clinical experience with buprenorphine to request an increase to the patient limit from 30 to 100 October 2009 Suboxone manufacturer loses exclusive rights to sell buprenorphine August 2010 Suboxone Film approved by FDA March 2013 Suboxone sublingual tablets discontinued July 2013 New manufacturer of combination buprenorphine/naloxone approved, product named Zubsolv Turner et al.
January 2015
27
influence the size of the population seeking opioid dependence treatment. In addition, changes in regulatory policies in response to the epidemic of prescription drug abuse may influence the availability and access to both methadone and buprenorphine. While policies to increase the patient limit have been enacted, it is important to note that fewer than 3% of the physicians in the US are currently permitted to prescribe buprenorphine for dependence, limiting patients’ access to this treatment.39 The costs of buprenorphine are also relevant to its adoption; although the direct costs of buprenorphine is far greater than methadone, its overall cost-effectiveness is also impacted by other features of its use, such as reductions in the costs of dispensing, supervision and regulation that are associated with methadone maintenance programs.40 Buprenorphine diversion and abuse have paralleled the growth in the market, though the misuse of these therapies remains lower than rates of methadone abuse.41 Interestingly, qualitative data suggest that illicit use of buprenorphine often occurs as self-medication for withdrawal symptoms, primarily with low doses.42 As buprenorphine utilization grows and treatment population shifts continue, rates of opioid poisonings, diversion, and admissions to addiction treatment facilities will be important outcomes to monitor. Such trends may also be impacted by an expanding role of naloxone in opioid overdose prevention efforts.43 There are several limitations to this analysis. First, although our data is based on a nationally representative audit of ambulatory care, the survey forms provide little clinical information from which to judge the overall quality of care and clinical appropriateness of the therapies used, and we are unable to examine differences between detoxification and maintenance treatment. Our study has other limitations as well, primarily due to the nature of the cross-sectional, aggregate data. These data do not provide the opportunity to examine other aspects of buprenorphine utilization in the broader context of opioid dependency treatment, such as individuals’ treatment patterns, treatment retention, and use of opioids and other medicines prior to or following buprenorphine therapy.
CONCLUSIONS Our results are important in the face of rapidly escalating rates of prescription opioid use and abuse in the United States and the complexities of opioid dependence treatment,1 as well as the potential role that buprenorphine plays in this therapeutic landscape. Despite efforts on the part of many stakeholders, the prevention of abuse and diversion of prescription drugs remains a major public health challenge. As this epidemic grows, an increasing number of individuals require care for opioid dependence. While methadone historically has been the mainstay of such treatment, we document rapid increases in buprenorphine/naloxone ambulatory utilization during the past decade. This potentially indicates an important expansion of opioid dependence treatment, particularly among individuals who struggle with 28
traditional methadone maintenance therapy. However, more research is needed to support widespread use. Important questions remain regarding buprenorphine/naloxone’s real world treatment effectiveness and cost effectiveness, patterns of abuse, diversion and misuse and its role in the future treatment of opioid dependence. Disclosures: Dr. Alexander is an ad hoc member of the FDA’s Drug Safety and Risk Management Advisory Committee, serves as a paid consultant to IMS Health and serves on an IMS Health scientific advisory board. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Dr. Kruszewski has served as general and case-specific expert for multiple plaintiff litigation involving OxyContin, Neurontin and Zyprexa and has had false claims settled as coplaintiff with the United States against Southwood Psychiatric Hospital, Pfizer (Geodon) and AstraZeneca (Seroquel). The statements, findings, conclusions, views, and opinions contained and expressed in this article are based in part on data obtained under license from the following IMS Health Incorporated information service(s): National Disease and Therapeutic Index1 (2003–2013), IMS Health Incorporated. All Rights Reserved. The statements, findings, conclusions, views, and opinions contained and expressed herein are not necessarily those of IMS Health Incorporated or any of its affiliated or subsidiary entities. Dr. Alexander is supported by the Agency for Healthcare Research and Quality (RO1 HS0189960). The funding sources had no role in the design and conduct of the study, analysis, or interpretation of the data; and preparation or final approval of the manuscript prior to publication.
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Trends in the Use of Buprenorphine by Office-Based Physicians in the United States, 2003–2013 Lydia Turner, MHS,1,2 Stefan P. Kruszewski, MD,3,4,2 G. Caleb Alexander, MD, MS1,2,5 1
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 3 Stefan P. Kruszewski, MD & Associates, Harrisburg, Pennsylvania 4 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 5 Department of Pharmacy Practice, University of Illinois at Chicago School of Pharmacy, Chicago, Illinois 2
Background and objectives: Despite buprenorphine’s promise as a novel therapy for opioid dependence, little is known about its clinical adoption. We characterized trends in ambulatory use of buprenorphine in the United States. Methods: Cross-sectional, descriptive analyses of buprenorphine utilization from 2003 to 2013 using the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory care. The primary unit of analysis was an office visit where buprenorphine was used for opioid dependence (treatment visit). Results: Between 2003 and 2013, there was significant uptake of buprenorphine in ambulatory treatment visits, from 0.16 million [M] (95% confidence interval [CI] 0.10–0.20) visits in 2003 to 2.1M (CI 1.9–2.3M) treatment visits during 2013. Approximately 90% involved the use of brand name combination buprenorphine/naloxone (Suboxone), although this percentage decreased modestly to 80% by the last quarter of 2013. Buprenorphine prescribing increased among all specialties, but the proportion accounted for by primary care physicians increased significantly from 6.0% in 2003 to 63.5% in 2013 and decreased among psychiatrists from 92.2% to 32.8% over the same time period. Conclusions: The use of buprenorphine products to treat opioid dependence has increased significantly in the past 10 years and has shifted to greater use by primary care physicians, indicating a rapidly changing face of opioid maintenance therapy in the United States. (Am J Addict 2015;24:24–29)
Received February 12, 2014; revised September 9, 2014; accepted October 12, 2014. Address Correspondence to Alexander, Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 N. Wolfe Street W6035, Baltimore, MD 21205. E-mail: [email protected] 24
INTRODUCTION Although opioids have been subject to abuse for centuries, during the past two decades, rates of abuse and misuse of these drugs in the United States have been particularly noteworthy.1–3 These changes have been fueled primarily by prescription opioid abuse and dependence, although rates of heroin use have also been increasing in many communities in recent years.4–8 Between 1999 and 2009, the death rate from prescription opioids increased by nearly 300% and was, by 2009, four times higher than the death rate from heroin.9 Pharmacologic management of opioid dependence is a vital component of most treatment strategies. Since the 1960s, methadone hydrochloride, a long-acting opioid, has been a mainstay of such treatment.10 However, because of its high potential for abuse, the production, distribution, and dispensing of methadone are highly regulated;11 only registered physicians and hospitals are permitted to dispense methadone for opioid dependence, and methadone maintenance programs face further regulations by state governments, most of which are more restrictive than federal standards.12 Although to some degree prescribers can circumvent restrictions by writing prescriptions for methadone for pain, existing restrictions have nevertheless substantially limited its adoption in ambulatory clinical practice. In October of 2002, the Food and Drug Administration (FDA) approved the fixed dose combination of buprenorphine/naloxone (Suboxone) and buprenorphine (Subutex) specifically for the treatment of opioid dependence.13 In contrast to methadone, buprenorphine hydrochloride is a partial mu-opioid agonist and Class III controlled substance, resulting in similar physiological results as methadone, but with a “ceiling” of certain effects such as respiratory depression.14 Combination buprenorphine/naloxone has a putative lower potential for abuse as well as a reported enhanced safety profile due to the inclusion of naloxone hydrochloride, an opioid
antagonist used to counteract the depression of the central nervous system and respiratory system caused by opioids.15 These pharmacologic properties, in the context of an increasing public health toll from opioid abuse and dependence, contributed to the passage of the Drug Addiction Treatment Act of 2000 that allowed qualified physicians to treat opioid addiction with Schedule III, IV, and V controlled narcotics that are FDA approved for that indication,16 paving the way for buprenorphine to be used in treatment settings other than traditional opioid treatment programs. Prior studies of buprenorphine adoption have suggested considerable uptake, but have been limited to veteran populations,17 behavioral health care settings,18 and were completed many years ago.19 We sought to update these analyses using a large, nationally representative, annual audit of ambulatory-based physicians. In addition to characterizing trends between 2003 and 2013, we were also interested in examining the effect of market changes on buprenorphine utilization, including the October 2009 patent expiry of buprenorphine for opioid dependence (Subutex), the February 2013 patent expiry of buprenorphine/suboxone (Suboxone) and the September 2013 approval of the newer buprenorphine/naloxone combination (Zubsolv), reformulated to increase the bioavailability of the molecules and improve the taste. Finally, we examined how the ambulatory use of buprenorphine has varied between psychiatrists and other specialists compared with primary care physicians.
METHODS
ambulatory practice conducted by the National Center for Health Statistics, have yielded comparable findings.21–23 Analysis We used descriptive statistics to examine trends in buprenorphine utilization. Our outcome of interest was a physician encounter where buprenorphine was used to treat opioid dependence, heretofore referred to as a treatment visit. To identify these visits, we first identified all buprenorphinecontaining products available during the period of interest, including: buprenorphine (Subutex, Butrans, Buprenex), buprenorphine/naloxone (Suboxone, Zubsolv) and generic formulations of these products. Second, we limited our data to dependence-related diagnoses (ICD-9 Codes 304.00, 304.01, 304.02, 305.50, 305.51, 305.52), and thus, we excluded the small proportion of treatment visits (annual range of 0–11%) where buprenorphine products were identified and used for a primary indication of pain or other non-opioid dependence diagnosis. Third, we aggregated monthly data available from the NDTI into calendar quarter estimates and calculated 95% confidence intervals using tables of relative standard errors that are derived to account for the survey’s complex sampling design. Analyses adjusting for seasonality and the differing length of each calendar quarter yielded virtually identical findings and are not presented herein. Finally, we examined buprenorphine utilization stratified by physician specialty, focusing on psychiatry, internal medicine, osteopathic medicine and family and general practice.
RESULTS
Data We analyzed data derived from the IMS Health National Disease and Therapeutic Index (NDTI) from 2003 through 2013.20 The NDTI provides nationally representative estimates of office-based physicians through a two-stage stratified sampling method by: (1) random selection of physician by specialty and geographic region; and (2) random selection of two consecutive workdays per calendar quarter for recording of all physician encounters. The random sample includes approximately 4800 physicians who participate each calendar quarter and for each patient encounter, physicians complete a patient record form that includes information on each condition that was evaluated or treated, as well as over-thecounter and prescription therapies that may have been recommended or prescribed. Data regarding physicians such as physician age and specialty are derived from the AMA Masterfile, which is the largest physician database in the United States. The Masterfile includes information both on AMA members and non-members. The majority of encounters within the NDTI take place in ambulatory offices; however, we excluded approximately 15% of visits which took place outside of ambulatory care, including long-term care institutions or hospitals. Studies comparing the NDTI with data from the National Ambulatory Medical Care Survey (NAMCS), a similar nationally representative audit of Turner et al.
Figure 1 depicts the quarterly treatment visits where buprenorphine and combination buprenorphine/naloxone products were used to treat dependence in ambulatory practice between 2003 and 2013. Overall, uptake of buprenorphine monotherapy has remained very low; quarterly treatment visits remained below 20,000 (K) (95% confidence intervals [CI] 18–22 K) until 2009, followed by a slight increase through 2013. The initial uptake of combination buprenorphine/naloxone was relatively modest over the first three years it was available, remaining below 100 K (CI 97–103 K) quarterly treatment visits. By the first quarter of 2006, quarterly treatment visits had more than doubled from the prior quarter, and continued to rapidly increase, reaching nearly 400 K (CI 393–497 K) quarterly visits by the end of 2008, where it leveled off around 300 K visits for the next two years. Another increase occurred in Q1 of 2011, with quarterly visits between 400 K and 500 K through 2013, or 1.7 million (M) annual treatment visits. Table 1 quantitatively depicts changes in the number of treatment visits over time, stratified by patient age, physician specialty and physician region. The majority of visits during each year were for individuals 20–39 years of age, although the proportion accounted for by these individuals decreased from 81% (CI 79–83%) in 2003 to 61% (CI 58–64%) in 2013, January 2015
25
FIGURE 1. Trends in ambulatory treatment visits using buprenorphine products for opioid dependency, 1997–2013.
with proportionate increases in the percent of visits accounted for by individuals aged 40–59 years of age. There were also important changes among the physicians treating dependence with buprenorphine. While the overall number of physicians in each specialty increased year after year, there were important shifts in the proportion of treatment visits accounted for by different physician specialties. Nearly all (92%) of the 78,000 treatment visits in 2003 were accounted for by psychiatrists; by 2013, of the more than two million treatment visits where buprenorphine products were used to treat dependence, only 32.8% involved psychiatrists, with the remainder accounted for primarily by internists (32.2%), osteopaths (13.9%) and family physicians (14.2%).
DISCUSSION In this analysis of a nationally representative audit of physician practices, we found rapid adoption of buprenorphine into ambulatory practice. Rates of buprenorphine treatment visits increased steadily over the period examined, and by 2013, there were more than two million annual treatment visits where buprenorphine was used to treat opioid dependence, 26
primarily accounted for by the fixed dose combination of buprenorphine/naloxone and increasingly prescribed by primary care physicians, including internists, osteopaths, family practitioners, and general practitioners. While buprenorphine exists in a fluid clinical and policy environment governing prescription opioids, several significant regulatory and clinical events have facilitated its rapid growth (Table 2). First, stigma associated with methadone maintenance programs has often been a barrier to treatment seeking,24 and thus the passage of the Drug Addiction Treatment Act of 2000 has served an important role in expanding treatment access for individuals with opioid dependence. Many methadone clinics also require daily visits for treatment, so the convenience of buprenorphine’s 30-day supply may also expand access.25 Second, FDA approval of both the fixed dose combination of buprenorphine and naloxone (Suboxone) in October 2002 and buprenorphine (Subutex) in October 2002 have been accompanied by marketing and promotion of these agents which in turn is a powerful driver of drug utilization.26 Third, in January of 2007, the patient limit each qualified physician could treat expanded from 30 to 100, more than tripling the provision of ambulatory treatment with buprenorphine.27 Finally, to some
Buprenorphine Use by Physicians in US, 2003–2013
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TABLE 1. Ambulatory utilization of buprenorphine products for dependency in the United States, 2003–2012
Patient age, % 10–19 20–39 40–59 60–64 65–74 75–84 Physician specialty, % Psychiatry Internal medicine* Osteopathic medicine* Family practice* General practice* All others Total visits, in thousands**
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
5.2 81.0 6.3 5.7 0.0 0.0
10.1 50.9 37.3 0.0 0.0 0.0
8.2 49.8 35.2 2.3 0.0 0.0
4.1 72.6 21.4 0.8 0.0 0.0
3.1 66.7 24.7 0.7 2.1 1.0
1.6 63.2 29.9 2.3 0.5 0.0
1.7 61.2 31.4 1.1 1.2 0.0
2.4 73.6 21.0 0.5 1.0 0.0
2.0 67.3 27.5 0.7 0.8 0.1
1.3 71.6 22.7 2.7 0.0 0.0
1.9 60.8 28.6 3.1 0.6 0.5
92.2 0.0 0.0 0.0 6.0 1.7 78
68.7 24.1 0.0 0.0 4.1 3.1 123
49.8 33.3 0.0 5.2 0.6 11.2 301
22.2 47.2 0.0 22.1 2.7 5.8 814
39.9 15.6 1.7 29.9 5.4 7.5 664
34.4 25.2 6.1 28.7 3.7 1.9 1,079
40.5 15.3 5.7 27.2 4.6 6.7 1,124
44.2 17.6 11.8 12.4 5.8 8.1 1,210
39.2 20.8 14.4 15.8 4.0 5.8 1,734
43.9 27.2 15.8 8.6 3.7 0.8 1,841
32.8 32.2 13.9 14.2 3.2 3.7 2,012
* Included in primary care physicians; **Values represent ambulatory office visits where buprenorphine mentioned in association with diagnosis of opioid dependency (see Methods); Source: IMS Health National Disease and Therapeutic Index1, 2003–2013, IMS Health Incorporated. All Rights Reserved.
degree buprenorphine itself contributes to opioid abuse as these products are frequently diverted, fueling the demand for them in both treatment settings and illicit markets.28 Many studies have compared the safety and efficacy of buprenorphine and methadone. Despite some reports of overdose, the majority of evidence and clinical opinion indicates the greater safety of buprenorphine.29 By contrast, most investigations suggest that buprenorphine and methadone offer overall comparable efficacy in managing symptoms of opioid dependence.30,31 This is important because although methadone has been the gold standard of opioid dependence treatment for decades, approximately 25% of patients do not respond to methadone treatment,32 and the retention rate for methadone maintenance programs is
relatively low, ranging from 25% to 60% at one year.33 While some studies have found methadone to be superior when the outcome is retention in a treatment program,34,35 evidence shows buprenophine can also effectively retain patients in both short and long term studies.36–38 More research is needed to identify subpopulations that may better respond to or continue either methadone or buprenorphine maintenance therapy. The extent to which buprenorphine use will increase further depends on a number of factors. The recent availability of generic buprenorphine/naloxone and Zubsolv could expand overall utilization of these products. Furthermore, public health and regulatory agencies are mounting numerous interventions to quell the rising prescription opioid abuse epidemic; the relative success of these interventions will
TABLE 2. Significant buprenorphine regulatory events
Date
Event
October 2000
Drug Addiction Treatment Act of 2000 (DATA 2000) granted authority to the Secretary of Health and Human Services to grant a waiver to physicians with certain training to prescriber and administer Schedule III, IV, and V narcotic drugs for the treatment of addiction or detoxification October 2002 DEA scheduled buprenorphine and buprenorphine-containing products under Schedule III of Controlled Substances Act October 2002 Buprenorphine sublingual preparations approved by FDA for management of opioid dependence; physicians limited to treating only 30 patients with buprenorphine in ambulatory setting December 2006 US Congress passed law allowing physicians with at least one year of clinical experience with buprenorphine to request an increase to the patient limit from 30 to 100 October 2009 Suboxone manufacturer loses exclusive rights to sell buprenorphine August 2010 Suboxone Film approved by FDA March 2013 Suboxone sublingual tablets discontinued July 2013 New manufacturer of combination buprenorphine/naloxone approved, product named Zubsolv Turner et al.
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influence the size of the population seeking opioid dependence treatment. In addition, changes in regulatory policies in response to the epidemic of prescription drug abuse may influence the availability and access to both methadone and buprenorphine. While policies to increase the patient limit have been enacted, it is important to note that fewer than 3% of the physicians in the US are currently permitted to prescribe buprenorphine for dependence, limiting patients’ access to this treatment.39 The costs of buprenorphine are also relevant to its adoption; although the direct costs of buprenorphine is far greater than methadone, its overall cost-effectiveness is also impacted by other features of its use, such as reductions in the costs of dispensing, supervision and regulation that are associated with methadone maintenance programs.40 Buprenorphine diversion and abuse have paralleled the growth in the market, though the misuse of these therapies remains lower than rates of methadone abuse.41 Interestingly, qualitative data suggest that illicit use of buprenorphine often occurs as self-medication for withdrawal symptoms, primarily with low doses.42 As buprenorphine utilization grows and treatment population shifts continue, rates of opioid poisonings, diversion, and admissions to addiction treatment facilities will be important outcomes to monitor. Such trends may also be impacted by an expanding role of naloxone in opioid overdose prevention efforts.43 There are several limitations to this analysis. First, although our data is based on a nationally representative audit of ambulatory care, the survey forms provide little clinical information from which to judge the overall quality of care and clinical appropriateness of the therapies used, and we are unable to examine differences between detoxification and maintenance treatment. Our study has other limitations as well, primarily due to the nature of the cross-sectional, aggregate data. These data do not provide the opportunity to examine other aspects of buprenorphine utilization in the broader context of opioid dependency treatment, such as individuals’ treatment patterns, treatment retention, and use of opioids and other medicines prior to or following buprenorphine therapy.
CONCLUSIONS Our results are important in the face of rapidly escalating rates of prescription opioid use and abuse in the United States and the complexities of opioid dependence treatment,1 as well as the potential role that buprenorphine plays in this therapeutic landscape. Despite efforts on the part of many stakeholders, the prevention of abuse and diversion of prescription drugs remains a major public health challenge. As this epidemic grows, an increasing number of individuals require care for opioid dependence. While methadone historically has been the mainstay of such treatment, we document rapid increases in buprenorphine/naloxone ambulatory utilization during the past decade. This potentially indicates an important expansion of opioid dependence treatment, particularly among individuals who struggle with 28
traditional methadone maintenance therapy. However, more research is needed to support widespread use. Important questions remain regarding buprenorphine/naloxone’s real world treatment effectiveness and cost effectiveness, patterns of abuse, diversion and misuse and its role in the future treatment of opioid dependence. Disclosures: Dr. Alexander is an ad hoc member of the FDA’s Drug Safety and Risk Management Advisory Committee, serves as a paid consultant to IMS Health and serves on an IMS Health scientific advisory board. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Dr. Kruszewski has served as general and case-specific expert for multiple plaintiff litigation involving OxyContin, Neurontin and Zyprexa and has had false claims settled as coplaintiff with the United States against Southwood Psychiatric Hospital, Pfizer (Geodon) and AstraZeneca (Seroquel). The statements, findings, conclusions, views, and opinions contained and expressed in this article are based in part on data obtained under license from the following IMS Health Incorporated information service(s): National Disease and Therapeutic Index1 (2003–2013), IMS Health Incorporated. All Rights Reserved. The statements, findings, conclusions, views, and opinions contained and expressed herein are not necessarily those of IMS Health Incorporated or any of its affiliated or subsidiary entities. Dr. Alexander is supported by the Agency for Healthcare Research and Quality (RO1 HS0189960). The funding sources had no role in the design and conduct of the study, analysis, or interpretation of the data; and preparation or final approval of the manuscript prior to publication.
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