The Department of Veterans Affairs (VA)1 requested that an ad hoc committee of the National Academies of Sciences, Engineering, and Medicine be assembled to “develop a protocol/study design to evaluate the relationship between concomitant opioid and benzodiazepine medication practices at the VA, for treating mental health and combat-related trauma, which potentially led to veteran’s deaths and suicides.” Thus, a committee was formed to address that task. The committee considered both the characteristics of randomized controlled trials (RCTs) that could address the Statement of Task directly—but would now be infeasible to conduct—and analysis strategies that leveraged existing observational data to emulate those (target) trials. The committee’s target trial protocols lay out the purpose and details of each trial (e.g., eligibility criteria, treatment strategies, outcomes, analysis plan), while the proposed observational designs specify how to emulate the target trials using existing VA clinical databases.
This first chapter will provide a brief background on the use of opioids and benzodiazepines for treating pain and anxiety in the general population, followed by a discussion of their use in the veteran population. The chapter is not meant to provide in-depth information on the neurobiology and pharmacology of those drugs, nor is it meant to provide a discussion of all possible uses of opioids and benzodiazepines; however, the committee has included a very brief section on the neurobiology and principles of
1 The Department of Veterans Affairs is composed of the Veterans Health Administration (VHA), the Veterans Benefits Administration, and the National Cemetery Administration. This report’s focus is the VHA.
addiction and tolerance. Finally, this chapter also provides a description of the committee’s approach to its task and the organization of the report.
Substances like opioids and benzodiazepines dysregulate brain systems that are involved with motivation, reward, decision making, and memory. Opioids act in multiple ways in the body, including altering body temperature, causing sedation, depressing respiration, decreasing gastrointestinal transit, and producing euphoria or dysphoria. Those effects are primarily mediated through three opioid receptor subtypes: mu, kappa, and delta (Jones et al., 2012).
The rewarding effects of opioids (e.g., morphine and heroin) are primarily caused by their agonism of the mu opioid receptor. The mu receptor is also responsible for analgesia and respiratory depression. Chronic opioid use is associated with the development of tolerance, which develops at different rates in different people. Opioid overdose can result in respiratory depression and death (Turton and Lingford-Hughes, 2016). Continual opioid use results in tolerance, while abrupt cessation results in the process of withdrawal.
The neurotransmitter2 gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA-A receptors are the site of action for several neuroactive drugs, including benzodiazepines, barbiturates, picrotoxin, and muscimol. Alcohol also binds to GABA-A receptors (Turton and Lingford-Hughes, 2016).
Benzodiazepines act to enhance the effects of GABA; their binding sites are part of the GABA-A receptor complex, and they act to open the chloride channel by GABA and result in inhibition, which in turn results in anxiolysis3 and sedation. As noted in McClure et al. (2017), the cumulative and synergistic effects from combining benzodiazepines and opioids result in depressing the central nervous system’s medullary controls for respiration, with the benzodiazepines working through the GABA receptors and opioids through mu (m) and delta (d) receptors.4 Furthermore, for patients
2 Neurotransmitters are chemicals that are released at the end of a nerve fiber in response to the arrival of a nerve impulse and that, by diffusing across the synapse or junction, cause the transfer of the impulse to another nerve fiber, a muscle fiber, or some other structure (Maiese, 2019).
3 Anxiolysis is caused by certain drugs and is used to help relieve anxiety during certain medical or surgical procedures. This is also called minimal sedation. See https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anxiolysis (accessed August 2, 2019).
and others with substance use disorder (SUD), combining opioid and benzodiazepine drugs increases the subjective peak strength of drug effects and sedation (Lintzeris et al., 2007). In 2010 greater than 30 percent of opioid-related deaths in the United States also involved benzodiazepines (Jones et al., 2013). Among U.S. military veterans who were prescribed opioids and who subsequently died of a drug overdose, approximately half of the overdoses involved concurrent prescriptions for benzodiazepines (Park et al., 2015). In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for prescribing opioids for chronic pain. The guidelines note that evidence for the long-term efficacy of opioids for chronic pain is limited and that long-term use is associated with serious risks, such as opioid use disorder and overdose (Dowell et al., 2016).
Pain falls broadly into three main categories: acute pain, chronic non-cancer-related pain, and cancer-related pain.5Acute pain is a normal response to tissue damage and typically resolves itself once the injured tissue heals or soon after; it is pain experienced after trauma or surgery. Chronic, non-cancer-related pain is commonly defined as pain that persists for longer than the expected time frame for healing or pain associated with progressive, nonmalignant disease (Ashburn and Staats, 1999). In clinical and research reports, chronic pain is often operationally defined as pain that has persisted for at least 3 months (Rosenblum et al., 2008). Similarly, Tompkins et al. (2017) define chronic pain as pain that has lasted beyond the normal healing time for a given injury, operationalized as pain lasting more than 3 months, and they note that chronic pain is divided further, for treatment purposes, according to whether or not it is associated with cancer. Cancer-related pain refers to pain resulting from primary tumor growth, metastatic disease, or the toxic effects of cancer treatments.
In 1996 the American Pain Society introduced the phrase “pain as the fifth vital sign,” which emphasized that pain assessment is as important as the assessment of the standard four vital signs6 and that clinicians need to take action when patients report pain. The Veterans Health Administration (the VHA) recognized the value of such an approach and included pain as the fifth vital sign in its national pain management strategy. The Joint
5 With regard to cancer pain, in the 1970s and 1980s palliative care specialists recognized that opioids brought relief to terminal cancer patients, and several studies were published that suggested that patients rarely developed opioid use disorder when opioids were prescribed for cancer pain. Concurrently, the World Health Organization was developing cancer pain treatment guidelines that included pain treatment as a universal right.
6 The four vital signs are body temperature, blood pressure, pulse (heart rate), and breathing/respiratory rate.
Commission on Accreditation of Healthcare Organizations7 mandated pain assessment and treatment in 2001 as a requirement of receiving federal health care dollars. The Federation of State Medical Boards stated that physicians would not receive excessive regulatory scrutiny for prescribing opioids, and the Drug Enforcement Administration agreed to follow a balanced policy in examining prescriber’s practices and to reduce the oversight of physicians that had high rates of opioid prescribing (Tompkins et al., 2017). Additionally, a few research studies, published during the 1990s and 2000, resulted in diminished concern among providers and patients, as they suggested that patients rarely developed addiction to opioids when they were prescribed for pain (see Tompkins et al., 2017). The combination of these factors led to an increasing reliance on prescription opioids for pain management.
Prevalence of Chronic Pain
In an effort to estimate the prevalence of chronic pain and high-impact chronic pain8 in the United States, CDC analyzed data from the 2016 National Health Interview Survey (NHIS). According to that analysis, an estimated 20.4 percent (50.0 million) of U.S. adults had chronic pain, and 8.0 percent of U.S. adults (19.6 million) had high-impact chronic pain. Chronic pain is a major cause of decreased quality of life and disability and is often challenging to treat effectively (Chou et al., 2014).
Opioid analgesics9 are commonly prescribed to treat chronic and acute pain and are available legally by prescription. In the mid-1990s, as noted above, professional societies argued that there was an epidemic of untreated pain, and wider use of opioid medications was encouraged (Evans et al., 2019). In 1996 Purdue Pharmaceuticals introduced OxyContin (oxycodone extended release). The Food and Drug Administration approved the drug labeling, which claimed that iatrogenic addiction was very rare and that the drug’s delayed absorption was believed to reduce abuse liability. That
7 The Joint Commission on Accreditation of Healthcare Organizations is a nonprofit organization based in the United States that accredits more than 20,000 health care organizations and programs in the country.
8 High-impact chronic pain is pain that has lasted 3 months or longer and is accompanied by at least one major activity restriction, such as being unable to work outside the home, go to school, or do household chores (Pitcher, 2018).
9 Opioids include drugs such as hydrocodone (e.g., Vicodin), morphine (e.g., Duramorph, MS Contin), oxycodone (e.g., OxyContin, Percocet), hydromorphone (e.g., Dilaudid), and fentanyl (e.g., Duragesic).
action resulted in an increase in the number of OxyContin prescriptions from 670,000 in 1997 to about 6.2 million in 2002, when the label was changed to drop the misleading language (Tompkins et al., 2017). However, beginning in the 1990s, as the frequency of opioid prescribing and the volume of opioids dispensed increased in the United States, the number of overdoses and deaths from prescription opioids also increased. From 1999 to 2017 about 218,000 people died in the United States from overdoses related to prescription opioids (CDC, 2019a). In 2017 there were 70,237 fatal drug overdoses in the United States and prescription opioids were involved in 17,029 (24.2 percent) of them (CDC, 2019b). Furthermore, adults aged 25–54 had higher rates of drug overdose deaths in 2017 than those aged 55 and over.
In 2016 CDC issued new guidelines10 for prescribing opioids for treating chronic pain in the United States. The guidelines address when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing the risk and addressing the harms of opioid use (Dowell et al., 2016). A study by Zhu et al. (2019) found that between July 2012 and December 2017 many providers stopped initiating opioid therapy, but a sub-group of providers continued to write high-risk initial opioid prescriptions.11
Treating Cancer Pain with Opioids
It should be noted that there has been some controversy surrounding the appropriateness of use of opioids for cancer pain, and guidelines recommend against using them along with benzodiazepines. With regard to cancer surgery, studies have emerged that highlight chronic opioid use. For example, Lee et al. (2017) found new and persistent use of opioids in cancer patients following curative-intent surgery. The study identified a total of 68,463 patients who had different types of cancer surgery with the intent of cure between 2010 and 2014. The primary outcomes examined were new and persistent opioid use (i.e., continued filling of opioid prescriptions for 90–180 days post-surgery in opioid-naïve patients). The risk of new persistent opioid use was 10.4 percent 1 year after surgery; furthermore, those patients continued filling prescriptions with daily doses similar to chronic opioid users (i.e., equivalent to six tablets per day of 5 mg of hydrocodone). A more recent study by Brescia et al. (2019) found new and persistent use
10 CDC developed the guidelines using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, and CDC notes that recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation.
11 High-risk prescriptions are those that are in doses or durations above those recommended by CDC.
of opioids following lung resection surgery conducted between 2010 and 2014. New and persistent use was defined by the authors as continued opioid prescription refills between 90 and 180 days following surgery. Data from that study were evaluated, and 14 percent of the 3,026 patients identified as “opioid-naïve” continued to fill opioid prescriptions after 90 days.
A study by Ilgen et al. (2016) that used a case-cohort design found evidence linking chronic non-cancer pain to an increased risk of suicide. Evidence of such a link has been consistently found in studies using varying methods of assessing pain, the population examined, and the primary outcome (suicide attempt, suicide death). The association between pain and suicide is partially attenuated once one controls for other psychiatric disorders, such as depression, but, even so, it remains significant.
The study’s authors note that the treatment of pain is controversial with regard to suicide risk, as under-treatment could place individuals with pain at risk for suicide. However, the use of prescription opioids also could increase the risk of suicide in some cases because of the lethality of opioids and the opioids’ potential negative effects on mental health in certain individuals. It is noteworthy that there is evidence in the literature of an association between the use of opioids and an increased risk of suicide (Sarchiapone et al., 2011).
A 2019 review by Bohnert and Ilgen examined the associations among opioid use, overdose, and suicide in the United States. The authors found that there are several key factors beyond opioid use that are related to suicide and overdose. Most mental health conditions are linked to an increased risk of suicide and unintentional overdose, including both illicit drug and medication-related overdoses, but the type of link differed according to the specific mental health condition. SUDs had a stronger association with unintentional overdoses, while other mental health conditions were generally linked more strongly with intentional overdose. The use of other medications and drugs in combination with opioids—for example, the concurrent use of recreational drugs, such as alcohol and cocaine, with opioids—can increase the risk of death as well. Additionally, some of the demographic characteristics associated with suicide and overdose in the United States are also associated with veteran status, such as male sex and white race.
Although the overall opioid prescribing rate in the United States has been declining since 2012, the amount of opioids in morphine milligram
equivalents (MMEs)12 prescribed is still about three times higher than it was in 1999 (CDC, 2018). Additionally, the pattern of drugs involved in drug overdose deaths has changed in recent years (Hedegaard et al., 2018a). The age-adjusted rate of drug overdose deaths involving synthetic opioids other than methadone (e.g., fentanyl, fentanyl analogs, and tramadol) increased by 45 percent between 2016 and 2017, from 6.2 to 9.0 per 100,000 (Hedegaard et al., 2018b). The rates of drug overdose deaths involving heroin (4.9 per 100,000), natural and semisynthetic opioids (4.4), and methadone (1.0) were the same in 2016 and 2017. There was also a shift from prescribed opioids to illegally obtained opioids (heroin and illegally manufactured fentanyl) as the predominant cause of opioid overdose deaths (Hedegaard et al., 2018b).
Patterns of Opioid Prescribing
A study by Schieber et al. (2019) examined trends and geographic patterns in opioid prescribing between January 1, 2006, and December 31, 2017. The authors abstracted data from outpatient prescribing records13 to obtain estimates of the number of opioid prescriptions dispensed from approximately 59,400 retail, non-hospital pharmacies, which dispense 93 percent of all retail prescriptions in the United States. Findings from this cross-sectional study of approximately 223.7 million retail opioid prescriptions, which were filled between 2006 and 2017, indicated that the amount of opioids prescribed annually increased up to 2010, then decreased, with a net reduction of 13 percent occurring between 2016 and 2017. Other findings noted in the study are that one in three opioids was prescribed for 30 days or more, increasing 3 percent annually (with a two- to three-fold variation among states). High-dose prescriptions decreased by 53 percent, but half of those were filled as extended-release and long-acting formulations. The authors note that the risk of opioid use disorder, overdose, and death from prescription opioids increases as dosage, duration, and use of extended-release and long-acting formulations increase.
Whereas opioids are primarily prescribed for pain, benzodiazepines are prescription sedatives that are typically prescribed for anxiety or insomnia,
12 MME is a way to calculate the total amount of opioids that takes into account the differences in opioid drug type and strength.
13 Records were abstracted from the IQVIA Xponent database. See https://www.iqvia.com/locations/united-states/commercial-operations/essential-information/prescription-information (accessed August 2, 2019).
and they include such drugs as diazepam (Valium), alprazolam (Xanax), and clonazepam (Klonopin) (Olfson et al., 2015). Benzodiazepines are medications that cause mild to severe depression of the nervous system and are also used for sedation during surgery. Benzodiazepines can lead to SUD; furthermore, long-term use can lead to tolerance and the need for higher doses (Fluyau et al., 2018). In a recent study examining benzodiazepine prescribing patterns in the United States, Agarwal and Landon (2019) found that the outpatient use of benzodiazepines had increased substantially—from 3.8 percent to 7.4 percent of ambulatory care visits between 2003 and 2015; concomitant prescribing with other sedating medications had also increased. Furthermore, between 2002 and 2014 the number of opioid recipients who were also dispensed benzodiazepines increased from 7 to 10 percent (a relative percent increase of almost 43 percent), with more than half of the concomitant users receiving both prescriptions from the same prescribers, typically family medicine or internal medicine providers (Hwang et al., 2016). A 2015 study by Olfson et al. examined the benzodiazepine prescribing practices in the United States and focused on patient age and duration of use. Findings indicate that roughly 1 in 20 adults filled a benzodiazepine prescription during the course of 1 year and that the use is substantially higher in women than men and increases with age. Furthermore, among benzodiazepine users there was an age-related increase in long-term use, which may pose added risks of fractures, cognitive decline, and benzodiazepine dependence in older adults. Despite a benzodiazepine-related risk of falls, fractures, and motor vehicle crashes among older people and guidelines that have suggested that older adults avoid the use of benzodiazepine (AGS, 2019), Olfson and colleagues (2015) found that the use of benzodiazepine was approximately three times more prevalent in older than in younger adults.
Concomitant use of opioids and any other central nervous system depressants, including commonly prescribed doses of benzodiazepines, can have significant adverse effects. Those adverse effects are often not fully appreciated by prescribers or by patients taking the medications. This section highlights a few recent studies that examine the concomitant prescribing of opioid and benzodiazepines in the general population and its potential risks, such as overdose and fatalities.
According to the National Institute on Drug Abuse (NIDA), greater than 30 percent of overdoses involving opioids also involve benzodiazepines (NIDA, 2018). Combining both drugs can be unsafe because both drugs sedate users and suppress breathing—often the cause of overdose fatality.
In 2015, 23 percent of people who died of an opioid overdose also tested positive for benzodiazepines. According to NIDA, in a study of more than 300,000 continuously insured patients receiving opioid prescriptions between 2001 and 2013, the percentage of persons also prescribed benzodiazepines rose from 9 percent in 2001 to 17 percent in 2013. The study showed that people concurrently using both drugs are at higher risk of visiting the emergency department or of being admitted to a hospital for a drug-related emergency (NIDA, 2018).
Overdoses and fatalities are of particular concern when opioids and benzodiazepines are prescribed concurrently. A study by Hirschtritt et al. (2018) examined annual trends in outpatient visits, which included prescriptions for opioids, benzodiazepines, and their combination among adults. Data from the 1993–2014 National Ambulatory Medical Care Survey among non-elderly (i.e., ages 18–64) adults were used to examine the probability of an ambulatory care visit including a prescription for an opioid, benzodiazepine, or both. From 1993 to 2014, benzodiazepine-with-opioid visits increased from 9.8 to 62.5 (odds ratio [OR] = 9.23, 95% confidence interval [CI] = 5.45–15.65) per 10,000 visits. The authors identified a significant increase in the outpatient co-prescription of opioids and benzodiazepines, notably among adults aged 50–64 years during primary care visits.
In a prospective, outpatient-based study of adult patients prescribed high-dose opioids, those concurrently being prescribed benzodiazepines were nearly 10 times more likely to die from overdose than those who were not (Dasgupta et al., 2016). Sun et al. (2017) found that privately insured, non-elderly adults who received prescriptions for both opioids and benzodiazepines were more likely to visit the emergency department or have an inpatient admission for opioid overdose than those prescribed opioids alone. Furthermore, in the emergency department setting between 2004 and 2011, the percentage of opioid overdose deaths among adults that also involved benzodiazepine use increased steadily from 18 to 31 percent (Jones and McAninch, 2015). Using 2013–2014 Medicare Part D data, Hernandez and colleagues (2018) found that in the first 90 days of concurrent opioid and benzodiazepine use, the risk of opioid-related overdose was five times greater than among those using only opioids. However, after 180 days the risk of overdose was no higher among those taking opioids and benzodiazepine concurrently than among those using opioids only. Another study (Yarborough et al., 2018) examining the correlates of benzodiazepine use and adverse outcomes among patients with chronic pain who were prescribed long-term opioid therapy found that dual use was associated with increased odds of falls and emergency department visits.
A study by Schepis et al. (2018) examined data from adults 50 years old and older who participated in the 2015–2016 National Survey on Drug
Use and Health14 for the purpose of evaluating a link between prescription opioid or benzodiazepine misuse and suicidal ideation. After controlling for many correlates, the authors found that past use without misuse of prescription opioids or benzodiazepines was not associated with past-year suicidal ideation in older adults.
According to the National Vital Statistics Reports (Hedegaard et al., 2018a), for the top 10 drugs involved in drug overdose deaths in 2016, the proportion of deaths involving both the referent drug and at least one other concomitant drug ranged from 50 percent for methamphetamine to 96 percent for the benzodiazepines alprazolam or diazepam. Approximately 70 percent of drug overdose deaths involving fentanyl or heroin—the top two drugs involved in drug overdose deaths in 2016—involved at least one other specific drug, and drug combinations often involved drugs of different drug classes. For example, the opioid oxycodone and the benzodiazepine alprazolam were mentioned concomitantly in more than 1,500 deaths. In some instances, the most frequently mentioned concomitant drug was in the same drug class as the referent drug (e.g., the opioids fentanyl and heroin were both mentioned in approximately 5,900 deaths). In 2016 unintentional drug overdose deaths most frequently mentioned fentanyl, heroin, and cocaine, while suicides by drug overdose more frequently mentioned oxycodone, diphenhydramine, hydrocodone, and alprazolam. In addition, benzodiazepine users tended to report a longer history of opioid use and prior detoxifications; to use higher doses of opioids; to have a higher frequency of injection drug use, needle sharing, co-occurring use of alcohol and cocaine; and to report greater criminal activity (Darke et al., 2010; Rooney, 1999; Ross and Darke, 2000; Stein et al., 2017). Clearly, concurrent prescribing of opioids and benzodiazepines conveys a significant risk that until recently was underappreciated by patients and health care providers.
The committee was tasked with designing a study to examine the association between concomitant prescribing of opioids and benzodiazepines and veterans’ deaths and suicides. This section of the chapter provides information on the VA patient population and briefly discusses mental health disorders and pain in veterans and how they are treated in the VA.
14 The National Survey on Drug Use and Health provides national and state-level data on the use of tobacco, alcohol, illicit drugs (including the non-medical use of prescription drugs), and mental health in the United States. It is a survey of self-reported substance use and mental health. It began in 1971 and is conducted every year in all 50 states and the District of Columbia.
The focus is on Iraq and Afghanistan war veterans because they have been well studied and recent research has provided a wealth of information about them. This section is not an in-depth look at mental health issues at the VA (NASEM, 2018), nor does it provide a detailed look at VA’s prescribing practices. The section also briefly describes the Clinical Practice Guideline for Opioid Therapy for Chronic Pain from the VA and the Department of Defense (DoD) as context for VA treatment practices and the VA’s Opioid Safety Initiative.
The VA Population
According to the VA population model estimates, there are approximately 624,000 World War II veterans, 1.5 million veterans from the Korean Conflict, 6.6 million Vietnam era veterans, and 7.2 million Gulf War veterans from Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) (VA, 2019). The demographic profile of veterans is expected to change in the next few decades. Currently, 91 percent are men and 9 percent are women, according to the VA’s 2016 population model estimates. Projections also indicate that the veteran population will become slightly younger by 2045, with 33 percent of veterans younger than 50 (compared with 27 percent in 2016), despite the overall aging of the U.S. population. The number of veterans ages 50–69 is expected to shrink from 39 percent to 33 percent, while the number of those 70 and older is predicted to be around one-third of the total (34 percent) by 2045.
Similar to trends in the overall U.S. population, the U.S. veteran population is predicted to become more racially and ethnically diverse. Between 2016 and 2045, the number of veterans who are non-Hispanic white is expected to drop from 77 percent to 64 percent; the number of veterans who are Hispanic is expected to nearly double from 7 percent to 13 percent; and the number of African American veterans is expected to increase from 12 percent to 16 percent (VA, 2019).
Mental Health and Pain in the VA Population
Many veterans returning from the wars in Iraq and Afghanistan15 have physical combat injuries, some of which had caused chronic pain or traumatic brain injury (TBI), or both, and are often associated with co-occurring SUDs and other mental health disorders such as posttraumatic stress disorder (PTSD), major depressive disorder, anxiety disorders, and
15 Often referred to jointly as OEF/OIF/OND for Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn.
accompanying serious mental health symptoms such as suicidal ideation (IOM, 2013; NASEM, 2018; Tanielian and Jaycox, 2008). Those co-occurring conditions create significant challenges for prescribing effective and well-tolerated treatments. Furthermore, there are high rates of SUD among veterans, especially those with mental health disorders. The highest rates of SUD comorbidities occur in veterans who have bipolar disorder and schizophrenia and in Vietnam veterans (Petrakis et al., 2011). SUDs in veterans continue to rise despite attempts by the VA to reduce them. SUDs are associated with negative correlates, including medical problems and other psychiatric disorders (e.g., depression and anxiety), interpersonal and vocational impairment, and increased rates of suicide attempts (Teeters et al., 2017).
As early as 2004 it was estimated that more than one-fourth of troops returning from OEF and OIF suffered from mental health disorders (Hoge et al., 2004). Later estimates suggested that one-fifth of the troops reported symptoms of PTSD or depression and that about the same fraction had experienced a probable TBI during deployment (Tanielian and Jaycox, 2008). RAND reports that a full one-third of returning OEF and OIF service members reported symptoms of mental health or cognitive problems (Hosek, 2011; Tanielian and Jaycox, 2008). Furthermore, 18.5 percent of a representative sample of returning service members met the diagnostic criteria for PTSD or depression, 19.5 percent reported a probable TBI during deployment, and 7 percent met the criteria for both a mental health problem and a probable TBI (Tanielian and Jaycox, 2008). In addition, the prevalence of SUD among OEF/OIF/OND veterans is greater than among the general population (Larson et al., 2012). A high incidence of suicide has been reported in veterans, and an average of 20 veterans die by suicide each day. In 2018 the VA identified suicide prevention as its highest priority (GAO, 2018).
Suicidal ideation also has been reported as a potential concerning outcome of the experiences common to veterans. A study of veterans recently returning from deployment reported a 12.5 percent prevalence of suicidal ideation in the previous 2 weeks. The authors found positive associations of suicidal ideation with depression and PTSD and negative associations with the availability of social support (Bossarte et al., 2012). In a more recent study, Arenson et al. (2018) examined the association of suicidal ideation with comorbid PTSD and depression and examined the role of military and psychosocial covariates. Seven hundred forty-six veterans were evaluated
for PTSD and depression and suicidal ideation using the CAPS16 and the PHQ-9,17 respectively. Forty-nine percent of veterans with co-occurring PTSD and depression reported suicidal ideation, a higher rate than those with depression alone (34 percent), PTSD alone (11 percent), or neither (2 percent). In fully adjusted models anger, hostility, anxiety, and alcohol use did not explain the elevated risk of suicidal ideation in the co-occurring group (Arenson et al., 2018). The authors note that, inasmuch as suicidal ideation is a known risk factor for suicide attempts and completed suicides, veterans with co-occurring PTSD and depression represent a vulnerable group that might need more intensive monitoring and treatment in order to reduce suicide risk.
Although one in three Americans has chronic non-cancer pain (NASEM, 2017), the proportion of veterans who report chronic pain (often related with military service) is higher. For example, in a survey of OEF and OIF veterans, 44 percent reported moderate to severe pain (Toblin et al., 2014).
The prevalence of pain in U.S. veterans was studied by Nahin (2017). The study author compared veterans with non-veterans of similar age and sex. Data from the 2010–2014 NHIS18 Sample Adult Core and the NHIS Adult Functioning and Disability supplement (AFD) were analyzed. The NHIS asks questions to determine veteran status. The first question is, “Are you currently serving in the armed forces?” If the respondent answers “yes,” he or she is coded as active military and is excluded from further questions. If the individual responds “no,” he or she is then asked about ever having served on active duty, and those individuals responding “yes” to this question are coded as veterans, while those responding “no” are coded as non-veterans.
Combining data from 5 consecutive years of the NHIS resulted in a population sample of 6,647 veterans and 61,049 non-veterans. Thus, approximately 67,700 adults completed the AFD, and participants with severe pain were identified using a validated pain severity coding system embedded in the NHIS AFD. More veterans (65.6 percent) than non-veterans (56.4 percent) reported having had pain in the previous 3 months. The rate of severe pain was almost 50 percent higher in veterans (9.1 percent) than in non-veterans (6.3 percent). Of the 5-year NHIS AFD sample, 9.7 percent were identified as U.S. military veterans. Veterans were older than non-veterans
16 CAPS = Clinician-Administered PTSD Scale for DSM-5.
17 PHQ-9 = Patient Health Questionnaire–depression module.
18 The NHIS collects data on a broad range of health topics through personal household interviews.
and more likely to be male. Veterans were also more likely to report having any pain in the prior 3 months than non-veterans (65.6 percent versus 56.4 percent). Nahin noted that the prevalence of severe pain was more common in veterans, particularly in veterans who served in recent conflicts, than in members of the general population (Nahin, 2017).
Another study on pain in veterans examined the combat exposure–pain relationship, with associated mediators and gender as a moderator. More than 2,000 veterans at the VA San Diego Healthcare System completed paper or electronic self-report measures of pain intensity and somatic pain. Analyses examined the associations of pain with combat exposure and PTSD, depression, and resilience as mediators of the combat exposure–pain association. The authors, controlling for age, found that veterans with combat exposure had significantly higher pain intensity and somatic pain. Further PTSD and depression scores significantly mediated the combat exposure–pain relationship. Gender was also found to moderate the combat exposure–pain intensity association through depression scores (Buttner et al., 2017). Thus, combat exposure is associated with pain intensity and somatic pain, with greater levels of PTSD and depression mediating the combat exposure–pain link and gender moderating the depression-mediated combat exposure–pain association.
Treatment of Chronic Pain in the VA
Treatment of chronic pain is complex, and the VA is focusing on veteran-centric approaches that can be tailored to individual veterans’ needs.19 This section highlights a few studies that focus on chronic pain treatment in the VA.
The prevalence of opioid prescriptions among veterans increased from 18.9 percent to 33.4 percent in fiscal years 2004 to 2012, and the groups with the highest prevalence of opioid use were women and young adults (i.e., 18–34 years old) (Mosher et al., 2015). Furthermore, within 3 months of returning from Afghanistan, 44 percent of the military veterans reported chronic pain, and 15 percent reported using opioids (Toblin et al., 2011, 2014). Chronic pain has also been associated with poorer physical function, independent of comorbid mental health problems, in OEF and OIF veterans.
A study by Bohnert et al. (2011) examined the association of maximum prescribed daily opioid dosage and dosing schedule (as needed, regularly scheduled, or both) with the risk of opioid overdose death among patients with cancer, chronic pain, acute pain, and SUDs. The authors examined
19 Laurence Meyer’s statement to the Senate Committee on Appropriations Subcommittee on Military Construction, Veterans Affairs, and Related Agencies, November 15, 2017.
VHA data from 2004 through 2008 for all unintentional prescription opioid overdose decedents (n = 750) and from a randomly selected cohort of patients (n = 154,684) who used medical services in 2004 or 2005 and received opioid pain therapy. That analysis demonstrated that, among patients receiving opioid pain medication, higher doses of opioids were associated with an increased risk of opioid overdose deaths.
Edlund et al. (2014) analyzed VHA administrative and pharmacy data from 2009 to 2011 in an effort to characterize the dosing and duration of opioid therapy for chronic non-cancer pain. The authors calculated the distribution of individual mean daily opioid doses, individual total days covered with opioids in 1 year, and individual total opioid dose in 1 year. They found that the median daily dose was 21 MMEs, but about 4.5 percent of individuals had a mean daily dose that was higher than 120 MMEs. The median days covered in 1 year was 115 to 120 for those receiving opioids. Fifty-seven percent had at least 90 days covered with opioids per year. Major depression and PTSD were positively associated with receiving high doses of opioids, but non-opioid SUDs were not. Among VHA patients with chronic non-cancer pain, opioid therapy was often prescribed, but for most patients the average daily dose was modest. Doses and duration of therapy were unchanged from 2009 to 2011.
Lisi et al. (2018) performed a cross-sectional analysis of VA administrative data to examine the sociodemographic and clinical characteristics associated with opioid use among veterans of OEF/OIF/OND. The analysis included only veterans who had at least one visit to a chiropractic clinic between 2004 and 2014 and at least one filled prescription for opioids within a window of 90 days before to 90 days after the index chiropractic clinic visit. More than 14,000 veterans with at least one chiropractic visit were identified, and 4,396 (31.3 percent) had received one or more opioid prescriptions.20 Moderate to severe pain, PTSD, depression, and current smoking were associated with a higher likelihood of receiving an opioid prescription. However, the percentage of veterans receiving opioid prescriptions was lower in each of the three 30-day time frames assessed after the index chiropractic visit than before. The authors did not attempt to assess causation or otherwise explain that observation.
Gellad et al. (2018) found that veterans receiving medications from the VA and Medicare (sometimes concurrently) were at an increased risk of high-dose opioid exposure. Specifically, among veterans dually enrolled in
20 Opioid medications included formulations from the CN101 VA drug class such as butorphanol, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, nalbuphine, opium, oxycodone, oxymorphone, pentazocine, propoxyphene, and tapentadol. Buprenorphine and methadone were excluded because they are predominantly used to treat opioid use disorder.
the VA and Medicare Part D, filing prescriptions from two different health care providers was associated with more than two to three times the risk of high-dose opioid exposure. The authors examined records of veterans enrolled in the VA and Medicare Part D who filled at least two opioid prescriptions in 2013. The outcomes examined were the proportion of patients with a Pharmacy Quality Alliance measure of opioid–benzodiazepine overlap (≥2 filled prescriptions for benzodiazepines with ≥30 days of overlap with opioids) and the proportion of patients with high-dose opioid–benzodiazepine overlap (≥30 days of overlap with a daily opioid dose >120 MMEs). Augmented inverse probability weighting regression was used to compare those measures by prescription drug source: the VA only, Medicare only, or the VA and Medicare. Of 368,891 eligible veterans, 18.3 percent received prescriptions from the VA only, 30.3 percent from Medicare only, and 51.4 percent from both the VA and Medicare. The proportion with Pharmacy Quality Alliance opioid–benzodiazepine overlap was larger among the veterans who had received prescriptions from two prescribers than in the VA-only group (23.1 percent versus 17.3 percent) and in the Medicare-only group (23.1 percent versus 16.5 percent). The proportion with high-dose overlap was also larger among the group who received prescriptions from two prescribers than in the VA-only group (4.7 percent versus 2.3 percent) and the Medicare-only group (4.7 percent versus 2.9 percent). Thus, among a national cohort of veterans dually enrolled in the VA and Medicare, receiving prescriptions from both sources was associated with a greater risk of receiving potentially unsafe overlapping prescriptions for opioids and benzodiazepines. However, as noted by the authors, the study had several weaknesses, including the data being from 2012, an inability to capture medications purchased without insurance, and the potential presence of unmeasured confounding.
Finally, a recent study found that more than half of VA medical enrollees are also covered by Medicare. Those veterans can choose where they get their prescriptions, which may lead to unsafe opioid use. Moyo et al. (2019) conducted a nested case-control study designed to evaluate the association between dual-system opioid prescribing and death from prescription opioid overdose. The cases and controls were identified from all veterans enrolled in both the VA and Medicare Part D. The 215 case patients who died of prescription opioid overdose in 2012 or 2013 were matched with 833 living control patients on the basis of date of death (i.e., the index date), using sex, race/ethnicity, disability, enrollment in Medicaid or low-income subsidies, managed care enrollment, region and rurality of residence, and a medication-based measure of comorbid conditions. The authors categorized the “exposure,” or the source of the opioid prescription within 6 months of the index date, as the VA only, Part D only, or the VA and Part D. The outcome measured was unintentional or undetermined-intent death from
prescription opioid overdose, identified from the National Death Index (NDI). The study found that, overall, 60 case patients (28 percent) and 117 control patients (14 percent) had received dual opioid prescriptions and that dual users had significantly higher odds of death from prescription opioid overdose than those who received opioids from the VA only or Part D only.
Commenting on the findings of the Moyo et al. (2019) study, Meyer and Clancy (2019) said in an accompanying editorial that the VA is taking steps to address its significant opioid problem, such as exploring and using non-pharmacological alternatives for pain management and expanding access to different treatment methods such as physical therapy, yoga, and acupuncture. Meyer and Clancy reported that the VA has documented decreases in opioid prescribing as well as in the number of patients prescribed opioids and benzodiazepines in combination.
The VA/DoD Clinical Practice Guidelines
In light of the epidemic of opioid misuse and opioid use disorder, including among veterans, the VA and DoD published Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain in 2010 and updated those guidelines in 2015 to assist health care providers (VA/DoD, 2017). The VA/DoD guidelines were developed specifically for service members, veterans, their families, and the communities to which they returned. The guidelines incorporate the characteristics and needs of those populations regarding specific risk factors (e.g., suicide, SUDs, and other co-occurring medical and mental health conditions).
The VA/DoD’s stated goal for the guidelines “is to improve the patient’s health and well-being by providing evidence-based guidance to providers who are taking care of patients on or being considered for LOT [long-term opioid therapy]” (VA/DoD, 2017, p. 5). The VA identifies the most important risk factors for the development of opioid-related adverse events in its population as being the duration and dose of opioid analgesic use, and it presents numerous additional factors that increase the risk of adverse outcomes that should be considered prior to or continuing opioid therapy (VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain, 2017).
The VA Opioid Safety Initiative
In 2013 the Opioid Safety Initiative (OSI) was launched by the VA in an effort to help ensure that veterans were prescribed opioids in a safe manner. Since that time (the fourth quarter of fiscal year 2013 to the first quarter of fiscal year 2018), the percentage of patients dispensed an opioid has
decreased from about 17 percent to about 10 percent, or by about 267,000 veterans (GAO, 2018). According to the VA, the requirements of the OSI were communicated to all veterans integrated service networks to ensure that opioids were used in a safe and effective manner. The implementation of the OSI included the provision of a clinical “dashboard,” based on the electronic health record data, that is used to identify patients who might be high risk for adverse outcomes with opioid use and identify providers whose prescribing practices might not reflect the best evidence for improving patient care. The OSI includes specific indicators, such as the number of unique pharmacy patients dispensed an opioid and the unique patients on long-term opioid therapy.
According to the VA, the goals of the OSI are related to increased education, monitoring, safe and effective prescribing and management methods, tool development, collaboration, and use of alternative pain treatment. Furthermore, the VA notes that as part of the OSI,
the VA launched the Opioid Overdose Education and Naloxone Distribution program, which was implemented as a risk mitigation strategy aimed at reducing deaths from opioid overdose. The program components included education and training regarding the following topics: opioid overdose prevention, recognition, and rescue response; risk mitigation strategies; and issuing naloxone kits, which can be used as an antidote to opioid overdose. Other initiatives are aimed at improving the safe use of opioids, including the OSI Toolkit and the patient guide Taking Opioids Responsibly for Your Safety and the Safety of Others: Patient Information Guide on Long-term Opioid Therapy for Chronic Pain. The OSI Toolkit was developed to provide clinicians with materials to inform clinical decision-making regarding opioid therapy and safe opioid prescribing. (VA, 2017)
In 2018 the U.S. Congress appropriated $500,000 to study outcomes in veterans prescribed both opioids and benzodiazepines. The Consolidated Appropriations Act of 201821 included the following language:
“Overmedication.—As indicated in the Senate report, and in addition to the funding levels highlighted for opioid abuse above, the agreement provides $500,000 for the National Academies of Sciences, Engineering, and Medicine to conduct an assessment of the potential overmedication
21 Public Law 141, 115th Congress (March 23, 2018).
of veterans during fiscal years 2010 to 2017 that led to suicides, deaths, mental disorders, and combat-related traumas.”
“Overprescription Prevention Report.—The Committee is discouraged by multiple GAO reports retaining VHA on the “high-risk” list and the unfathomable increase in polydrug use and narcotics prescriptions by VA related to pain management and mental health treatment. Specifically, combinations of opioid and Benzodiazepines have proven fatal when taken concurrently, with research demonstrating this phenomenon for nearly 40 years. The Committee provides $500,000 to enter into an agreement with the National Academies of Sciences, Engineering, and Medicine to conduct an assessment to research, collect, and analyze the potential overmedication of veterans during fiscal years 2010–2017 that led to veterans deaths, veterans suicides, treatment of mental disorders, pain management practices, mental health staffing levels, and combat related trauma.”
The VA contacted the National Academies to address the language in the Consolidated Appropriations Act. To address the intent of the congressional language and given the appropriated resources, the VA and the National Academies agreed on the following Statement of Task (see Box 1-1).
The VA and the National Academies understood that to actually conduct such a study (i.e., as specified by congressional language), a protocol and study design would need to be proposed. Thus, this report can be considered as a first step in addressing the congressional language.
The National Academies appointed an eight-person committee with expertise in pharmacoepidemiology, RCTs, pain management, addiction, and psychiatry to address the task. The committee held three in-person
meetings and one phone meeting over a 6-month period. In an effort to better understand the task and the intent of the congressional language, the committee met, at its first meeting, with VA leadership responsible for opioid and benzodiazepine prescribing policy in addition to those involved in research and data collection and oversight. Following that meeting the committee interpreted the congressional language and committee charge as a desire on the part of the Congress to study the concomitant prescribing of opioids and benzodiazepines in veterans when used to treat mental disorders and pain and in the context of high levels of combat-related trauma, including PTSD, as well as the potential impact of those medications on veterans’ deaths and suicides. Given that understanding of the task and with a consideration of the existing literature on this topic, the committee focused on the following research question: What were the effects of (1) opioid initiation and (2) tapering (i.e., discontinuing or reducing opioid dosage) strategies in the presence of benzodiazepines in veterans on all-cause mortality and suicide mortality from 2010 to 2017?
Thus, in addressing its task, the committee proposes target trial protocols and corresponding observational studies to answer the research question. The committee agreed that, ideally, one or more RCTs would be conducted to answer questions about the comparative effectiveness or safety of opioids and benzodiazepines. However, RCTs are frequently impractical in this situation (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. Causal inference from large observational databases can be viewed as an attempt to emulate a randomized experiment in order to answer the question of interest (Hernán and Robins, 2016). The committee describes observational data analysis strategies to emulate two target trials—one for the initiation of opioids in the presence of benzodiazepines and one for the tapering of opioids in the presence of benzodiazepines.
In Chapter 2 the committee describes protocols for target trials for opioid initiation and tapering to respond to the charge. In Chapter 3 the committee proposes strategies and analytic plans for implementing observational studies to emulate the target trials using existing VA data. The committee notes that the proposed studies are not the only way to respond to the Statement of Task. Should the VA or others be interested in conducting related studies, such as the tapering of benzodiazepines for patients prescribed both opioids and benzodiazepines, those studies can be modeled on the committee’s approach.
Agarwal, S. D., and B. E. Landon. 2019. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Network Open 2(1):e187399.
AGS (American Geriatrics Society). 2019. American Geriatrics Society 2019 updated AGS Beers Criteria(R) for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society 67(4):674–694.
Arenson, M. B., M. A. Whooley, T. C. Neylan, S. Maguen, T. J. Metzler, and B. E. Cohen. 2018. Posttraumatic stress disorder, depression, and suicidal ideation in veterans: Results from the Mind Your Heart study. Psychiatry Research 265:224–230.
Armstrong, K. 2012. Methods in comparative effectiveness research. Journal of Clinical Oncology 30(34):4208–4214.
Ashburn, M. A., and P. S. Staats. 1999. Management of chronic pain. Lancet 353(9167): 1865–1869.
Bohnert, A. S. B., and M. A. Ilgen. 2019. Understanding links among opioid use, overdose, and suicide. New England Journal of Medicine 380(1):71–79.
Bohnert, A. S., M. Valenstein, M. J. Bair, D. Ganoczy, J. F. McCarthy, M. A. Ilgen, and F. C. Blow. 2011. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 305(13):1315–1321.
Bossarte, R. M., K. L. Knox, R. Piegari, J. Altieri, J. Kemp, and I. R. Katz. 2012. Prevalence and characteristics of suicide ideation and attempts among active military and veteran participants in a national health survey. American Journal of Public Health 102(Suppl 1):S38–S40.
Brescia, A. A., C. A. Harrington, A. A. Mazurek, S. T. Ward, J. S. J. Lee, H. M. Hu, C. M. Brummett, J. F. Waljee, P. A. Lagisetty, and K. H. Lagisetty. 2019. Factors associated with new persistent opioid usage after lung resection. Annals of Thoracic Surgery 107(2):363–368.
Buttner, M. M., K. M. Godfrey, E. Floto, J. Pittman, L. Lindamer, and N. Afari. 2017. Combat exposure and pain in male and female Afghanistan and Iraq veterans: The role of mediators and moderators. Psychiatry Research 257:7–13.
CDC (Centers for Disease Control and Prevention). 2018. Opioid data analysis and resources. https://www.cdc.gov/drugoverdose/data/analysis.html (accessed May 2, 2019).
CDC. 2019a. CDC WONDER. https://wonder.cdc.gov (accessed July 16, 2019).
CDC. 2019b. Opioid prescribing rates in nonmetropolitan and metropolitan counties among primary care providers using an electronic health record system—United States, 2014–2017. Morbidity and Mortality Weekly Report 68(2):25–30.
Chou, R., R. Deyo, B. Devine, R. Hansen, S. Sullivan, J. G. Jarvik, I. Blazina, T. Dana, C. Bougatsos, and J. Turner. 2014. The effectiveness and risks of long-term opioid treatment of chronic pain. Evidence Report/Technology Assessment 218:1–219.
Darke, S., J. Ross, K. Mills, M. Teesson, A. Williamson, and A. Havard. 2010. Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. Drug and Alcohol Review 29(3):250–255.
Dasgupta, N., M. J. Funk, S. Proescholdbell, A. Hirsch, K. M. Ribisl, and S. Marshall. 2016. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Medicine (United States) 17(1):85–98.
Dowell, D., T. M. Haegerich, and R. Chou. 2016. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA 315(15):1624–1645.
Edlund, M. J., M. A. Austen, M. D. Sullivan, B. C. Martin, J. S. Williams, J. C. Fortney, and T. J. Hudson. 2014. Patterns of opioid use for chronic noncancer pain in the Veterans Health Administration from 2009 to 2011. Pain 155(11):2337–2343.
Evans, C. J., and C. M. Cahill. 2016. Neurobiology of opioid dependence in creating addiction vulnerability. F1000Research 5:PMC4955026.
Evans, W. N., E. M. J. Lieber, and P. Power. 2019. How the reformulation of oxycontin ignited the heroin epidemic. Review of Economics and Statistics 101(1):1–15.
Fluyau, D., N. Revadigar, and B. E. Manobianco. 2018. Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation. Therapeutic Advances in Psychopharmacology 8(5):147–168.
GAO (Government Accountability Office). 2018. VA health care: Progress made towards improving opioid safety, but further efforts to assess progress and reduce risk are needed. GAO-18-380. https://www.gao.gov/products/GAO-18-380 (accessed July 16, 2019).
Gellad, W. F., J. M. Thorpe, X. Zhao, C. T. Thorpe, F. E. Sileanu, J. P. Cashy, J. A. Hale, M. K. Mor, T. R. Radomski, L. R. M. Hausmann, J. M. Donohue, A. J. Gordon, K. J. Suda, K. T. Stroupe, J. T. Hanlon, F. E. Cunningham, C. B. Good, and M. J. Fine. 2018. Impact of dual use of Department of Veterans Affairs and Medicare Part D drug benefits on potentially unsafe opioid use. American Journal of Public Health 108(2):248–255.
Hedegaard, H., B. A. Bastian, J. P. Trinidad, M. Spencer, and M. Warner. 2018a. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports 67(9):1–14.
Hedegaard, H., A. M. Minino, and M. Warner. 2018b. Drug overdose deaths in the United States, 1999–2017. NCHS Data Brief 329:1–8.
Hernán, M. A., and J. M. Robins. 2016. Using big data to emulate a target trial when a randomized trial is not available. American Journal of Epidemiology 183(8):758–764.
Hernandez, I., M. He, and Y. Zhang. 2018. Comparing state, regional, and local variation in concurrent opioid and benzodiazepine use. Drug and Alcohol Dependence 191:141–144.
Hirschtritt, M. E., K. L. Delucchi, and M. Olfson. 2018. Outpatient, combined use of opioid and benzodiazepine medications in the United States, 1993–2014. Preventive Medicine Reports 9:49–54.
Hoge, C. W., C. A. Castro, S. C. Messer, D. McGurk, D. I. Cotting, and R. L. Koffman. 2004. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. New England Journal of Medicine 351(1):13–22.
Hosek, J. 2011. How is deployment to Iraq and Afghanistan affecting U.S. service members and their families? An overview of early Rand research on the topic. Santa Monica, CA: Department of Defense.
Hwang, C. S., E. M. Kang, C. J. Kornegay, J. A. Staffa, C. M. Jones, and J. K. McAninch. 2016. Trends in the concomitant prescribing of opioids and benzodiazepines, 2002−2014. American Journal of Preventive Medicine 51(2):151–160.
Ilgen, M. A., A. S. Bohnert, D. Ganoczy, M. J. Bair, J. F. McCarthy, and F. C. Blow. 2016. Opioid dose and risk of suicide. Pain 157(5):1079–1084.
IOM (Institute of Medicine). 2013. Returning home from Iraq and Afghanistan: Assessment of readjustment needs of veterans, service members, and their families. Washington, DC: The National Academies Press.
Jones, C. M., and J. K. McAninch. 2015. Emergency department visits and overdose deaths from combined use of opioids and benzodiazepines. American Journal of Preventive Medicine 49(4):493–501.
Jones, C. M., K. A. Mack, and L. J. Paulozzi. 2013. Pharmaceutical overdose deaths, United States, 2010. JAMA 309(7):657–659.
Jones, J. D., S. Mogali, and S. D. Comer. 2012. Polydrug abuse: A review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence 125(1–2):8–18.
Larson, M. J., N. R. Wooten, R. S. Adams, and E. L. Merrick. 2012. Military combat deployments and substance use: Review and future directions. Journal of Social Work Practice in the Addictions 12(1):6–27.
Lintzeris, N., T. B. Mitchell, A. J. Bond, L. Nestor, and J. Strang. 2007. Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients. Drug and Alcohol Dependence 91(2–3):187–194.
Lee, J. S., H. M. Hu, A. L. Edelman, C. M. Brummett, M. J. Englesbe, J. F. Waljee, J. B. Smerage, J. J. Griggs, H. Nathan, J. S. Jeruss, and L. A. Dossett. 2017. New persistent opioid use among patients with cancer after curative-intent surgery. Journal of Clinical Oncology 35(36):4042–4049.
Lisi, A. J., K. L. Corcoran, E. C. Derycke, L. A. Bastian, W. C. Becker, S. N. Edmond, C. M. Goertz, J. L. Goulet, S. G. Haskell, D. M. Higgins, T. Kawecki, R. D. Kerns, K. Mattocks, C. Ramsey, C. B. Ruser, and C. A. Brandt. 2018. Opioid use among veterans of recent wars receiving Veterans Affairs chiropractic care. Pain Medicine (United States) 19:S54–S60.
Maiese, K. 2019. Neurotransmission. https://www.merckmanuals.com/professional/neurologicdisorders/neurotransmission/neurotransmission (accessed July 2, 2019).
McClure, F. L., J. K. Niles, H. W. Kaufman, and J. Gudin. 2017. Concurrent use of opioids and benzodiazepines: Evaluation of prescription drug monitoring by a United States laboratory. Journal of Addiction Medicine 11(6):420–426.
Meyer, L. J., and C. M. Clancy. 2019. Care fragmentation and prescription opioids. Annals of Internal Medicine 170(7):497–498.
Mosher, H. J., E. E. Krebs, M. Carrel, P. J. Kaboli, M. W. V. Weg, and B. C. Lund. 2015. Trends in prevalent and incident opioid receipt: An observational study in Veterans Health Administration, 2004–2012. Journal of General and Internal Medicine 30(5):597–604.
Moyo, P., X. Zhao, C. T. Thorpe, J. M. Thorpe, F. E. Sileanu, J. P. Cashy, J. A. Hale, M. K. Mor, T. R. Radomski, J. M. Donohue, L. R. M. Hausmann, J. T. Hanlon, C. B. Good, M. J. Fine, and W. F. Gellad. 2019. Dual receipt of prescription opioids from the Department of Veterans Affairs and Medicare part D and prescription opioid overdose death among veterans: A nested case–control study. Annals of Internal Medicine 170(7):433–442.
Nahin, R. L. 2017. Severe pain in veterans: The effect of age and sex, and comparisons with the general population. Journal of Pain 18(3):247–254.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. Pain management and the opioid epidemic: Balancing societal and individual benefits and risks of prescription opioid use. Washington, DC: The National Academies Press.
NASEM. 2018. Evaluation of the Department of Veterans Affairs mental health services. Washington, DC: The National Academies Press.
NIDA (National Institute on Drug Abuse). 2018. Benzodiazepines and opioids. https://www.drugabuse.gov/drugs-abuse/opioids/benzodiazepines-opioids (accessed March 7, 2019).
Olfson, M., M. King, and M. Schoenbaum. 2015. Benzodiazepine use in the United States. JAMA Psychiatry 72(2):136–142.
Park, T. W., R. Saitz, D. Ganoczy, M. A. Ilgen, and A. S. B. Bohnert. 2015. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: Case-cohort study. BMJ (Online) 350.
Petrakis, I. L., R. Rosenheck, and R. Desai. 2011. Substance use comorbidity among veterans with posttraumatic stress disorder and other psychiatric illness. American Journal of Addiction 20(3):185–189.
Pitcher, M. H. 2018. The impact of exercise in rodent models of chronic pain. Current Osteoporosis Reports 16(4):344–359.
Rooney, S. 1999. Co-abuse of opiates and benzodiazepines. Irish Journal of Medical Science 168(1):36–41.
Rosenblum, A., L. A. Marsch, H. Joseph, and R. K. Portenoy. 2008. Opioids and the treatment of chronic pain: Controversies, current status, and future directions. Experimental and Clinical Psychopharmacology 16(5):405–416.
Ross, J., and S. Darke. 2000. The nature of benzodiazepine dependence among heroin users in Sydney, Australia. Addiction 95(12):1785–1793.
Sarchiapone, M., L. Mandelli, M. Iosue, C. Andrisano, and A. Roy. 2011. Controlling access to suicide means. International Journal of Environmental Research and Public Health 8(12):4550–4562.
Schepis, T. S., C. J. Teter, L. Simoni-Wastila, and S. E. McCabe. 2018. Prescription tranquilizer/sedative misuse prevalence and correlates across age cohorts in the U.S. Addictive Behaviors 87:24–32.
Schieber, L. Z., G. P. Guy, Jr., P. Seth, R. Young, C. L. Mattson, C. A. Mikosz, and R. A. Schieber. 2019. Trends and patterns of geographic variation in opioid prescribing practices by state, United States, 2006–2017. JAMA Network Open 2(3):e190665.
Stein, B. D., J. Mendelsohn, A. J. Gordon, A. W. Dick, R. M. Burns, M. Sorbero, R. A. Shih, and R. Liccardo Pacula. 2017. Opioid analgesic and benzodiazepine prescribing among Medicaid enrollees with opioid use disorders: The influence of provider communities. Journal of Addictive Diseases 36(1):14–22.
Sun, E. C., A. Dixit, K. Humphreys, B. D. Darnall, L. C. Baker, and S. MacKey. 2017. Association between concurrent use of prescription opioids and benzodiazepines and overdose: Retrospective analysis. BMJ (Online) 356:j760.
Tanielian, T., and L. H. Jaycox (eds.). 2008. Invisible wounds of war: Psychological and cognitive injuries, their consequences, and services to assist recovery. Santa Monica, CA: RAND Corporation.
Teeters, J. B., C. L. Lancaster, D. G. Brown, and S. E. Back. 2017. Substance use disorders in military veterans: Prevalence and treatment challenges. Substance Abuse and Rehabilitation 8:69–77.
Toblin, R. L., K. A. Mack, G. Perveen, and L. J. Paulozzi. 2011. A population-based survey of chronic pain and its treatment with prescription drugs. Pain 152(6):1249–1255.
Toblin, R. L., P. J. Quartana, L. A. Riviere, K. C. Walper, and C. W. Hoge. 2014. Chronic pain and opioid use in U.S. soldiers after combat deployment. JAMA Internal Medicine 174(8):1400–1401.
Tompkins, D. A., J. G. Hobelmann, and P. Compton. 2017. Providing chronic pain management in the “fifth vital sign” era: Historical and treatment perspectives on a modern-day medical dilemma. Drug and Alcohol Dependence 173:S11–S21.
Turton, S., and A. Lingford-Hughes. 2016. Neurobiology and principles of addiction and tolerance. Medicine (United Kingdom) 44(12):693–696.
VA (Department of Veterans Affairs). 2017. Management of opioid therapy (OT) for chronic pain (2017)—VA/DoD clinical practice guidelines. https://www.healthquality.va.gov/guidelines/Pain/cot (accessed December 17, 2018).
VA. 2019. National Center for Veterans Analysis and Statistics. https://www.va.gov/vetdata (accessed July 11, 2019).
VA/DoD (Department of Veterans Affairs and Department of Defense). 2017. VA/DoD clinical practice guideline for opioid therapy for chronic pain. https://www.healthquality.va.gov/guidelines/Pain/cot/VADoDOTCPG022717.pdf (accessed July 16, 2019).
Yarborough, B. J. H., S. P. Stumbo, A. Stoneburner, N. Smith, S. K. Dobscha, R. A. Deyo, and B. J. Morasco. 2018. Correlates of benzodiazepine use and adverse outcomes among patients with chronic pain prescribed long-term opioid therapy. Pain Medicine. doi: 10.1093/pm/pny179 [Epub ahead of print].
Zhu, W., M. E. Chernew, T. B. Sherry, and N. Maestas. 2019. Initial opioid prescriptions among U.S. commercially insured patients, 2012–2017. New England Journal of Medicine 380(11):1043–1052.