7

The Path Forward

The clinician caring for a patient whose acute pain cannot be adequately relieved with nonopioid approaches has two intertwined goals: to relieve the patient’s acute pain and to minimize the adverse consequences of opioids for the patient receiving an opioid prescription, for third parties, and for the community. The experience of acute pain is highly variable and depends on many factors, such as the severity of the causative factor, the person’s perception of the pain, and the effectiveness of treatment, including opioids. Acute pain may resolve with no or minimal intervention, but it may also require pharmacologic interventions, nonpharmacologic interventions, or both.

Patients for whom opioids are prescribed may be at risk for adverse outcomes including opioid misuse, chronic opioid use, and opioid use disorder. In addition, unused opioids may be available for misuse by family members or for diversion to others, further fueling opioid-related morbidity and mortality. Although opioids are effective for the management of acute pain, the continuing morbidity and mortality related to opioid analgesics in the United States underscores the need for evidence-based clinical practice guidelines (CPGs) to prescribe these medications safely, appropriately, and effectively.

The U.S. Department of Health and Human Services’ Pain Management Best Practices Inter-Agency Task Force has emphasized the need for evidence-based acute pain management guidelines with this recommendation: “Encourage public and private stakeholders to develop acute pain management guidelines for common surgical procedures and trauma management, carefully considering how these guidelines can serve both to improve clinical outcomes and to avoid unintended negative consequences” (HHS, 2019, p. 22). The 2017 report by the National Academies of Sciences, Engineering, and Medicine (the National Academies), Pain Management and the Opioid Epidemic, began by explicitly calling attention to the two simultaneous public health challenges of “reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications” (NASEM, 2017, p. 1).

In response to the opioid epidemic in the United States, the U.S. Food and Drug Administration (FDA) tasked the National Academies committee with the following:

• Develop a framework to evaluate existing CPGs on opioid prescribing for acute pain;
• Identify existing opioid prescribing guidelines;
• Identify a prioritized list of specific surgical procedures and medical conditions associated with acute pain for which opioids are commonly prescribed;
• Evaluate selected existing opioid prescribing guidelines for acute pain using the framework to indicate whether they are sufficiently evidence-based; and
• Develop a prioritized research agenda that indicates deficiencies in the evidence base for the guidelines and what additional information would be required to have the guidelines meet the standards in the committee’s framework.

ADDRESSING THE COMMITTEE’S TASKS

To accomplish the first task, the committee developed the frameworks presented in Chapter 4. Two frameworks were developed—an analytic framework that identifies the elements to determine which outcomes may occur following different opioid prescribing strategies and an evidence evaluation framework that provides an approach to determine how reliable and useful a study may be in assessing each element of the analytic framework. Chapter 4 also discussed the implementation, dissemination, and uptake of CPGs by health care providers and organizations. The committee considered the frameworks and approaches used by other organizations, particularly those of the U.S. Preventive Services Task Force (USPSTF) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, when developing its own frameworks. Several CPGs addressing opioid prescribing for acute pain were identified (e.g., AAPD, 2018; Qaseem et al., 2017; VA/DoD, 2017), but few of them provided specific evidence-based recommendations on the appropriate opioid dosage, the number of pills prescribed, and the duration of opioid use for a particular surgical or medical indication.

In response to its other tasks, the committee, with input from experts and stakeholders at its three public sessions, developed a list of surgical procedures and medical conditions that should be priority indications for the development of CPGs based on their public health impact. The public health impact of a particular indication was a function of its prevalence and how likely opioid over-prescribing was for that intervention, as over-prescribing results in pills that remain unused and available for diversion to unintended users. The prioritized surgical and medical indications were listed in Tables 5-2 and 5-3, respectively, along with a list of available guidelines for each indication.

In Chapter 6, the committee further evaluated the most relevant guidelines for three particular surgical indications and four medical indications. The guidelines were assessed against the analytic framework presented in Chapter 4. This analysis led to the identification of data gaps and research needs for each indication, which together formed the basis for the research agenda discussed in this chapter. In this chapter, the committee presents cross-cutting findings, conclusions, and recommendations based on the evidence presented in Chapters 4, 5, and 6.

A FRAMEWORK FOR EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES

As discussed in Chapter 3, there are several types of guidelines for opioid prescribing for acute pain. Chapter 5 provided examples of the guidelines that are publicly available for the indications the committee prioritized for guideline development. As was evident in Tables 5-2 and 5-3, not all of the listed guidelines meet the committee’s definition of evidence-based CPGs.¹ Some guidelines are specific to acute pain, whereas others are focused on chronic pain with some recommendations on acute pain. Many are evidence-based, but others are based on expert opinions with or without supporting evidence, and some guidelines are developed on the basis of studies conducted by researchers at a single or several health care organizations. Some guidelines do not describe specific prescribing strategies that could be easily replicated by other clinicians (e.g., specifying only a maximum or initial quantity of opioid to be prescribed) or tailored to condition- or patient-specific characteristics. The guidelines may be based on data collected from organizational records (e.g., electronic health records [EHRs] and health insurance claims) and patient-reported outcomes, or they may be developed on the basis of in-depth, formal, systematic assessments of a body of published literature.

Although the committee’s Statement of Task (see Chapter 1) asked it to address evidence-based CPGs developed and disseminated by medical specialty societies, the committee broadened its considerations of possible guideline developers to include other organizations that have developed opioid prescribing guidelines, policies, or regulations, such as health care organizations; federal, state, and local governments; state medical boards; health insurers; and even individual researchers. The committee recognized that the majority of evidence-based CPGs have been or will be developed by professional societies (medical and other health care professionals) for use by their members. Some guidelines, such as the Centers for Disease Control and Prevention (CDC) CPG for chronic pain, and those developed by professional societies are intended to be national in scope, whereas others apply primarily to a single health care organization (e.g., the Mayo Clinic). Some guidelines are specific regarding opioid prescribing (e.g., those of Colorado, the Michigan Opioid Prescribing Engagement Network [OPEN], Philadelphia, Oregon, and the Washington Bree Collaborative), whereas others are framed in broader terms of pain management or pharmacotherapies rather than opioid prescribing per se (e.g., those of the American Academy of Pediatric Dentistry [AAPD], the American College of Surgeons, and the American Geriatrics Society).

In addition to guidelines developed by professional societies or health care organizations, there are laws, regulations, and policies of various states, health insurers, and health care organizations, including state medical boards, that govern the actions of clinicians prescribing opioids for acute pain. As noted in Chapter 3, as of 2018, 33 states (NCSL, 2019) and several health insurers (e.g., Darshak Sanghavi, United Health, presentation to the committee, July 9, 2019) have restrictions on the amount of opioids that may be prescribed to a given patient or on the number of days that an opioid may be prescribed or on both; the federal Centers for Medicare & Medicaid Services also has policy guidelines on opioid prescribing (CMS, 2019). In spite of the number of states with prescribing limits on opioids, particularly those with restrictions on the length of prescribing for acute pain indications, there has not yet been a thorough study of the potential unintended and intended consequences that such prescribing limits may have with regard to decreasing the effectiveness of pain control and reducing opioid misuse,

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¹ The committee adopted the definition of an evidence-based CPG as given in the 2011 Institute of Medicine (IOM) report Clinical Practice Guidelines We Can Trust, that is, “statements that included recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms or alternative care options” (IOM, 2011, p. 4).

overdoses, and death. The committee notes that recommendations on length of prescribing may be of limited usefulness in guiding clinician prescribing behavior because for many indications there is a lack of clarity regarding the quantity of opioids that constitutes a day’s supply. This lack of clarity argues for the use of a common metric for opioid prescribing such as morphine milligram equivalents (MMEs) (see Recommendation G).

Several health care organizations, including Brigham and Women’s Hospital, the Dartmouth-Hitchcock Medical Center, John Hopkins, and the Mayo Clinic, have also implemented opioid prescribing recommendations (Delgado et al., 2018; Holland et al., 2019; Thiels et al., 2017). These recommendations include specific guidance on opioid prescribing quantities for conditions and procedures, changes to the default number of pills prescribed in EHRs, and increased clinician and patient education. EHRs frequently have default settings for prescriptions, and modifications to EHR prescribing defaults may present an opportunity to reduce opioid prescribing for postsurgical discharge, while still giving surgeons the option to increase the quantity of opioid pills by providing a brief explanation (Stulberg et al., 2019).

Although many of these opioid initiatives have been implemented at a single health care organization or system (e.g., the Mayo Clinic), others have engaged multiple health care organizations, such as state health agencies, private industry, and insurers, to develop guidelines that span systems. For example, the Michigan OPEN in the state of Michigan and the Bree Collaborative in Washington State both have developed CPGs as collaborative efforts among researchers, clinicians, administrators, and regulators.

Regardless of who has developed guidelines on prescribing opioids for acute pain, the committee identified data gaps in each of the guidelines that argues for a more consistent approach to their development. The guidelines listed in Tables 5-2 and 5-3 varied from thoroughly researched guidelines that met many, but not all, of the standards laid out in the 2011 Institute of Medicine (IOM) report Clinical Practice Guidelines We Can Trust, to simply lists of opioid prescribing ranges for a particular indication. The committee notes that several of the guidelines followed a standardized development process that met some of the IOM standards for trustworthy CPGs, such as identifying any conflicts of interest for the developers, presenting the development methodology, and describing in detail the evidence on which the guideline was based. For example, CDC; the American Pain Society; the National Health, Lung, and Blood Institute; the American College of Occupational and Environmental Medicine; and the American Academy of Orthopaedic Surgeons have all developed evidence-based CPGs that discuss pain management, although not all of them specifically address opioid prescribing for acute pain.

The guidelines considered by the committee also varied in whether and how they addressed each of the key elements in the committee’s analytic framework—that is, identifying the specific patient populations to which the guideline is applicable, presenting an evidence-based opioid prescribing strategy, identifying potential intermediate outcomes, and specifying the expected health outcomes associated with the strategy. With regard to patient populations, for many surgical and medical indications there is a lack of evidence on the outcomes of opioid prescribing strategies in such populations as the elderly, children and adolescents, minority populations, patients with chronic opioid use or opioid use disorder, and patients for whom first-line nonopioid medications are contraindicated (e.g., the use of nonsteroidal anti-inflammatory drugs [NSAIDs] in renal failure or following gastric bypass procedures). Although some guidelines have been developed for specific populations (e.g., pregnant women with opioid use disorder [ACOG, 2017] and the perioperative management of the geriatric surgical patient [Mohanty et al., 2016]), other guidelines may not specify when or how opioids should be used in such populations or how to manage acute pain. Even when there is evidence of different opioid prescribing needs for certain populations, the guideline may not address these differences in its recommendations. In many instances, opioid prescribing for acute pain may be stated simply as the lowest possible effective dose for the shortest time necessary, which does not provide either clinicians or patients with specific guidance.

Recommendations on the amount of opioids needed for particular acute pain situations, such as breakthrough pain or for patients who cannot use nonopioid alternatives, are not given.

Other important gaps in most guidelines include a lack of data on the amount of MMEs prescribed for patients relative to the amount used, patient reports of pain control and functioning, longer-term health outcomes such as possible transition from acute pain to chronic pain, chronic opioid use, and the development of opioid use disorder. Using a standardized CPG development process and presenting the information in a uniform format will facilitate the assessment of the impact of the CPG across multiple health outcomes (e.g., pain control, adverse effects, and public health harms) and indicate where further research is necessary.

Evaluating the evidence base for an opioid prescribing strategy is best accomplished using well-established approaches, such as GRADE. The committee recommends the GRADE approach because it is used widely, the study evaluation process is readily accessible online, and there are clear instructions for its use. Furthermore, GRADE provides an accepted, robust, and systematic approach to evaluating evidence with explicit criteria for evaluating studies that support a CPG. The GRADE method is used by numerous organizations, such as USPSTF, the World Health Organization, and the Agency for Healthcare Research and Quality.

DEVELOPING CLINICAL PRACTICE GUIDELINES FOR OPIOIDS

Appropriate Use of Opioids and Nonopioid Interventions

Because opioids may not always be appropriate for acute pain indications or patients, it is important that CPGs address when to use them in addition to identifying which specific opioids to use (e.g., hydrocodone versus oxycodone), and what dose and duration to use. For many surgical and medical indications, such as vaginal delivery and low back pain, evidence shows that opioids are no more effective for relieving acute pain than nonopioid interventions (see Chapter 6). As discussed in Chapter 4 and demonstrated in Chapter 6, many CPGs consider the use of opioids for pain control in the context of a broader nonopioid and nonpharmacologic approach to pain management. For example, the CPG for low back pain developed by the American Pain Society recommends the use of nonopioid interventions (Qaseem et al., 2017). The American College of Obstetrics and Gynecology recommends the use of cold packs for perineal analgesia, reserving opioids for breakthrough pain (ACOG, 2018).

However, evidence gaps remain regarding the role of opioids in the context of alternative strategies, particularly with respect to timing and dosing. Many studies that evaluate opioid prescribing do not mention other interventions that may be prescribed to or used by the patient, including the use of over-the-counter medications, the administration of local anesthetics, and interventions such as yoga and

acupuncture. For example, numerous studies describe the effect of enhanced-recovery-after-surgery pathways using nonopioid and nonpharmacologic interventions (including multimodal approaches such as regional anesthesia and injections) for pain management following procedural care. These studies highlight the role of opioid alternatives, such as NSAIDs, acetaminophen, and gabapentinoids, alongside opioid analgesics in the management of acute pain. A greater body of evidence regarding the comparative effectiveness of these strategies could inform the role of opioids for acute pain and provide guidance concerning their role in the context of alternative interventions.

The committee recognizes that obtaining and reporting such information may be difficult, particularly for interventions that may be prescribed by clinicians in other health care settings (e.g., determining if NSAIDs have been prescribed by a primary care provider for a surgical patient) or for interventions used by the patient but not noted in the EHR (e.g., acupuncture, meditation). The increased use of EHRs, however, may help reduce the burden of collecting such data, particularly for patients who receive their care at integrated health care systems. As there is always the potential for adverse or synergistic effects, reporting on all potential interventions can provide more accurate data on the long- and short-term outcomes of opioid prescribing.

Patient Population Considerations

The analytic framework given in Chapter 4 requires that the patient populations and surgical and medical indications to be evaluated be explicitly stated. However, given the current knowledge gaps and the burden of morbidity and mortality because of opioid use, there may be little or no data on intermediate or health outcomes for some populations in the literature.

As discussed in Chapter 3, acute pain, its management, and its associated outcomes are patient and setting specific (Bjorland et al., 2017; Nobrega et al., 2018; Radcliff et al., 2017; Rahim-Williams et al., 2007; Smith et al., 2019), and the context in which a patient presents with pain is dependent on many factors that will affect both how patients perceive their pain and how they respond to treatment. Although a guideline for opioid prescribing for an acute pain indication might result in reduced opioid use while providing adequate relief of pain across an entire population, a particular patient or subpopulation of patients (e.g., obese patients) may not experience the same benefits and might require prescribing adjustments (Chua et al., 2019; Schug and Raymann, 2011). For acute pain, individualized pain management is complicated by the many factors that may influence opioid requirements, including patient demographics, the underlying cause of the pain, prior pain history, substance use history, opioid use history, comorbid psychiatric and medical conditions including kidney and liver impairment, the duration of the symptoms, clinical settings, the use of nonopioid therapies, and other factors. As noted in the discussion of Recommendation B, not all opioids may be suitable for all patients. Consideration should be given to patient characteristics and situations that may affect or support the use of certain opioids, such as substance use disorder or allergies or an inability to follow prescribing directions. For example, in women who have postpartum pain and wish to breastfeed their infants, the use of codeine

is not recommended as it causes excessive maternal sedation and may cause serious adverse effects in the nursing infant; tramadol is also not recommended because its pharmacologic properties are similar to codeine (AGOG, 2018).

As discussed in Chapters 4 and 5, the contextual aspects of the health care setting may also influence treatment decisions. For example, opioids may be prescribed for acute pain following surgical care performed as an inpatient or prescribed at discharge for outpatients following ambulatory surgery. Other acute pain indications, including many medical indications such as renal stones and fractures, may first present in emergency departments (EDs) or urgent care facilities or, for indications such as migraine headache and low back pain, in a primary care clinician’s office. Prescribing can be influenced by the resulting differences, such as the episodic or longitudinal nature of patient–provider relationships, the duration of care (inpatient stay versus outpatient care), or the availability of subspecialist care.

To date, CPGs for many indications for opioid prescribing for acute pain lack granularity regarding these nuances in care. For example, CPGs for obstetrics could encompass prescribing across perinatal care, postoperative care, and outpatient follow-up visits. Other CPGs, such as the guideline for sickle cell disease, have recommendations on treatments for inpatients, EDs, and at home. For example, the CPG for pain management in patients with sickle cell disease provides no opioid prescribing recommendations for patients who are discharged from inpatient or ED care to home (NHLBI, 2014). Studies suggest that ED clinicians are among the top prescribers of opioids (Barnett et al., 2017; Volkow et al., 2011), and CPGs have been developed for them (ACEP, 2017). Other setting-specific guidelines are the American Dental Association recommendations on treating acute pain resulting from dental procedures, particularly third molar extractions (ADA, 2018), and the AAPD policy document that states that “combining opioid analgesics with NSAIDs or acetaminophen for moderate to severe pain may decrease overall opioid consumption” (AAPD, 2018, p. 102). CPGs need to be clear about the setting for which the opioid prescribing recommendations pertain and should distinguish between those for inpatient, ED, and discharge situations.

Evidence Linkages

Developing CPGs for acute pain following surgical care is an important opportunity to reduce unnecessary prescriptions, prevent the prolonged use of opioids, and optimize postoperative pain management. Recently, studies have demonstrated wide variation in opioid prescribing within procedures and indications for surgery and some approaches for reducing postsurgical opioid use (Berger et al., 2019; Eid et al., 2018; Hill et al., 2017; Howard et al., 2018a; Thiels et al., 2017). Moreover, there is substantial evidence suggesting that for many surgical procedures, opioids are prescribed in excess (Hill et al., 2017; Howard et al., 2018a,b; Kim et al., 2016; Lee et al., 2019; Sabatino et al., 2018). However, it is often challenging to balance sufficient opioid prescribing to relieve acute pain with preventing the adverse effects associated with having unused pills (which can be diverted for unintended use) and with prolonged use, misuse, and abuse (Bicket et al., 2017). On the one hand, guidelines and policies that are more restrictive regarding the MMEs in an initial prescription for acute pain (such as those of many states) may lead to fewer unused pills available for misuse or diversion (Bicket et al., 2017, 2019;

Prabhu et al., 2018; Thiels et al., 2017). On the other hand, such guidelines also may result in more patients having severe acute pain that persists beyond the initial prescription and thus needing a refill or requiring a follow-up phone call, clinic visit, or ED visit (Chiu et al., 2018; Reid et al., 2019; Thiels et al., 2017). These differences have an impact on patients, communities, and society more broadly, and it is critical to consider each of these outcomes when developing CPGs. Attention to patient-centered outcomes, such as improved functional status or return to work, may be more important for some patients than complete pain relief, and may offer an opportunity to reduce individual and population-level risks of long-term or excessive opioid use.

CPG developers may also examine basic research on the tolerance, dependence, and addiction potential of opioids. This information should be considered when conducting the systematic review of the literature as described in Chapter 4. The committee recognizes that different opioids are metabolized differently; have different mechanisms of action for pain relief, tolerance, and addiction; and these mechanisms, and the populations likely to be at risk, need to be considered when recommending an opioid prescribing strategy in a CPG.

For guideline developers to strike an appropriate balance between relieving acute pain and reducing the number of unused opioids, evidence is needed on the relevant intermediate outcomes and their links to health outcomes at both the patient and community levels (Wolff et al., 2018). Currently, however, there is little evidence to link lower opioid MME prescriptions to population-level outcomes, such as opioid use disorder and opioid overdoses.

Guideline Implementation

The 2011 IOM report Clinical Practice Guidelines We Can Trust emphasized that simply developing an evidence-based CPG does not ensure that it will have the desired impact on patient health and well-being. To improve the uptake of CPGs by clinicians and health care organizations, guideline development groups should strive to develop recommendations that are clear and actionable. The committee found that although guidelines may be available for some indications, there is evidence to suggest that guidelines are not always followed (Khalid et al., 2015). Recommendations that are based on high-quality evidence have greater acceptance and uptake than those based on lower-quality evidence (Hoesing, 2016; Mazrou, 2013; Murad, 2017).

Promoting the uptake of CPGs into clinical practice may require the development of strategies to expand their use through clinician education, clinical decision support tools, and other resources. The reasons for any lack of adherence and uptake should be investigated. Guideline developers should also consider implementation strategies, such as the development of tools to facilitate use by clinicians (e.g., algorithms, calculators, pocket guides, and Web-based applications), efforts to support integration of CPGs into clinical workflow through EHR dashboards or other tools, and dissemination activities such as webinars, journal publications, meeting presentations, and resources to support continuous quality improvement (QI) activities.

An evidence-based CPG that presents opioid prescribing strategies that are acceptable to both clinicians and patients also will reach a broader audience. Educating patients about pain management is an integral aspect of aligning patients’ expectation about pain control with opioid prescribing practices. As noted in Chapter 4, a multidisciplinary patient education effort that engages clinicians and other health care providers including nurses and pharmacists may be effective in reducing opioid prescribing without sacrificing patient satisfaction with their pain control (Kaafarani et al., 2019). These health care providers can educate patients and their caregivers about the benefits and harms of opioids, ensure patients understand how to take them appropriately, and explain that the elimination of all pain may not be a feasible or necessary goal when taking opioids. Such education may be particularly valuable for populations that are already vulnerable to opioid harms, such as patients with chronic pain who already use opioids, patients with substance use disorders, or those with mental health issues.

In light of the ongoing opioid overdose epidemic, there is a need to not only provide patients with the best possible pain control, but also to improve public health by reducing the opportunities for opioid diversion, misuse, overdose, and death. This can be accomplished by monitoring relevant outcomes at the patient and population levels. The committee reviewed many studies that reported on the short- and long-term intermediate effects of reduced opioid prescribing in various health care systems (e.g., Hill et al., 2017; Thiels et al., 2017); several of these studies also report health outcomes in terms of patient reports of satisfaction with their care and pain control. However, there is a paucity of studies that examine the effects of opioid prescribing strategies on population-level outcomes, such as fewer opioid overdoses seen in the ED, fewer first responders using naloxone rescue therapy, and fewer opioid-related deaths in the community. Although efforts to address the opioid overdose epidemic underpin many of the strategies to reduce opioid prescribing, the societal impacts of such strategies are not clearly understood and require further research. The committee appreciates that such studies may be challenging to conduct, particularly efforts to link the introduction of CPGs to distal population-level health outcomes, such as opioid use disorder and opioid overdose deaths. While it seems intuitive that reducing opioid prescribing may result in fewer opioid overdoses and deaths, the impact of such reductions on patient pain control and the risk of unintended consequences for patients, their support systems, and their communities cannot be assumed and should be informed by accurate and comprehensive data. Such unintended consequences may include the increased use of illicit and more potent opioids should fewer prescription opioids be available, which in turn may lead to more opioid overdoses and death (NASEM, 2017).

Furthermore, as the awareness of opioid-related morbidity and mortality has increased, CPGs will need to address the new literature. Thus, it is important for guideline developers to include a plan for monitoring the literature for new evidence and updating the guidelines on a periodic or as-needed basis when new information suggests that changes in prescribing practices are warranted. This underscores the need to have a dynamic framework that can adjust as the knowledge of pain management and opioid stewardship grows in the coming years. As additional research is carried out, organizations that produce CPGs on opioid prescribing for acute pain can modify their guidelines to take into account new evidence and strengthen the effectiveness of the CPG.

Increased efforts to link government and private data resources can also provide new information on prescribing practices, patient outcomes, and community outcomes. Private–public partnerships between all levels of government (including health departments, medical societies or boards, and law enforcement) and academic and health care system researchers can help identify short- and long-term adverse effects, morbidity, and mortality resulting from current and future opioid use. Examples of such partnerships include a Massachusetts effort to simultaneously analyze 10 state datasets with information on opioid deaths in the state (Bharel, 2016) and join research efforts between FDA and academic researchers to review health care records in the database of a large national health insurer (i.e., Optum’s

Clinformatics DataMart™ [Mundkur et al., 2018]). To ensure that the CPG reaches a broad audience, the committee encourages guideline developers to consider collaborative, multidisciplinary CPG efforts such as Optimal Perioperative Management of the Geriatric Patient: Best Practices Guideline from ACS NSQIP/American Geriatrics Society (Mohanty et al., 2016).

To avoid unintended consequences resulting from the inappropriate use of a CPG, guideline developers should clearly describe the patients and settings for which recommendations apply. Furthermore, they should work with policy makers to ensure appropriate implementation, and monitor the impacts of CPGs on clinical practice and health outcomes to ensure that they are applied in the manner for which they were intended.

DEVELOPING THE EVIDENCE BASE

Study Design

Evidence-based CPGs require the identification, review, synthesis, and ranking or grading of the evidence to support the opioid prescribing recommendations for an indication. As discussed in Chapter 4, multiple types of evidence can be used to support guidelines, such as randomized controlled trials (RCTs), observational studies, and QI initiatives. Although RCTs, which produce the most rigorous type of evidence, have been conducted for a few indications, the urgency for generating information on best practices to help curtail the opioid epidemic demands efficient models to generate the necessary evidence to improve care expeditiously. Moreover, the committee notes that conducting RCTs for many prescribing strategies may be precluded, given the logistical, ethical, and financial constraints of those trials. There is an increasing number of observational studies and assessments of QI initiatives regarding opioid prescribing that may provide evidence for CPGs. The strengths and limitations of each of these evidence sources are discussed briefly below.

Randomized Controlled Trials

Evidence from RCTs for opioid prescriptions for acute pain has several methodological strengths and weaknesses. The major strength of RCTs is that they provide the most robust evidence of cause and effect—that is, that different prescribing strategies may produce different outcomes. Evidence for causality is strong because the randomization of patients to the study arms controls for baseline differences between the two strategies. Thus, ideally the only difference between the two arms is the assignment to the intervention or control group.

However, RCTs also have certain limitations that may restrict their use. They are typically resource intensive, require the recruitment of an appropriate patient population that must meet enrollment criteria, are lengthy to conduct, and their results may not be applicable to the general patient population. Furthermore, RCTs may be difficult to conduct for relatively uncommon indications, such as sickle cell disease, because the affected population may be a minority group, there may be few patients at any given health care research facility, or the patients may not trust the health care establishment (Smith, presentation to

committee, July 9, 2019). RCTs also may not be able to assess relatively rare, but clinically important health outcomes such as opioid misuse, opioid use disorder, and overdose.

Observational Studies

Observational studies can be retrospective or prospective and can assess the effects of opioid prescribing over time or across populations. Observational studies can be designed to evaluate QI initiatives such as patient and provider education, changing the EHR defaults or organizational policies for opioid prescriptions, and increasing the use of nonopioid medications and nonpharmacologic approaches. Studies employing observational designs should include appropriate comparator groups and strategies to specify and account for confounding factors.

Compared with RCTs, the strengths of observational studies are that they are usually less resource intensive, they include populations that are more representative of the range of patients seen in clinical practice (e.g., a diverse population with regard to age, sex, comorbidities, use of concomitant treatments, and race or ethnicity) (Corrigan-Curay et al., 2018), they use larger study populations and therefore may have greater statistical power to detect infrequent outcomes (such as chronic opioid use after acute pain in opioid-naïve patients), and they can be used to study special populations (e.g., people using chronic opioids or with opioid use disorder, pregnant women, children and adolescents, those from socially disadvantaged communities, or from geographical areas that have high rates of opioid use disorder and opioid overdoses).

As with RCTs, observational studies have limitations. These can include poor validity, measurement bias, observation bias, recall bias, population attrition, low levels of follow-up, reliance on patient-reported outcomes for past events such as pain intensity, confounding factors (e.g., pre-existing opioid use), and poor response rates. In addition, interventions and outcomes may lack clarity, particularly for data gathered for purposes outside of research. For example, although many study types rely on administrative data, these often lack the granularity and accuracy needed to develop prescribing guidelines due to challenges with accurate coding. In addition, administrative data may not capture patient-reported outcomes such as pain control, function, and quality of life.

Quality Improvement Initiatives

In addition to evidence-based CPGs for prescribing opioids, health care organizations and consortia have used QI initiatives to provide evidence for some of the key linkages in the analytic framework. QI initiatives typically complete data collection and analysis in a shorter time than can an RCT (Pletcher et al., 2014). Moreover, the QI results may be more directly and promptly applied to improve clinical practice. For example, the Michigan Surgical Quality Collaborative and Michigan OPEN used QI measures to develop and disseminate prescribing guidelines for nine surgical procedures (PDOAC, 2018). Follow-up of prescribing practices after release of the guidelines showed that the amount of opioids prescribed and the opioid consumption were both reduced and that neither patient satisfaction with the surgery nor pain ratings in the first week after surgery were significantly changed (Vu et al., 2019).

Reporting Opioid Prescribing Strategies

As noted in the discussion of Recommendation A, there is a lack of consistency in reporting opioid doses or durations that may make it difficult to compare findings among studies. Sometimes only the number of pills prescribed or the duration of therapy is provided, without information on the drug and strength prescribed. For this reason, MMEs are recommended as a means to standardize reporting, and details on how MMEs were calculated should be provided (Rennick et al., 2016). As reported in Chapter 1, 50 MMEs per day is equal to 50 mg of hydrocodone (10 tablets of hydrocodone/acetaminophen 5/300) or 33 mg of oxycodone (~2 tablets of oxycodone sustained-release 15 mg). Furthermore, patients may receive different types of opioids that come in different strengths. For example, Barteis et al. (2016) found that following cesarean delivery, patients were prescribed hydrocodone, hydromorphone, or oxycodone at discharge that ranged from 254 to 284 MMEs, and following thoracic surgery, the MMEs prescribed at discharge ranged from 564 to 986, and four different opioids were prescribed. The committee suggests that converting the opioid prescription to MMEs in research studies would facilitate evidence evaluation and study comparisons.

PRIORITIZING INDICATIONS

FDA requested that the committee identify and prioritize surgical and medical indications that are associated with acute pain and for which opioid analgesics are commonly prescribed and considered clinically necessary. In addition, the committee was asked to recommend where evidence-based CPGs would help inform prescribing practices. The committee found that there are numerous relatively prevalent surgical procedures and medical conditions for which opioids are commonly prescribed for acute pain. In response to its tasks, the committee began by identifying surgical procedures for which opioids are commonly prescribed at discharge. Opioid administration in the immediate postsurgical period while the patient is in recovery or is an inpatient was not considered for this report because it is outside the committee’s Statement of Task and there is less opportunity for misuse or diversion. Medical indications for which opioids are commonly prescribed for acute pain were more difficult to identify, but some studies indicated that opioids are commonly prescribed in EDs and primary care settings for indications such as low back pain, headache, and renal stones. Studies conducted by several health care organizations have shown that opioid prescribing for both surgical and medical indications frequently results in unused pills (see Tables 5-2 and 5-3). The tables also highlight the variability in guidelines that are available for these indications, ranging from evidence-based CPGs to a single study published in a medical journal. The priority surgical and medical indications for CPG development are given in Table 7-1.

Although the committee used the prevalence of an indication and evidence of opioid over- or under-prescribing as the criteria for prioritization, it recognizes that some organizations may have other criteria for prioritizing topics for CPG development. Such criteria may include indications frequently associated with opioid misuse, new treatments to replace opioids, or patient and provider preference.

The committee recognizes that the management of acute pain from different surgical procedures or indications might be addressed in a single aggregated CPG (see Chapter 5). For example, it may be possible that the acute pain following one laparoscopic procedure is similar in intensity and duration to

TABLE 7-1 Priority Indications for Acute Pain for Clinical Practice Guideline Development or Modification (listed alphabetically)

that following a different laparoscopic procedure and therefore that opioid prescribing strategies might be similar for both procedures. The CPG development process is not prescriptive in its approach as to which indications might be appropriate to aggregate (see Chapter 5 for more information on aggregating indications) or what extrapolations from one indication or population to another are most appropriate. However, decisions to aggregate or extrapolate indications in guidelines should be based on an explicit rationale from guideline developers, such as the nature of the procedure, the duration of surgery, the extent of tissue damage, or opioid prescribing practices being similar across the aggregated indications. Furthermore, there should be evidence that a single opioid prescribing strategy has similar intermediate and patient health outcomes for each procedure that is covered in the aggregate guideline. For example, one guideline might seek to aggregate laparoscopic surgery for appendicitis and cholecystitis. The aggregation and extrapolation of studies might bolster the applicability and implementation of CPGs for opioid prescribing for acute pain by expanding the available evidence on which they are based. Without such aggregation and extrapolation, it is less likely that a cogent approach would be developed for the many varied surgical and medical indications requiring opioid therapy.

A RESEARCH AGENDA FOR OPIOID PRESCRIBING FOR ACUTE PAIN

Many health care organizations are reducing their use of opioids and turning to other interventions to control pain. There are many interventions that are being explored for acute pain control, both pharmacologic and nonpharmacologic. For example, new interventions for postsurgical pain control that reduce reliance on opioids include peripheral nerve blockades for total knee arthroplasty (AAOS, 2015), the use of gabapentinoids for postoperative pain management (Hah et al., 2018), and enhanced recovery after cesarean delivery (Peahl et al., 2019). Research on such interventions may be particularly helpful for at-risk populations, such as obese patients in whom the use of postsurgical opioids must be closely monitored (Lloret-Linares et al., 2013; Schug and Raymann, 2011). New guidelines on third molar extractions recommend the use of NSAIDs as a first-line treatment (AAOMS, 2007), as is also the case for renal stones (Türk et al., 2016). Many nonpharmacologic interventions (e.g., acupuncture, heat/cold packs, physical therapy, and transcutaneous electrical nerve stimulation) may also be used as either adjuvants or alternatives to opioids. The committee recognizes that there are numerous nonopioid and nonpharmacologic interventions for pain control and that it may be difficult to conduct well-designed observational studies, let alone RCTs, to compare these interventions with opioids. Nevertheless, such studies may be useful for assessing interventions that are widely used in clinical practice. Comparative effectiveness research studies may also be useful. Such studies would help determine not only if opioids should be the first-line treatment for some indications, and if so, which ones provide optimal outcomes, but also which, if any, nonopioid alternative treatments might reduce opioid use and adverse outcomes. Compounding the issue of using nonopioids to treat acute pain is the fact that many health insurers either do not cover nonpharmacologic interventions or else cover them only to a limited extent and that the copay for some covered services may be prohibitively high for some patients.

Few of the opioid prescribing guidelines reviewed in this report discuss the different prescribing needs of subpopulations, and this lack of guidance can result in inappropriate prescribing for some patients. As more research is conducted on how people metabolize and react to opioids and the potential genetic differences in opioid metabolism and physiology (see Chapter 2), there is a greater need to address these variations in evidence-based CPGs. Research shows that the elderly have different opioid needs than younger adults (Santosa et al., 2019). Comorbidities can also affect the use of opioids or other nonopioid interventions. For example, research might examine whether people with kidney disease have more risks of adverse effects when using NSAIDs than when using opioids for acute pain. More research on how different populations react to acute pain and to opioid treatment, including the influence of pain biomarkers and genomic variations, will help in personalizing treatment and reducing

opioid over-prescribing. Basic research on how opioids cross the blood–brain barrier, and on the differences in the pharmacodynamics of the various types of opioids will all help refine and optimize opioid prescribing for acute pain.

Similar research is needed to identify factors that can help align opioid prescribing practices in various settings with CPG recommendations. Such research might include determining if clinician and patient education or the use of reduced prescribing defaults in the EHR are effective approaches to reducing inappropriate opioid prescribing.

Research on whether the reduced opioid prescriptions recommended in CPGs will provide adequate pain relief to patients is also needed. Chapter 2 showed that while a majority of patients with an acute pain indication do not require more than a certain number of MMEs, some percentage of patients—around 20%, depending on the indication and the opioid prescribing amount in the guideline—do not have adequate pain control and need further assessment or an opioid refill. In order to adequately achieve the dual aims of relieving acute pain and reducing the harms of opioids, researchers need to examine whether patients who continue to have pain are able to access additional care to adequately relieve their pain. This issue may become more pressing as new opioids are approved and enter the market, as was recently the case for Dsuvia, a sublingual formulation of sufentanil (Gottlieb, 2018). New research will be required to determine the appropriate use of these new and potentially more potent and addictive opioids. Basic research on the mechanisms of action of these opioids on brain chemistry and their potential for tolerance, dependence, and addiction will need to be conducted. Evidence will also be needed to determine if these new opioids can be used as replacements for or supplements to existing opioid and nonopioid treatments. In light of the widespread disparities in access to health care in the United States, it is important that vulnerable populations have access to additional evaluation if their acute pain does not resolve satisfactorily.

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