Clinical Review & Education
From The JAMA Network
Treating Prescription Opioid Dependence Charles Ruetsch, PhD
JAMA PSYCHIATRY A Randomized, Double-blind Evaluation of Buprenorphine Taper Duration in Primary Prescription Opioid Abusers
MAIN OUTCOMES AND MEASURES The percentage of participants negative for illicit opioid use, retention, naltrexone ingestion, and favorable treatment response (ie, retained in treatment, opioid abstinent, and receiving naltrexone at the end of the study).
Stacey C. Sigmon, PhD; Kelly E. Dunn, PhD; Kathryn Saulsgiver, PhD; Mollie E. Patrick, MA; Gary J. Badger, MS; Sarah H. Heil, PhD; John R. Brooklyn, MD; Stephen T. Higgins, PhD IMPORTANCE Although abuse of prescription opioids (POs) is a significant public health problem, few experimental studies have investigated the treatment needs of this growing population.
OBJECTIVE To evaluate, following brief stabilization with a combination of buprenorphine hydrochloride and naloxone hydrochloride dihydrate, the relative efficacy of 1-, 2-, and 4-week buprenorphine tapering regimens and subsequent naltrexone hydrochloride therapy in PO-dependent outpatients.
DESIGN, SETTING, AND PARTICIPANTS A double-blind, 12-week randomized clinical trial was conducted in an outpatient research clinic. Following a brief period of buprenorphine stabilization, 70 PO-dependent adults were randomized to receive 1-, 2-, or 4-week tapers followed by naltrexone therapy. INTERVENTION During phase 1 (weeks 1-5 after randomization),
participants visited the clinic daily; during phase 2 (weeks 6-12), visits were reduced to thrice weekly. Participants received behavioral therapy and urine toxicology testing throughout the trial.
With the continued increase of opioid analgesic use in the United States,1 there is a parallel increase in opioid use disorder specifically involving prescription opioids (POs).2 The percentage of admissions into substance abuse treatment facilities for pharmaceutical opioid dependence treatment has increased from less than 1.0% during and before 1997 to 9.8% in 2011.3 By contrast, admissions for heroin treatment have fluctuated between 14% and 15.5% for the past 15 years. Increases in drug-related crime and spread of infectious disease are 2 societal consequences of increased opioid use disorder. Treatment usually begins by reducing or eliminating uncontrolled use of the abused opioid agonists. Widespread methadone maintenance treatment availability provides an alternative to acute withdrawal followed by self-monitored abstinence facilitating reduced relapse to the abused opioid. Strengths and weaknesses of
RESULTS Opioid abstinence at the end of phase 1 was greater in the 4-week compared with the 2- and 1-week taper conditions (P = .02), with 63% (n = 14), 29% (n = 7), and 29% (n = 7) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. Abstinence at the end of phase 2 was also greater in the 4-week compared with the 2- and 1-week conditions (P = .03), with 50% (n = 11), 16% (n = 4), and 20% (n = 5) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. There were more treatment responders in the 4-week condition (P = .03), with 50% (n = 11), 17% (n = 4), and 21% (n = 5) of participants in the 4-, 2-, and 1-week groups considered responders at the end of treatment, respectively. Retention and naltrexone ingestion also were superior in the 4-week vs briefer tapers (both P = .04). Experimental condition (ie, taper duration) was the strongest predictor of treatment response, followed by buprenorphine stabilization dose.
CONCLUSIONS AND RELEVANCE This study represents a rigorous experimental evaluation of outpatient buprenorphine stabilization, brief taper, and naltrexone maintenance for treatment of PO dependence. Results suggest that a meaningful subset of PO-dependent outpatients may respond positively to a 4-week taper plus naltrexone maintenance intervention. JAMA Psychiatry. 2013;70(12):1347-1354. doi:10.1001/jamapsychiatry.2013.2216.
methadone maintenance have been studied and well documented. More recently, buprenorphine replacement therapy has capitalized on many of the strengths of the methadone model while reducing barriers to treatment with its availability in mainstream medical care settings. With both methadone and buprenorphine as tools, agonist maintenance therapy reduces opioid use in patients. However, significant barriers to accessing agonist maintenance therapy remain.4 The study by Sigmon et al5 published in JAMA Psychiatry highlights a different treatment model in the general class of treatments known as buprenorphine medication-assisted treatment (BMAT). Although most patients with opioid use disorder receiving agonist therapy continue to receive maintenance therapy for 6 months or more, Sigmon et al demonstrated short-term treatment
jama.com
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
1145
Clinical Review & Education From The JAMA Network
outcomes using a simpler approach: buprenorphine-assisted detoxification followed by a brief taper off of buprenorphine. After a 2-week stabilization period of buprenorphine-assisted detoxification from the abused opioid, 70 patients who abused POs were randomized to undergo either a 1-, 2-, or 4-week taper off buprenorphine followed by naltrexone therapy. Patients in the 4-week group had the most positive outcomes, with the largest proportion (14 patients, 63%) retained in treatment and having negative urine toxicology testing 2 weeks after discontinuation of buprenorphine. In addition to describing and testing short-term outcomes of an alternative BMAT treatment approach, this study had 2 features worth noting: severity of abuse was measured as the baseline dose of buprenorphine used to control withdrawal symptoms, and this sample abused POs and had little or no heroin use. The study by Sigmon et al5 shows that the commonly used 6-month (minimum) maintenance period for treating opioid abuse may be compressed to 2 weeks of buprenorphine stabilization. Of the 3 time periods in the study, the 4-week taper was the most effective. However, when compared with current standards for maintenance therapy outcomes, the study by Sigmon et al had lower rates than expected for short-term abstinence.6 It is not clear from the report what patient or clinician characteristics, if any, contributed to treatment success. For example, successful patients may have been more motivated or may have abused opioids for a relatively short period. Future studies should facilitate identification of patients for whom the approach by Sigmon et al is adequate. Then, clinicians will be better able to triage patients to the most appropriate treatment: methadone maintenance, buprenorphine maintenance, or buprenorphine-assisted detoxification followed by brief taper. There are several well-established methods for measuring baseline severity of opioid dependence, such as the Addiction Severity Index (ASI)7 and the Michigan Assessment-Screening Test for Alcohol and Drugs.8 These assess drug and alcohol use severity as well as multiple functional areas known to be affected by opioid abuse and dependence. Because addiction is a multidimensional disease of psychological, physiological, and social impairment, a single proxy measure for severity would not be expected to capture the entire range of disease severity or provide sufficient information to match individual patients to appropriate treatment regimens. Sigmon et al5 used baseline buprenorphine dose as a proxy for addiction seARTICLE INFORMATION Author Affiliation: Health Analytics, Science, Columbia, Maryland. Corresponding Author: Charles Ruetsch, PhD, Health Analytics, Science, 9200 Rumsey Rd, Ste 215, Columbia, MD 21045 (charles.ruetsch @healthanalytic.com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
/NSDUH/2012SummNatFindDetTables/Index.aspx. Accessed August 25, 2014.
buprenorphine dose. Am J Drug Alcohol Abuse. 2011;37(5):453-459.
3. Results from the 1992-2011 Treatment Episode Data Set: Admissions (TEDS-A): concatenated, 1992 to 2011 [ICPSR25221-v7: January 27, 2014]. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.
7. McLellan AT, Cacciola JC, Alterman AI, Rikoon SH, Carise D. The Addiction Severity Index at 25. Am J Addict. 2006;15(2):113-124.
4. Olsen Y, Sharfstein JM. Confronting the stigma of opioid use disorder—and its treatment. JAMA. 2014;311(14):1393-1394.
1. Ruetsch C. Empirical view of opioid dependence. J Manag Care Pharm. 2010;16(1)(suppl B):S9-S13.
5. Sigmon SC, Dunn KE, Saulsgiver K, et al. A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. JAMA Psychiatry. 2013; 70(12):1347-1354.
2. Results from the 2012 National Survey on Drug Use and Health. http://www.samhsa.gov/data
6. Hillhouse M, Canamar CP, Doraimani G, Thomas C, Hasson A, Ling W. Participant characteristics and
REFERENCES
1146
verity. Establishing an adequate buprenorphine dose to achieve relief of detoxification symptoms is subjective and confounded with patient physiology, experience with the medication, and provider biases.9 Future studies could better control for baseline severity of opioid use disorder using 1 or more of many available self-reported severity measures together with urine toxicology screens or other available biomarkers of drug use. All patients in the study by Sigmon et al5 reported abusing POs, implying that PO abusers may be more amenable to this brief treatment regimen than abusers of other opioids. However, it is unlikely that PO abusers are less severely addicted and more likely to respond to this study’s approach compared with heroin users. There are issues to consider before generalizing the findings by Sigmon et al into clinical practice. Basing relative severity of opioid use disorder or its resilience to treatment on the specific abused opioid molecule (heroin vs PO) may not serve in matching patient to treatment regimen. Heroin abusers are often characterized as having more severe addiction than PO abusers, but the addiction severity and response to treatment can be equivalent for these populations. However, the functional ramifications of the addictions may differ.10 In a study comparing 2 groups of patients with opioid use disorder, one group was largely urban and heroin-using, derived from the Drug Evaluation Network System, and the other group consisted of suburban PO users.10 There was little difference in opioid use severity between the groups based on the ASI7 drug composite score. However, the suburban sample who abused POs had more alcohol use, psychiatric, and family or social functioning problems. By contrast, the urban sample who largely used heroin had more legal and employment problems.10 Careful assessment of patient characteristics, background, length of time abusing opioids and other drugs and alcohol, and available social support may be more important than the specific opioid that was abused or the adequate starting dose of buprenorphine (or other MAT medicine). It cannot be assumed that PO users rather than heroin users are more likely to succeed in a detoxification with a brief taper treatment approach without follow-up maintenance. When matched to patient requirements, the treatment model studied by Sigmon et al5 adds a powerful new treatment option. By providing a simplified approach to opioid abuse treatment that works for some patients, the report by Sigmon et al should help clinicians treat an increasingly common and difficult problem.
8. Westermeyer J, Yargic I, Thuras P. Michigan assessment-screening test for alcohol and drugs (MAST/AD). Am J Addict. 2004;13(2):151-162. 9. Albright J, Ciaverelli R, Essex A, Tkacz J, Ruetsch C. Psychiatrist characteristics that influence use of buprenorphine medication-assisted treatment. J Addict Med. 2010;4(4):197-203. 10. Ruetsch C, Cacciola J, Tkacz J. A national study of a telephone support service for patients receiving office-based buprenorphine medication-assisted treatment. J Subst Abuse Treat. 2010;39(4):307-317.
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
jama.com
From The JAMA Network
Treating Prescription Opioid Dependence Charles Ruetsch, PhD
JAMA PSYCHIATRY A Randomized, Double-blind Evaluation of Buprenorphine Taper Duration in Primary Prescription Opioid Abusers
MAIN OUTCOMES AND MEASURES The percentage of participants negative for illicit opioid use, retention, naltrexone ingestion, and favorable treatment response (ie, retained in treatment, opioid abstinent, and receiving naltrexone at the end of the study).
Stacey C. Sigmon, PhD; Kelly E. Dunn, PhD; Kathryn Saulsgiver, PhD; Mollie E. Patrick, MA; Gary J. Badger, MS; Sarah H. Heil, PhD; John R. Brooklyn, MD; Stephen T. Higgins, PhD IMPORTANCE Although abuse of prescription opioids (POs) is a significant public health problem, few experimental studies have investigated the treatment needs of this growing population.
OBJECTIVE To evaluate, following brief stabilization with a combination of buprenorphine hydrochloride and naloxone hydrochloride dihydrate, the relative efficacy of 1-, 2-, and 4-week buprenorphine tapering regimens and subsequent naltrexone hydrochloride therapy in PO-dependent outpatients.
DESIGN, SETTING, AND PARTICIPANTS A double-blind, 12-week randomized clinical trial was conducted in an outpatient research clinic. Following a brief period of buprenorphine stabilization, 70 PO-dependent adults were randomized to receive 1-, 2-, or 4-week tapers followed by naltrexone therapy. INTERVENTION During phase 1 (weeks 1-5 after randomization),
participants visited the clinic daily; during phase 2 (weeks 6-12), visits were reduced to thrice weekly. Participants received behavioral therapy and urine toxicology testing throughout the trial.
With the continued increase of opioid analgesic use in the United States,1 there is a parallel increase in opioid use disorder specifically involving prescription opioids (POs).2 The percentage of admissions into substance abuse treatment facilities for pharmaceutical opioid dependence treatment has increased from less than 1.0% during and before 1997 to 9.8% in 2011.3 By contrast, admissions for heroin treatment have fluctuated between 14% and 15.5% for the past 15 years. Increases in drug-related crime and spread of infectious disease are 2 societal consequences of increased opioid use disorder. Treatment usually begins by reducing or eliminating uncontrolled use of the abused opioid agonists. Widespread methadone maintenance treatment availability provides an alternative to acute withdrawal followed by self-monitored abstinence facilitating reduced relapse to the abused opioid. Strengths and weaknesses of
RESULTS Opioid abstinence at the end of phase 1 was greater in the 4-week compared with the 2- and 1-week taper conditions (P = .02), with 63% (n = 14), 29% (n = 7), and 29% (n = 7) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. Abstinence at the end of phase 2 was also greater in the 4-week compared with the 2- and 1-week conditions (P = .03), with 50% (n = 11), 16% (n = 4), and 20% (n = 5) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. There were more treatment responders in the 4-week condition (P = .03), with 50% (n = 11), 17% (n = 4), and 21% (n = 5) of participants in the 4-, 2-, and 1-week groups considered responders at the end of treatment, respectively. Retention and naltrexone ingestion also were superior in the 4-week vs briefer tapers (both P = .04). Experimental condition (ie, taper duration) was the strongest predictor of treatment response, followed by buprenorphine stabilization dose.
CONCLUSIONS AND RELEVANCE This study represents a rigorous experimental evaluation of outpatient buprenorphine stabilization, brief taper, and naltrexone maintenance for treatment of PO dependence. Results suggest that a meaningful subset of PO-dependent outpatients may respond positively to a 4-week taper plus naltrexone maintenance intervention. JAMA Psychiatry. 2013;70(12):1347-1354. doi:10.1001/jamapsychiatry.2013.2216.
methadone maintenance have been studied and well documented. More recently, buprenorphine replacement therapy has capitalized on many of the strengths of the methadone model while reducing barriers to treatment with its availability in mainstream medical care settings. With both methadone and buprenorphine as tools, agonist maintenance therapy reduces opioid use in patients. However, significant barriers to accessing agonist maintenance therapy remain.4 The study by Sigmon et al5 published in JAMA Psychiatry highlights a different treatment model in the general class of treatments known as buprenorphine medication-assisted treatment (BMAT). Although most patients with opioid use disorder receiving agonist therapy continue to receive maintenance therapy for 6 months or more, Sigmon et al demonstrated short-term treatment
jama.com
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
1145
Clinical Review & Education From The JAMA Network
outcomes using a simpler approach: buprenorphine-assisted detoxification followed by a brief taper off of buprenorphine. After a 2-week stabilization period of buprenorphine-assisted detoxification from the abused opioid, 70 patients who abused POs were randomized to undergo either a 1-, 2-, or 4-week taper off buprenorphine followed by naltrexone therapy. Patients in the 4-week group had the most positive outcomes, with the largest proportion (14 patients, 63%) retained in treatment and having negative urine toxicology testing 2 weeks after discontinuation of buprenorphine. In addition to describing and testing short-term outcomes of an alternative BMAT treatment approach, this study had 2 features worth noting: severity of abuse was measured as the baseline dose of buprenorphine used to control withdrawal symptoms, and this sample abused POs and had little or no heroin use. The study by Sigmon et al5 shows that the commonly used 6-month (minimum) maintenance period for treating opioid abuse may be compressed to 2 weeks of buprenorphine stabilization. Of the 3 time periods in the study, the 4-week taper was the most effective. However, when compared with current standards for maintenance therapy outcomes, the study by Sigmon et al had lower rates than expected for short-term abstinence.6 It is not clear from the report what patient or clinician characteristics, if any, contributed to treatment success. For example, successful patients may have been more motivated or may have abused opioids for a relatively short period. Future studies should facilitate identification of patients for whom the approach by Sigmon et al is adequate. Then, clinicians will be better able to triage patients to the most appropriate treatment: methadone maintenance, buprenorphine maintenance, or buprenorphine-assisted detoxification followed by brief taper. There are several well-established methods for measuring baseline severity of opioid dependence, such as the Addiction Severity Index (ASI)7 and the Michigan Assessment-Screening Test for Alcohol and Drugs.8 These assess drug and alcohol use severity as well as multiple functional areas known to be affected by opioid abuse and dependence. Because addiction is a multidimensional disease of psychological, physiological, and social impairment, a single proxy measure for severity would not be expected to capture the entire range of disease severity or provide sufficient information to match individual patients to appropriate treatment regimens. Sigmon et al5 used baseline buprenorphine dose as a proxy for addiction seARTICLE INFORMATION Author Affiliation: Health Analytics, Science, Columbia, Maryland. Corresponding Author: Charles Ruetsch, PhD, Health Analytics, Science, 9200 Rumsey Rd, Ste 215, Columbia, MD 21045 (charles.ruetsch @healthanalytic.com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
/NSDUH/2012SummNatFindDetTables/Index.aspx. Accessed August 25, 2014.
buprenorphine dose. Am J Drug Alcohol Abuse. 2011;37(5):453-459.
3. Results from the 1992-2011 Treatment Episode Data Set: Admissions (TEDS-A): concatenated, 1992 to 2011 [ICPSR25221-v7: January 27, 2014]. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.
7. McLellan AT, Cacciola JC, Alterman AI, Rikoon SH, Carise D. The Addiction Severity Index at 25. Am J Addict. 2006;15(2):113-124.
4. Olsen Y, Sharfstein JM. Confronting the stigma of opioid use disorder—and its treatment. JAMA. 2014;311(14):1393-1394.
1. Ruetsch C. Empirical view of opioid dependence. J Manag Care Pharm. 2010;16(1)(suppl B):S9-S13.
5. Sigmon SC, Dunn KE, Saulsgiver K, et al. A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. JAMA Psychiatry. 2013; 70(12):1347-1354.
2. Results from the 2012 National Survey on Drug Use and Health. http://www.samhsa.gov/data
6. Hillhouse M, Canamar CP, Doraimani G, Thomas C, Hasson A, Ling W. Participant characteristics and
REFERENCES
1146
verity. Establishing an adequate buprenorphine dose to achieve relief of detoxification symptoms is subjective and confounded with patient physiology, experience with the medication, and provider biases.9 Future studies could better control for baseline severity of opioid use disorder using 1 or more of many available self-reported severity measures together with urine toxicology screens or other available biomarkers of drug use. All patients in the study by Sigmon et al5 reported abusing POs, implying that PO abusers may be more amenable to this brief treatment regimen than abusers of other opioids. However, it is unlikely that PO abusers are less severely addicted and more likely to respond to this study’s approach compared with heroin users. There are issues to consider before generalizing the findings by Sigmon et al into clinical practice. Basing relative severity of opioid use disorder or its resilience to treatment on the specific abused opioid molecule (heroin vs PO) may not serve in matching patient to treatment regimen. Heroin abusers are often characterized as having more severe addiction than PO abusers, but the addiction severity and response to treatment can be equivalent for these populations. However, the functional ramifications of the addictions may differ.10 In a study comparing 2 groups of patients with opioid use disorder, one group was largely urban and heroin-using, derived from the Drug Evaluation Network System, and the other group consisted of suburban PO users.10 There was little difference in opioid use severity between the groups based on the ASI7 drug composite score. However, the suburban sample who abused POs had more alcohol use, psychiatric, and family or social functioning problems. By contrast, the urban sample who largely used heroin had more legal and employment problems.10 Careful assessment of patient characteristics, background, length of time abusing opioids and other drugs and alcohol, and available social support may be more important than the specific opioid that was abused or the adequate starting dose of buprenorphine (or other MAT medicine). It cannot be assumed that PO users rather than heroin users are more likely to succeed in a detoxification with a brief taper treatment approach without follow-up maintenance. When matched to patient requirements, the treatment model studied by Sigmon et al5 adds a powerful new treatment option. By providing a simplified approach to opioid abuse treatment that works for some patients, the report by Sigmon et al should help clinicians treat an increasingly common and difficult problem.
8. Westermeyer J, Yargic I, Thuras P. Michigan assessment-screening test for alcohol and drugs (MAST/AD). Am J Addict. 2004;13(2):151-162. 9. Albright J, Ciaverelli R, Essex A, Tkacz J, Ruetsch C. Psychiatrist characteristics that influence use of buprenorphine medication-assisted treatment. J Addict Med. 2010;4(4):197-203. 10. Ruetsch C, Cacciola J, Tkacz J. A national study of a telephone support service for patients receiving office-based buprenorphine medication-assisted treatment. J Subst Abuse Treat. 2010;39(4):307-317.
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
jama.com
