Marc R. Larochelle, MD, MPH; Dana Bernson, MPH; Thomas Land, PhD; Thomas J. Stopka, PhD, MHS; Na Wang, MA; Ziming Xuan, ScD, SM; Sarah M. Bagley, MD, MSc; Jane M. Liebschutz, MD, MPH; Alexander Y. Walley, MD, MSc
Financial Support: By grant 1UL1TR001430 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Larochelle was supported by award K23 DA042168 from the National Institute on Drug Abuse and a Boston University School of Medicine Department of Medicine Career Investment Award. Dr. Stopka was supported by award 33924399 from the GE Foundation.
Disclosures: Dr. Larochelle reports grants from the National Center for Advancing Translational Sciences, National Institute on Drug Abuse, and Boston University School of Medicine Department of Medicine during the conduct of the study. Dr. Stopka reports grants from the GE Foundation during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-3107.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Larochelle (e-mail, firstname.lastname@example.org).
Corresponding Author: Marc R. Larochelle, MD, MPH, Boston Medical Center, 801 Massachusetts Avenue, 2nd Floor, Boston, MA 02118; e-mail, email@example.com.
Current Author Addresses: Drs. Larochelle, Bagley, and Walley: Boston Medical Center, 801 Massachusetts Avenue, 2nd Floor, Boston, MA 02118.
Ms. Bernson and Dr. Land: Massachusetts Department of Public Health, 250 Washington Street, 6th Floor, Boston, MA 02108.
Dr. Stopka: Tufts University School of Medicine, 136 Harrison Avenue, MV244, Boston, MA 02111.
Ms. Wang and Dr. Xuan: Boston University School of Public Health, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118.
Dr. Liebschutz: University of Pittsburgh School of Medicine Center for Research on Health Care, 200 Lothrop Street, Suite 933W, Pittsburgh, PA 15213.
Author Contributions: Conception and design: M.R. Larochelle, T. Land, S.M. Bagley, A.Y. Walley.
Analysis and interpretation of the data: M.R. Larochelle, D. Bernson, T. Land, T.J. Stopka, N. Wang, Z. Xuan, S.M. Bagley, J.M. Liebschutz, A.Y. Walley.
Drafting of the article: M.R. Larochelle, T. Land, A.Y. Walley.
Critical revision of the article for important intellectual content: M.R. Larochelle, D. Bernson, T. Land, T.J. Stopka, Z. Xuan, S.M. Bagley, J.M. Liebschutz, A.Y. Walley.
Final approval of the article: M.R. Larochelle, D. Bernson, T. Land, T.J. Stopka, N. Wang, Z. Xuan, S.M. Bagley, J.M. Liebschutz, A.Y. Walley.
Statistical expertise: T. Land, Z. Xuan.
Obtaining of funding: M.R. Larochelle, T.J. Stopka, A.Y. Walley.
Administrative, technical, or logistic support: M.R. Larochelle, D. Bernson, T. Land, A.Y. Walley.
Collection and assembly of data: M.R. Larochelle, D. Bernson, T. Land.
Opioid overdose survivors have an increased risk for death. Whether use of medications for opioid use disorder (MOUD) after overdose is associated with mortality is not known.
To identify MOUD use after opioid overdose and its association with all-cause and opioid-related mortality.
Retrospective cohort study.
7 individually linked data sets from Massachusetts government agencies.
17 568 Massachusetts adults without cancer who survived an opioid overdose between 2012 and 2014.
Three types of MOUD were examined: methadone maintenance treatment (MMT), buprenorphine, and naltrexone. Exposure to MOUD was identified at monthly intervals, and persons were considered exposed through the month after last receipt. A multivariable Cox proportional hazards model was used to examine MOUD as a monthly time-varying exposure variable to predict time to all-cause and opioid-related mortality.
In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified.
Few events among naltrexone recipients preclude confident conclusions.
A minority of opioid overdose survivors received MOUD. Buprenorphine and MMT were associated with reduced all-cause and opioid-related mortality.
National Center for Advancing Translational Sciences of the National Institutes of Health.
MOUD exposure classification.
For the primary classification (with discontinuation), MOUD exposure extends through the month after discontinuation (light and dark-green months). For the secondary classification (on treatment), exposure is limited to months in which treatment is received (light-green months only). In the illustrative examples, participant 1 is not exposed to MOUD through follow-up; participant 2 is exposed in months 1–2 and 7–12 for the primary classification and months 1 and 7–12 for the secondary classification. In the month of death, participant 3 would be considered exposed in the primary classification only, participant 4 would be considered exposed in both primary and secondary exposure classifications, and participant 5 would be considered not exposed to MOUD. MOUD = medication for opioid use disorder.
Table 1. Baseline Patient Characteristics Before and Treatments After Index Nonfatal Opioid Overdose*
Monthly receipt of treatments/services, by cohort.
In the 12 mo before and after index opioid overdose, Massachusetts, 2012–2014 (n = 17 568). MMT = methadone maintenance treatment; MOUD = medication for opioid use disorder.
* Enrollment in MMT.
† Clinical stabilization/step-down or transitional support services.
Extended Kaplan–Meier cumulative incidence of all-cause mortality (A and B) and opioid-related mortality (C and D), by monthly exposure to MOUD after index overdose.
Massachusetts, 2012–2014 (n = 17 568). MMT = methadone maintenance treatment; MOUD = medication for opioid use disorder.
* MOUD exposure extends through the month of discontinuation.
† Exposure is limited to months in which treatment was received.
Table 2. Crude Incidence Rates and Multivariable Cox Proportional Hazards Analyses for All-Cause and Opioid-Related Mortality, by Receipt of Treatments
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In this video, Marc R. Larochelle, MD, MPH, offers additional insight into the article, "Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality. A Cohort Study."
Lawrence Brennan MD
St. Elizabeth Medical Center
August 21, 2018
Motivation as a factor in recovery from addiciton
I appreciate the efforts of Dr. Larochelle and his colleagues (1) to address the association of opiate agonist therapy with subsequent mortality in people who have overdosed on opiates. They propose that enrollment in an opiate agonist program is associated with a decreased risk of mortality from both opiates and from any cause. Their subjects were persons who had a non-fatal drug overdose, and they observed fewer deaths in those who subsequently elected to enter into an opiate maintenance program. I do, however, feel compelled to point out an inherent factor that they did not address.
They do not discuss the factor of patient motivation in their article. It is logical to conclude that patients who are motivated to recover from their addiction are more likely to both enter a program, and also to stay in such a program than those not motivated. The latter group is more likely to return to their usual behavior pattern following their recovery. As a result, they can be expected to be more likely to experience an adverse effect of such behavior.
In 2006, Lee (2) reported a group of patients who had been incarcerated, and randomly assigned half to naltrexone, and the other half to usual care, which consisted of counseling and referral to outreach centers. Even in this more motivated population, the average time to relapse was only 10 weeks with naltrexone versus 5 in the control population. Kinlock (3), on the other hand, found an improvement in recidivism in a prison population. In our own community in rural Kentucky, the county jail has a naltrexone program in which, if patients test positive for drugs, it is considered a probation violation and they will go back to jail. The hope is that this will result in a cohort of people motivate to stay out of jail. The success rate still needs to be determined.
Therefore, no firm conclusions can be drawn from Dr. Larachelle’s study, other than to state that patients motivated to recover do better than those who are not as motivated. One cannot draw the conclusion that intervention with an opiate agonist had any effect upon this outcome any more than one can deny the possibility that they are effective. While difficult to do a randomized study in this patient population, an observational study such as this one is always subject to inherent flaws.
Lawrence V Brennan, M.D
Chair, Campbell County Kentucky Board of Health
1. Larochellle, MP, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, Bagley SM, Leibschutz JM, Walley AY. Medication for Opioid use disorder after nonfatal opioid overdose and association with mortality. Ann Int Med 2018; 169: 137-135. DOE 10.7326/M17-3017
2. Lee, JD, Friedmann PD, M.D., M.P.H., Kinlock T., Nunes EV, Boney TY, Hoskinson RA, Wilson D, McDonald R, Rotrosen J, Gourevitch MN, Gordon M, Fishman M, Chen DT, Bonnie RJ, Cornish JW, Murphy SM, O’Brien CP. Extended release Naltrexone to prevent opioid relapse in criminal justice offenders. New Eng J Med. 2016 N Engl J Med 2016; 374:1232-1242 DOI:10.1056/NEJMoa1505409
3. Kinlock,TW, Gordon R, Schwartz, RP, Fitzgerald TT, O’Grady KE. A randomized clinical trial of methadone maintenance for prisoners: Results at 12 months postrelease. J Subst Abuse Treat 2009, 37:3 277-285. DOI: 10.1016/jsat.2009.03.02
Marc R. Larochelle, MD, MPH Thomas J. Stopka, PhD, MHS Ziming Xuan, ScD, SM Jane M. Liebschutz, MD, MPH Alexander Y. Walley, MD, MSc
October 16, 2018
Dr. Brennan suggests that our study’s findings of reduced mortality for patients treated with methadone or buprenorphine following a nonfatal opioid overdose are compromised by not accounting for motivation as a potential confounder. We reiterate that unmeasured confounding is a limitation of our study and that findings should be interpreted as associative rather than causal. However, dismissing the results based on this argument fails to acknowledge the broader context of what is known. Multiple high quality randomized clinical trials have demonstrated a consistent benefit of methadone and buprenorphine in improving opioid use disorder outcomes, including treatment retention and suppressing opioid use.1,2 Due to the randomized design, these studies are not subject to unmeasured confounding from motivation or other factors. Our study extends prior findings by examining mortality as an outcome as well as providing evidence on “real-world” experience outside the context of a clinical trial. Motivation is a complex concept that varies with time and can be the target of addiction treatment.3 It is unclear if motivation acts as a confounder, moderator, or mediator of the treatment-outcome relationship. While motivation was not measured in our study, in a sensitivity analysis, we found comparable results when stratifying our cohort by whether or not individuals had received drug treatment in the twelve months prior to their overdose, a potential proxy for prior motivation for treatment. The focus on patient motivation fails to acknowledge addiction as a chronic disease in which people use substances compulsively despite negative consequences. Focusing on patient motivation alone stigmatizes the disease, the patients, and effective treatments. Dr. Brennan identified a local program in Kentucky that considers continued illicit drug use while receiving naltrexone to be a probation violation. The criminalization and incarceration of individuals for using substances has repeatedly failed to yield positive public health impact over decades in the United States and is bioethically unsound as a treatment strategy.4 Although legal, it is unethical to withhold effective medications and punish someone for having an uncontrolled chronic disease. Buprenorphine and methadone are established, effective treatments for opioid use disorder; they are substantially underutilized. Stigma perpetuated by providers, the criminal justice system and the general population hinders uptake.5 Efforts are urgently needed to increase the adoption of buprenorphine and methadone, and address stigma that hinders their widespread use.Sincerely,Marc R. Larochelle, MD, MPHThomas J. Stopka, PhD, MHSZiming Xuan, ScD, SMJane M. Liebschutz, MD, MPHAlexander Y. Walley, MD, MSc1. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009:CD002209.2. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2014:CD002207.3. Carroll KM, Ball SA, Nich C, et al. Motivational interviewing to improve treatment engagement and outcome in individuals seeking treatment for substance abuse: A multisite effectiveness study. Drug and Alcohol Dependence 2006;81:301-12.4. Werb D, Kamarulzaman A, Meacham MC, et al. The effectiveness of compulsory drug treatment: A systematic review. Int J Drug Policy 2016;28:1-9.5. Chou R, Korthuis PT, Weimer M, et al. Medication-Assisted Treatment Models of Care for Opioid Use Disorder in Primary Care Settings [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Dec. (Technical Briefs, No. 28.) Available from: https://www.ncbi.nlm.nih.gov/books/NBK402352/
Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, et al. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Ann Intern Med. ;169:137–145. doi: 10.7326/M17-3107
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Published: Ann Intern Med. 2018;169(3):137-145.
Published at www.annals.org on 19 June 2018
Emergency Medicine, Tobacco, Alcohol, and Other Substance Abuse.
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