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Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use (2017)

Chapter: 3 Progress and Future Directions in Research on Pain and Opioid Use Disorder

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Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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3

Progress and Future Directions in Research on Pain and Opioid Use Disorder

The past several years have seen a number of advances in research on pain and opioid use disorder (OUD). This chapter provides a brief overview of some of these key developments, with a focus on those that have taken place since the publication of the 2011 Institute of Medicine (IOM) report Relieving Pain in America (IOM, 2011). It also identifies areas for future research to inform efforts by the U.S. Food and Drug Administration (FDA) and other organizations to address the opioid epidemic. The chapter reviews developments and research needs in basic pain research; the neurobiology of the reward pathway and the intersection of pain and OUD; preclinical and translational research, including the development of new analgesics; clinical pain research, including optimizing opioid analgesia in the context of comprehensive pain management and opioid risks, the role of interventional pain therapies, and the potential of precision health care; and research at the intersection of pain and OUD. The chapter concludes with a summary that includes the committee’s recommendation for this portion of its charge. The evidence presented in this chapter strongly argues for research to elucidate the biology of pain, to discover novel nonaddictive analgesics, and to refine substantially the ability to deliver analgesia at the level of the individual patient—that is, precision analgesia.

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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BASIC PAIN RESEARCH

Opioid Analgesics

The search for an effective means of relieving pain and suffering has been ongoing since the dawn of civilization. What overarching lessons have been learned and successes achieved that may help propel identification of the next generation of analgesic agents with reduced risk of addiction or organ toxicity? Clearly opioid analgesics, originally derived from the opium poppy and acting principally at the µ opioid receptors (MOPRs), represent one of the most effective analgesic classes to date. Much of modern synthetic opioid analgesic development revolves around the original action of morphine at the MOPRs. The success of exogenous opioids in treating painful conditions reflects the fact that MOPRs are expressed at multiple sites along the pain detecting and modulating pathway, which includes specialized peripheral sensory neurons, signaling through the dorsal horn of the spinal cord, and ultimately transmission to and from multiple centers of the brain. Therefore, MOPR activation functions in a highly coordinated manner to provide a reduction in pain perception.

Unfortunately, MOPR activation also is linked to a range of unwanted side effects, including its action on reward centers (dependence, addiction); reduced intestinal motility (constipation); and suppression of respiratory drive, which can result in overdose and death (Fields, 2007). Until recently, it had been fanciful to consider that the analgesic properties of MOPR agonists could be separated from these unwanted side effects. However, as a result of leveraging advances in MOPR signaling, it is now appreciated that Gi/o coupling drives predominantly analgesic responses, whereas MOPR coupling to β-arrestin may drive opioid reward and respiratory depression. The concept of identifying a G protein “biased” ligand that can preferentially activate the Gi/o analgesic linkage of MOPR signaling away from β-arrestin is being pursued through classical screening of compounds (Chen et al., 2013b; DeWire et al., 2013) and computational screening of MOPR-biased ligand candidates (Manglik et al., 2016). Although it remains to be seen whether these MOPR-biased candidates will translate into useful analgesics in humans, encouraging steps are being taken, including an active clinical trial of one of the candidate compounds (DeWire et al., 2013).

Inflammation

A tissue’s response to injury, whether caused by infection, trauma, metabolic catastrophe, progression of disease/cancer, or ischemia, involves a complex cellular cascade of responses designed to alert and protect the organism and begin the process of healing. This response typically entails

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

inflammation of the affected tissue and pain and/or heightened pain sensitivity (hyperalgesia and allodynia, respectively) that when it persists can degrade a person’s quality of life. Inflammation that continues well past the period of expected healing or despite appropriate treatment remains one of the great medical challenges. Regardless of its source, the management of inflammatory pain often is limited to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for short periods because of the reduced risk of gastrointestinal bleeding, kidney injury, and adverse cardiovascular effects. Given the multiple overlapping pathways recruited during inflammation, effective analgesic management would appear to require action at multiple points of the inflammatory cascade, analogous to the sites of action of opioids throughout the pain pathway. What research advances in this area show promise for the development of novel analgesic strategies that would both spare protective and restorative pathways and act effectively against inflammatory pain?

Part of the answer may lie at the intersection between the primary afferent nociceptor (peripheral nervous system) and the innate immune system (Guan et al., 2016). Nociceptors are specialized C-type and thinly myelinated Aδ sensory neurons dedicated to the detection of painful stimuli, especially products of inflammation. Two important receptor channels, TRPV1 and TRPA1, expressed in nociceptors, have been identified and found to respond to multiple endogenous inflammatory products and noxious physical stimuli (Julius, 2013; Schumacher, 2010; Zygmunt and Högestätt, 2014). Importantly, because of the relatively high level of TRPV1/TRPA1 expression in nociceptors (rather than in sensory neurons responsible for simple touch or proprioception), the development of a high-affinity antagonist has been pursued in the hope of identifying compounds capable of blocking nociceptor activation (pain) despite the ongoing tissue production of inflammatory mediators. Considerable challenges have arisen in the clinical translation of TRPV1 antagonists with the concurrent development of hyperthermia (fever) due to core temperature dysregulation (Gavva et al., 2008). Research is ongoing to devise a TRPV1 antagonist that provides analgesia while maintaining the detection of acute pain and central homeostatic mechanisms (Gomtsyan and Szallasi, 2015). Investigation into the development of TRPA1 receptor antagonists for the treatment of pain also is ongoing (Schenkel et al., 2016).

While efforts to develop clinically useful TRP channel antagonists are under way, numerous complementary efforts are focused on identifying and blocking the action of inflammatory mediators at prostanoid and purinergic receptors. These receptor systems play multiple roles, including augmenting the responsiveness of TRPV1 under inflammatory conditions. In this regard, one of the principal proinflammatory products of arachidonic acid metabolism, the prostanoid PGE2, is understood to drive inflammatory

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

hyperalgesia through various receptor subtypes (Chen et al., 2013a). For example, the inflammation and pain that arise from endometriosis have been linked to EP2 and EP4 receptor activation, and specific antagonists acting at these receptor sites show therapeutic promise in preclinical models (Arosh et al., 2015; Greaves et al., 2017). Moreover, the development of antagonists to certain purinergic (ATP [adenosine triphosphate]-gated channel) receptor subtypes (P2X3) and the metabotropic P2Y receptor show promise in the treatment of inflammatory pain (Burnstock, 2016; Park and Kim, 2017; Viatchenko-Karpinski et al., 2016).

Another perspective is the observation that pain-transducing components are upregulated under persistent tissue inflammation/injury. Therefore, the relative overexpression (or underexpression) of critical gene products within the pain pathway (peripheral and central) represents both a point of dysregulation and, in turn, an opportunity to better study what is driving changes in nociceptive gene expression, one type of plasticity change proposed to drive chronic pain. Research into whether there is a plausible way to reverse such pathophysiologic changes in a network of genes, perhaps through the control of nuclear transcription factors or micro–ribonucleic acids (RNAs), is emerging (Chu et al., 2011; Neumann et al., 2015; Zavala et al., 2014).

Pain Transmission

The ability of nociceptor activation to signal the central nervous system of real or impending tissue damage relies on the transmission of that signal by specialized voltage-gated sodium channels (VGSCs) that propagate depolarizing action potentials along axons. As presented in Chapter 2, the analgesic properties of local anesthetic action rely on the ability to block VGSCs expressed in nociceptors. Although the pharmacology of local anesthetics has been exploited for anesthesia and analgesia based on their discrete application adjacent to nerves and the spinal cord, their general properties to block all sodium channels, including those expressed in heart and motor neurons, have significantly limited their widespread application as analgesic agents. With advances in molecular pharmacology and genetics over the past decade, one subtype of VGSCs has risen to prominence as a plausible analgesic target. Nav1.7 is a VGSC that has been linked to human pain conditions, based on defects in its gene SCN9A leading to either loss-of-function (congenital insensitivity to pain) or gain-of-function mutations that drive a rare spontaneous pain syndrome (erythromelalgia), as well as other painful neuropathies. The development of Nav1.7-selective blocking agents has been highly challenging; however, several lead candidates have emerged and are under advanced preclinical testing or clinical trial (Cao et al., 2016; Shcherbatko et al., 2016). Research on selective antagonists

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

of other members of this family of VGSCs (Nav1.8, 1.9) is under way, but also faces tremendous challenges.

Beyond the proposed Nav1.7 selectivity of candidate blocking agents, properties that allow blockade of only activated (open) forms of the channel may provide an additional measure of clinical safety and reduction of potential offsite effects. Research in this area may also reveal the effectiveness of previously established pharmaceuticals for subsets of neuropathic pain conditions, such as carbamazepine, an agent typically reserved for the treatment of trigeminal neuralgia (Alexandrou et al., 2016; Geha et al., 2016). Whether this class of channel blockers will be applicable to a broad range of neuropathic pain conditions or only for rare conditions is unknown. Given the limited scope of existing disease-based preclinical models of neuropathic pain and the complexity of the human genetic and epigenetic factors that influence susceptibility, much more work is required to synthesize these concepts for broader therapeutic utility.

Despite their prominent role in the detection of noxious stimuli (pain transduction), primary afferent nociceptors do not necessarily encode the final perception of pain. Rather, perception of pain is the result of a complex set of neural, glial, and cellular connections with both ascending and descending modulatory components (for a review, see Peirs and Seal, 2016). The basic structure of this pain pathway begins with the majority of nociceptive input entering the central nervous system through the spinal dorsal horn, roughly dividing into the superficial layers of the dorsal spinal cord as well as input into deeper layers associated with non-nociceptive sensory input, such as simple touch. Whether at superficial or deeper spinal levels, nociceptive input is dynamically regulated by both local spinal circuits and synaptic connections with descending pathways onto the secondary-order dorsal horn neurons. Following crossover, nociceptive signaling is transmitted to higher centers via the spinothalamic tracts that split, divide, and project into and through multiple brain nuclei within the pons, midbrain, and thalamic regions. Although the somatosensory cortex is considered a potential resting place for the perception of pain, the experience of pain is inherently complex and dependent on multiple brain regions.

Building on advances in the peripheral nociceptors mentioned above, a better understanding of spinal neural circuits, especially those that modulate mechanical allodynia, could reveal modality-specific excitatory microcircuits and distinct pain pathway “gates” that could be modified to better treat inflammatory and neuropathic pain (Peirs and Seal, 2016). Although interventions capable of selectively influencing the perception of pain at higher brain centers remain elusive, advances in understanding of the cognitive processing of pain perception offer hope. Something as apparently simple as distraction that reduces pain illustrates that the perception of pain relies on cognitive processes and learning (Wiech, 2016). Therefore,

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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a detailed understanding of placebo analgesia and how individual expectations of an effective resolution of pain impact the success of any particular analgesic strategy is a critical area for further research (see the discussion of placebo analgesia in Chapter 2).

Innate Immunity

Intersecting with the transduction/transmission of nociceptive pain is activation of the innate immune system designed to initiate the acute inflammatory response to both infectious and sterile injury (Guan et al., 2016). In the case of bacterial infection, innate immune responses are triggered through pattern recognition receptors (PRRs) by components of microorganisms known as pathogen-associated molecular patterns (PAMPs) and/or by factors released by stressed or injured host cells that are collectively known as damage-associated molecular patterns (DAMPs) (Takeuchi and Akira, 2010). The binding of PAMPs or DAMPs to their cognate PRRs triggers a cascade that ultimately leads to the expression and/or activation of numerous inflammatory mediators including cytokines and chemokines with enhanced leukocyte trafficking and activation within tissues. PRRs are expressed not only in leukocytes but also in glial and neuronal cells and are postulated to contribute to neuropathic pain and other pain syndromes, such as sickle cell disease (Guan et al., 2016; Qi et al., 2011). DAMPs also can induce acute inflammation via PRRs and have been implicated in chronic neuropathic pain.

Although early leukocyte responses are designed to contain the extent of infection or injury, dysregulation of the inflammatory response with overexpression of proinflammatory mediators can be deleterious. In this regard, monocytes and macrophages are major contributors to later-phase inflammatory infiltrates and are well known to drive peripheral hyperalgesia (Ji et al., 2016). CCL2, a monocytic chemokine linked to neuropathic pain, also has been implicated in inflammatory pain, in part through its action on CCR2-expressing macrophages and the release of reactive oxygen species (ROS) (Hackel et al., 2013). With recent advances in understanding of the structure of CCR2 and its binding to antagonists (Zheng et al., 2016), it may be hoped that a new generation of CCR2 antagonists with properties to treat both inflammatory and neuropathic pain will emerge.

Members of the toll-like receptor (TLR) family and the receptor for advanced glycation end products (RAGE) are emerging as significant contributors to the pathogenesis of inflammation and pain (Brederson et al., 2016), as both are bound and activated by multiple endogenous agonists, including high-mobility group box 1 protein (HMGB1). TLRs also are expressed on monocytes and macrophages. Targeting cross-talk molecules such as HMGB1 and its receptors represents a novel direction in inflamma-

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

tion and chronic pain research. Since the immune system and nervous system are linked bidirectionally, there is evidence that activation of TLR- and RAGE-dependent pathways contributes to the development of chronic pain. Importantly, TLR agonists can directly activate nociceptors and increase levels of TRPV1 expression in dorsal root ganglion neurons (Wadachi and Hargreaves, 2006). Since the TLR4 and RAGE agonist HMGB1, a molecule previously associated with sepsis, has emerged as an important participant in neuroinflammatory pain states, strategies based on the blockade of HMGB1 and/or downregulation of the overexpression of TLR4 or RAGE also represent novel directions in inflammatory pain research.

Although this section has thus far focused on either blocking or down-regulating proinflammatory receptors/factors, an alternative paradigm is the enhancement of molecules that combat excessive inflammation and pain. Within this category is another class of molecules with therapeutic potential in the treatment of inflammatory pain—resolvins—which not only regulate the resolution of acute inflammation but also can directly inhibit nociceptor activation (Park et al., 2011; Xu et al., 2013). However, evidence for their importance as an endogenous system regulating inflammation is lacking (Skarke et al., 2015).

Emerging from basic science on the metabolism of the insect juvenile hormone mimic R20458 (Gill et al., 1972, 1974), a new group of chemical mediators—the epoxy fatty acids (EpFAs)—has come to light and been found to play important roles in cellular signaling and pain (Zhang et al., 2014). Following purification of the enzyme (soluble epoxide hydrolase [sEH]) responsible for the degradation (hydrolysis) of this class of fatty acids, inhibitors of the sEH enzyme were developed. It was found that inhibition of sEH prevented experimental models of acute inflammation and concomitant pain behaviors (Schmelzer et al., 2005). Curiously, other models of pain not considered “inflammatory,” such as mechanical nerve injury or diabetic neuropathy, also were prevented by sEH inhibition (Inceoglu et al., 2012). More recently, research has focused on the mechanism underlying the prevention of experimental neuropathic pain, with a focus on the prevention of subcellular organelle stress in the peripheral nervous system.

EpFA-mediated analgesia, if translated successfully to treat human pain, may represent a promising analgesic approach. EpFA is inactive in the absence of pain, is nonsedating, is active over a large range of pain models, synergizes with NSAIDs, and has no addictive properties in rodents. Its preclinical profile has been shown to be as good as or better than that of other medications currently used to treat neuropathic pain, and it may have other applications in the field of pain that have yet to be explored.

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

Neuropathic Pain

Following peripheral nerve injury, spinal cord microglia, the tissue-resident immune-like macrophages of the central nervous system, become activated, signaling the central nervous system in a pattern of neuroinflammation (Guan et al., 2016). The pain associated with partial nerve injury is of a type that appears to engender fundamentally different mechanisms driving the sensation of pain. This is exemplified not only by certain unique characteristics of the associated painful sensations but also by the relative resistance of this pain to analgesics typically effective in the treatment of inflammatory pain, such as NSAIDs. The pain is incited by a range of insults, from postherpetic neuralgia, to diabetic neuropathy, to traumatic disruption (surgical interventions), to chemotherapy. From the perspective of the nervous system, the chronic pain resulting from such injuries may represent the consequence of unexpected survival.

Despite the extensive use of anticonvulsants, tricyclic antidepressants, opioids, and topical preparations, the majority of patients suffering from chronic neuropathic pain obtain only partial relief in the face of significant medication side effects (see also Chapter 2). Efforts to develop new and more effective therapies rely on understanding of the underlying mechanism(s) of neuropathic pain, an area of ongoing research. Understanding how spinal microglia drive neuropathic pain may hold promise for the development of a new class of analgesic agents. Based on findings derived from experimental models of nerve injury, research continues to focus on the role of microglial activation in the development of chronic neuropathic pain and possible therapeutic targets (Ji et al., 2014). Importantly, the link between peripheral nerve injury and microglial activation has been poorly understood. A recent study identified colony-stimulating factor 1 (CSF1) as a critical signaling factor, upregulated in injured sensory neurons and transported to the spinal cord, where it targeted the microglial CSF1 receptor (CSF1R). Moreover, the downstream microglial membrane adaptor protein DAP12 was required for nerve injury upregulation of pain-related microglial genes and the ensuing experimental neuropathic pain behaviors. These findings suggest that both CSF1 and DAP12 are potential targets for further investigation and pharmacotherapy of neuropathic pain (Guan et al., 2016).

However, spinal microglial activation is not triggered solely by nerve injury, as there is evidence that certain peripheral inflammatory stimuli (e.g., formalin) can activate spinal microglia that can be reduced by the downregulation of microglial p38 (Tan et al., 2012). Surprisingly such formalin-induced spinal microglial activation cannot be blocked by local anesthetic treatment of the peripheral nerve, suggesting multiple routes of microglial activation. Under these inflammatory conditions, it has been proposed that caspase-6 (CASP6) is upregulated in the central terminals of

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

primary afferent neurons and is released in the spinal cord. The resultant cascade activates spinal cord microglia and stimulates microglial TNF (tumor necrosis factor)-α synthesis and release through p38 and extracellular signal-regulated kinase (ERK)-mediated pathways. The blockade of spinal CASP6 under painful pathophysiologic conditions such as bone cancer, sickle cell disease, and inflammatory bowel disease may represent an important research opportunity in analgesic development.

The Need for Improved Research Methods

If the perception of pain is not “caused” by a single factor, looking for a single, highly restricted receptor target may be an inherently limited approach from the outset. The notion of a “blockbuster” analgesic drug that can be utilized on a widespread population basis with little physician oversight, propelled forward by a simple pain model in genetically identical male rodents, is fraught with difficulties. Absent a change in approach, the current problem with the use of opioids in the treatment of severe chronic pain may be repeated. One size clearly does not fit or help all. Therefore, research aimed at determining the impact of genetics, sex, and other variables in experimental models of pain is essential. Another critical stumbling block is the inability to translate reliably what appeared to be extremely promising preclinical analgesic targets developed in rodents (mice or rats), but when tested in humans had little to no analgesic efficacy and/or were associated with intractable adverse effects/toxicity. As described elsewhere, the development of humanized preclinical models of pain (in vitro and in vivo) will be required to establish more reliably clinically relevant basic and translational pain science. Progress in this regard cannot come too soon, as investigators are experiencing increased pressure to demonstrate earlier and earlier proof of concept. Providing additional review and revision of current pain research methods and models may hold promise for a more successful translation of the basic science of pain.

The need for improved research methods is evidenced by the fact that, despite robust research in pain-related areas of neuroscience, inflammation, and other fields, few novel analgesics have been introduced in the past 20 years. New drugs have been designed primarily to interact with established targets such as opioid receptors, cyclooxygenase, neurotransmitter reuptake proteins, and previously targeted ion channel constituents. Thus, while drugs offering improved pharmacokinetics and side effect profiles are available, the efficacy of pharmacological tools has not improved appreciably. This failure is not due to a lack of targets identified using animal models. In fact, analgesic programs targeting NK1 receptors, NMDA (N-Methyl-d-aspartate) receptors, cytokine/chemokine signaling, and other targets strongly supported in animal studies have been successful in bringing mol-

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

ecules to advanced stages of human testing, only to have poor efficacy and side effects halt their development. The costs of these failures have been high. This failure of translation has been widely recognized, and many have commented on the challenges facing this type of research (Chaplan et al., 2010; Clark, 2016; Mao, 2012; Woolf, 2010).

One of the principal problems believed to limit analgesic development efforts relates to the pain models selected for laboratory use. Many investigators and pharmaceutical companies have used models bearing little similarity to the clinical syndromes they were intended to represent. For example, such irritants as carrageenan and formalin often are used to represent inflammatory pain such as that resulting from trauma-induced tissue injury or inflammatory arthritis even though there is little evidence for shared mechanisms. Another example is the common use of models of nerve injury, typically within days of the occurrence of injuries. The typical forms of clinical neuropathic pain, however, often do not entail discrete injury to isolated branches of peripheral nerves (e.g., diabetic neuropathy) and may entail symptoms present for years. Degenerative diseases of the joints and axial spine, as well as trauma, are among the most common etiologies for pain complaints bringing patients to pain clinics (Crombie et al., 1998), but animal models designed specifically to mimic these conditions are employed relatively infrequently in pain research. For many types of pain, there are models possessing higher face validity, and they might be used preferentially. It is also possible, although more expensive and perhaps less convenient, to use large-animal models for some types of pain studies, such as large-breed dogs for studies of osteoarthritis, which may occur naturally or after surgically induced injuries (Brimmo et al., 2016; Harman et al., 2016; Knazovicky et al., 2016). Likewise, analgesic research in dogs and other species that develop cancers has been employed successfully (Brown et al., 2015).

Another approach to selection of a laboratory pain model is to choose one for which there is strong evidence of a mechanism present in the test animal that likely exists in the human pain patient as well (Woolf, 2010). Such a model would in theory provide a system in which observations might be most relevant to improving analgesia in clinical populations. Yet while laboratories are starting to adopt this approach, understanding of the mechanisms supporting pain conditions, including back pain, fibromyalgia, and others, is relatively limited, which in turn limits the confidence one can have in the selection of laboratory models.

A set of factors closely related to pain models themselves comprises factors known to affect the prevalence of painful diseases, pain intensity, rates of response to treatments, and side effects of medications. Many such factors have been identified, including sex, weight, age, nutritional status, genetic background, depression, and anxiety (see also the discussion of

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

differences in pain experiences and treatment effectiveness among subpopulations in Chapter 2). Clearly, some of these factors are more easily represented in laboratory research than others. Relevant laboratory observations demonstrating the importance of some of these factors are the mouse strain dependence in displaying nociceptive sensitization after nerve injury (Mogil et al., 1999), the strain dependence of responsiveness to analgesics such as opioids (Liang et al., 2006), and the sex dependence of analgesic responses to modulators of glial activity (Brings and Zylka, 2015). Likewise, genetic differences have a strong impact on the degrees of tolerance (Liang et al., 2006), physical dependence (Liang et al., 2006), and use of reinforcement behaviors (Berrettini et al., 1994) displayed by laboratory animals, suggesting that care is necessary in selecting a particular strain or breed of animal for pain and analgesic research.

A second major area of concern surrounding the use of animals in preclinical pain research involves the types of measures used in assessing pain-like responses. Because pain is defined as a sensory and emotional experience, one cannot directly infer that pain in animals is identical to that experienced by humans. Researchers therefore tend to rely on behavioral responses. Some of the more popular methods for assessing “pain” in animals actually assess withdrawal behaviors in response to noxious stimuli, such as heat and mechanical pressure applied to an animal’s hind paw. These evoked responses are rapidly available, readily quantifiable, and easy for laboratory staff to employ, but they do not well represent major drivers of clinical pain complaints, which are more likely to involve spontaneous pain (Maier et al., 2010). In some types of pain syndromes, allodynia can be reduced by the use of medication; however, the resulting differences in spontaneous or overall pain are small (Rauck et al., 2015). To address this problem, laboratories have recently turned to more sophisticated methods of testing involving operant pain models or models in which place preference is used to detect an ongoing aversive pain state (King et al., 2009b). Quantifying flinching, guarding, vocalization and other nonevoked pain measures may also provide means of assessing spontaneous aspects of pain. Another approach to assessment of the effects of a candidate analgesic molecule on model animals involves quantifying an activity or function, such as running on an exercise wheel or the normalization of abnormal gait (Amagai et al., 2013; Cobos et al., 2012; Ishikawa et al., 2015). Conducting such measurements in the preclinical setting is consistent with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines for analgesic research, which emphasize incorporating measures of function into clinical studies (Turk et al., 2003).

Beyond the models and measures used for preclinical research, however, is the issue of improving the transparency of reporting and reproducibility of the research. Problems related to faulty study design, inappropriate data

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

processing, and other procedural issues are believed to contribute to the poor reproducibility of laboratory results, an issue that results in approximately $28 billion in wasted research and development efforts each year in the United States (Freedman et al., 2015). To address these problems two sets of guidelines have been developed. First is the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines (Drummond et al., 2010), aimed at enhancing the transparency of laboratory research by requiring the reporting of details of the experimental design, animal care, disposition of animal subjects, blinding of investigators, and other factors potentially affecting the experimental results. A second, related effort is the construction and dissemination of the guidelines of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group (Andrews et al., 2016), which stress the identification of a primary hypothesis and outcome measure, as well as the use of power calculations to justify cohort sizes.

Summary

Basic pain research is progressing across multiple interconnected fronts. These include mechanisms related to MOPR-biased analgesia, inflammation, pain transmission, innate immunity, and treatment of neuropathic pain. MOPR-biased analgesia may one day allow the separation of opioid-induced analgesia from opioid-induced respiratory depression or addiction by uncoupling MOPRs from the β-arrestin pathway. The diverse approaches discussed in this section demonstrate that one-size-fits-all pain management is neither achievable nor preferable, however, and that difficulties in translating discoveries into clinical pain medicine persist. Further studies to determine the impact of clinical characteristics (e.g., genetics and sex) are necessary to improve experimental models of pain.

The translation of the basic science of pain into effective therapies is limited by the failure of preclinical models to reflect the human condition and the inability to target pain networks. The development of humanized preclinical models of pain (in vitro and in vivo) could be instrumental to more reliably establishing clinically relevant basic and translational pain science. Such models could incorporate the functional as well as the organic response to pain, and assess pain’s affective and cognitive components. Such research would benefit from quantitative biomarkers of pain and its relief that translate from model systems to humans, as well as studies of the impact of sex and aging on pain. These efforts, in turn, would require precise molecular phenotyping of both animal models of pain and patients to identify those models with the highest predictive validity for specific human pain phenotypes. The reproducibility of basic pain research and its

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

subsequent impact on clinical pain medicine could be improved through more rigorous reporting guidelines and greater transparency.

THE NEUROBIOLOGY OF THE REWARD PATHWAY AND THE INTERSECTION OF PAIN AND OPIOID USE DISORDER

Neurobiology of the Reward Pathway

Although multiple brain regions constitute a reward network, the mesolimbic system is a key network node that regulates reward. Dopamine (DA) transmission in the mesolimbic system via the ventral tegmental area (VTA) to the nucleus accumbens (NAc) has long been recognized for its role in motivation (Wise et al., 1995). Natural rewards, as well as rewarding drugs (such as opioids), activate mesolimbic neurons to elicit DA release in the NAc (Devine et al., 1993; Giuliano et al., 2013; Le et al., 2009; Xiao and Ye, 2008). DA neurons in the VTA respond by burst firing following salient stimuli, and phasic bursting of DA neurons is sufficient to produce reward-seeking behavior (Kim et al., 2013; Tsai et al., 2009). The GABAergic input onto DA neurons includes the NAc, the ventral pallidum, the rostromedial tegmental nucleus (RMTg), and the bed nucleus of stria terminalis, among others, and has been estimated to make up at least 70 percent of synaptic input onto DA neurons (Matsui et al., 2014; Omelchenko and Sesack, 2005; Tepper and Lee, 2007; Watabe-Uchida et al., 2012).

The opioid system is involved in modulating pain and reward. Opioid receptors are a group of G protein-coupled receptors divided into three families: the MOPRs, the delta opioid receptors (DOPRs), and the kappa opioid receptors (KOPRs). These receptors are activated by three classes of endogenous opioid peptides—beta-endorphin, dynorphin, and enkephalin—that are derived from three precursor peptides. The selectivity and distribution of the opioid peptide and receptor systems suggest that encephalin and beta-endorphin act through the MOPRs and DOPRs, and dynorphin through the KOPRs. The opioid receptors and their peptides are distributed throughout the central and peripheral nervous system in a distinct but overlapping manner (Mansour et al., 1988). The MOPRs are widely distributed throughout the brainstem, midbrain, and forebrain structures, and mediate most of the analgesia and reinforcing effects of opioid agonists such as morphine (Kieffer and Gavériaux-Ruff, 2002). DOPRs, on the other hand, are highly expressed in forebrain regions (Mansour et al., 1988). Activation of DOPRs produces minimal analgesia in acute pain models but develops an analgesic effect in rodent models of chronic pain (Cahill et al., 2007; Pradhan et al., 2011). KOPR and MOPR expression overlaps throughout the brain. MOPRs located in the mesolimbic pathway are thought to mediate the reinforcing properties of opioids and natural

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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reinforcers via regulation of extracellular DA within the NAc (Devine et al., 1993; Giuliano et al., 2013; Le et al., 2009; Xiao and Ye, 2008). This effect is mediated by inhibition of GABA release in the VTA through activation of local presynaptic MOPRs on GABA interneurons or on GABA projections from the RMTg (Matsui et al., 2014; Siuda et al., 2015). MOPR activation on these GABA neurons then leads to an increase in DA release in the NAc through a disinhibition mechanism (Johnson and North, 1992) and/or through local activation of MOPRs in the NAc core and shell (Hipólito et al., 2008).

In contrast to MOPRs, KOPR agonists block the rewarding effects of MOPR agonists by acting to decrease DA release in the NAc (Niikura et al., 2010). As mentioned above, KOPR and MOPR expression overlaps widely throughout the brain, and in these regions the two have a “push-and-pull” relationship. Expression of KOPRs has been detected in the VTA, NAc, prefrontal cortex, amygdala, and other areas implicated in the modulation of reward (Peckys and Landwehrmeyer, 1999; Shippenberg, 2009). KOPR activation in the NAc leads to dysphoria and other aversive effects (Land et al., 2008; Shirayama et al., 2004; Van’t Veer and Carlezon, 2013). Expression and release of dynorphin, the endogenous KOPR agonist, is dynamically regulated by reward, stress, and the opioid or other drug taken (Carlezon et al., 1998; Land et al., 2008). Thus, these dynorphin/KOPR-mediated alterations in reward states are likely to be directly linked with changes in DA transmission.

Neurobiology of the Pain Processing Pathway

As described by Garland and colleagues (2013), the brain actively regulates nociception via interactions between descending pain modulatory system (Heinricher et al., 2009; Reynolds, 1969) and corticocortical networks (Rainville, 2002) rather than passively receiving nociceptive information from the body. The descending pain modulatory system influences nociceptive input from the spinal cord through a network of cortical, subcortical, and brainstem structures (including the prefrontal cortex, anterior cingulate cortex, insula, amygdala, hypothalamus, periaqueductal grey region, rostral ventromedial medulla, and dorso-lateral pons) (Tracey and Mantyh, 2007). This system is believed to be the means by which the central nervous system inhibits nociceptive signals at the spinal outputs (Heinricher et al., 2009). Endogenous and exogenous opioids have been found to relieve pain by targeting the descending pain modulatory system, particularly in the periaqueductal grey region of the brain, which is involved in processing the placebo analgesia (Besson, 1999; Tracey, 2010). In addition, acute single-dose administration of opioids has been found to lead to analgesia in healthy individuals by reducing sensory evaluation processes, as is demonstrated by

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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reductions in activation of brain regions that correspond with lower-level afferent processes (Wagner et al., 2007; Wise et al., 2002) and by modulation of neurotransmission in the substantia gelatinosa of the dorsal horn of the spine (Le Bars et al., 1980; Yaksh, 1987).

In addition, a recent review alluded to earlier highlights the influence of cognitive processes on pain perception (Wiech, 2016). It is thought that pain perception is determined by expectations and their modification through learning. The powerful influence of cognitive processes and learning mechanisms on the way pain is perceived is highlighted by placebo analgesia and pain relief through distraction (see also Chapter 2).

Opioid analgesia operates through both neuropharmacologic and psychological mechanisms. In addition to lessening the sensory aspects of pain, opioids may alleviate the affective dimensions of pain (e.g., suffering) (Garland et al., 2013). Analgesia induced through acute opioid administration in healthy individuals has been found to operate in part through the modulation of neural circuits that play a role in the regulation of attention, emotion, and neurovisceral integration (Becerra et al., 2006; Oertel et al., 2007; Thayer and Lane, 2009; Wagner et al., 2007). As with other drugs that are misused, opioids also stimulate mesolimbic DA reward systems (Johnson and North, 1992), and opioid-induced DA release in the NAc associated with positive mood and reward may promote pain management. While most of the available evidence regarding the psychobiological mechanisms of opioid-induced analgesia comes from research involving healthy individuals exposed to pain induction in the laboratory setting, the development of co-occurring chronic pain and OUD over time may modify the neurobiological response to opioids in ways that are of clinical importance (Garland et al., 2013), as discussed in the next section.

Neurobiology of the Intersection Between Pain and Opioid Use Disorder

It is well documented that positive reinforcement is decreased in the presence of chronic pain (Cahill et al., 2013; Hipólito et al., 2015; Leitl et al., 2014a,b; Martin et al., 2004; Shippenberg et al., 1988). This chronic pain-induced alteration has been linked to a decrease in reinforcer-induced dopaminergic transmission (Hipólito et al., 2015; Loggia et al., 2014; Niikura et al., 2010). Despite this evidence, only a few preclinical studies have assessed the impact of pain on opioid intake. Most studies have used a conditioned place paradigm to test the reinforcing properties of opioids in rodents undergoing neuropathic or chronic pain (Cahill et al., 2013; Narita et al., 2005; Ozaki et al., 2002; Taylor et al., 2015). Of interest, Wu and colleagues (2014) revealed that the known reinforcing doses of morphine were unable to induce a place preference under painful conditions. However, animals exposed to chronic pain developed a clear preference for the

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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morphine-paired side when the dose of morphine was increased (Wu et al., 2014). In line with these findings, rodents self-administering opioids while experiencing pain showed a decrease in their consumption of low drug doses compared with controls (Hipólito et al., 2015; Lyness et al., 1989; Martin and Ewan, 2008; Taylor et al., 2015; Wade et al., 2013), but this opioid consumption increased when high doses were accessible (Hipólito et al., 2015). Together these important results suggest a rightward shift in the dose response for opioid consumption in conditions of chronic pain that correlates with modifications in dopaminergic transmission from the VTA to the NAc (Hipólito et al., 2015). The dopaminergic release in the NAc is highly controlled by the opioid system, and Hipolito and colleagues (2015) demonstrated that inflammatory pain induces a desensitization of MOPRs in the VTA. These changes in opioid receptor function lead to decreased heroin- and DAMGO ([d-Ala2, N-MePhe4, Gly-ol]-enkephalin)-induced DA release in the NAc. As mentioned above, the KOPR system may also be involved in these changes in DA release. Evidence points to a role for the KOPR system in many of the changes induced by chronic pain (Cahill et al., 2014).

In conjunction with the data showing that inflammatory pain decreases morphine- and heroin-induced NAc DA release and impairs the rewarding effects of morphine (Hipólito et al., 2015; Narita et al., 2005), Narita and colleagues (2005) showed that pain-induced attenuation in place preference can be reversed by systemic or local NAc blockade of KOPRs using norbinaltorphimine (NorBNI), a highly selective antagonist for KOPRs. The aversive component of exogenous KOPR stimulation, measured by place preference conditioning, also is suppressed when animals are experiencing inflammatory pain conditions (Shippenberg et al., 1988), suggesting the presence of a kappa opioid tone during painful conditions that induces a sustained dysphoric state.

There is, however, some controversy regarding the role of the dynorphin/kappa opioid system in the regulation of reinforcing properties of reward during pain. Some studies showed that KOPR antagonism did not reverse the pain-induced decrease in intracranial self-stimulation of the mesolimbic pathway in rats (Leitl et al., 2014a,b). These discrepancies could be explained by the presence of hot and cold spots (areas that appear particularly attuned to either accentuate or suppress reward response), two distinct areas in the NAc shell in which activation of KOPRs can drive either aversive or reinforcing behaviors (Al-Hasani et al., 2015; Castro and Berridge, 2014). Systemic application of KOPR antagonists likely targets both of these discrete areas, while microinjections of KOPR agonists/antagonists to specifically target these discrete areas in the NAc could yield opposing behaviors and interpretations.

Finally, it is important to acknowledge the role of other brain regions (besides the VTA and the NAc) critical in the regulation of pain, stress, and

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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reward responses. The amygdala is very much involved in the processing of both positive and negative valence (see the review by Janak and Tye, 2015). Specifically, the basolateral amygdala (BLA) and the central nucleus of the amygdala play important roles in affective pain, in addition to better-studied roles in the processing of mood and fear disorders, as well as reinforcement (Pare and Duvarci, 2012; Veinante et al., 2013). More recently, it has been shown that the habenula and NAc dopaminergic neurons drive inhibitory antireward tone during stress and pain conditions (Lee and Goto, 2011). The lateral hypothalamus, a region critical to positive reinforcement, also plays a role in the pain response through sensory mechanisms (Ezzatpanah et al., 2015). These structures contribute as well to increases in norepinephrine, corticotropin-releasing hormone (CRH), vasopressin, hypocretin, and substance P, driving a stress-like emotional state.

Summary

Pain and reward are processed by overlapping brain structures. This finding is supported by clinical and preclinical evidence showing that positive or negative reinforcement (i.e., rewarding properties of opioids or the rewarding effect of pain relief, respectively) is decreased by the presence of pain. In this regard, preclinical studies have shown that pain promotes opioid dose escalation in animals with a prior history of opioid intake. However, additional studies are needed at both the preclinical and clinical levels. Much of the available evidence regarding the mechanisms underlying opioid analgesia and reward comes from studies of healthy individuals, and such studies would benefit from including individuals with chronic pain.

PRECLINICAL AND TRANSLATIONAL RESEARCH

Development of New Analgesics

Despite the complexity entailed in researching pain described thus far, modern approaches examining pain at the genetic and mechanistic levels are relatively recent. Much more remains to be discovered by researchers seeking to translate their findings into clinical applications. This section describes some of these opportunities toward the development of nonaddictive alternatives to the opioid analgesics currently on the market.

Biased Opioid Receptor Ligands

The concept of ligands interacting with receptors differentially to modulate their interaction with downstream signaling pathways and effector systems has been extant for decades but has gained considerable traction in

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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the past 5 years (Kenakin, 2015; Reiter et al., 2012). The recognition that receptor conformation may be dynamically and variably altered by interaction with distinct ligands has coincided with the emergence of diverse tools relevant to dissection of spatiotemporal patterns of opioid receptor (OR) signaling, consequences of downstream pathway activation, and the in vivo consequences of such biased approaches. Developments of direct relevance to the opioid field include structural elucidation of µ, κ, and δ ORs in the basal and bound state; intracellular OR domains complexed with the rat rhodopsin receptor (optogenetic activation); and tissue-specific deletions of ORs and their endogenous ligands in mice (Bruchas and Roth, 2016). Although the clinical importance of these discoveries remains to be established, several examples illustrate the speed at which this field is evolving.

Engagement of MOPRs by a ligand such as morphine recruits both inhibitory guanosine-5'-triphosophate (GTP) binding proteins such as Gi/o and β-arrestin, which serves ultimately to terminate G protein-dependent signaling. The βγ subunit of the G protein dissociates, permitting the α subunit to inhibit adenylate cyclase and indirectly activate kinases such as JNK (c-Jun N-terminal kinases) and ERK. In the meantime, the βγ subunit activates inwardly rectifying potassium channels to increase membrane hyperpolarization and inhibit voltage-gated calcium ion channels and hence neuronal hyperpolarization. These actions combine to explain the analgesia consequent to MOPR activation (Dogra and Yadav, 2015). However, ligand engagement also activates G protein receptor kinases that phosphorylate the intracellular tails of ORs, attracting β-arrestins that result directly and indirectly in activation of the ERK and p38 signaling pathways. Experiments in β-arrestin-depleted mice revealed this to be the pathway that may drive such effects as tolerance, respiratory depression, and constipation with certain opioids, such as morphine (Raehal and Bohn, 2014). Yet while the ability to segregate analgesic efficacy from a range of troubling adverse effects has clear translational implications, screening for such biased ligands is complicated by contextual influences that complicate translation of ligand bias from in vitro systems to rodent systems, let alone to humans (Kenakin, 2015). Nonetheless, several promising examples have emerged (Gupta et al., 2016; White et al., 2014), and one compound already has advanced from encouraging results of conserved analgesia with reduced respiratory and gastrointestinal adverse effects in 200 abdominoplasty patients in phase II to a larger randomized trial (Kingwell, 2015).

An exciting element of this work is the increasing recognition of OR heterodimerization as an in vivo phenomenon and the possibility that what are regarded as specific OR ligands may also engage, perhaps preferentially, heterodimers, perhaps to augment their analgesic efficacy. Screening approaches have yielded bivalent ligands, antibodies, and membrane permeable peptides that target heterodimers, for example, of the MOPRs/

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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DOPRs. These approaches, combined with approaches mentioned above, should clarify the underlying biology and the promise of such heterodimers as drug targets (Fujita et al., 2015). Heterodimerization may extend beyond the OR family; for example, heterodimerization of the KOPRs with the neurotensin receptor induces a switch of the former from G protein activation to β-arrestin-based signaling (Liu et al., 2016).

Abuse-Deterrent Formulations of Opioids

Although not representing an innovation in changing the intrinsic activity of opioid action, abuse-deterrent formulations (ADFs) are opioid medications that have been reformulated to reduce the likelihood that the medication will be “abused.” For example, some opioids have been reformulated to discourage manipulation by either making the pill difficult to manipulate or rendering it ineffective or unpleasant once manipulated. In addition to ADFs currently on the market, such as agonist/antagonist combinations (e.g., oxycodone plus naloxone) and crush-resistant extended-release (ER) formulations (e.g., oxymorphone), a number of new technologies are in development. These include formulations designed to limit the rate or extent of release of opioids when multiple pills are ingested; cause the pill to turn to gel if dissolved; irritate the nasal passages if snorted; and slow the release of the drug into the brain, thereby reducing euphoria (Bulloch, 2015). Many opioid analgesics, such as morphine, activate primarily the MOPRs, which relieves pain but is also associated with such side effects as respiratory depression. KOPR agonists currently in development are intended instead to activate the KOPRs, potentially providing pain relief without the MOPR-associated side effects (Beck et al., 2016).

Eicosanoids, Cannabinoids, and Transient Receptor Potential Channels

As mentioned in Chapter 2, prostaglandins E2 and I2, particularly but not exclusively formed by cyclooxygenase (COX)-2, mediate pain and inflammation; suppression of their formation accounts for the analgesic and anti-inflammatory actions of NSAIDs. Unfortunately, COX-2-dependent formation of these same eicosanoids serves a protective function in the cardiovascular system, where their suppression has resulted in myocardial infarction and stroke; hypertension and heart failure; and in mice, evidence of accelerated atherogenesis (Grosser et al., 2010). For these reasons, attention has focused on the microsomal prostaglandin E (PGE) synthase (S)-1, the enzyme downstream of COX that largely accounts for PGE2 formation (Chandrasekhar et al., 2016). When this enzyme is blocked or deleted, its prostaglandin H2 (PGH2) substrate, formed by COX, is available for rediversion to other PG synthases. Global deletion of microsomal

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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prostaglandin E synthase (MPGES)-1 in mice largely retains the analgesic efficacy of NSAIDs as assessed in mice, but augments rather than depresses prostacycline (PCI2). This coincides with attenuation or abrogation of the enhanced thrombogesis, hypertension, and atherogenesis seen in COX-2 knockout mice (Yang and Chen, 2016). Indeed, deletion of MPGES-1 in myeloid cells conserves this profile (Chen et al., 2014), and the impact of targeting macrophage MPGES-1 is under investigation. A phase II study of an MPGES-1 inhibitor found rediversion to augment PGI2 formation in volunteers (Jin et al., 2016). An open question is how faithfully MPGES-1 inhibitors will conserve the analgesic efficacy of NSAIDs in human pain syndromes, given that in some settings in rodent models, PGI2 has been shown to mediate pain and inflammation (Sugita et al., 2016). PGE2 activates 4 E prostanoid (P) receptors. As mentioned previously, EP3 mediates the hyperthermic effects of PGE2 and the EP1 (Johansson et al., 2011), EP2 (Ganesh, 2014), and EP4 (St-Jacques and Ma, 2014) receptors, just as the I prostanoid receptor (Honda et al., 2006) may mediate pain. While antagonists for all four of these receptors have been developed, it is unclear how safely such drugs could be used as analgesics given the importance of these PGs in cardioprotection.

These PGs mediate pain, at least in part, by sensitizing transient receptor potential (TRP) channels in nociceptors to activation by thermal, mechanical, or chemical stimuli. TRPs have particular relevance to the neuropathic pain that complicates diabetes, traumatic nerve injury, and chemotherapeutic drug administration. Besides PGs, other inflammatory mediators, such as bradykinin, nitric oxide (NO), and nerve growth factor (NGF), can sub-serve a similar function (Basso and Altier, 2017). Aside from the PG metabolites of arachidonic acid, p450 catalyzed metabolites (epoxyeicosatrienoic acids [EETs]) can sensitize nociceptors, especially TRPA1 and TRPV4, and deletion and inhibition of the soluble epoxide hydrolase that catalyzes their formation has shown promise in preclinical models (Wagner et al., 2016). Yet while TRPs themselves (TRPV1/A1, TRPV4/M8) have emerged as diverse and attractive targets for analgesic drug development given their role in inflammatory and neuropathic pain, concurrent impairment of their endogenous signaling functions (e.g., thermal regulation for TRPV1) may limit their clinical application (Dai, 2016; Mickle et al., 2016). Indeed, the fact that TRPs sustain some physiological functions, such as thermoregulation and hyperthermia, has complicated the early human pharmacology of TRPV1 antagonists. Also in model systems, their role may be highly context dependent: they serve as protective cellular sensors of warning signals under physiological conditions, but may contribute to pain and inflammation under pathological conditions (Dai, 2016).

Cannabinoids are lipids closely related to the eicosanoid family. The principal endogenous cannabinoids, anandamide and 2-arachidonoylglyc-

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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erol (2-AG), are formed in postsynaptic neurons and act centrally on cannabinoid receptor type 1 (CB1) G protein-coupled receptors (GPRs) that are expressed on presynaptic neurons, thereby regulating neurotransmitter release. Although there is some evidence that they are also expressed centrally, CB2 receptors generally are expressed peripherally on both neurons and immune cells. The principal psychoactive constituent of cannabis, Δ9-tetrahydro cannabinol (THC) is active on both CB1 and CB2 receptors. Anandamide levels are regulated by its breakdown through the action of fatty acid amide hydrolase (FAAH), while 2-AG levels are regulated by monoacylglycerol lipase (MAGL), which accounts for ~85 percent of the hydrolysis, and by α/β hydrolase domain-containing 6 (ABHD6) and ABHD12, which also hydrolyze 2-AG to arachidonic acid and glycerol. Cannabinoids act as well on other receptors, such as GPR18 and GPR55, and may act in concert with TRP channels and MOPRs (Maguire and France, 2016) in a bidirectional manner (Zádor and Wollemann, 2015) to modulate the expression of pain.

Cannabinoid action in the amygdala is of particular interest given the coincidence of pain with depression and the modulating effects of cannabinoids on both the physical perception of and emotive response to pain (Huang et al., 2016). Cannabinoids have been shown to be effective in several settings as analgesics in humans, albeit limited by central side effects such as drowsiness. There is some evidence for sex-dependent differences in mice in the analgesic response to cannabinoids (Cooper and Haney, 2016). Legalization of cannabis use for cancer pain has been advancing at the state level. Beyond the development of biased agonist ligands for cannabinoid receptors as novel analgesics with an improved adverse effect profile (Diez-Alarcia et al., 2016; Mallipeddi et al., 2016), interest in enhancing the formation of anadamide by inhibition of FAAH (Guindon, 2017; Pawsey et al., 2016) has been tempered by a severe reaction (a cerebellar syndrome including generalized ataxia, dysarthria, and nystagmus) to at least one such compound in healthy volunteers (Kerbrat et al., 2016).

Sodium Channel Blockade

VGSCs are crucial to the transmission of electrical signals in sensory neurons, and specific patterns of sodium current activity, such as persistent and resurgent currents, also are likely to be relevant to nociception (Barbosa and Cummins, 2016). The importance of sodium channels in pain is illustrated nicely by human genetics; gain-of-function mutations of Nav1.7, Nav1.8, and Nav1.9, which are expressed preferentially in peripheral neurons, cause pain in such syndromes as erythromelalgia (Brown, 2016; Rolyan et al., 2016), while loss-of-function mutations of Nav1.7 result in loss of pain in otherwise healthy people (Emery et al., 2016). A

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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painful neuropathy caused by the chemotherapeutic oxaliplatin has been linked to mutations in Nav1.6, a VGSC linked also to the conversion of acute to chronic pain (Barbosa and Cummins, 2016). Optogenetic silencing of Nav1.8 positive afferents alleviates inflammatory and neuropathic pain (Daou et al., 2016).

While mutational analysis has tied pain perception particularly to the α subunit of VGSCs, auxiliary subunits, such as β, and multiple auxiliary proteins, such as fibroblast growth factor homologous factors, may bind to and regulate α subunits and modulate aspects of nociception. Acid-sensing ion channels (ASICs) are activated with acidification of the synaptic cleft and exhibit specificity for sodium, although some also allow passage of calcium. Gene depletion in mice has implicated ASICs in mechanosensation, and several drugs targeting ASICs are in clinical trials (Boscardin et al., 2016).

VGSCs are complex drug targets given their multiple subunits, numerous configurations, and auxiliary binding proteins and the necessity of restricting targeting to the periphery. For example, to achieve selectivity with respect to tissue expression requires avoiding disruption of cardiac conductivity. Selectivity also may be enhanced by targeting microproteins to less conserved elements of VGSCs, such as voltage sensing, rather than pore residues (Barbosa and Cummins, 2016; Shcherbatko et al., 2016).

Nerve Growth Factor

NGF sensitizes and proliferates nociceptors augmenting the response to painful stimuli and has an established place in both neuropathic and inflammatory models of pain. Proliferation of nociceptor axons and terminals in target tissues is a particular feature of NGF action in cancer pain (Miyagi et al., 2016), driving a dramatic increase of small nerve fiber proliferation in bone (Kelleher et al., 2017). Perhaps unsurprisingly, NGF is believed to play an important role in the transition of acute to chronic pain. NGF (and its pro-NGF form) activates (1) a high-affinity tropomyosin receptor kinase (trk)A receptor, selectively expressed on peripheral terminals of Aδ and peptidergic unmyelinated C fibers, and (2) a lower-affinity, more ubiquitously expressed and promiscuous p75 neurotropin receptor, a member of the TNF receptor superfamily. While activation of the former promotes neuronal proliferation, activation of the latter promotes apoptosis. Despite these contrasting effects, the two receptors also can interact to modulate downstream effects, adding a layer of complexity that is incompletely understood. Although several anti-NGF monoclonal antibodies completed phase III trials and were effective analgesics, they also accelerated disease progression in patients with osteoarthritis and were put on clinical hold in 2010 by the FDA (Chang et al., 2016). This hold was released in March

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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2015, and translational and clinical trials (Miller et al., 2017) of diverse therapeutic modalities, including sequestration of free NGF, prevention of NGF binding, and inhibition of trk function, are being pursued (Chang et al., 2016).

Interleukin (IL)-6

This T cell-derived cytokine plays a central role in host defense against infection but also has been implicated in neuropathic pain. Unlike NGF, which is restricted to the periphery but transported retrogradely along axons complexed with its trkA receptor, IL-6 is upregulated in the central nervous system, where it promotes neuronal proliferation and restrains apoptosis. Both IL-6 and its soluble receptor can sensitize nocireceptors. This has prompted interest in the possibility that targeting the sIL-6R, leaving the canonical IL-6R untouched, might achieve analgesia while leaving the immunologic functions of the cytokine intact (Kelleher et al., 2017).

Emerging Drug Targets

Human genetic studies have revealed a relationship between variants in guanosine triphosphate (GTP) cyclohydrolase 1, which reduces tetrahydrobiopterin (BH4), and decreased pain. In mice, production of BH4 is increased by damaged nerves and attendant infiltrating macrophages, while reduction of BH4, by interfering with its degradation, reduces injury-induced hypersensitivity without interfering with the protective properties of nociception (Latremoliere et al., 2015). BH4 is an essential cofactor for enzymes relevant to generation of catecholamines, NO, and serotonin, all of which are mediators of hypersensitivity. For example, nitric oxide synthase (NOS)1 in neurons and NOS2 in macrophages have cumulative effects on NO generation and hypersensitivity (Choi et al., 2016; Kuboyama et al., 2011).

Purinoreceptors are activated by adenosine (P1) or adenosine triphosphate (ATP)/adenosine diphosphate (ADP) (P2; P2X ion channels and P2Y G protein-coupled receptors). Such nucleotides are released by most cells in response to mechanical stimulation and are rapidly inactivated by ecto-ADPases. P2Y-dependent ATP-induced hyperalgesia is transduced via TRPV1 channels. P2X7 receptors mediate pain caused by the chemotherapeutic oxaliplatin, while activation of glial P2Y12 receptors appears to be important in neuropathic pain. P2X3, P2X2/3, P2X4, P2X7, and P2Y12 have attracted attention as drug targets for both neuropathic and inflammatory pain (Burnstock, 2016; Matsumura et al., 2016; Teixeira et al., 2016).

Other areas of emerging interest include the potential of potassium channel openers as analgesics (Busserolles et al., 2016) and elucidation of

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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the role of store-operated calcium channels in the biology of nociception (Munoz and Hu, 2016).

Summary

A number of opportunities have emerged in recent years toward the development of nonaddictive alternatives to the opioids available on the market. Those of direct relevance to opioids include biased ligands directed at opioid receptors and continued development of new abuse-deterrent technologies. Other developments include inhibitors of the microsomal PGE synthase, drugs targeting VGSCs, anti-NGF biologics, transient receptor potential cation channel antagonists, cannabinoid receptor agonists, excitatory amino acid receptor blockers, anticytokine signaling drugs, neuromodulation, and agents directed at other targets. Specialized channels expressed in primary afferent nociceptors, such as TRP channels, serve as cellular sensors of actual or impending tissue injury and are targets for a new class of analgesic development. The selective blockade of pain transmission from the sensory terminals to the spinal cord may be possible through targeting of subtypes of VGSCs.

CLINICAL RESEARCH

Clinical pain research has continued since the IOM (2011) report Relieving Pain in America was issued. As discussed in Chapter 2 of the present report, opioids, while effective in the short and intermediate terms, lack data to support their chronic long-term use. Moreover, significant adverse effects are associated with chronic use of high-dose opioids (Chou et al., 2015). Research aimed at separating the beneficial pain-relieving effects of opioids from those that cause harm is under way (Manglik et al., 2016; Schneider et al., 2016). This section summarizes promising clinical research into the management of pain and opioid risk, including nonpharmacologic and interventional approaches, and the potential role of precision health care in improving clinical practice and health outcomes with respect to pain management.

Optimizing Opioid Analgesia in the Context of Comprehensive Pain Management and Opioid Risk

Opioid Prescribing for Chronic Pain

Many professional organizations have published standards of care for judicious prescribing of opioids for chronic pain (Dowell et al., 2016; Mai et al., 2015; Nuckols et al., 2014). Full disclosure of the risks versus benefits

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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of initiating opioid therapy is encouraged, along with individual assessment of the risk of opioid misuse. Several instruments have been developed to assess this risk based on patient self-report, including the Screener and Opioid Assessment for Patients in Pain, Revised (SOAPP-R) (Butler et al., 2009), the Opioid Risk Tool (ORT) (Webster and Webster, 2005), and the Current Opioid Misuse Measure (COMM) (Butler et al., 2010), among others. Such instruments can be used along with other information to guide decision making regarding an appropriate pain management plan. A review that involved an analysis of studies on the accuracy of the SOAPP-R, the ORT, and other instruments for predicting opioid misuse showed mixed results, with several studies having methodological shortcomings (Chou et al., 2015). Another review of studies on instruments (including the COMM and other self-report measures) used to assess the safety, efficacy, or misuse of current opioid therapy found that most studies demonstrated statistical significance, but had bias and generalizability limitations. Data on feasibility of use in clinical settings were limited by a lack of testing in those settings (Becker et al., 2013). Additional research could examine the accuracy of opioid risk assessment tools across multiple populations, including their role in improving outcomes related to misuse, overdose, and OUD, and test their use in clinical practice (Becker et al., 2013; Chou et al., 2015).

Given the potential to reduce dose-dependent risks, opioid dose reduction in the context of long-term opioid therapy is an area of ongoing research. Von Korff and colleagues (2016) report results from an interrupted time series analysis in Washington State examining changes between 2006 and 2014 in percentages of (1) patients being prescribed opioid therapy in doses exceeding 120 morphine-equivalent dose (MED)/day, and (2) patients receiving excess opioid days supplied. After release of a state-level chronic pain management guideline, as well as a health plan’s initiative to reduce high-dose opioid prescribing, the authors found that while prescribers exposed to the state guideline alone decreased high-dose prescribing (from 20.6 percent to 13.6 percent) and excess opioid days supplied (from 20.1 percent to 14.7 percent), those prescribers additionally receiving guidance from the health plan initiative displayed significantly higher decreases on the same metrics (from 16.8 percent to 6.3 percent and 24 percent to 10 percent, respectively) (Von Korff et al., 2016). Similarly, research on an opioid dose reduction program in a U.S. Department of Veterans Affairs (VA) health care system found dramatic relative changes in prescribing of a variety of opioid medications before and after program implementation (notably, with a parallel increase in prescription of oxycodone immediate-release [IR]) (Westanmo et al., 2015). Importantly, the authors report that patient complaints were lower than they had anticipated, but stress that prescribers, despite believing that patient safety had improved, continued to express a need for more comprehensive pain management services. Becker

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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and colleagues (2017) report similar success at an Opioid Reassessment Clinic to which high-complexity patients with pain (e.g., with co-occurring OUD) could be referred by primary care physicians.

Stepped Care

Stepped care is a patient-centered, multimodal approach to pain management that emphasizes treatment goals and a stepwise modification plan should goals fail to be reached or other complications arise (Cleeland et al., 2003). Research demonstrates improved outcomes for patients with chronic pain compared with usual care, including reduced pain-related disability, pain interference, and pain severity (Bair et al., 2015), and the approach also is associated with improved quality of life and cost savings (Hill et al., 2011). The Stepped Care to Optimize Pain Care Effectiveness (SCOPE) study showed success at integrating stepped care models into the primary care setting through the use of telehealth mechanisms (e.g., automated symptom monitoring via phone or Internet, with related optimization of analgesic management) (Kroenke et al., 2014).

Nonpharmacologic Pain Therapies

As discussed in Chapter 2, nonpharmacologic therapies are a promising option for various types of pain, and research has begun to formally establish associations with improved outcomes. For example, multiple studies have demonstrated the effectiveness of various nonpharmacologic therapies in chronic low back pain. Massage has been found to be superior for improving function and decreasing pain compared with usual care, with benefit extending many weeks after treatment (Cherkin et al., 2011). Similarly, Lamb and colleagues (2012) report durable improvement in pain and disability outcomes 1 year after group cognitive-behavioral therapy for low back pain; their long-term data indicate an average duration of effect of 34 months. Randomized trials studying other treatment modalities, such as tai chi, yoga, stretching classes, spinal manipulation, and physical therapy, also have demonstrated effectiveness for such conditions as low back pain, subacute neck pain, and osteoarthritis (Bronfort et al., 2012; Sherman et al., 2011; Wang et al., 2016).

Interventional Pain Therapies

Research in the area of interventional pain therapies, traditionally comprising small case series, observational studies, nonrandomized trials, and trials without controls, is slowly improving in quality. (See Chapter 2 for further discussion of these therapies.) Low back and neck pain account

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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for the majority of medical visits for pain and the majority of disability in industrialized nations. Epidural steroid injections, most often administered for painful radiculopathy, are the most frequently performed of all pain procedures (Bicket et al., 2015), and epidural injections for chronic radicular pain have increased dramatically over the past 10 years (Manchikanti et al., 2013). The mechanism of pain relief from the injections remains unclear. Unlike NSAIDs, which are cyclooxygenase inhibitors resulting in prostaglandin reduction, steroids act via the lipoxygenase pathway, reducing leukotriene formation. Steroids also inhibit phospholipase A2, the enzyme responsible for arachidonic acid production (Baqai and Bal, 2009).

The data on efficacy for epidural steroid injections are varied despite more than 45 randomized controlled trials (RCTs) and many reviews. Review articles by interventional physicians tend to find more positive results relative to reviews by noninterventional physicians, and patient selection is important in the variability of the results (Cohen et al., 2013). A review of articles published from 1953 to 2013 found that there was evidence of a positive result lasting less than 3 months from epidural steroid injections in more than half of the controlled studies in selected individuals, and the incidence of serious complications was rare if the injections were administered with proper precautions. More positive results were seen with use of transforaminal versus interlaminar or caudal techniques, and in radicular pain from lumbar herniated disc compared with spinal stenosis or axial pain (Cohen et al., 2013).

A systematic review of 3,641 patients in 43 studies evaluating control injections found that what is injected in the epidural space is not as important as previously thought, and injection of steroid may not be essential for pain relief. Epidural injection of local anesthetic only or even saline may provide similar results, a finding that may have relevance in diabetic patients with radicular pain (Bicket et al., 2013). Spine surgery rates also have increased significantly over the past 10 years, as has disability from spinal pain. A 2015 systematic review and meta-analysis of 26 studies, 22 of which were RCTs, provided unconvincing results regarding the surgery-sparing effect of epidural steroids. There was moderate evidence, falling short of statistical significance, that epidural steroid injections had a small effect on preventing surgery in the short term, and there was no effect on the need for surgery in the long term (Bicket et al., 2015).

An area in which research activity has recently increased is the field of neuromodulation for the treatment of pain. Spinal cord stimulation (SCS) has been used to treat neuropathic pain of the extremities for many years (Deer et al., 2014). A 2005 RCT found that SCS provided superior analgesia and was more cost-effective relative to repeat surgery for failed back surgery patients with persistent lumbar radicular pain who were candidates for surgery (North et al., 2005).

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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A Cochrane review found that SCS provided better pain relief and analgesic sparing with decreased amputations compared with standard conservative treatment for nonreconstructable chronic critical leg ischemia (Ubbink and Vermeulen, 2013). Although lumbar radicular pain frequently is treated successfully with SCS, low back pain often is more challenging. Traditional SCS is at 40–60 Hz. High-frequency (10 kHz) SCS recently emerged as another form of SCS, and evidence for the claim of superior relief of low back and leg pain is discussed below.

With the emergence of new paresthesia-free SCS it is now possible to conduct placebo-controlled trials. In an RCT of 198 patients with chronic back and leg pain, 84.5 percent of participants who received the 10 kHz SCS experienced 50 percent relief of their back pain and 83 percent relief of their leg pain at 3 months. By contrast, participants who received traditional SCS experienced 43.8 percent and 55.5 percent reductions in their back and leg pain, respectively (Kapural et al., 2015). Likewise, a multicenter RCT showed that high-frequency stimulation provided at least 50 percent relief of low back and leg pain and was superior to traditional low-frequency SCS for 2 years (Kapural et al., 2016).

The new burst SCS, like high-frequency stimulation, is paresthesia-free. Burst stimulation (40 Hz burst with five spikes at 500 Hz/burst) is described as using both spinal and supraspinal analgesic mechanisms in relieving pain and suffering. Electroencephalogram (EEG) activity and current density were measured in the anterior cingulate and prefrontal cortex of patients with SCS with traditional tonic (40 Hz), burst, and placebo stimulation. Pain was reduced with tonic stimulation, then further reduced with burst stimulation, with EEG activity suggesting a supraspinal effect. Prior functional magnetic resonance imaging studies had demonstrated that tonic stimulation modulates the lateral pain pathways, whereas burst stimulation activates both the medial affective and lateral pain pathways (DeRidder et al., 2010). A small randomized, placebo-controlled trial comparing tonic, burst, and placebo stimulation found that all types of SCS provided better analgesia relative to placebo. Burst stimulation improved back, limb, and general pain by more than 50 percent, versus 30–52 percent relief with tonic stimulation (DeRidder et al., 2013). More recently, spinal stimulation has been compared with a more selective targeting of the dorsal root ganglion (DRG) for the treatment of complex regional pain syndromes, with promising outcomes (Deer et al., 2017).

It is important to note that clinical research on interventional pain therapies often is observational and involves low numbers of patients. Nonetheless, some organizations are attempting to extract quality data from these studies that practitioners can apply to their practice. The Spine Intervention Society (SIS) has published guidelines on intervention for spine

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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pain (SIS, 2014), and a few reviews suggest that adherence to these guidelines may improve outcomes.

Clinical interventions for the treatment of chronic headache also have been investigated. For example, cervical medial branch injections can be administered to provide analgesia for cervicogenic headache and neck pain. A 2016 systematic review of eight publications on radiofrequency denervation found that if performed as described by SIS guidelines, cervical radiofrequency neurotomy is effective, with minor risks. (One of the authors served in the standards division of SIS.) The majority of patients were pain-free at 6 months, and more than one-third were pain-free at 1 year. The number of sessions needed to provide complete pain relief was two, and side effects were minor and temporary (Engel et al., 2016).

When peripheral nerve blocks are performed for headaches, they are most often occipital, particularly for posterior headaches. A review of five RCTs of greater occipital nerve blocks, four of which were double-blinded, found that all were small studies with 4- to 8-week follow-up that showed partial or complete relief of headache. The addition of a steroid to local anesthetic was not found to offer additional benefit (Ambrosini and Schoenen, 2016).

Botulinum toxin was FDA approved in 2010 for chronic migraine in patients who experienced at least 15 headaches per month for 3 or more months and whose headaches had migraine features for at least 8 of those days (Khalil et al., 2014). The largest double-blind, placebo-controlled trials were all industry sponsored (Aurora et al., 2011).

Precision Health Care and Pain Management

Precision health care is focused on defining a true disease state/condition using pathophysiological mechanisms, congruent with the concept of clinical validity. In contrast, personalized health care applies to optimization of a therapeutic approach specific to an individual versus a population. This section highlights the differences in these concepts as applied to the state of the science on opioid prescribing for chronic pain management.

Diagnosis of Chronic Pain

Pain diagnosis currently depends on clinical examination and testing (laboratory, imaging) to identify the etiology of the pain. The pain condition is described in terms of the pain’s location (e.g., orofacial pain, temporomandibular joint disorder, migraine, low back pain) and/or type (somatic pain is caused by injury to skin, muscles, bone, joints, or connective tissues and is nociceptive; visceral pain arises from the internal organs and is nociceptive; and neuropathic pain is presumed to be caused by a

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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demonstrable lesion or disease of the peripheral or central somatosensory nervous system). Duration of pain is commonly defined as acute (less than 6 weeks), subacute (6–12 weeks) or chronic (more than 12 weeks). In many instances, pain has no identifiable cause (i.e., is idiopathic), a feature that largely encompasses many of the pain syndromes diagnosed today, such as complex regional pain syndrome, fibromyalgia, and chronic pelvic pain. Even for the most common chronic musculoskeletal pain condition, chronic low back pain, many cases have no identifiable etiology (Giesecke et al., 2004).

Studies suggest that genetics contribute substantially to the risk of developing chronic pain (Hocking et al., 2012; Nielsen et al., 2012). In an analysis of data from a Scottish cohort study (n = 7,644 people in 2,195 extended families), for example, the heritability of any chronic pain and severe chronic pain was found to be 16 percent and 30 percent, respectively, after adjusting for shared household effects, age, body mass index, occupation, and physical activity, among other factors (Hocking et al., 2012). A systematic review of more than 50 twin studies of pain showed heritability of 50 percent for migraine, tension-type headache, and chronic widespread pain; 35 percent for back and neck pain; and 25 percent for irritable bowel syndrome (Nielsen et al., 2012). Other than rare monogenetic familial pain conditions (e.g., familial migraine with aura or erythromelalgia), however, chronic pain does not follow the Mendelian transmission model but encompasses aggregates of endophenotypes, each of which may be governed by Mendelian law (Zorina-Lichtenwalter et al., 2016). Criteria for the endophenotype construct state that the endophenotypes must (1) be associated with the disease of interest, (2) be heritable, (3) be manifest in subjects independently of active pathology, and (4) cosegregate with disease in pedigree studies (Gottesman and Gould, 2003). Endophenotypes of chronic pain include the pain phenotype (location, severity, frequency, duration, presence of peripheral and central sensitization such as hyperalgesia and allodynia) and associated symptoms, including anxiety, depression, and sleep disturbance (Zorina-Lichtenwalter et al., 2016).

Precision health care could improve diagnosis of pain by using omic approaches (genomics, metabolomics) to understand the pathophysiology of specific pain conditions and symptom phenotypes, along with advanced imaging techniques to detect functional changes in pain processing. There is significant interest in this area with respect to the potential for improving the prediction and diagnosis of pain, as well as advancing preventive strategies. At present, however, studies using candidate gene approaches have largely failed in reproducibility.

In summarizing the literature on analysis of single nucleotide polymorphisms (SNPs) associated with chronic pain, more than 200 of which are known to exist, Crow and colleagues (2013) note that three (GCH1, which

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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encodes GTP cyclohydrolase; COMT, an enzyme that eliminates catecholamines; and OPRM1, the MOPR gene) are particularly noteworthy for demonstrating the often contradictory findings in the field.

Studies of healthy volunteers and patients reporting persistent leg pain have shown associations between lower pain ratings and a GCH1 haplotype (Campbell et al., 2009; Tegeder et al., 2006). In a larger cohort, however, neither the same association nor even the same haplotype was identified (Kim and Dionne, 2007), and similarly negative results were found in patients from a different ethnic population with HIV-associated neuropathy (Wadley et al., 2012). Likewise, research into the association between pain and COMT has thus far produced inconclusive and contradictory evidence. The first COMT SNP associated with pain was reported in 2003 (Zubieta et al., 2003) and has been confirmed in multiple patient and healthy volunteer groups (Diatchenko et al., 2005, 2006; Mukherjee et al., 2010), as well as animal models (Segall et al., 2010). Nevertheless, controversy exists over the importance of the original SNP (Val158Met) (Kim et al., 2006), and the association between increased pain and other COMT variants does not replicate across populations. For example, no association was found between chronic pain and COMT SNPs in a large study of more than 7,000 people (Hocking et al., 2010). Rather, the authors found an entirely different haplotype within the ADRB2 gene (responsible for encoding the beta-2 adrenergic receptor) that predicted both pain severity and duration, even after controlling for gender, social class, body mass index, and other confounding factors (Hocking et al., 2010). Finally, while relationships between pain and SNPs in OPRM1 have been reported for more than a decade (Bond et al., 1988; Wendel and Hoehe, 1998), a larger metaanalysis was unable to confirm these findings (Walter and Lotsch, 2009).

Heterogeneity in chronic pain may explain this lack of consensus, as inter- and intracohort variability could confound results (Crow et al., 2013). Thus, moving toward a more mechanism-based pain syndrome classification, aided by rigorous phenotyping, is a promising next step (Maier et al., 2010). Another issue, common in genetic association studies, is the exceedingly population-specific nature of findings, resulting in varying results across different ethnic cohorts.

Moreover, genome-wide association studies often capture gene variants that are more common (e.g., with a minor allelic frequency of ≥5 percent). Discouragingly small effect sizes frequently are identified for most variants, which explain only a fraction of the genetic contribution to a particular condition (Hardy and Singleton, 2009). More successful approaches could include examining structural variation, such as copy number variation (WTCC, 2010), or even highly penetrant rare variants (e.g., those with a minor allelic frequency of less than 1 percent) (Gibson, 2011). Recent studies examining variants in European, South Asian, and African popula-

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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tions used exon sequencing across large cohorts and found the vast majority of variants (about 90 percent) to be rare (Nelson et al., 2012; Tennessen et al., 2012). In a healthy twin cohort study, an attempt to demonstrate an association between pain sensitivity and rare variants was inconclusive, but the authors (Williams et al., 2012) did identify a cluster of 30 genes within the angiotensin II pathway that segregated with thermal pain perception.

Better methods for precisely identifying the mechanisms underlying an individual patient’s pain could improve pain management. If clinical research is focused on advancing the methods of pain phenotyping and classification of pain endophenotypes, therapeutics can be targeted to the individual’s physiology. Such potential avenues being explored in patients with chronic pain include quantitative sensory phenotyping, imaging of peripheral nociceptors, study of pain mediators in bodily fluids (i.e., “inflammatory soup”), and the genetic and epigenetic approaches outlined above (Sommer, 2016).

Among patients with chronic pain, however, variability in the etiologies and types of pain and the high frequency of mental health comorbidities in this population (Campbell et al., 2015) make it difficult to determine whether long-term opioid analgesics are effective for improving pain severity, function, and quality of life (Chou et al., 2015; Knaggs, 2015; Robinson et al., 2015; Sehgal et al., 2013). Until researchers and clinicians have a better understanding of the mechanisms underlying chronic pain and improved diagnostic accuracy for chronic pain conditions is achieved, the treatment of chronic pain will continue to be driven by a hypothesis about the source of pain and traditional trial and error.

Pain Modulation Profile

Painful conditions can undergo modulation, either suppression or augmentation at the central nervous system. The inhibitory modulation system is known to be activated by painful stimuli, exercise, and muscle contraction (Nir and Yarnitsky, 2015). The exact mechanisms of pain modulation are not fully understood; however, it is widely believed that activation of the endogenous opioid system and release of peripheral and central beta-endorphins (Bement and Sluka, 2005; Stagg et al., 2011) play a major role in this phenomenon. Other suggested mechanisms include activation of neurotransmitters such as serotonin and norepinephrine (Dietrich and McDaniel, 2004) and involvement of the adenosinergic (Martins et al., 2013) and endocannabinoid systems.

A faulty pain modulation system has been shown to be associated with such chronic pain conditions as fibromyalgia (Graven-Nielsen et al., 2000; Price et al., 2002; Staud et al., 2003), tension-type headache, musculoskeletal pain (Ashina et al., 2006; Pielsticker et al., 2005), trigeminal

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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neuropathies (Nasrin-Heir et al., 2015), migraine (Weissman-Fogel et al., 2003), chronic low back pain (Kleinbohl et al., 2006), irritable bowel syndrome (King et al., 2009a), and temporomandibular disorders (Maixner et al., 1998; Raphael et al., 2009; Sarlani and Greenspan, 2005; Sarlani et al., 2004). Among healthy subjects, pain modulation competence is reduced with age (Edwards et al., 2003), which may explain the increase in chronic pain among older adults.

Recent studies have shown that patients with less efficient pain modulation suffer more from chronic postsurgical pain (Yarnitsky et al., 2008) and experience greater therapeutic efficacy from certain medications, such as duloxetine, relative to patients with a normal pain modulation system (Yarnitsky et al., 2012). This finding may suggest that a pain modulation profile can be used as a tool for predicting the development of chronic pain and individualized pain management outcomes (Yarnitsky, 2015). Further research could examine the association among pain modulation profile, pain intensity, and treatment outcome in various chronic pain conditions and in response to various treatment options.

Relevance to Opioid Prescribing for Chronic Pain

Studies estimate that approximately 50 percent of the likelihood an individual will suffer from addiction has a genetic basis (Meshkin et al., 2015). The exposure to opioid medications in the health care setting could be a triggering event for some people (as noted in Chapter 2). In addition, individual differences in drug metabolism affect opioid efficacy. For instance, some opioids, such as hydrocodone and codeine, are known to be pro-drugs, and require metabolic conversion to an active metabolite (e.g., hydromorphone and morphine, respectively) for pharmacodynamic benefit. Genetic polymorphism of the enzyme CYP2D6 has been reported to lead to variable hydrocodone and codeine metabolism (Monte et al., 2014). Patients with deficient CYP2D6 activity produce very low concentrations of active drug, leading to suboptimal pain relief. In contrast, patients with duplication of active CYP2D6 genes are ultra-rapid metabolizers and produce relatively high concentrations of active drug, which can lead to toxicity. Therefore, testing the metabolic profile of the patient ahead of prescribing could assist with the selection of an opioid medication.

Genetic screening tests have been developed based on identified genes involved in opioid response, opioid metabolism, and addiction risk (Arthur, 2013; Deer et al., 2013). Further research could determine whether these tools can guide pain management practice by providing prescribers with important information regarding patients’ risk for opioid tolerance and OUD.

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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Summary

The movement toward pragmatic, practice-based trials is an important current trend in pain research. Many such trials are still under way, but they represent a critical step forward in clinical pain research. The ideal balance of opioid reduction in the context of more comprehensive pain management (e.g., stepped care models) continues to be investigated. Nonpharmacologic therapies can be effective, particularly for lower back pain, and can have long-lasting effects on such outcomes as pain intensity and disability. Interventional techniques to relieve pain hold promise, but research on these techniques is still developing. Precision health care (broadly defined) has the potential to improve clinical pain research and management. However, further research could better characterize the association among pain modulation profiles, pain intensity, and treatment outcomes in various pain conditions and in response to various treatment options.

INTERSECTION OF PAIN AND OPIOID USE DISORDER

As discussed briefly at the end of Chapter 2, pain and reward are processed within overlapping brain structures. Before this report turns in earnest from pain management and relevant research to addressing the opioid epidemic, this section addresses several key issues related to the critical intersection of the two. In keeping with the focus of this chapter, research gaps are identified that if filled could prove crucial to helping to resolve the current crisis.

Motivations for Initiating Misuse of Prescription Opioids

As indicated in the discussion of terminology in Box 1-2 in Chapter 1, this report uses the term “misuse” to refer to any use of prescription opioids outside the specifications of a prescription, whether by patients for whom the drugs have been prescribed or by other persons. This definition encompasses a heterogeneous cluster of situations, such as using medications without a prescription, using more medication than prescribed, combining prescribed drugs with other drugs or alcohol, and engaging in activities not recommended while taking the medication. A number of studies have found that misuse of prescription opioid medications is common (SAMHSA, 2013), although how common is difficult to determine in light of the wide range of motivations and behaviors encompassed by the term and the varied circumstances under which patients for whom opioids were lawfully prescribed initiate misuse. The purpose of this section is to anchor the dry term “misuse” in the diverse desires and frailties of humankind and the vicissitudes of social life, and to call attention to the need to operationalize

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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various motivations and behaviors bearing on the transition from initiation of use of prescription opioids to misuse and subsequent problems.

Pervasiveness of Misuse

Any prescription medication that produces pleasurable effects or potential functional benefits poses an inherent risk of misuse. For instance, using leftover antibiotics to treat a self-diagnosed sinus infection or using nonprescribed Adderall (indicated for the treatment of attention deficit hyperactivity disorder and narcolepsy) to facilitate studying for a school test constitutes prescription drug misuse. In addition to alleviating pain, opioid medications can produce feelings of pleasure, relaxation, and contentment (NIDA, 2017), and because of their broad effects, it can be challenging to determine specifically why people initiate misuse. As a consequence, some motives for misuse (e.g., the undertreatment of pain) may be difficult to recognize. How opioid medications are prescribed can further complicate the task of classifying misuse. Under the directive of a health professional to “take when necessary to control pain,” patients have flexibility in determining how often they use a dose of a prescription opioid they have been prescribed. If patients are using opioid medications in a way they believe is necessary to control their pain, the concept of misuse may not apply or be impossible to distinguish from prescribed use. This can generally pose a challenge to prescribers because opioids can produce tolerance, meaning that with use over time, they become less effective. In an effort to control pain, a logical clinical outcome might be to increase the medication dose, something the patient may desire. It is therefore unsurprising that a number of studies have found that the most common type of opioid medication misuse involves users self-escalating the prescribed dose. Among an 85-patient sample being discharged from the emergency department, for example, Beaudoin and colleagues (2014) discovered that 42 percent self-reported misusing their opioid medications. Of those misusers, 92 percent reported escalating their dose without a health care provider’s direction, while 36 percent reported using the drug for a reason other than pain.

Equally important, opportunities for misuse of opioid medications may arise as a benign consequence of a patient (or a patient’s parent or guardian) not knowing the proper way to take or store the medication or dispose of medication that is unused. In a large study (n = 501) of 8th and 9th graders, for example, Ross-Durow and colleagues (2013) found that 46 percent of the adolescents had been prescribed controlled medications, including pain medications, in the past 6 months, and the majority had unsupervised access to these drugs. Patients may even share their opioid medications in an honest effort to help others, such as family members, who are in pain (Kennedy-Hendricks et al., 2016).

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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Pain

The complexity of the relationship between pain and addiction is highlighted by the multiple trajectories of opioid misuse. Consider, for example, an all-too-common trajectory reported in open-ended/qualitative interviewing: a person is prescribed opioids for a legitimate pain condition and then starts using more than was prescribed after becoming tolerant to the drug’s effects. Increases in level of use can also produce neurobiologic effects that, in turn, can create a new motive for increased use. Because patients are now taking higher doses, or after exhausting their supply have begun to experience symptoms of opioid withdrawal, a more potent form and/or route of administration (e.g., injecting) may become appealing, or heroin may become an alternative because it costs less and involves fewer barriers to use relative to opioid medications (Mars et al., 2014). The motive for misuse of opioid medication thus transitions from initial prescribed use to control pain, to misuse to manage pain, to nonmedical use, and then finally to heroin use. If a person is in acute pain from an injury, it is commonly believed that opioids will act to help relieve the suffering that follows, regardless of its duration and whether the source is prescribed or nonmedical. As this example illustrates, however, as use of opioids continues from days to weeks to months, the motivation to continue using them may become more complex, going well beyond the drugs’ original purpose or capability, and being in pain and not having legitimate (i.e., prescribed) or consistent access to opioids may motivate some people to seek and misuse these drugs.

Another common scenario is described by Rigg and Monnat (2015), who found that in rural areas of the country with large populations of laborers who worked in mining and other intensely physical industries, levels of untreated or undertreated chronic pain were high. Because of the limited numbers of health care facilities in these often-remote areas, prescribing large volumes of pain medicines was a common and efficient practice. It should also be noted that early in the opioid epidemic, these communities did not have local heroin markets to compete with pain medications, which allowed the demand for those medications to grow unabated and saturate the community.

Such scenarios may be attributable to a host of factors, such as difficulties in diagnosing and measuring pain, variations in prescribers’ training and practices, and the maldistribution of health care facilities and health care providers. These localized factors may, in turn, be a product of much larger shortcomings of the health care system that have unintended consequences. Some studies have shown that people of color are less likely than whites to be prescribed opioids (Pletcher et al., 2008; Singhal et al., 2016), while others have shown that providers may have different expectations

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

regarding the risk of opioid misuse based on a patient’s race (Becker et al., 2011; Vijayaraghavan et al., 2011). Although on balance this observation may be equivocal with regard to the current opioid crisis, such structural barriers demonstrate why misuse may occur more frequently among certain groups than others.

Emotional Distress

The pain-relieving and other effects of opioids (e.g., the feelings of pleasure, relaxation, and contentment that opioids can induce) (NIDA, 2017) may give rise to use of these drugs to manage stress, depression, anxiety, or other acute psychological states or chronic mental health disorders (DiJulio et al., 2016; Feingold et al., 2017; Vorspan et al., 2015), which may be caused or worsened by social conditions (such as poverty, unemployment, lack of opportunity, and hopelessness). In these instances of misuse, the intended medical indications of opioids to alleviate physical pain may be coopted by treatment of these mental or social conditions. In the absence of a diagnosed medical condition verifying physical pain, this sort of misuse often is viewed as unacceptable. Nevertheless, people do use opioid medications to self-medicate. Even if this type of use is characterized as nonmedical use, users may perceive specific benefits in relieving some health-related conditions. Complicating this situation is the co-occurrence of mental health challenges and other chronic conditions, especially functionally debilitating pain. The inability to work, walk, or engage in enjoyable activities can greatly impact even the most resilient of patients with extensive coping skills and supports, leading to depression, anxiety, and potentially initiation or reinitiation of substance misuse. Data support the correlation between depression (Turner and Liang, 2015) and diagnosis of substance use disorder (SUD) (Zedler et al., 2014) among people prescribed opioids as a risk factor for overdose. Moreover, medications used to treat anxiety and depression (e.g., benzodiazepines) may be coprescribed with an opioid, contributing to an increased risk of overdose (Park et al., 2015; Sun et al., 2017). The ways in which the dynamics of hopelessness, lack of opportunity, poverty, undertreated pain (both physical and emotional), and reduced access to medical care have collided with nonmedical use of opioids are perhaps most obvious in the rural communities devastated by the opioid epidemic discussed above. It should be noted, moreover, that during the time in which these communities were being inundated with these medications from pill mills and other legal and illegal suppliers, they were also suffering from the effects of an economic recession.

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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Nonmedical Use

As motives for the initiation of misuse of opioid medications become increasingly removed from or unrelated to the drugs’ original or intended medical purpose, one could argue that the term “misuse” no longer applies. The final, and perhaps most important, group to consider here are the many people who misuse prescription opioids with no pretense, thought, or concern regarding their medical uses. Here the ability of these drugs to alter consciousness in a pleasurable way motivates use, and such misuse is simply another form of illegal recreational drug use. There is no intended medical purpose for the use, and the user is only seeking the euphoric condition these drugs produce. A major challenge for understanding the problems and consequences associated with the initiation of opioid misuse is identifying the different ways people might misuse these drugs while understanding that misusers may have multiple motives for their use and that their motives may change or adapt over time. Distinguishing empirically between motivations related to alleviation of pain or distress and reward seeking is a challenging but important task at both the neural and experiential levels.

Considerations for Research on Pain and Opioid Use Disorder

Much attention in the literature has been paid to pain as a potential precondition in some opioid misuse and addiction (Fishbain et al., 2008, Martell et al., 2007; Wasan et al., 2009). Pain is a trigger for self-medication, and is without question a significant risk factor for opioid misuse (Amari et al., 2011). However, one of the challenges hindering understanding of opioid risks in pain patients is the lack of consensus on the definition of terms such as “misuse,” “problematic use,” and “aberrant use” (as reflected in the COMM questionnaire; the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV]; Portenoy’s Prescription Drug Use Questionnaire [PDUQ]; the Brief Risk Interview; ORT; the Aberrant Drug Behavior Index; and the Prescription Opioid Therapy Questionnaire). Even if these assessments are used accurately, clinicians often are unable to predict misuse and addiction liability. For instance, chronic pain patients may develop tolerance and physical dependence, often in the absence of an OUD diagnosis, yet still resort to such aberrant behaviors as dose escalation to control poorly alleviated pain (Back et al., 2009). Even if there were universal agreement on the definition of misuse, efforts to use self-report assessments to identify pain patients who may be at risk for opioid misuse have been largely ineffective (Chou et al., 2014). An important first step in adequately identifying opioid risk is characterization of the neurobiological interaction between chronic pain and opioid use. Given the role of the brain’s reward circuitry in opioid addiction (Martin-Soelch et al., 2001;

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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Ross and Peselow, 2009), discussed earlier, this circuit is an ideal target for study of pain-induced vulnerability to opioid risk.

Treating chronic pain while avoiding misuse is particularly difficult in patients with a history of SUD. This is not an inconsiderable problem given that an estimated 5–17 percent of the U.S. population has a diagnosed SUD (Prater et al., 2002; SAMHSA, 2014; Warner et al., 1995). Unfortunately, nearly half of chronic pain patients with SUD diagnoses have reported that opioids prescribed to relieve their pain were the root cause of their disorder (Jamison et al., 2000). It is well established that prior substance use (including use of nicotine and alcohol) is a strong predictor of opioid misuse (Novy et al., 2012; Turk et al., 2008). At the same time, however, there is a significant risk of undertreating people with serious pain, particularly if the SUD diagnosis involves opioids. In fact, 80 percent of methadone maintenance patients in one study reported recent pain, and 37 percent reported chronic pain (Rosenblum et al., 2003). It is this population in particular that is at greatest risk; the presence of pain creates a vicious downward spiral (described by Garland et al., 2013) whereby pain may trigger hypervigilance and catastrophizing and lead to self-medication. The relative low cost and abundance of heroin (compared with prescription opioid analgesics) is an important motivating factor when patients transition from prescription opioids to illicit drugs (Cicero et al., 2015). This cascade of events substantially increases the risk for misuse and overdose, given the unpredictable purity of illicit fentanyl and heroin (DEA, 2015; Mars et al., 2015). On the other hand, a recent meta-analysis (Dennis et al., 2015) suggests that pain may actually be a protective factor in the consumption of illicit opioids. These discrepancies in the literature further highlight the importance of mechanistic investigations into the neurobiology of opioid-treated pain in populations with prior opioid exposure.

Considerations Relating to Developmental Neuroscience and Adolescence

Exposure to opioids at a vulnerable point in time increases the potential for SUD, and younger age is a known vulnerability (85 percent of SUDs are manifested by age 35 [Trigeiro et al., 2016]). Nonmedical use of opioids in adolescence has been classified into subtypes, including reward seeking (or sensation seeking) and self-treatment for various sources of pain. In the latter group, prescription opioids are thought to be used to self-treat physical pain and psychological symptoms following traumatic or stressful events (Young et al., 2012). In one survey of 7th to 12th graders, for example, the most common reason for nonmedical use was “to relieve pain” (n = 91, 62.8 percent), followed by “to get high” (n = 23, 15.9 percent) and “to experiment” (n = 16, 11.0 percent). Of this sample, 12.3 percent (n = 323) were identified as medical users, 2.7 percent (n = 70) as nonmedical self-

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

treaters, and 2.5 percent (n = 66) as nonmedical sensation seekers. Thus, pain provides a pathway to adolescent misuse of opioids, which began to rise in the 1990s in concert with the development of stronger medications and more aggressive pain treatment (although rates for 12th graders are down significantly from a peak of 9.5 percent in 2004 [Johnston et al., 2017]). And high school seniors who misuse prescription pain medications are more likely to misuse other controlled substances as young adults (McCabe et al., 2013).

More generally, as noted earlier in this report, nonmedical use of opioids is most prevalent among young adults aged 18–25, and exposure to opioids represents a major risk for OUD. Risk taking, including experimentation with illicit drugs and alcohol, peaks in adolescence and young adulthood (IOM and NRC, 2011, 2015), laying the groundwork for substance misuse. During this developmental period, social, cognitive, and biological factors combine to create inordinate vulnerabilities to substance misuse and, ultimately, SUD (Casey et al., 2011; Reyna and Farley, 2006; Rudolph et al., 2017). Although many of these outcomes play out over a lifetime, increases in overdose deaths caused by heroin and synthetic opioids can be detected beginning at age 15 (Rudd et al., 2016a,b). Understanding these developmental factors is an essential part of designing effective risk communications, public health programs, and policies to combat nonmedical use of opioids. Moreover, prevention and intervention at this stage of life has tremendous potential for improving lifelong educational, economic, and health outcomes.

Specifically, behavioral and brain research indicates that adolescents are more responsive to rewards (e.g., food, money, and drugs) than are children or adults, and this is related to their risk taking (Bjork and Pardini, 2015; Galvan et al., 2007; Reyna et al., 2011; Romer and Hennessy, 2007). Neurodevelopmental theories of risk taking build on this finding and point to the earlier maturation of subcortical reward and emotional circuitry, especially in the amygdala and striatum, compared with emotional regulation and cognitive control areas of the brain (e.g., prefrontal cortex [Casey et al., 2015]). In addition, connectivity between these regions develops. For example, resting-state connectivity analyses have shown greater connectivity between the amygdala (an emotion area used as a seed region) and the prefrontal and parietal cortices (e.g., the right middle frontal gyrus, left cingulate gyrus, left precuneus, and right inferior parietal lobule) in risk-taking compared with non-risk-taking adolescents (Dewitt et al., 2014). (Note that greater rather than lesser connectivity between emotional and cognitive systems, as postulated in neural imbalance models, is associated with risk taking, a contradiction that could be resolved by further research.) Nevertheless, research supports the conclusion that the risk of SUD is present for young people without psychological disease because these drugs

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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hijack the normal reward system, which is already primed and is less likely to be inhibited by cognitive control systems.

Neural imbalance between reward responsiveness and cognitive control appears to be an inevitable product of brain maturation. Although brain development is known to be shaped by experience, however, not enough is known about how experience (and what specific features of experience) sculpts the brain. For example, research could examine what kinds of experience lead to what kinds of brain growth, pruning, and neural connectivity and the functional implications of these developments for human behavior. Indeed, Feldstein Ewing and colleagues (2017) have shown that response to treatment for SUD in adolescents is associated with changing connectivity to the orbitofrontal part of the brain. Thus, considering research on risk taking as a whole, it is likely that adolescent brain development can be modified by specific experiences that reduce vulnerabilities to SUD.

In addition, effects of cognitive representation (i.e., how people “frame” or interpret the gist of their options) on risk taking have been established, and initial research has demonstrated that these mental representations can be modified and that doing so can reduce self-reported risk taking in adolescents (e.g., Fischhoff, 2008; Reyna and Mills, 2014). These effects illustrate the fact that pain, SUD, and other psychological phenomena are a function of subjective constructions rather than purely objective reality. Cognitive representations influence risk perceptions, risk preferences, and emotional responses, which in turn determine decisions to misuse substances. These decisions also occur in a social context that determines behavior, but is rarely understood beyond noting superficial differences in demographics or countries. Social norms are just one example of a highly relevant social factor. Social norms interact with developmental and individual differences in risk taking, changing the frequencies and kinds of risk taking manifested in adolescence (Mills et al., 2008; Rudolph et al., 2017; Steinberg et al., 2017). Therefore, cognitive representation, reward responsiveness, and cognitive control are likely modifiable—providing inroads for prevention and treatment—and their effects on vulnerability to SUD require a deeper mechanistic understanding of the interplay among social, cognitive, emotional, and neurobiological factors.

Basic Research on the Intersection Between Pain and Opioid Use Disorder

As discussed earlier, opioids, like other drugs that are misused, activate the structures within the mesolimbic reward pathway via MOPRs, DOPRs, and KOPRs. Binding of opioid agonists within this circuitry elicits the release of the neurotransmitter dopamine, which is critically involved in encoding reward and reinforcement. It is worth noting that pain relief

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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itself is rewarding, a phenomenon that is attributed to the activation of this system (Becker et al., 2012). Data from both human and animal studies indicate that chronic pain induces dramatic changes in the functionality of the reward system, both directly through diminished dopamine neurotransmission and indirectly through dysregulation of the opioid receptor systems (Hipólito et al., 2015; Martikainen et al., 2015; Narita et al., 2004; Taylor et al., 2015). During inflammatory pain, MOPRs in this circuitry are desensitized, which may be due to a pain-induced increase in the release of endogenous opioid peptides (Schrepf et al., 2016). There is also top-down management of these processes by the hippocampus, given the role this structure plays in the reinstatement of drug-seeking behavior (Portugal et al., 2014). Pain-induced alterations in the reward pathway, including the altered value of reward and opioids (Loggia et al., 2014), could play a vital role in the vulnerability of patients to opioid misuse. Despite recent efforts to characterize pain-induced sensitivity to opioids, many unanswered questions remain. Although heroin use has recently been linked to several genetic polymorphisms (Hancock, 2015; Nelson et al., 2016), these have not been studied specifically in pain patients. The identification of “abuse-vulnerable” genetic markers or implementation of other biological screening tools would be of great utility, given the relative inadequacy of self-report and provider assessments of “abuse liability” (Chou et al., 2014).

The alterations in the dopaminergic system induced by either pain or stress can generate long-term modifications in the reinforcing values of opioids and thus lead to misuse. Therefore, it is important to elucidate how these modifications manifest at the cellular level in the mesolimbic pathway. To date, few studies have assessed the impact of pain and stress together on opioid intake in rodent models. One critical factor that is particularly pertinent when studying chronic pain–induced disorders is experimental/sampling time. Many preclinical models used previously were deemed failures (Yalcin and Barrot, 2014), but this may simply have been due to timing. Many of the same studies carried out during the first 3 weeks of pain induction versus after the first 3 weeks have shown strikingly opposite results (see the review by Yalcin and Barrot, 2014).

In addition to the importance of improving models of chronic pain and stress to assess their involvement in misuse liability, a deeper understanding of the intricate details of neuromodulation and signaling within key brain structures is critical. Recently, two studies revealed that KOPR activation in discrete regions of the NAc not only is anhedonic and aversive but also can be reinforcing (Al-Hasani et al., 2015; Castro and Berridge, 2014). Remarkably, these studies revealed the presence of both hedonic and anhedonic KOPR areas in the NAc in both mice and rats (Al-Hasani et al., 2015; Castro and Berridge, 2014). These findings enhance understanding of the

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
×

complexity of the KOPR system in regulating the rewarding and aversive components of external stimuli and demand further study of how these newly identified systems modulate the pain experience.

There is clear comorbidity between chronic pain and stress-induced pathologies. Concomitant dysregulation of mesolimbic dopaminergic transmission is thought to increase vulnerability to opioid misuse. To reduce the misuse potential of opioid analgesics, a better understanding of the interactions between pain and stress systems is required. Stress-related systems, such as the kappa opioid system, have been identified as key to the regulation of dopamine release during pain and stress. This system may be crucially involved in driving the pathological changes that result in misuse and potential fatalities.

Summary

A major challenge for understanding the problems and consequences associated with the initiation of opioid misuse is identifying the different ways in which people may misuse these drugs while understanding that misusers may have multiple motives that may evolve over time (e.g., pain relief; management of stress, depression, or anxiety). These complexities need to be borne in mind as this report reviews the scientific literature bearing on the use and misuse of prescription opioids and strategies for ensuring the public’s health.

An important first step in identifying opioid risk is characterization of the neurobiological interaction between chronic pain and opioid use. Pain is a trigger for self-medication and a significant risk factor for opioid misuse. Treating chronic pain while avoiding misuse is particularly problematic for patients with a prior history of SUD, and more evidence could help determine the degree of risk for OUD when people with serious pain are undertreated.

During adolescence and young adulthood, social, cognitive, and biological factors combine to create inordinate vulnerabilities to substance misuse and, ultimately, SUD. Effective prevention and treatment of OUD requires a deeper mechanistic understanding of how cognitive representation, reward responsiveness, and cognitive control interact in the developing brain; their interplay with pain; how these factors are shaped by the social context of risk taking in youth; and how these factors can be modified to reduce unhealthy risk taking.

A better understanding of the interactions among pain, reward, and stress systems, including pain-induced alterations in the reward pathway, will help inform and reduce the misuse potential of opioids.

Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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SUPPORT FOR RESEARCH

In the absence of an institute dedicated to pain medicine, it appears that the National Institute on Drug Abuse (NIDA) has been the partner most willing to venture beyond its initial mandate in support of education and research for state-of-the-art pain management and prevention. This initiative has taken the form of various workshops, editorials, and position papers (Reuben et al., 2015; Volkow et al., 2016), but these have been mainly supportive efforts, valuable insofar as they help chart a course forward but unable to meet the need for a sustained research program. Moving forward, it will take a unified mandate across all National Institutes of Health (NIH) institutes to muster the resources needed to adequately address the area of pain medicine and, in turn, the opioid crisis. A recent commitment by NIDA and NIH to invest in overdose-reversal interventions, treatments for OUD, and nonaddictive treatments for chronic pain holds great promise (Volkow and Collins, 2017).

SUMMARY AND RECOMMENDATION

Chronic pain and OUD represent complex human conditions affecting millions of Americans and causing untold disability and loss of function. Helping individuals experiencing chronic pain regain meaningful function will require the development of therapies beyond new medications alone. Little is known about why individuals who use prescribed opioids to alleviate pain develop OUD, yet this outcome has become a driving force in the opioid epidemic. Research aimed at improving understanding of OUD and the relationships among pain, opioids, and the brain reward pathways is an essential prerequisite for developing successful treatments. Research is needed to improve understanding of the neurobiology of pain and support the discovery of innovative treatments, including nonaddictive analgesics and nonpharmacologic approaches at the level of the individual patient.

Recommendation 3-1. Invest in research to better understand pain and opioid use disorder. Given the significant public health burden of pain and opioid use disorder (OUD) in the United States, the National Institutes of Health, the Substance Abuse and Mental Health Services Administration, the U.S. Department of Veterans Affairs, industry, and other relevant research sponsors should consider greater investment in research on pain and OUD, including but not limited to research aimed at

  • improving understanding of the neurobiology of pain;
  • developing the evidence on promising pain treatment modalities and supporting the discovery of innovative treatments, including
Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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  • nonaddictive analgesics and nonpharmacologic approaches at the level of the individual patient; and

  • improving understanding of the intersection between pain and OUD, including the relationships among use and misuse of opioids, pain, emotional distress, and the brain reward pathway; vulnerability to and assessment of risk for OUD; and how to properly manage pain in individuals with and at risk for OUD.

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Suggested Citation:"3 Progress and Future Directions in Research on Pain and Opioid Use Disorder." 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. doi: 10.17226/24781.
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Next: PART II: ADDRESSING THE OPIOID EPIDEMIC »
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Drug overdose, driven largely by overdose related to the use of opioids, is now the leading cause of unintentional injury death in the United States. The ongoing opioid crisis lies at the intersection of two public health challenges: reducing the burden of suffering from pain and containing the rising toll of the harms that can arise from the use of opioid medications. Chronic pain and opioid use disorder both represent complex human conditions affecting millions of Americans and causing untold disability and loss of function. In the context of the growing opioid problem, the U.S. Food and Drug Administration (FDA) launched an Opioids Action Plan in early 2016. As part of this plan, the FDA asked the National Academies of Sciences, Engineering, and Medicine to convene a committee to update the state of the science on pain research, care, and education and to identify actions the FDA and others can take to respond to the opioid epidemic, with a particular focus on informing FDA's development of a formal method for incorporating individual and societal considerations into its risk-benefit framework for opioid approval and monitoring.

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