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The Opioid Crisis and the Future of Addiction and Pain Therapeutics S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2019/09/03/jpet.119.259408.DC1 1521-0103/371/2/396–408$35.00 https://doi.org/10.1124/jpet.119.259408 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 371:396–408, November 2019 U.S. Government work not protected by U.S. copyright Special Section on The Opioid Crisis The Opioid Crisis and the Future of Addiction and Pain Therapeutics s Nathan P. Coussens, G. Sitta Sittampalam, Samantha G. Jonson, Matthew D. Hall, Heather E. Gorby, Amir P. Tamiz, Owen B. McManus, Christian C. Felder, and Kurt Rasmussen Downloaded from National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland (N.P.C., G.S.S., S.G.J., M.D.H.); Orvos Communications, LLC (H.E.G.); National Institute of Neurologic Disorders and Stroke (A.P.T.) and National Institute on Drug Abuse (K.R.), National Institutes of Health, Bethesda, Maryland; Q-State Biosciences, Cambridge, Massachusetts (O.B.M.); and VP Discovery Research, Karuna Therapeutics, Boston, Massachusetts (C.C.F.) Received April 23, 2019; accepted August 29, 2019 jpet.aspetjournals.org ABSTRACT Opioid misuse and addiction are a public health crisis resulting in discovery of novel targets and regulatable pain circuits for safe debilitation, deaths, and significant social and economic impact. and effective therapeutics, as well as relevant biomarkers to Curbing this crisis requires collaboration among academic, ensure adequate testing in clinical trials. Applications of improved government, and industrial partners toward the development of technologies including reagents, assays, model systems, and effective nonaddictive pain medications, interventions for opioid validated probe compounds will likely increase the delivery of at ASPET Journals on September 25, 2021 overdose, and addiction treatments. A 2-day meeting, The testable hypotheses and therapeutics to enable better health Opioid Crisis and the Future of Addiction and Pain Therapeutics: outcomes for patients. The symposium goals were achieved by Opportunities, Tools, and Technologies Symposium, was held at increasing interdisciplinary collaboration to accelerate solutions the National Institutes of Health (NIH) to address these concerns for this pressing public health challenge and provide a framework and to chart a collaborative path forward. The meeting was for focused efforts within the research community. supported by the NIH Helping to End Addiction Long-TermSM (HEAL) Initiative, an aggressive, trans-agency effort to speed SIGNIFICANCE STATEMENT scientific solutions to stem the national opioid crisis. The event This article summarizes key messages and discussions resulting was unique in bringing together two research disciplines, from a 2-day symposium focused on challenges and opportu- addiction and pain, in order to create a forum for crosscommu- nities in developing addiction- and pain-related medications. nication and collaboration. The output from the symposium will Speakers and attendees came from 40 states in the United be considered by the HEAL Initiative; this article summarizes the States and 15 countries, bringing perspectives from academia, scientific presentations and key takeaways. Improved under- industry, government, and healthcare by researchers, clinicians, standing of the etiology of acute and chronic pain will enable the regulatory experts, and patient advocates. Introduction (Volkow and Koroshetz, 2019). Moreover, more than 25 million adults in the United States are affected by chronic The opioid misuse and addiction public health crisis in the pain (Collins et al., 2018). With a lack of effective and safe United States is rapidly evolving. In 2016, the opioid crisis was nonopioid options for pain management, for some, there is no responsible for 42,000 overdose fatalities in the United States relief in sight. These numbers do not capture the full extent of the damage of the opioid crisis, which reaches across every The content of this work is solely the responsibility of the authors and does domain of family and community life—from lost productivity not necessarily represent the official views of the National Institutes of Health. and economic opportunity to intergenerational and childhood This work was supported (in part) by the Intramural Research Program of the National Institutes of Health National Center for Advancing Translational trauma and extreme strain on community resources, includ- Sciences Division of Pre-Clinical Innovation [Grants 1ZIATR000346 and ing first responders, emergency rooms, hospitals, and treat- 1ZIJTR000340]. https://doi.org/10.1124/jpet.119.259408. ment centers. Moving forward, there is a major need to s This article has supplemental material available at jpet.aspetjournals.org. develop therapies for pain without addiction liability, to ABBREVIATIONS: CSDS, chronic social defeat stress; DRG, dorsal root ganglion; GPCR, G-protein–coupled receptor; LHA, lateral hypothalamic area; MD, molecular dynamics; MRI, magnetic resonance imaging; NAC, N-acetylcysteine; Nav, voltage-gated sodium channel; NK1R, neurokinin 1 receptor; OUD, opioid use disorder; RGS, regulator of G-protein signaling; TRP, transient receptor potential. 396 The Future of Addiction and Pain Therapeutics 397 develop anti-addiction medications, and to better understand Today, most analgesics act by reducing nociceptor activa- the transition from acute to chronic pain (Volkow and Collins, tion, decreasing inflammation, modulating excitability, in- 2017). creasing inhibition, or blocking synaptic transmission. To To help address these needs, the National Institutes of move forward, the field should recognize the complexity of Health National Center for Advancing Translational Sciences, pain; there are several quite distinct types driven by different in collaboration with the National Institutes of Health mechanisms that require different therapeutic interventions, National Institute on Drug Abuse and National Institute of and the field should learn from past mistakes (what went Neurologic Disorders and Stroke, sponsored the Opioid Crisis wrong and why in analgesic drug development). Dr. Woolf and the Future of Addiction and Pain Therapeutics: Opportu- emphasized that there is a need for multiple, independent, nities, Tools, and Technologies Symposium on February 7 and and unbiased approaches to target identification for pain 8, 2019, in Bethesda, MD (agenda included as Supplemental therapeutics that include omics profiling using transcriptomic Material). The meeting was supported by the National and proteomic analysis of relevant cells and circuits in healthy Institutes of Health Helping to End Addiction Long-TermSM and diseased conditions, as well as combining patient pheno- Initiative, an aggressive, trans-agency effort to speed scien- typic and genotypic approaches (Cobos et al., 2018; Khera tific solutions to stem the national opioid crisis. The sympo- et al., 2018). There is also a need for targeting disease sium convened scientific leaders from academia, industry, modification, not just symptom control, by identifying those healthcare, and government to highlight challenges and at risk and preventing diseases from manifesting. Given the opportunities in the precompetitive, preclinical stage of de- genetic complexities of pain and high heritable contribution, Downloaded from velopment for addiction- and pain-related medications, and to large-scale studies of polygenic risk factors for chronic pain provide a framework for more focused efforts within the could aid in the identification and development of new targets, research community. The speakers and attendees came from as they have done successfully for coronary artery disease, 40 states in the United States and 15 countries, and contrib- atrial fibrillation, type 2 diabetes, inflammatory bowel dis- uted their perspectives as researchers, clinicians, regulatory ease, and breast cancer (Khera et al., 2018). experts, and patient advocates. Preclinical models that accurately capture the disease jpet.aspetjournals.org The overarching purpose of the symposium was to join two phenotype present in patients could lead to more effective relatively independent research disciplines, addiction and treatments. There is a need for better surrogate measures of pain, in a forum to promote communication and collaboration pain in animal models, such as nonreflexive models and among these fields. The 2-day agenda encompassed a wide surrogates of spontaneous pain. One methodological example range of lectures and discussions, including 62 poster pre- that should be widely adopted is to look at disease phenotypes sentations. Keynote lectures provided a high-level overview of in neurons from human patient–derived induced pluripotent novel targets and pathways in pain and addiction. The first stem cells to model disease, conduct CRISPR genome-wide at ASPET Journals on September 25, 2021 session of lectures highlighted current and next-generation screens to identify targets, and run drug screens to find targets as well as lessons learned from clinical successes and compounds that act selectively on diseased human neurons. failures. Lectures of the second session focused on biomarkers A proof-of-principle study used nociceptors differentiated from that can enable clinical trials. Speakers of the third session a single patient’s induced pluripotent stem cells to predict described assays to improve predictive therapeutic efficacy
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