1

Introduction

Acute pain can limit an individual’s physical activities and participation in family, work, and social roles. Acute pain can be self-managed as recovery occurs. However, some acute pain caused by a medical condition or injury can require medical interventions, including nonpharmacologic and pharmacologic treatments for pain as well as treatments aimed at the underlying cause of pain.

Opioids have long been prescribed to relieve acute pain; morphine and opium have been used for centuries (Collier, 2018). In the United States, opioid prescribing increased steadily from 1999 to 2010 but has decreased since 2012 (Guy et al., 2017). Even with that decrease, however, the amount of opioids in morphine milligram equivalents (MMEs¹) prescribed per person in 2017 was still around 3 times higher than it was in 1999.

Opioid prescribing in the United States is much higher than in other countries. In 2015, nearly 4 times as many opioids were prescribed in the United States than in Europe (Guy et al., 2017). In 2010, the United States consumed approximately 80% of world’s opioid supply despite constituting less than 5% of the world’s population (Duthey and Scholten, 2014; Rose, 2018). Opioid prescribing in the United States is higher for some medical specialties and for acute as well as chronic pain. For example, dentists in the United States prescribed opioids 37² times more frequently than did dentists in the United Kingdom (35.4 prescriptions/1,000 U.S. population versus 0.5 prescriptions/1,000 UK population) (Suda et al., 2019). For pain management after low-risk surgical procedures (e.g., laparoscopic cholecystectomy or appendectomy, arthroscopic knee meniscectomy, and breast excision), U.S. patients were prescribed opioids at rates 7 times higher than those in Sweden (76% versus 11%) (Ladha et al., 2019).

Along with the rise in opioid prescribing, the number of deaths from drug and opioid overdoses has also risen since 1999. This has led to what many refer to as the “opioid crisis or epidemic” or “opioid

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¹ MMEs are used to standardize reporting of the dose of opioids a person receives across different opioids. For example, 50 MMEs per day is equal to 50 mg of hydrocodone (10 pills of hydrocodone/acetaminophen 5/300) or 33 mg of oxycodone (approximately two 15 mg pills of sustained-release oxycodone). See https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf (accessed September 18, 2019).

² This text has been revised since prepublication release.

overdose crisis.” Even as the amount of opioids prescribed has decreased over the past several years, the rate of opioid-related deaths has continued unabated. Although the reasons for this are multifactorial, unused opioids from excessive prescriptions serve as the most common initial opioid exposure for individuals who use heroin. The use of heroin and its synthetic derivatives is a major factor in the current rise of opioid-related deaths (Cicero et al., 2014). In 2016, 42,249 people died of opioid overdoses (CDC, 2018a). This equates to about 130 Americans dying every day from opioid overdose (CDC, 2018b). By comparison, an estimated 42,000 people will die of breast cancer in 2019 (ACS, 2018). Between 1999 and 2016 the mortality rate among children and adolescents due to prescriptions and illicit opioid use increased by approximately 268% (Gaither et al., 2018).

Thus, clinicians caring for patients with acute pain have two distinct goals: relieving the patient’s pain and minimizing the risks of opioids to the patient and to the public health. The committee recognizes that the treatment of acute pain with opioids is one of many contributing factors to the national opioid epidemic. Over the past several years, the opioid overdose epidemic has received national attention and numerous governmental and private organizations have sought to reduce the number of deaths, overdoses, and addictions related to the use of opioids. The 2017 National Academies of Sciences, Engineering, and Medicine (the National Academies) report Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use contains a comprehensive review of the legal, regulatory, and policy context of opioid prescriptions for pain. The National Academies report summarizes this situation thus:

OPIOID PRESCRIBING PATTERNS

When one examines opioid prescribing trends in detail, a complex picture emerges. In 2006, health care providers wrote 72.4 opioid prescriptions per 100 persons. This rate increased annually by 3.0% from 2006 to 2010, decreased 1.6% annually from 2010 to 2014, and continued to decrease annually by 8.2% until 2017, reaching a rate of 58.5 prescriptions per 100 persons. The average prescribed dose for adults decreased between 2006 and 2016, from 59.7 daily MMEs to 45.3 MMEs. For high-dose opioids (daily MMEs>90), the annual prescribing rate per 100 persons decreased from 11.5 to 5.0 between 2006 and 2017. On the other hand, the average days of supply per opioid prescription increased from 13.3 to 18.3, although the rate of increase was slowing in recent years (CDC, 2018a,b). A recent study showed that between 2005 and 2015, overall opioid prescribing rates for adolescents and young adults (aged 13–17 years and 18–22 years, respectively) in emergency departments (EDs) was 14.9% and 2.8% in outpatient clinic visits (Hudgins et al., 2019). The highest rates of opioid prescribing in the ED for both age groups were for dental disorders, followed by clavicle fractures (adolescents only), and low back pain (young adults only).

The recent reduction in opioid prescribing has been widespread across different specialties and patient populations. A 2019 study found that among enrollees in a large commercial insurer’s database, about 54% fewer enrollees received new opioid prescriptions in December 2017 than in July 2012 (0.75% versus 1.63%) (Zhu et al., 2019). Furthermore, the number of clinicians who wrote new prescriptions fell by about 30%, with reductions occurring across all provider specialties and for all diagnostic codes. Dentists were least likely to write prescriptions for long courses of opioids, and primary care clinicians were most likely (Zhu et al., 2019). Data from pediatric populations also indicate a decrease in opioid prescribing. In a study of 1,795,329 patients with a median age of 10 years who underwent ambulatory

surgery from 2010 to 2017, opioid use was found to have dropped from 75% to 67% (Rizeq et al., 2019). Other studies have also documented a similar pattern of reductions in opioid use in pediatric populations (Gagne et al., 2019).

OPIOID-RELATED MORBIDITY AND MORTALITY

Although opioids can relieve acute pain, their use can also lead to short- and long-term risks to the patient, particularly in the case of initial exposures and larger dosages for opioid-naïve patients. One risk is the development of persistent opioid use in opioid-naïve patients who start opioids for acute pain (Barnett et al., 2017; Bateman et al., 2016; Brummett et al., 2017; Delgado et al., 2018; Deyo et al., 2017; Harbaugh et al., 2018; Meisel et al., 2019; Shah et al., 2017; Sun et al., 2016). According to one study, between 4.5% and 9.9% of opioid-naïve patients who fill a prescription for opioids around the time of common surgical procedures end up filling one or more prescriptions for opioids between 90 and 180 days after surgery (Brummett et al., 2017). Another study found that 12 months after total knee arthroplasty, 1.41% of opioid-naïve patients filled more than 10 opioid prescriptions—or more than a 120-day supply—in the 12 months after surgery, as did 1.18% of patients after open cholecystectomy, but only 0.12% of patients had chronic opioid use after cesarean delivery (Sun et al., 2016).

Prescription quantities are also associated with continued use. Prescriptions with higher quantities, based on the number of opioid pills or greater number of days supplied—resulting in a higher total number of MMEs prescribed—are associated with higher rates of persistent opioid use (Barnett et al., 2017; Delgado et al., 2018; Deyo et al., 2017; Meisel et al., 2019; Shah et al., 2017).

Data suggest that a substantial percentage of patients who receive opioids for acute pain do not use all the prescribed pills, particularly after surgery (Bicket et al., 2017; Kumar et al., 2017; Maughan et al., 2016; Monitto et al., 2017). Studies have shown that after cesarean delivery about 50% to 75% of patients had unused opioids (Bateman et al., 2017; Osmundson et al., 2017). After joint or lumbar spine surgery, of the 71% of patients who had stopped opioids at 1 month 37% had more than 200 MMEs in their possession, and fewer than 10% had securely stored or properly disposed of their leftover opioids (Bicket et al., 2019).

A 2017 study in Michigan of patients undergoing 12 common operations found that the quantity of opioid prescribed was significantly greater than quantity consumed (Howard et al., 2018). For 11 of the 12 procedures, the median opioid consumption was less than half of the quantity prescribed. For the entire study population the median number of leftover oral morphine equivalents was 100 (interquartile range [IQR], 25–150). Furthermore, the quantity of opioid prescribed was associated with higher patient-reported opioid consumption even after controlling for postoperative pain, the surgical procedure, and patient-related factors. On the average, patients consumed 5 more pills for every 10 additional pills prescribed (Howard et al., 2018).

Opioids pose risks not only to the patients for whom they are prescribed, but also to family members and to the community. Unused opioid pills from opioid prescriptions can be diverted to family members and friends (Bicket et al., 2019; Hill et al., 2017; Howard et al., 2019; Thiels et al., 2017). These unused pills, which often are not disposed of properly, may be used by the patient for indications other than those for which they were prescribed (e.g., as a sleep aid), or they may be used by someone other than the patient (Bicket et al., 2017; Jones et al., 2014). Individuals with opioid use disorder commonly report that they started by misusing prescription opioids (Ali et al., 2019; Becker et al., 2008; Cicero et al., 2014; NASEM, 2019). Furthermore, there is an association between the size of a patient’s opioid prescription and the likelihood of an opioid overdose among the patient’s family members (Khan et al., 2019). This association is present in children and adolescents as well as in adults (Khan et al., 2019). Among individuals who misuse prescription opioids, the most common source of opioids was pills

from family members and friends. Among individuals who use heroin, the majority (66%) previously misused prescription opioids (Cicero et al., 2014). Thus, opioid overprescribing, that is, prescribing more opioids than are necessary to control a patient’s acute pain, is a factor contributing to the public health epidemic of opioid overdoses.

STANDARDIZING OPIOID PRESCRIBING PRACTICES

The inappropriate variation in opioid prescribing for surgical and medical conditions and the fact that overprescribing is a factor in the continuing opioid epidemic suggest that some guidelines for acute pain management for these conditions would be beneficial for both prescribers and their patients. One approach to setting such standards would be to establish evidence-based prescribing guidelines for opioids for pain management. Although there is considerable literature and guidance on the use of opioids for treating chronic pain, guidelines on acute pain are a relatively recent development.

To address the overprescribing of opioids for acute pain, numerous organizations, ranging from state and local governments to professional societies, individual health care organizations, and hospital departments, have instituted some form of opioid prescribing guidance. For example, New York City has enacted nine recommendations for opioid prescribing in EDs modeled after the Washington State initiatives for regulating opioid prescribing in the ED (Chu et al., 2012; Juurlink et al., 2013). Similar opioid prescribing guidelines have been promulgated by the American Academy of Emergency Medicine (Cheng et al., 2013). Florida used a more conservative approach and passed a bill in 2018 imposing a 3-day limit on opioid prescriptions, unless strict conditions are met for more liberal prescribing of 7 days. Other guidelines vary from a short list of prescription recommendations for the number and dose of opioids to evidence-based clinical practice guidelines (CPGs) developed by professional societies (e.g., the American College of Occupational and Environmental Medicine) or by federal agencies such as the Centers for Disease Control and Prevention (CDC) (Dowell et al., 2016).

Despite widespread efforts to reduce opioid prescribing over the past 5 years—and resulting modest reductions—opioid prescribing remains highly variable within specific indications (as later chapters discuss in detail), and more work is needed to optimize prescribing guidelines. Opioid prescribing practices vary by geographic region (Paulozzi et al., 2014; Schieber et al., 2019), within and among patient populations (Sinnenberg et al., 2017; Tomaszewski et al., 2018), and by providers (Guy and Zhang, 2018; Volkow et al., 2011). This variation in opioid prescribing, together with a lack of guidelines that have been rigorously developed based on evidence, has led to uncertainty among clinicians and regulators about the efficacy and appropriateness of opioid use.

To address the need for a more consistent approach to the development of CPGs, the U.S. Food and Drug Administration (FDA) asked the National Academies to recommend an evidence-based framework that could be used by professional societies, health care organizations, and local, state, and national agencies to develop CPGs for opioid prescribing for acute pain. Such a framework could inform the development of opioid prescribing guidelines and ensure systematic and standardized methods for evaluating evidence, translating knowledge, and formulating recommendations for practice.

COMMITTEE’S CHARGE

FDA tasked the National Academies with establishing a committee to develop a framework to evaluate existing CPGs for prescribing opioids for acute pain indications, to recommend indications for which new evidence-based guidelines should be developed, and to recommend a future research agenda to assist

specialty organizations in the development and dissemination of evidence-based CPGs for prescribing opioids to treat acute pain indications (see Box 1-1 for the committee’s Statement of Task).

COMMITTEE’S APPROACH

To accomplish its task, the National Academies empaneled a committee of 15 experts from a diverse group of medical specialties who have experience in the development and use of CPGs (see Appendix A for the committee biographical sketches). The committee recognized that the audience for its report would include not only FDA and other government agencies at the federal, state, and local level that are engaged in mitigating the opioid overdose epidemic, but also professional societies (i.e., medical

and other health care professional societies, such as nurses, physical therapists, and pharmacists), health care organizations, and health insurers that have developed or may develop CPGs for opioid prescribing. Finally, the committee recognized that individual health care providers, and patients, their caregivers, and their communities all have an interest in optimal opioid prescribing not only to manage patients’ acute pain, but also to prevent opioids from causing harm.

The committee held five in-person meetings, three of which included public sessions (see Appendix C for the public session agendas). At the first public session, the committee heard from FDA and CDC representatives. The committee gathered information at two subsequent public sessions that convened national experts who delivered specific content relevant to the committee’s tasks and engaged in discussions with the committee. The public session in February 2019 focused on identifying surgical procedures and medical conditions associated with acute pain for which opioid analgesics are prescribed. The public session in July 2019 focused on prioritizing a research agenda for selected medical and surgical indications for which no CPGs exist or for which more evidence is required to support existing guidelines. Experts presented state-of-the-science content on acute pain conditions and identified specific gaps in research concerning opioid prescribing.

The committee conducted literature searches to identify current opioid prescribing practices and trends, existing opioid prescribing guidance, information on the use of opioids to treat acute pain for the priority medical and surgical indications it identified, and information on the prevalence and incidence of the selected medical and surgical indications. Literature searches focused on the retrieval and evaluation of evidence-based publications in referred journals with an emphasis on randomized controlled trials, clinical trials, and large observational and cohort studies as an evidence base for opioid prescribing. Committee members also examined available evidence-based CPGs, other guidelines, white papers, national and state reports, and other literature that has informed opioid prescribing for acute pain. Unpublished data presented to the committee during public sessions (e.g., information about the experiences of health care institutions examining the impact of opioid prescribing guidelines and practices on patient-, clinical-, and systems-level outcomes) were also considered by the committee in its deliberations.

Review of the Literature

The committee began developing its list of possible indications by conducting literature searches to identify the most prevalent surgical procedures and medical conditions associated with acute pain or opioid prescribing (see Appendix B). Literature searches were conducted for both adult and pediatric populations. Many of the studies focused on single or selected groups of procedures and were primarily in inpatient settings.

On the basis of the few studies identified from the literature searches, the committee created a preliminary list of approximately 50 surgical and medical indications. For surgical procedures, the committee reviewed peer-reviewed publications on the frequency of surgical procedures performed in the United States. Studies that used large national databases such as those developed for the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project 2014 National Inpatient Sample, the nationwide ambulatory surgery analytic file created from the State Ambulatory Surgery and Services Databases (e.g., Steiner et al., 2017, for surgical procedures), and the research database InVision for Data Mart, a product of OptumInsight Life Sciences, were used as primary data sources by the committee.

For medical conditions, the committee also requested data analyses from CDC. The CDC National Center for Health Statistics, using data collected from the 2016 National Hospital Ambulatory Medical

Care Survey (NHAMCS), provided the committee with the estimated number and percentage distribution of hospital ED visits at which opioids were prescribed at discharge, categorized by diagnosis group. NHAMCS collects annual data on ambulatory care services in hospital EDs and outpatient departments and ambulatory surgery locations based on a national sample of visits to those departments in approximately 500 noninstitutional general and short-stay hospitals (CDC, 2019). The committee was also provided with a list of medical conditions for which opioids are prescribed most frequently in primary care, based on administrative data from a large national health insurer (Brian Bateman, Brigham and Women’s Hospital, personal communication, September 3, 2019). This provided the committee with a list of medical indications to consider for prioritization.

The committee also sought the advice of key experts and stakeholders with knowledge of pain management in geriatric, pediatric, and underserved populations; general and specialty surgeries such as dental, obstetric, and orthopedic surgery; emergency medicine; sports medicine; internal medicine; and family medicine. These experts were asked to provide their priority indications for CPG development and the reasons for their selections at the committee’s second public session. Committee members also added priority indications to the list based on their own expertise. These sources resulted in a preliminary list of more than 100 surgical and medical indications for which acute pain was considered to be common and for which opioids might be prescribed. The list was then refined to fewer than 50 surgical and medical indications on the basis of the criteria described in Chapter 5, Box 5-1. Further literature searches using PubMed were then conducted for each individual indication to identify studies in adult and pediatric patients that described opioid prescribing practices for that indication. Some studies identified in the peer-reviewed literature reported that a substantial proportion of prescribed opioids were unused following care, and others indicated that some patients requested refills or otherwise sought additional pain relief after receiving an initial opioid prescription. The committee considered that such studies indicated a lack of optimal opioid prescribing and that CPGs could enhance care. The committee sought to identify not more than five studies for each indication that reported on opioid use in a specified U.S. adult or pediatric population, described the methods used to assess opioid use, and detailed opioid prescribing outcomes, such as number of pills remaining after a certain time, number of refills requested, and patient satisfaction with pain control. The existence of such studies was considered in refining the priority list of indications. Further details of how the committee developed its priority list of indications are described in Chapter 5.

ORGANIZATION OF THE REPORT

Chapter 2 of this report focuses on a conceptual model of opioid prescribing for acute pain management. The committee lays out the definition of and background concerning acute pain and examines many of the patient factors that affect acute pain presentation and treatment response, such as age and genetics. Attention is focused on access to acute pain management and the impact of the social determinants of health and other factors on a patient’s pain management. In Chapter 3 the committee examines the current state of CPGs, including limitations, common use, and existing guidance on their development as well as examples of organizations, both government and private, that are producing guidelines on opioid prescribing. The committee presents and explains two frameworks for developing evidence-based CPGs in Chapter 4, an analytical framework and an evidence-based framework. It also assesses factors that affect the implementation of CPGs at the provider, organization, and patient levels. Chapter 5 lists the priority surgical and medical indications that the committee identified for which opioids are prescribed and for which evidence-based CPGs would help inform the prescribing practices of health care providers. This chapter also responds to the committee’s task to identify existing opioid prescribing guidelines

for acute pain indications. The focus of Chapter 6 is the application of the frameworks developed in Chapter 4 to seven selected surgical and medical indications from the lists in Chapter 5. This chapter shows how the frameworks can be used to identify gaps in the literature and indicates what types of studies are necessary to fill those gaps. These gaps can be used to inform an agenda for future research efforts. Finally, in Chapter 7, the committee summarizes its recommendations for developing or improving evidence-based CPGs for prescribing opioids for acute pain, including which research needs should be emphasized. Appendix A presents short biographical sketches of the committee members, Appendix B provides the committee’s literature search strategies, and Appendix C contains the agendas for the committee’s public sessions.

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