Consensus Study Report

NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

This activity was supported by a contract between the National Academy of Sciences and the Department of Veterans Affairs (36C24E22C0030). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-73133-1
International Standard Book Number-10: 0-309-73133-X
Digital Object Identifier: https://doi.org/10.17226/28584
Library of Congress Control Number: 2025931448

This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu.

Copyright 2025 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved.

Printed in the United States of America.

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2025. Veterans, prescription opioids and benzodiazepines, and mortality, 2007–2019: Three target trial emulations. Washington, DC: The National Academies Press. https://doi.org/10.17226/28584.

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president.

The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president.

The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president.

The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine.

Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task.

Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies.

Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release.

For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

COMMITTEE ON EVALUATING THE EFFECTS OF OPIOIDS AND BENZODIAZEPINES ON ALL-CAUSE MORTALITY IN VETERANS

BRIAN L. STROM (Chair), Rutgers, The State University of New Jersey

AMY S. B. BOHNERT, University of Michigan and VA Center for Clinical Management Research

ADAM P. BRESS, University of Utah and VA Salt Lake City Health Care System

CARL CASTRO, University of Southern California

LESLEY H. CURTIS, Duke University

PATIENCE MOYO DOW, Brown University

JOHN FARRAR, University of Pennsylvania

ROBERT D. KERNS, Yale University

MATHEW V. KIANG, Stanford University

HSIEN-CHANG LIN, San Diego State University

MIGUEL MARINO, Oregon Health & Science University

ANNE MARIE MCKENZIE-BROWN, Emory University

KATIE J. SUDA, University of Pittsburgh and VA Pittsburgh Healthcare System

National Academy of Medicine Osteopathic Medicine Fellow

R. STERLING HARING, Interventional Pain Physician at Southwell (until August 2024)

Study Staff

DONNA ALMARIO DOEBLER, Senior Program Officer

AASHAKA SHINDE, Associate Program Officer

EMMA FLETCHER, Research Associate

MIA SALTRELLI, Senior Program Assistant

GRACE READING, Senior Program Assistant (through October 2024)

ROSE MARIE MARTINEZ, Senior Board Director

Y. CRYSTI PARK, Program Coordinator

Consultants

Westat Consultants

JOSEPH GASPER

JENNIFER EDWARDS

ANNE ROUBAL

CHRIS MANGLITZ

SHERRIE JI

CARINA TORNOW

University of Pennsylvania’s Center for Evidence Based Practice

NIKHIL MULL

BRIAN LEAS

SHAZIA MEHMOOD SIDDIQUE

This page intentionally left blank.

Reviewers

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following individuals for their review of this report:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by LINDA C. DEGUTIS, Yale School of Public Health, and DAN G. BLAZER, II, Duke University Medical Center. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

This page intentionally left blank.

Acknowledgments

Many people were critical in helping the committee complete this report and accomplish its charge. The committee sincerely appreciates the speakers at its public meetings, whose participation ensured that our public meetings would include a collection of relevant and diverse viewpoints, which allowed us to learn about Department of Veterans Affairs policies, and prescribing practices surrounding opioids and benzodiazepines, as well as the effects of their co-prescribing, which were central to our charge.

The committee is also grateful for the support provided by our Westat consultants: Joseph Gasper, Jennifer Edwards, Anne Roubal, Chris Manglitz, Sherrie Ji, and Carina Tornow. Additionally, the committee’s work benefited from consultation with the University of Pennsylvania’s Center for Evidence Based Practice with Nikhil Mull, Brian Leas, and Shazia Mehmood Siddique regarding existing literature on opioid tapering practices and its effects on mortality.

The committee thanks the staff of the National Academies of Sciences, Engineering, and Medicine who contributed to producing this report, especially the remarkable, dedicated, and tireless study staff as well as other staff in the Health and Medicine Division who provided additional support, including Monica Feit, Samantha Chao, Amber McLaughlin, Marguerite Romatelli, Leslie Sim, Taryn Young, and Lori Brenig. This project also received important guidance from Megan Lowry (Office of News and Public Information), Wahidullah Nazari and Misrak Dabi (Office of Financial Administration), and Constance Citro (NASEM IRB). Valuable research assistance was provided by Anne Marie Houppert and Rebecca Morgan, senior research librarians at the National Academies Research Center. Finally, gratitude is expressed to Tasha Bigelow, who assisted the committee with editing the report.

This page intentionally left blank.

Contents

ABSTRACT

SUMMARY

Context of the Opioid Epidemic

Clinical Guidelines, Policies, and Legislation Relevant to Understanding the Context of the Opioid Epidemic

Congressional Mandate to Address Concerns About Prescribing Opioids and Benzodiazepines in the Veteran Population

Study Charge and Approach

Analytic Approach

Findings

Conclusions

1 INTRODUCTION

Overview

Context of the Opioid Epidemic

Congressional Mandate to Address Concerns About Prescribing Opioids and Benzodiazepines in the Veteran Population

Statement of Task

Approach to the Task and Organization of the Report

References

2 A HISTORY OF THE POLICY LANDSCAPE

Strategies Implemented to Combat the Opioid Epidemic

References

3 SETTING THE STAGE

Introduction

Target Trial Emulation Framework

Application of Target Trial Emulation Framework to Address the Statement of Task

Developing the Causal Research Questions from the Statement of Task

Study Population, Data Sources, and Medications of Interest

Specifications for the Emulated Target Trials

Limitations

References

4 THE EFFECT OF OPIOID PRESCRIPTION ON ALL-CAUSE MORTALITY, INCLUDING SUICIDE MORTALITY, AMONG THOSE WITHOUT AND WITH CURRENT BENZODIAZEPINE PRESCRIPTION

Introduction

Study 1 Methods

Specifications for the Emulated Target Trial 1

Results

Discussion

Findings

Conclusions

Annex: Supplementary Figures and Tables

References

5 THE EFFECT OF OPIOID ESCALATION ON ALL-CAUSE MORTALITY, INCLUDING SUICIDE MORTALITY

Introduction

Study 2 Methods

Specifications for the Emulated Target Trial 2

Results

Discussion

Findings

Conclusions

Annex: Supplementary Figures and Tables

References

6 THE EFFECT OF BENZODIAZEPINE CO-PRESCRIBING ON ALL-CAUSE MORTALITY, INCLUDING SUICIDE MORTALITY, AMONG INDIVIDUALS ON CONSISTENT OPIOID PHARMACOTHERAPY

Introduction

Study 3 Methods

Specifications for the Emulated Target Trial 3

Results

Discussion

Findings

Conclusions

Annex: Supplementary Figures and Tables

References

APPENDIXES

A Committee Member and Staff Biosketches

B Open Session Meeting Agendas

C Public Law 116-171

D Detailed Policy Landscape

E Opioid Tapering and All-Cause Mortality, Including Suicide Mortality

F Report of Preliminary Results: Opioid Dose Reduction Trial Emulation

G Perspectives from the Department of Veterans Affairs PAIN/Opioid Consortium on Research Veteran Engagement Panel

H Approach to Data Analysis and Code Library

I Covariate International Classification Disease Code Table

This page intentionally left blank.

Boxes, Figures, and Tables

BOXES

S-1 Statement of Task

1-1 Physiology of Respiratory Depression

1-2 Statement of Task

FIGURES

2-1 Timeline of relevant federal laws, clinical guidelines, and policies related to opioid prescribing in the United States (2001–2024)

4-1 Study 1 design

4-2 Selection of veterans in study 1 through each stage of the emulated target trial (2007–2019)

4-3 Study 1a. Among veterans without a current dispensed benzodiazepine pharmacotherapy, adjusted survival curves for all-cause mortality (top panel) and suicide mortality (bottom panel) in those newly dispensed opioid pharmacotherapy compared to veterans newly dispensed non-opioid pain pharmacotherapy (2007–2019; N = 5,636,207)

4-4 Study 1b. Among veterans with a current dispensed benzodiazepine pharmacotherapy, adjusted survival curves for all-cause mortality (top panel) and suicide mortality (bottom panel) in those newly dispensed opioid pharmacotherapy compared to veterans newly dispensed non-opioid pain pharmacotherapy (2007–2019; N = 319,990)

4-5 Study 1a. Among veterans without a current benzodiazepine pharmacotherapy, propensity score distribution of initiating opioid pharmacotherapy among those newly dispensed opioid pharmacotherapy (top panel) and those newly dispensed non-opioid pain pharmacotherapy (bottom panel) (2007–2019; N = 5,636,207)

4-6 Study 1a. Among veterans without current benzodiazepine pharmacotherapy, baseline covariate balance between those newly dispensed opioid pharmacotherapy compared to those newly dispensed non-opioid pain pharmacotherapy before and after inverse probability treatment weights (IPTW) (2007–2019; N = 5,636,207)

4-7 Study 1a. Time to discontinuation. Among veterans without current benzodiazepine pharmacotherapy, time to discontinuation of pharmacotherapy in those newly dispensed opioid pharmacotherapy compared to those newly dispensed non-opioid pain pharmacotherapy (2007–2019; N=5,636,207)

4-8 Study 1a. Among those without current benzodiazepine pharmacotherapy, the adjusted hazard ratios of all-cause mortality between veterans newly dispensed opioid pharmacotherapy versus veterans newly dispensed non-opioid pain pharmacotherapy by subgroups (forest plots)

4-9 Study 1a. Among those without current benzodiazepine pharmacotherapy, the adjusted hazard ratios of suicide mortality between veterans with newly dispensed opioid pharmacotherapy versus veterans with non-opioid pain pharmacotherapy subgroups (forest plots)

4-10 Study 1b. Among veterans with current benzodiazepine pharmacotherapy, propensity score distribution of newly dispensed opioid pharmacotherapy among those newly dispensed opioid pharmacotherapy (top panel) and those newly dispensed non-opioid pain pharmacotherapy (bottom panel) (2007–2019; N = 319,990)

4-11 Study 1b. Among veterans with a current dispensed benzodiazepine pharmacotherapy, baseline covariate balance between those newly dispensed opioid pharmacotherapy compared to those newly dispensed non-opioid pain pharmacotherapy before and after inverse probability treatment weights (IPTW) (2007–2019; N = 319,990)

4-12 Study 1b. Time to discontinuation. Among veterans with a current dispensed benzodiazepine pharmacotherapy, time to discontinuation of treatment in those newly dispensed opioid pharmacotherapy compared to those newly dispensed non-opioid pharmacotherapy (2007–2019; N = 319,990)

4-13 Study 1b. Among those with a current dispensed benzodiazepine pharmacotherapy, adjusted hazard ratios of all-cause mortality between newly dispensed opioid pharmacotherapy versus non-opioid pain pharmacotherapy by subgroups, 2007–2019; N = 319,990) (forest plots)

4-14 Study 1b. Among those with a current dispensed benzodiazepine pharmacotherapy, adjusted hazard ratios of suicide mortality between veterans with newly dispensed opioid pharmacotherapy versus veterans with newly dispensed non-opioid pain pharmacotherapy by subgroups (2007–2019; N = 319,990) (forest plots)

5-1 Study 2 design

5-2 Selection of veterans through each stage of the emulated target trials (study 2a and study 2b) (2007–2019)

6-1 Study 3 design

6-2 Selection of veterans for the emulation of a target trial evaluating the effects of newly dispensed benzodiazepine versus alternative non-benzodiazepine pharmacotherapy, among individuals consistently dispensed opioid pharmacotherapy

6-3 Among VHA veterans consistently dispensed opioid pharmacotherapy, adjusted survival curves for all-cause mortality (top panel) and suicide mortality (bottom panel) among those newly dispensed benzodiazepine pharmacotherapy versus non-benzodiazepine pharmacotherapy at 3 months (2007–2019) (veterans: N = 637,793, veteran episodes: n = 1,379,093)

6-4 Among VHA veterans consistently dispensed opioid pharmacotherapy, distribution of the propensity scores for those newly dispensed benzodiazepine pharmacotherapy (top panel) versus those newly dispensed alternative non-benzodiazepine pharmacotherapy (bottom panel)

6-5 Among VHA veterans consistently dispensed opioid pharmacotherapy, baseline covariate balance between those newly dispensed benzodiazepine pharmacotherapy versus those newly dispensed alternative non-benzodiazepine pharmacotherapy before and after inverse probability treatment weights (IPTW)

6-6 Among VHA veterans consistently dispensed opioid pharmacotherapy, newly dispensed benzodiazepine pharmacotherapy versus alternative non-benzodiazepine pharmacotherapy on weighted all-cause mortality in subgroup forest plots

6-7 Among VHA veterans consistently dispensed opioid pharmacotherapy, adjusted hazard ratios of suicide mortality between those newly dispensed benzodiazepine pharmacotherapy versus alternative non-benzodiazepine pharmacotherapy by subgroup

6-8 Among VHA veterans consistently dispensed opioid pharmacotherapy, adjusted survival curves for all-cause mortality (top panel) and suicide mortality (bottom panel) among those newly dispensed benzodiazepine pharmacotherapy versus alternative non-benzodiazepine pharmacotherapy within 12 months (2007–2019)

E-1 Study flow diagram

E-2 Year of publication of included studies

F-1 Selection of patients

F-2 Mean daily dosage over 12 months by treatment group, within baseline dose categories

F-3 Opioid dosage for a hypothetical patient

F-4 Cloning and censoring for two hypothetical patients

F-5 Standardized mean difference (%) in potential confounders at 6 months after inverse- probability-of-censoring weighting (IPCW) for small decrease group versus no decrease group

F-6 Standardized mean difference (%) in potential confounders at 6 months after inverse- probability-of-censoring weighting (IPCW) for the large decrease group versus no decrease group

TABLES

S-1 Study 1a Results. The Effect of Newly Dispensed Opioid Pharmacotherapy on All-Cause Mortality, Including Suicide Mortality, Among VHA Veterans Without Current Benzodiazepine Pharmacotherapy (2007–2019; N = 5,636,207)

S-2 Study 1b Results. The Effect of Newly Dispensed Opioid Pharmacotherapy^† on All-Cause Mortality, and Suicide Mortality Among VHA Veterans with Current Benzodiazepine Pharmacotherapy (2007–2019; N = 319,990)

S-3 Study 2a Results. Among VHA Veterans Newly Dispensed Full Agonist Opioid Pharmacotherapy, the Estimated Risk of All-Cause Mortality and Risk Ratio by Initial Opioid Dosage (2007–2019; N = 5,639,108)

S-4 Study 2b Results. Among VHA Veterans Newly Dispensed Full Agonist Opioid Pharmacotherapy, the Estimated Risk of All-Cause Mortality and Risk Ratio by Dosage Escalation Strategies (2007–2019; N = 5,639,108)

S-5 Study 3. The Effect of Benzodiazepine Pharmacotherapy Co-Prescribing on All-Cause Mortality, Including Suicide Mortality, Among VHA Veterans with Consistently Dispensed Opioid Pharmacotherapy (2007–2019; N = 637,793)

2-1 Opioid Policy Landscape

3-1 Assumptions Required for Valid Causal Inference

3-2 Pharmacotherapy by Drug Class Included by Study

3-3 Key Components of a Target Trial Protocol

3-4 Key Methodological Terms: National Academies VA Opioids Study

4-1 Specifications for Study 1 Target Trial Protocol

4-2 Pharmacotherapies of Interest in Study 1

4-3 Study 1a. Among Veterans Without a Current Dispensed Benzodiazepine Pharmacotherapy, Baseline Characteristics of Individuals Before and After Inverse Probability Treatment Weights (IPTW) (2007–2019; N = 5,636,207)

4-4 Study 1a. Among Veterans Without a Current Dispensed Benzodiazepine Pharmacotherapy, Unweighted and Adjusted All-Cause and Suicide Mortality Rates and Hazard Ratios in Veterans Newly Dispensed Opioid Pharmacotherapy Compared to Veterans Newly Dispensed Non-Opioid Pain Pharmacotherapy (2007–2019; N = 5,636,207)

4-5 Study 1b. Among Veterans with a Current Dispensed Benzodiazepine Pharmacotherapy, Baseline Characteristics of Individuals Before and After IPTW (2007–2019; N = 319,990)

4-6 Study 1b. Among Veterans with Current Dispensed Benzodiazepine Pharmacotherapy, Unweighted and Adjusted All-Cause and Suicide Mortality Rates and Hazard Ratios in Veterans Newly Dispensed Opioid Pharmacotherapy Compared to Veterans Newly Dispensed Non-Opioid Pain Pharmacotherapy (2007–2019; N = 319,990)

4-7 Study 1a. Subgroup Results—All-Cause Mortality: Among Veterans Without Current Dispensed Benzodiazepine Pharmacotherapy, Adjusted Mortality Rates and Hazard Ratios of All-Cause Mortality Between Individuals Newly Dispensed Opioid Pharmacotherapy Compared to Those Newly Dispensed Non-Opioid Pain Pharmacotherapy by Subgroups (2007–2019; N = 5,636,207)

4-8 Study 1a. Subgroup Results—Suicide Mortality: Among Veterans Without Current Benzodiazepine Pharmacotherapy, Adjusted Mortality Rates and Hazard Ratios of Suicide Mortality Between Individuals Newly Dispensed Opioid Pharmacotherapy Compared to Those Newly Dispensed Non-Opioid Pain Pharmacotherapy by Subgroups (2007–2019; N = 5,636,207)

4-9 Study 1b. Subgroup Results—All-Cause Mortality: Among Veterans with Current Dispensed Benzodiazepine Pharmacotherapy, Adjusted Mortality Rates and Hazard Ratios of All-Cause Mortality Between Individuals Newly Dispensed Opioid Pharmacotherapy Compared to Those Newly Dispensed Non-Opioid Pain Pharmacotherapy by Subgroups (2007–2019; N = 319,990)

4-10 Study 1b. Subgroup Results—Suicide Mortality: Among Veterans with Current Dispensed Benzodiazepine Pharmacotherapy, Adjusted Mortality Rates and Hazard Ratios of Suicide Mortality Between Individuals Newly Dispensed Opioid Pharmacotherapy Compared to Those Newly Dispensed Non-Opioid Pain Pharmacotherapy by Subgroups (2007–2019; N = 319,990)

4-11 Study 1a. Missing Percentages of Variables in the Model. Among Those Without Current Benzodiazepine Pharmacotherapy, Missingness of Variables Included in the Current Analysis by Total, Those Newly Dispensed Opioid Pharmacotherapy, and Those Newly Dispensed Non-Opioid Pain Pharmacotherapy (2007–2019; N = 5,636,207)

4-12 Study 1b. Missing Percentages of Variables in the Model. Among Those with a Current Dispensed Benzodiazepine Pharmacotherapy, Missingness of Variables Included in the Current Analysis by Total, Those Newly Dispensed Opioid Pharmacotherapy, and Those Newly Dispensed Non-Opioid Pain Pharmacotherapy (2007–2019; N = 319,990)

5-1 Specifications for Study 2 Target Trial Protocol

5-2 Study 2a. Initial Dosage Strategies

5-3 Study 2b. Dosage Escalation Trajectories

5-4 Pharmacotherapies of Interest in Study 2

5-5 Among VHA Veterans Newly Dispensed Full-Agonist Opioid Pharmacotherapy, Baseline Characteristics of Individuals (2007–2019; N = 5,639,108)

5-6 Study 2a. Among VHA Veterans Newly Dispensed Full-Agonist Opioid Pharmacotherapy, Estimated Risk of All-Cause Mortality and Risk Ratio by Initial Dosage (2007–2019; N = 5,639,108)

5-7 Study 2b. Among VHA Veterans Newly Dispensed Full-Agonist Opioid Pharmacotherapy, Estimated Risk of All-Cause Mortality and Risk Ratio by Dosage Escalation Strategies (2007–2019; N = 5,639,108)

5-8 Missing Percentages of Variables in the Model. Among VHA Veterans Newly Dispensed Full-Agonist Opioid Pharmacotherapy, Missingness of Variables Included in the Current Analysis (2007–2019; N = 5,639,108)

6-1 Specifications for Study 3 Target Trial Protocol

6-2 Pharmacotherapies of Interest in Study 3

6-3 Among VHA Veterans Consistently Dispensed Opioid Pharmacotherapy, Baseline Characteristics of Veterans Included in the Current Analysis by Newly Dispensed Pharmacotherapy Group (Benzodiazepine Pharmacotherapy Versus Alternative Non-Benzodiazepine Pharmacotherapy) Before and After Inverse Probability Treatment Weights (IPTW) (2007–2019)

6-4 Among VHA Veterans Consistently Dispensed Opioid Pharmacotherapy, All-Cause Mortality and Suicide Mortality Rates and Hazard Ratios in Those Newly Dispensed Benzodiazepine Pharmacotherapy Versus Alternative Non-Benzodiazepine Pharmacotherapy at 3 Months (2007–2019) (veterans: N = 637,793, veteran episodes: n = 1,379,093)

6-5 Among VHA Veterans Consistently Dispensed Opioid Pharmacotherapy, Inverse Probability Treatment Weighting Death Rates and Hazard Ratios for the All-Cause Mortality and Suicide Mortality Overall at 3 Months with Any Amount of Benzodiazepine and Sensitivity Analysis Outcomes (Those Dispensed at Least Five Tablets of Benzodiazepines Versus Alternative Non-Benzodiazepine Over 3 Months or Those Dispensed at Least One Tablet with an Extended Follow-Up (12 months) (2007–2019)

6-6 Among VHA Veterans Consistently Dispensed Opioid Pharmacotherapy, Missingness of Variables Included in the Current Analysis by Total, by Those Newly Dispensed Benzodiazepine Pharmacotherapy or Alternative Non-Benzodiazepine Pharmacotherapy

6-7 Subgroup and Sensitivity Results—All-Cause Mortality. Among VHA Veterans Consistently Dispensed Opioid Pharmacotherapy, Adjusted All-Cause Mortality Rates and Hazard Ratios Between Individuals Newly Dispensed Benzodiazepine Pharmacotherapy Compared to Those Newly Dispensed Alternative Non-Benzodiazepine Pharmacotherapy

6-8 Subgroup and Sensitivity Results—Suicide Mortality. Among VHA Veterans Consistently Dispensed Opioid Pharmacotherapy, Adjusted Suicide Mortality Rates and Hazard Ratios Between Individuals Newly Dispensed Benzodiazepine Pharmacotherapy Compared to Those Newly Dispensed Alternative Non-Benzodiazepine Pharmacotherapy

E-1 Studies Examining the Effect of Opioid Tapering on All-Cause and Suicide Mortality

E-2 Randomized Controlled Trial Studies Identified from Search of NIH Reporter, ClinicalTrials.gov, and PCORI Portfolio

E-3 Exclusion Criteria

E-4 Study Data

E-5 Study Design

E-6 Mortality Results

E-7 Nonfatal Adverse Outcomes

E-8 Health Care Utilization

E-9 Interpreting Risk of Bias Assessment by Domain for ROBINS-I

E-10 Overall Risk of Bias Assessment for ROBINS-I

F-1 Target Trial and Observational Trial Emulation Design Features

F-2 Unadjusted Deaths Within One Year According to Trial Emulation Treatment Group Assignment (N = 207,204)

F-3 Weighted Estimates of the Effect of Dose Reduction Strategies vs. No Dose Reduction Control on Time to All-Cause Mortality with 1-Year Follow-Up Time, Overall and by Baseline Dosage Category, Hazard Ratio (95% CI)

F-4 Timing of Opioid “Restart” Among 16,646 Patients Who Filled an Opioid Prescription After the First Month with a Daily Dosage of 0 Mg

F-5 Weighted Estimates of the Effect of Dose Reduction Strategies vs. No Dose Reduction Control on Time to All-Cause Mortality with 1-Year Follow-Up Time, Overall and by Baseline Dosage Category, with Exploratory Subgroup Analysis Within Large Dose Reduction Treatment Group, Hazard Ratio (95% CI)

F-6 Qualifying Opioid Analgesics Indicated for Chronic Pain Treatment with Conversion Factors for Dosage Calculations

F-7 Baseline Characteristics by Trial Emulation Treatment Group Assignment for Patients Who Had At Least One Follow-Up Data Point* (N = 206,353)

F-8 Baseline Characteristics by Vital Status at One Year (N = 207,204)

H-1 Data Preparation Programs

H-2 Data Analysis Programs

I-1 Covariate International Classification of Diseases (ICD) Codes

Preface

Prescribing patterns for opioids and benzodiazepines, and the outcomes associated with the use of these medications, especially in the veteran population, have been of long-standing concern to researchers and policy makers alike. Recent questions have raised concerns that the concomitant use of these medications may be contributing to increased mortality via a variety of pathways of action. To address these questions, the National Academies of Sciences, Engineering, and Medicine (the National Academies) Committee on Evaluating the Effects of Opioids and Benzodiazepines on All-Cause Mortality in Veterans was charged with doing the new analyses needed to determine the effects of opioid and benzodiazepine prescribing on the risk of death among veterans who received care from the Department of Veterans Affairs (VA) between 2007 and 2019. The wide scope, practical challenges, and far-reaching consequences of addressing this question presented a humbling prospect for me and my fellow committee members.

The committee’s deliberations also touched on other questions and topics of public health significance, such as the difficulty in measuring the access to and use of unprescribed opioid and benzodiazepines and a lack of dialogue between data sources concerning veterans’ access to medications. Ultimately, we could only accept that these challenges are insurmountable in the context of these analyses and address them analytically and in our stated limitations.

To begin to accomplish our charge and ensure that our deliberations were well informed, in addition to drawing on published literature, we heard from a variety of expert speakers, veterans, and veteran advocates. The public was also free to submit testimony to the committee. In its closed sessions, the committee deliberated on the design recommendations from the 2019 report on this same topic and worked to identify the best strategies to address adequately its charge while working around the analytical obstacles presented to it. Ultimately, the committee met over 11 times to deliberate on the design and later the results and met regularly in smaller groups to prepare this report.

We are greatly appreciative of the support provided by the study staff, who worked tirelessly over many months to support our deliberations and report writing. The committee would like to specifically thank Donna Almario Doebler, who served as study director and provided both assistance and direction to the committee’s work, and Rose Marie Martinez, for her insight and feedback on the report. Other members of the National Academies staff who supported this study include Aashaka Shinde, Emma Fletcher, Mia Saltrelli, and Grace Reading. We would

also like to thank Anne Roubal, Jennifer Edwards, and Joseph Gasper from Westat. The committee would also like to acknowledge Amanda Borsky, Jenifer Stelmack, and Lolita Kachay at the VA for facilitating data access.

Last, as committee chair, I would especially like to thank my colleagues, many of whom are first-time National Academies committee members, for serving as an exceptional team, and sharing their time and expertise for this project over almost 3 years. They put in tremendous work and creative and careful methodologic and clinical insight, providing drafts of the report text and critiquing each other’s work to ensure that the report was concise, and the methods used were at the cutting edge of research.

Brian L. Strom, Chair
Committee on Evaluating the Effects of Opioids and Benzodiazepines on All-Cause Mortality in Veterans

Acronyms and Abbreviations

This page intentionally left blank.