Veterans, Prescription Opioids and Benzodiazepines, and Mortality, 2007–2019: Three Target Trial Emulations (2025)
Chapter: 1 Introduction
1
Introduction
OVERVIEW
Deaths associated with the co-prescribing of opioid and benzodiazepine pharmacotherapy have raised concerns among health care providers, federal agencies, and the public. Concerns about the outcomes associated with prescribing patterns of opioid pharmacotherapy, benzodiazepine pharmacotherapy, and opioid-benzodiazepine co-prescribing persist, given the high prevalence of pain with evidence of less-than-optimal management and high rates of excessive prescription and nonprescription opioid use, misuse, and opioid use disorder (OUD) and related harms, including overdose and mortality. This chapter provides an overview of the trends in prescribing of opioid, benzodiazepine, and concomitant opioid and benzodiazepine pharmacotherapies in the context of the opioid epidemic and the need for pain management among the veteran population. This chapter also describes the committee’s approach in addressing the statement of task. In Chapter 2, the committee describes the clinical practice guidelines, policies, and federal legislations relevant to understanding the context of the opioid epidemic, which developed over several decades as a result of complex, interconnected factors and therapeutic decisions made by clinicians, health systems, regulators, and professional organizations to address growing concerns about unrelieved pain (Jones et al., 2018). This report does not explore the full history as to how, and why, the opioid epidemic came to be, as it has been discussed at length in prior National Academies of Sciences, Engineering, and Medicine (National Academies) reports (NASEM, 2017, 2020; IOM, 2011). This chapter provides a brief summary of the opioid epidemic in the context of the committee’s study period (2007–2019).
CONTEXT OF THE OPIOID EPIDEMIC
Pain Is, and Continues to Be, a Public Health Challenge
Multiple factors contribute to pain as an ongoing public challenge, as outlined in the 2011 Institute of Medicine (IOM) report Relieving Pain in America, specifically the large number of people impacted, disparities in pain prevalence and treatment, differences in the burden on different subgroups, large indirect and direct economic impact on individuals and society, and consequential impact of pain treatments. Pain, defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” (Raja et al., 2020), has been linked to higher rates of morbidity, mortality, suicide, and disability (IOM, 2011). Furthermore, there is a clear association between pain and mental health. Pain, particularly chronic pain,
and psychiatric disorders tend to co-occur, and the presence of more than one psychiatric disorder is significantly associated with increased pain-related disability (APA, 2020; McWilliams et al., 2003). The treatment of pain is complex given the heterogeneity of individuals experiencing pain, the need for multimodal approaches to therapy, a lack of understanding of why individuals transition from acute to chronic pain,1 and the overlapping effects of pain with depression, anxiety, and other psychosocial conditions (IPRCC, 2016; IOM, 2011). The effective treatment of chronic pain almost always requires multidisciplinary and multimodal approaches.
Opioid Pharmacotherapy Helps Manage Pain but Can Contribute to Adverse Outcomes, Including Mortality
In the mid-1990s, professional societies, patients, and patient advocacy groups argued that there was an epidemic of untreated pain, and wider use of opioid pharmacotherapy was encouraged (Evans et al., 2019; NASEM, 2019). In 1995, the Food and Drug Administration (FDA) approved the controlled-release formulation of Oxy-Contin™ (FDA, 2024), an extended-release semisynthetic opioid produced by Purdue Pharmaceuticals (DEA, 2023; Tompkins et al., 2017; Van Zee, 2009). For a variety of reasons described elsewhere, a marked increase in prescribing of opioid pharmacotherapy occurred in the United States from the mid-1990s to around 2012 (NASEM, 2019; Guy et al., 2017). The populations impacted by changes in access to opioids were not affected equally, with varying outcomes between racial and ethnic groups as well as across different geographic locations (Hirani et al., 2024; NIDA, 2024a; Wilkes et al., 2021; Schieber et al., 2019).
Although opioid pharmacotherapies are prescribed to control pain, they are known to produce feelings of euphoria and sedation, which may contribute to opioid misuse and increased risk of overdose and other drug-related problems (Schuckit, 2016). However, rapid increases in opioid medication dosage can inhibit respiration and even lead to death (Schuckit, 2016). Receiving higher amounts of morphine milligram equivalents is associated with increased risk of tolerance, dependence, OUD,2 overdose, mortality, and suicide.
Increases in opioid medication prescribing coincided with rising mortality from OUD. Between 2001 and 2016, U.S. opioid-related mortality increased by 345 percent, from 9,489 to 42,245 deaths (NIDA, 2024b; Gomes et al., 2018; Bohnert et al., 2011). In 1999, the number of deaths due to opioid overdose (excluding non-methadone synthetics) was 3,300 (1.2 per 100,000 population), increasing to 12,195 (4.0 per 100,000) by 2007, reaching its peak in 2011 at 14,251 (4.6 per 100,000) and then decreasing to 8,263 (2.4 per 100,000) in 2019 (NIDA, 2024b). Studies also document an increasing risk of suicide (fatal or attempted) during this same period (Fenton et al., 2022; Oliva et al., 2020; Ashrafioun et al., 2019; Gordon and Volkow, 2019). These trends are compounded by the increased use of illicit synthetic opioids, which are now the main drivers of drug overdose deaths (CDC, 2023).
The Co-Occurrence of Opioids and Benzodiazepines in Overdose Death Raised Concerns About Co-Prescribing
Whereas opioid pharmacotherapy is primarily prescribed for pain, benzodiazepine pharmacotherapy is typically prescribed for anxiety, panic disorders, insomnia, and to reduce seizures (Edinoff et al., 2021; FDA, 2020; Lembke et al., 2018; Olfson et al., 2015). Between 2002 and 2014, the percentage of outpatient individuals nationally prescribed both opioid and benzodiazepine pharmacotherapies increased from 6.8 to 9.6 percent, with more than half of individuals receiving both prescriptions from the same prescribers (NASEM, 2019; Hwang et al., 2016). Since 2016, the percentage of patients co-prescribed these pharmacotherapies has decreased (IQVIA Institute, 2020). In the United States, the percent of individuals with a concomitant prescription continued its decline, from 10.5 percent in 2017 to 8.3 in 2019.3
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1 Acute pain defined as pain, usually resulting from injury, surgery, or trauma, that lasts for less than 3 months, disappearing when the underlying cause is treated (IASP, 2021). Chronic pain is defined as pain persisting longer than the expected, such as at least 3 months, for healing or pain (IASP, 2021; NASEM, 2019; Treede et al., 2019; Rosenblum et al., 2008; Ashburn and Staats, 1999).
2 The Diagnostic and Statistical Manual of Mental Disorders defined OUD as “a problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the [11 diagnostic criteria], occurring within a 12-month period” (APA, 2013).
3 Dr. Christopher Jones. Presentation to the committee on March 9, 2023. Trends in Opioid and Benzodiazepine Use, Misuse, and Overdose.
BOX 1-1
Physiology of Respiratory Depression
Our understanding of the control mechanisms for respiration and what can lead to respiratory depression has progressed substantially in the last 30 years. The control of respiration is a critical component of maintaining the homeostatic conditions necessary for life. The primary sites of respiratory control are the brain stem and peripheral sensors, specifically the carotid body. The three primary blood-level drivers of breathing are hypercapnia (increasing amounts of carbon dioxide), lower Ph (increased amount of acidity), and hypoxia (lack of sufficient oxygen). A number of drugs affect one or more of these components, and combined effects can lead to greater suppression that potentially leads to respiratory arrest and death.
Opioids have been shown to directly suppress the sensitivity of central chemoreceptors to CO2 in the medulla, resulting in suppression of the respiratory response to blood carbon dioxide levels in a dose-dependent manner in normal individuals (Radke et al., 2014; Cepeda et al., 2001). At higher doses, opioids also lead to central nervous system (CNS) depression that reduces overall brain activity, including the respiratory center’s response to hypoxia (lower oxygen levels), which can lead to respiratory arrest and death. Benzodiazepines are not known to have direct effects on the respiratory centers at normal doses in normal individuals (Mak et al., 1993). At higher doses, they do cause dose-dependent CNS depression by reducing overall brain activity, including respiratory centers, which can lead to respiratory depression. The amount of respiratory depression is variable across drugs and individuals, especially with the more rapid-onset intravenous administration of drugs, such as midazolam (Murciano et al., 1993; Forster et al., 1983). These components of respiratory depression are the most apparent when treating people who are drug naïve and need acute therapy, such as perioperatively. Given the substantial variability in patients’ responses to opioids and benzodiazepines, careful monitoring of patients in the post-anesthesia care unit is imperative to prevent clinically relevant respiratory depression.
In chronic use, the relationship is more complex, with a demonstration of significant tolerance to opioid respiratory depression (Algera et al., 2021) and reduction in receptor sensitivity in chronic benzodiazepine users (Potokar et al., 1999). While the risk of respiratory depression can be quite different than that seen in acute use (Teichtahl et al., 2005), it remains a potential danger in overdose situations when the doses taken are substantially higher than the patient’s usual dose.
The combination of opioid and benzodiazepine pharmacotherapies is known to have potential adverse respiratory effects, as the sedating effects of benzodiazepines can further suppress breathing in individuals experiencing opioid-induced respiratory depression (Box 1-1). Data on causes of death in overdose fatalities collected and published by the National Institute of Drug Abuse indicate that the percent of overdose deaths with concomitant benzodiazepine pharmacotherapy rose dramatically in the initial period of the opioid epidemic from 1999 to 2010, maintaining its peak through 2012, and has been falling slowly since (NIDA, 2023; Guy et al., 2017). However, the level of risk and the relationship of these deaths to the concomitant prescribing of opioid and benzodiazepine pharmacotherapies compared to the use of other pharmacotherapies has never been carefully studied.
Using 2013–2014 Medicare Part D data, Hernandez and colleagues (2018) found that in the first 90 days of concomitant use of opioid and benzodiazepine pharmacotherapies, the risk of opioid-related overdose was five times greater than among those using only opioid pharmacotherapy (NASEM, 2019). Overdose mortality resulting from concomitant benzodiazepine and opioid pharmacotherapies more than doubled from 2007 to 2019, although the percentage of all overdose deaths due to benzodiazepine and opioid pharmacotherapies have increased slightly (10.0 to 11.8 percent). Between 2007 and 2019, the percent of overdose deaths attributable to benzodiazepine and synthetic opioid medications (not methadone) increased (from 1.2 to 7.3 percent) (NIDA, 2023).
Pain and Opioid Prescribing in the Veteran Population
Studies have demonstrated that a higher percentage of veterans4 experience pain compared to non-veterans (civilians), which is attributable to the physical demands of military service, including training and combat-related injuries (Reif et al., 2018; Nahin, 2017; Gironda et al., 2006; Clark, 2004). Veterans5 are also more likely to experience chronic health conditions, psychological distress, and a higher incidence of suicide than non-veterans (Moore et al., 2023; VA, 2018; Nahin, 2017; Kramarow and Pastor, 2012). As a result, veterans are more likely than the general population to need care for chronic pain and other conditions.
About 9 million U.S. veterans receive health care services from the Veterans Health Administration (VHA) each year (VA, 2023). The VHA is the largest integrated U.S. health care network, with over 1,300 health care facilities, including over 170 medical centers and 1,100 outpatient clinics (VA, 2024). Through the VHA’s integrated health care system, eligible veterans can receive the full array of health care services, including primary, specialty, and tertiary care. Additional services and care for eligible veterans include home health, long-term care, and coverage for prescriptions and prosthetic devices. The VHA also provides mental health services for posttraumatic stress disorder (PTSD), military sexual trauma, depression, and problems with substance use.
VHA veterans (those who obtain care through the VHA) differ from non-VHA veterans (veterans who obtain health care from non-VHA health care providers). Compared to non-VHA veterans, VHA veterans had a twofold higher prevalence of physical health conditions and mental health disorders6 (such as PTSD), as well as anxiety and depression, even after adjusting for demographic characteristics (Meffert et al., 2019; Eibner et al., 2015; Kramarow and Pastor, 2012). In addition, a third of VHA veterans reported chronic pain; furthermore, VHA veterans are found to be more likely than non-VHA veterans to have chronic pain (45.2 percent versus 26.8) (Mannes et al., 2022). Among VHA veterans, the rate of OUD was 7 times higher than that of non-VHA veterans (Ahonle et al., 2020).
Similar to national trends, the prevalence of receiving an opioid prescription increased within the VHA7—from 18.9 percent of individuals in 2004 with at least one outpatient VHA visit and a history of regular VHA medication to 33.4 percent in 2012 (Mosher et al., 2015). Studies have demonstrated that opioid prescribing slowed in the VHA from 2012 to 2020 (Hadlandsmyth et al., 2018; Gellad et al., 2017) and was reduced overall by 64 percent (VA, 2020).
In considering the co-prescribing of opioid and benzodiazepine pharmacotherapies between 2004–2009, one study found that 27 percent of VHA veterans received both drugs and accounted for nearly half of the opioid-related overdose deaths (Park et al., 2015). Another study compared the risk of adverse outcomes (accidents and injuries, non-fatal overdose events, and death) in VHA veterans who received a long-term opioid prescription only8 (N = 924,656) to VHA veterans (N = 110,305) concurrently prescribed opioid and benzodiazepine pharmacotherapies. VHA veterans with co-prescriptions had a 35.9 percent higher risk of experiencing an adverse outcome (e.g., opioid-related overdose, self-inflicted injuries, all-cause mortality) compared to long-term opioid prescriptions alone (Gressler et al., 2018).
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4 See also Appendix G for perspectives from the Department of Veterans Affairs PAIN/Opioid CORE Veteran Engagement Panel.
5 The National Health Interview Study defines veteran status using two questions: “Are you currently in the armed forces?” Individuals responding “yes” are coded as active military. Individuals responding “no” are then asked: “Have you ever served on active duty in the U.S. Armed Forces, Military Reserves, or National Guard?”
6 Mental health disorders included ICD-9 codes 290–310, 311, and V11 (Eibner et al., 2015).
7 Opioid prescription based on the receipt of an opioid prescription, using VHA outpatient prescription fill (Mosher et al., 2015).
8 Individuals receiving long-term opioid prescription were categorized as “chronic” or “high-risk.” “Chronic” was defined as receiving a 90-day or greater opioid prescription, with less than a 30-day gap in supply and within a 180-day period. “High-risk” was defined as those with ≥1 substance use disorder diagnosis (excluding tobacco) and/or an average opioid dose of ≥100 morphine milligram equivalent/day (MME/day). Concomitant prescribing was defined as the receipt of both opioid and benzodiazepine prescriptions, with a >7 days of overlap of both prescriptions.
CONGRESSIONAL MANDATE TO ADDRESS CONCERNS ABOUT PRESCRIBING OPIOIDS AND BENZODIAZEPINES IN THE VETERAN POPULATION
The concerns of the U.S. Congress drew attention to two concurrent public health issues, the high prevalence of pain with evidence of less-than-optimal pain management and high rates of excessive prescription and nonprescription opioid use, misuse, OUD, and their related harms, including overdose and mortality, especially related to veterans. In 2019, through the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019 (Hannon Act),9 Congress mandated that the Department of Veterans Affairs (VA) request an ad hoc committee of the National Academies be assembled to “to evaluate the effects of opioids and benzodiazepine on all-cause mortality of veterans, including suicide, regardless of whether information relating to such deaths has been reported by the Centers for Disease Control and Prevention.” The Hannon Act requested “a revised study design to fulfill the goals of the 2019 study design of the National Academies.” The protocols conducted for this report reflect the study designs presented in the congressionally mandated 2019 National Academies report10 An Approach to Evaluate the Effects of Concomitant Prescribing Opioids on Veteran Deaths and Suicides.
The 2019 National Academies report outlined the target trial emulation (TTE) framework in its proposed study designs to emulate, using observational data, randomized controlled trials (RCTs). RCTs represent the gold standard for identifying reliable causal effects of an intervention, such as medication effects on important outcomes. Given the exposure (opioid and benzodiazepine pharmacotherapies) and outcomes of interest (all-cause mortality and suicide mortality), RCTs have ethical and feasibility barriers in responding to the statement of task. The 2019 National Academies report proposed two study designs (“opioid treatment initiation” and “opioid tapering”) to address the effect of prescribed opioid pharmacotherapy on all-cause mortality and suicide mortality. In the report, the committee outlined specific study components to consider: eligibility criteria, treatment strategies, treatment assignment, start and end of follow-up, outcomes, causal contrasts, and statistical approach.
STATEMENT OF TASK
In response to the congressional mandate, the National Academies convened a 13-member committee with expertise in pain, mental health, neurology, addiction, epidemiology, pharmacoepidemiology, statistics, VHA health data systems, and VHA and non-VHA care of mental health and pain in veterans. The committee held 11 meetings over 18 months. In addition, the committee engaged with the Veteran Engagement Panel of the VA’s Health Systems Research Pain/Opioid Consortium on Research and appreciates the veterans who shared their lived experiences of managing pain (more details in Appendix G).
This committee leveraged and refined the 2019 National Academies report’s proposed TTE protocols to respond to the statement of task. The committee developed causal research questions to align with the statement of task and refined the TTE protocols to make use of available observational electronic health record (EHR) data, data from VHA administrative and clinical databases, and mortality data from the National Death Index. For the complete statement of task, see Box 1-2.
APPROACH TO THE TASK AND ORGANIZATION OF THE REPORT
Committee Interpretation of Statement of Task (Causality Questions)
To better understand the task and sponsor expectations, the committee sought clarifications from the VA and Congress before initiating modifications to the study designs. Additionally, the committee sought clarifications from the VA regarding the quality and comprehensiveness of available data to select the best primary outcome for the studies and assess the availability of data necessary to study the effects of tapering on all-cause mortality and suicide mortality using the protocol outlined by the 2019 committee as the starting point. After these clarifications, the committee interpreted the congressional mandate as a desire to refine and implement the 2019 protocol
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9 Public Law 116-171, 116th Congress, October 17, 2020.
10 Mandated by the Consolidated Appropriations Act, 2018, Number 115-141, Session: 115th Congress (Second Session).
BOX 1-2
Statement of Task
An ad hoc committee of the National Academies of Sciences, Engineering, and Medicine will evaluate the effects of opioid and benzodiazepine use on all-cause mortality of U.S. veterans, including suicide, regardless of whether information relating to such deaths has been reported to the U.S. Centers for Disease Control and Prevention. Specifically, the committee will quantify 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. In their analysis, the committee will focus on:
- the effect of opioid prescribing for pain, relative to alternative non-opioid pain treatments,
- the effects of higher doses relative to lower doses of opioids,
- the effect of co-prescribing a benzodiazepine among patients already receiving opioids, relative to alternative treatments for anxiety and other indications for benzodiazepines, and
- the effect of initiating opioids among patients already taking benzodiazepines.
to additionally assess the impact of concomitant prescribing of opioid and benzodiazepine pharmacotherapies on all-cause mortality and suicide mortality in veterans.
To address the research questions, the current committee chose to propose TTE protocols and corresponding observational studies. The committee agrees with the 2019 committee that while one or more RCTs could be conducted to answer questions about the comparative effectiveness or safety of opioid and benzodiazepine pharmacotherapies, RCTs are impractical for studies, particularly those posing ethical dilemmas (e.g., administering opioids) (NASEM, 2019; Armstrong, 2012). The committee also agreed that observational data could be analyzed to approximate an RCT when conducting an RCT was not possible or practical. The 2019 committee proposed applying the TTE framework, an approach that leverages observational data to emulate an RCT, to examine the effect of prescribed opioid and benzodiazepine pharmacotherapies on mortality. The 2019 report laid out proposed trial protocols, which have been leveraged for the studies conducted in the current report. The present committee refined the causal research questions that align with the VA statement of task and refined the TTE protocols (e.g., eligibility criteria, treatment strategies, outcomes, analysis plan), using available observational EHR data from the VA administrative and clinical databases and mortality data from the National Death Index. Causal inference from large observational databases can be viewed as an attempt to emulate an RCT to answer the researchers’ question of interest (NASEM, 2019; Hernán and Robins, 2016).
Considering the available data, the committee operationalized the statement of task into the following causal questions, which are addressed in three distinct studies:
- Among veterans receiving care in the VHA who were not consistently11 dispensed12 pain pharmacotherapy between 2007 and 2019, what is the effect of newly dispensed13 opioid versus non-opioid pain pharmacotherapy on all-cause mortality (primary outcome) and suicide mortality (secondary outcome) among those without and with current use of benzodiazepine pharmacotherapy within a 12-month follow-up period? (Study 1)
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11 Not dispensed any qualifying opioid or non-opioid pain pharmacotherapy in the 90-day pre-index period.
12 The committee notes differences in types of pharmacy data measures. Pharmacy data can be categorized into three measures: prescribed (prescriber submits a prescription to a pharmacy), filled (pharmacy completes the requested prescription), and dispensed (individual picks up/is mailed the prescription from the pharmacy). The committee used dispensed pharmacy data in its analyses.
13 The committee operationalized the term “initiation” in the statement of task as “newly dispensed” pharmacotherapy in analyses. In the committee’s studies, “newly dispensed” was defined as pharmacotherapy of interest not dispensed (or initiation of pharmacotherapy) to the individual in the 90 days before the start date.
- Among veterans receiving care in the VHA newly dispensed full agonist14 opioid pharmacotherapy between 2007 and 2019, what is the effect of different initial opioid dosage and escalation strategies on all-cause mortality (primary outcome) and suicide mortality (secondary outcome) within a 12-month follow-up period? (Study 2)
- Among veterans receiving care in the VHA who were consistently dispensed opioid pharmacotherapy between 2007 and 2019, what is effect of newly dispensed benzodiazepine versus alternative non-benzodiazepine pharmacotherapy for anxiety and other common indications for benzodiazepines on all-cause mortality (primary outcome) and suicide mortality (secondary outcome) within a 3-month follow-up period? (Study 3)
Topics Not Included in the Statement of Task
For all studies, the committee did not include “chronic pain” in the causal question or as a covariate for several reasons. There are multiple factors that limit the reliability of pain-relevant diagnosis codes and their utility in observational research. First and foremost, there are challenges in its measurement and capture, such as potential underreporting of the large variety of diagnoses associated with chronic pain diagnoses and the underlying painful conditions. Preliminary analysis indicated that 37.7 percent of eligible participants who were dispensed an opioid pharmacotherapy did not have a diagnosis code related to chronic pain as defined in Mayhew et al., 2019. Accurate diagnosis can be complicated and emerge over time as a comprehensive assessment proceeds (e.g., diagnosis of low back pain). Further, providers may vary in the reporting of pain-relevant diagnostic codes, which may further contribute to unreliability. Additionally, individuals with chronic pain report multiple sites of pain and multiple pain conditions, further complicating the use of diagnosis codes to characterize the pain experience and to reliably associate diagnosis with treatment decisions (Edwards et al., 2016). Yet, opioid pharmacotherapy is used for a wide variety of pain conditions (Pasricha et al., 2018). Given the challenges in capturing pain and chronic pain, the committee assumed that most individuals who were dispensed an opioid prescription received it to manage pain (via opioids’ known analgesic effects). The indication of pain was used to choose the non-opioid pharmacotherapies included in study 1, to control for confounding by indication. Finally, the term is not reflected in the statement of task.
The committee noted that there are several aspects of opioid prescribing that were not stated in the statement of task and not reflected in the committee’s analyses. The committee did not implement the opioid tapering trial protocol suggested in the 2019 report, considering the following factors in its decision. First, the current statement of task did not direct the committee to examine the effect of opioid tapering on mortality. Second, the committee was aware of studies based on the 2019 report protocol that had been or were being completed and commissioned a review of these and other relevant studies conducted since the 2019 report (see Appendix E). Based on the review, the committee determined that the risk of immortal time and selection biases is high and substantially limits the extent to which retrospective observational studies can infer causality between opioid tapering and mortality. Of note, Dr. Erin Krebs and her colleagues applied the 2019 protocol in an unpublished study (see Appendix F) included in the review. It was noted that the study’s findings and conclusions were highly sensitive to different study design, statistical modeling, and measurement strategies. In addition, the treatment assignment was based on pharmacy records and as such may not accurately reflect whether a tapering was intended or actually took place. Based on these observations, not available at the time of the 2019 report, the committee concludes that additional efforts to implement such a study is unlikely to yield more definitive results and, for these reasons, the committee chose not to implement the tapering trial suggested in the 2019 report. The committee focused the main report to reflect findings from the analyses addressing the statement of task.
The statement of task also did not direct the committee to compare mortality of veterans prescribed opioids and benzodiazepines in the VHA to veterans prescribed opioids and benzodiazepines in other health care systems.
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14 There are two types of opioids: full agonist and partial opioid agonist. Full opioid agonists fully activate the mu brain receptors, enabling the opioid to have “full” effect, such as morphine, codeine, oxycodone, and fentanyl. Partial opioid agonists also activate mu receptors in the brain but to a lesser degree, such as butorphanol or tapentadol.
Thus, comparing VHA and non-VHA providers was not part of the committee’s work. In addition, the committee notes that the focus of the statement of task is to examine the risk, not the benefits, of opioid and benzodiazepine prescribing. The committee did not investigate the impact of non-pharmacological approaches to pain treatment on all-mortality, including suicide mortality, as this was outside the scope of the statement of task.
Furthermore, the committee notes that the statement of task specifically mandated the study period (2007–2019) to understand the implications of opioid treatment on mortality in veterans. Therefore, the findings of this report are not intended to be applicable to current practices or behaviors, including those of the VHA. In addition, these retrospective studies are inherently forensic, reflecting the effect of care that occurred in the past rather than being indicative of the mortality risks of current practices, particularly given the ongoing changes in opioid prescribing practices, the policy landscape, mental health care, and the nature of the opioid overdose epidemic in the intervening years.
The report is laid out the following way. Chapter 2 provides a detailed overview of the policies, regulations, and clinical practice guidelines regarding prescribing opioids and benzodiazepines released during, and around, the study period (2007–2019).
Chapter 3 sets the stage of the methodological approach taken to address the statement of task, especially the application of the TTE framework. The chapter describes the data sources used, medications selected, and inclusion rationale for the studies. In addition, the committee’s specifications for the target trial components (e.g., eligibility criteria, treatment strategies and assignments, statistical analyses) are outlined. Specific and detailed information on each of the target trial specifications is found in Chapters 4, 5, and 6.
Chapters 4, 5, and 6 outline the details of each TTE to address the statement of task. All studies examine two outcomes: all-cause mortality (primary outcome) and suicide mortality (secondary outcome). Study 1 examines the effect of the initiation of opioid versus non-opioid pain pharmacotherapy15 (e.g., non-steroidal anti-inflammatory drugs) among those without (study 1a) and with (study 1b) current benzodiazepine pharmacotherapy. Study 2 employs two target trials: study 2a assesses the effect initial opioid dosage at baseline, and study 2b assesses the effect of escalating dosage strategies. Study 3 examines the effect of newly dispensed benzodiazepine pharmacotherapy versus alternative non-benzodiazepine pharmacotherapy among veterans consistently dispensed opioid pharmacotherapy.
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