Pain Management and the Opioid Epidemic Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use (2017) / Chapter Skim
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3 Progress and Future Directions in Research on Pain and Opioid Use Disorder
3 Progress and Future Directions in Research on Pain and Opioid Use Disorder
Pages 119-184
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From page 119... ...
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.
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From page 120... ...
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.
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From page 121... ...
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)
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Nav1.7 is a VGSC that has been linked to human pain conditions, based on defects in its gene SCN9A leading to either lossof-function (congenital insensitivity to pain) or gain-of-function mutations that drive a rare spontaneous pain syndrome (erythromelalgia)
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. Whether this class of channel blockers will be applicable to a broad range of neuropathic pain conditions or only for rare conditions is unknown.
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. 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)
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. 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.
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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)
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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.
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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)
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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.
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MOPR-biased analgesia may one day allow the separation of opioidinduced 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.
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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)
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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)
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, 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)
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demonstrated that inflammatory pain induces a desensitization of MOPRs in the VTA. These changes in opioid receptor function lead to decreased heroinand DAMGO ([d-Ala2, N-MePhe4, Gly-ol]
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. 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)
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. 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)
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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)
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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.
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Beyond the development of biased agonist ligands for cannabinoid receptors as novel analgesics with an improved adverse effect profile (DiezAlarcia et al., 2016; Mallipeddi et al., 2016) , interest in enhancing the formation of anadamide by inhibition of FAAH (Guindon, 2017; Pawsey et al., 2016)
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. Optogenetic silencing of Nav1.8 positive afferents alleviates inflammatory and neuropathic pain (Daou et al., 2016)
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-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.
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From page 142... ...
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)
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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)
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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)
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Spinal cord stimulation (SCS) has been used to treat neuropathic pain of the extremities for many years (Deer et al., 2014)
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for the treatment of complex regional pain syndromes, with promising outcomes (Deer et al., 2017)
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. 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.
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, 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)
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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)
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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.
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. 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)
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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.
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From page 153... ...
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.
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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.
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, 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.
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. 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)
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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)
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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.
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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)
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. 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)
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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.
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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.
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2016. Ensuring trans parency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations.
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Techniques in Regional Anesthesia and Pain Management 13(4)
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2010. Cross validation of the current opioid misuse measure to monitor chronic pain patients on opioid therapy.
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2016. Anti-nerve growth factor in pain management: Current evidence.
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2003. Rapid improvement in pain management: The Veterans Health Administration and the Institute for Healthcare Improvement Collaborative.
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1993. Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic do pamine release: In vivo microdialysis studies.
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2013. The downward spiral of chronic pain, prescription opioid misuse, and addiction: Cognitive, affective, and neuropsychopharmacologic pathways.
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2016. Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity.
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2015. Inflam matory pain promotes increased opioid self-administration: Role of dysregulated ventral tegmental area μ opioid receptors.
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2009b. Unmasking the tonic-aversive state in neuropathic pain.
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2011. Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases.
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: Somatosensory abnormalities in 1,236 patients with different neuropathic pain syndromes.
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2013. High-intensity swimming exercise reduces neuropathic pain in an animal model of complex regional pain syndrome type I: Evidence for a role of the adenosinergic system.
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2002. Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: Implication of the reduction in mu-opioid receptor functions in the ventral tegmental area.
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2002. Successful pain management for the recov ering addicted patient.
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rural differences in prescription opioid misuse among adults in the United States: Informing region specific drug policies and interven tions. International Journal on Drug Policy 26(5)
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1988. Motivational effects of opioids in an animal model of prolonged inflammatory pain: Alteration in the effects of kappa- but not of mu-receptor agonists.
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2011. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: Role of endogenous opioids.
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2008. Predicting opioid misuse by chronic pain patients: A systematic review and literature synthesis.
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2007. Imaging human cerebral pain modulation by dose-dependent opioid analgesia: A positron emis sion tomography activation study using remifentanil.
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2013. Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury.
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TRPA1. In Mammalian transient receptor potential (TRP)
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