Full Summary — Understanding the Neurobiological Mechanisms of Pain

July 7, 2017

As part of a government-wide effort to address the opioid crisis, NIH is initiating a public-private collaborative research initiative on (1) new and innovative medications and biologics to treat opioid addiction and for overdose prevention and reversal; (2) safe, effective, and non-addictive strategies to manage chronic pain; and (3) neurobiology of chronic pain.

To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH brought together NIH brought together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. NIH seeks to identify and pursue promising opportunities for addressing the opioid crisis, with the aim of developing new safe and effective therapeutics for opioid addiction, overdose, and chronic pain in half the time it currently takes.

The first of these meetings was held on June 5^th, entitled Medications Development for Opioid Use Disorders and Overdose Prevention and Reversal. The second meeting, entitled Development of Safe, Effective, and Non-Addictive Pain Treatments, was held on June 16^th. The third meeting, held on July 7^th and summarized below, focused on Understanding the Neurobiological Mechanisms of Pain.

Dr. Francis Collins, Director of the National Institutes of Health (NIH), highlighted the urgency of the opioid crisis, and the high priority agencies throughout the federal government have placed on ending this crisis. This meeting is the final of three that were convened to identify areas for a public private partnership recently initiated by NIH to address the opioid crisis. Dr. Collins and Dr. Nora Volkow, Director, National Institute on Drug Abuse (NIDA), published a Special Report in the New England Journal of Medicine to describe the initiative which focuses on three scientific areas:

1. developing better overdose reversal and prevention interventions to reduce mortality, saving lives for future treatment and recovery;
2. finding new, innovative medications and technologies to treat opioid addiction; and
3. finding safe, effective, nonaddictive interventions to manage chronic pain.

The previous two meetings identified the need to develop new therapeutics to treat opioid use disorder (OUD), overdose, and pain, including new formulations of existing medications, novel targets, and medical devices. Possible strategies identified to address these needs include a focus on data sharing across sectors, a targeted effort to develop biomarkers and objective measures of pain, and the strengthening of clinical trials infrastructure -- incorporating providers, real world health care settings – such as primary care and emergency departments – and patient cohorts with severe pain and unmet treatment needs for which a rare disease model can be applied.

The goal of this initiative is to develop public private partnerships to cut in half the time to develop new treatments. NIH has successfully used this model to address other scientific priority areas. For example, the Accelerating Medicine Partnership with NIH, FDA, The Foundation for NIH, and 10 pharma companies aims to develop treatments for three disease areas, with 50/50 contributions from government and industry for a total of $230 million over 5 years.

While this initiative is focused on what can be accomplished with a partnership with the pharmaceutical and biotechnology industries, NIH is also committed to research on nonpharmacological treatments for pain, and will continue to support research in this area. The goal for the day is to identify research priorities that will advance our understanding of the neurobiological mechanisms of pain in the short, medium, and long term. NIH is working to develop a strategic framework including a workplan identifying resources that can be leveraged for this effort. Engagement of leadership across sectors will be needed.

Christin Veasley: Chronic Pain Research Alliance

Christin Veasley, co-founder and director of the Chronic Pain Research Alliance, provided insights from her perspective as a chronic pain patient and patient advocate. She noted that pain receives limited research investment, is frequently dismissed by health care professionals, and is not regarded as a major public health problem, despite being the most prevalent, costly and disabling condition in the Nation. Attitudes may be shaped in part by the lack of understanding as to the distinction between “pain” as an acute sensation, or symptom, to “pain” as a dysfunctional state of the nervous system, or chronic condition in its own right. Furthermore, “chronic pain” is used as an umbrella term to encompass numerous conditions, such as arthritis, migraine, or diabetic neuropathy, a distinction which may not be clear to the public or patients, particularly those that may suffer from intermittent pain disorders, such as migraine. Pain is a complex highly individual experience that impacts many domains (mood, sleep, social function), and admitting that pain impacts one’s life in any significant way is still a source of significant stigma and viewed by society as a sign of weakness.

Ms. Veasley also highlighted issues with the treatment system, which suffers from a shortage of pain specialists and a dearth of training in pain treatment for primary care physicians who most frequently treat pain patients. A lack of quality evidence leads to trial and error-based clinical decision making. To improve care for pain patients, objective and dynamic measures of pain are needed, along with preclinical models and clinical trials that account for the complexity and individuality of the chronic pain experience. Common comorbidities, such as sleep and mood disorders, as well as function and health-related quality of life should be assessed. Further, precision medicine efforts are needed to understand how genetics, environmental factors, and personal preferences influence treatment response and outcomes for different individuals. Further, she highlighted that pain research will greatly benefit from broad inclusion of stakeholders vital to clinical translation, such as patients, clinicians and payers.

Ms. Veasley noted that patients feel trapped by their pain, but the promise of advances from science and research brings them hope.

Nora Volkow: Challenges to Advancing Research on Pain Mechanisms

Dr. Nora Volkow, Director of the National Institute on Drug Abuse, reviewed the participant responses to a pre-meeting survey on the challenges of research on pain mechanisms (see Appendix A). Two case study presentations were introduced to frame the discussion.

Märta Segerdahl Storck: EuroPain Project Lessons Learned

Dr. Märta Segerdahl Storck, Chief Medical Specialist at H. Lundbeck A/S, shared insights from the EuroPain Project of the Innovative Medicines Initiative, a large-scale, public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. The goal of the EuroPain project was to speed up discovery and development of safer and more effective drugs for chronic pain treatment through exchange of knowledge and expertise across sectors.

Dr. Segerdahl Storck shared the successes of EuroPain. The project:

• A predefined framework for addressing legal concerns was incorporated to help with the inevitable issues associated with intellectual property that arose
• Significantly increased collaborations between academia and pharma
• Included an emphasis on operational excellence
• Incorporated public funding of small and medium sized enterprises, thereby supporting commercial implementation of innovations.
• Standardized methods were successfully developed to ensure reproducibility across experimenters and laboratories and led to the development and validation of several new animal models and endpoints.
• Supported the publication of over 200 papers
• Established two clinical measures of sensory phenotype (using by Quantitative Sensory testing (QST) and electrophysiology) that impacted the development of pain treatment medication guidelines by the European Medicines Agency.

Four additional projects that were funded by the European Union also arose from EuroPain, including a project on placebo effects that will kick off in summer 2017.

Dr. Segerdahl Storck also identified the challenges associated with such large-scale collaboration:

• At project start, there was no incentive for regulatory agencies to partner, which likely led to avoidable delays in obtaining regulatory acceptance of the clinical biomarker tools.
• Shifting business priorities led to a constantly changing pool of pharmaceutical company involvement, as companies left or joined the project.

Robert W. Gereau IV: Challenges of Translational Research

Dr. Robert W. Gereau IV, Director of the Washington University Pain Center, studies chronic pain as a condition of maladaptive plasticity. He spoke about the challenges he encountered in his efforts to develop a new pain medication based on preclinical findings. The ability of mGluR5 to induce sensitization at a variety of pain system loci identified it as a promising target, which Dr. Gereau’s team confirmed in animal models. Eager to advance to proof of concept trials, Dr. Gereau reached out to pharmaceutical companies for candidate mGluR5 antagonists, but none were willing to collaborate.

Fenobam is a compound that was developed as an anxiolytic and has subsequently been shown to be an mGluR5 antagonist. After validating its effectiveness in animal models, Dr. Gereau tried to advance to human studies; it took 6 years to complete the processes required for compound synthesis for use in human studies, Investigational New Drug status, and Institutional Review Board approval. Despite decreasing sensitization in a small human trial, fenobam is unlikely to be a useful medication due to problems with plasma concentration variability.

Dr. Gereau’s experience highlighted the issues associated with moving from basic to translational science:

• Novel pain targets may already have compounds available, but there is no incentive for pharmaceutical companies to share proprietary compounds.
• If a compound can be tested, current animal models are not reliable predictors of efficacy or toxicity.
• The lack of disclosure of negative trials or toxicity findings from pharmaceutical companies may result in wasted time spent repeating that work.

Major Themes

• A large, coordinated initiative is needed to make rapid progress in developing new, effective analgesics without abuse liability. This initiative could coordinate efforts to:
  • Develop and provide access to new compounds targeting promising molecular pathways.
  • Validate animal models and standardized processes for screening compounds.
  • Coordinate pre-clinical research on a broader range of pain conditions (e.g. those with lower prevalence, musculoskeletal pain conditions).
  • Facilitate researcher access to research tools such as induced pluripotent stem cells (iPSCs) and transgenic animals with pain-relevant genotypes.
• Data and expertise sharing across pharmaceutical companies and academic laboratories could significantly accelerate research progress.
  • Overall, the pharmaceutical industry spent hundreds of millions of dollars on TRP antagonists, for example, and the same side effect profile derailed each separate project.
  • Sharing negative findings early on would save time and resources.
  • Precedent for sharing proprietary material in cases of public health crisis was established for HIV and Ebola.
• Preclinical models are needed that reflect the complexity and heterogeneity of pain.
  • Back-translation of findings in humans to refine animal models is a viable strategy that has led to progress in this area.
• Objective standards are needed to stratify patients by clinically relevant factors including risk for transition to chronic pain, predicted efficacy of specific treatment modalities, and risk of developing an opioid use disorder (OUD).

Research Opportunities

• Consider pain mechanisms as an area within methods development and circuitry mapping efforts in the BRAIN initiative.
• Explore the mechanisms of opioid induced pain sensitization including the higher levels of pain in people with OUD.
• Explore development of opioid compounds with strong analgesic potency and reduced potential for addiction and overdose.
  • Determine the magnitude of respiratory depression at equivalent analgesic doses of currently approved opioid medications to guide clinical decision making and to help elucidate the mechanisms underlying these properties.
• Focus on spatial and molecular specificity; tools for more selective treatment delivery directed to specific targets (e.g. selective ligands for receptor heteromers).
• Determine mechanisms of transition and resilience from acute to chronic pain, and the contribution of chronic opioid use.
• Leverage available epidemiological and clinical data to develop standards for stratification of risk for transition to chronic pain and for developing OUD following opioid treatment.

Structural Approaches

• Consider ways to lengthen the timeline of projects supported through the Small Business Innovation Research (SBIR) program.
• Share pharmaceutical industry expertise in compound manufacturing, compound selection, and trial design.
• Establish a shared data repository for common knowledge on targets and other unpublished data.

Walter J. Koroshetz: Current/Future Research to Better Understand Pain Mechanisms

Dr. Walter J. Koroshetz, Director of the National Institute on Neurological Disorders and Stroke (NINDS), provided an overview of the current state of the field of pain research. NINDS leads the NIH Pain Consortium that was established to enhance pain research and promote collaboration among researchers across the many NIH Institutes and Centers that have programs and activities addressing pain. The consortium supports initiatives, development of research resources and tools, and hosts events to promote collaboration and highlight advances in pain research. A summary of the Interagency Pain Research Portfolio database showed an NIH investment in 2016 of $483M on pain research.

Dr. Koroshetz highlighted the advance of an αCGRP-R mAb to phase 3 clinical trials as a success story of molecular to clinical target validation, and summarized the plethora of other potential drug targets that have been discovered, including:

• HSV vector driven expression of analgesic signals in DRG
• Transient receptor potential channels (TRPA1/4)
• TRPA1 gain of function mutation causes familial episodic pain syndrome
• Voltage activated Ca++ channel blockers
• K+ channel blockers
• Chemokine receptor antagonists
• Tetrahydrobiopterin from GTP release from injured neurons, polymorphisms in BCH1 enzyme linked to pain vulnerability
• Alpha2 adrenergic agonist
• Bivalent MOR with linked mGluR5 antagonist, CCR5 antagonist, delta OR antagonist,
• Epigenetic mechanisms involved in chronic pain
• microRNA cluster 183
• PD-L1 inhibition of acute and chronic pain
• Neurokinin 1 receptor signaling in endosomes

Dr. Koroshetz emphasized the relevance of each of the seven areas of the BRAIN initiative to pain research. Tools developed through BRAIN could be applied to the pain field, to achieve the long-term goal of making circuit abnormalities the basis of diagnostics, and normalization of circuit function the target of intervention.

Advances in the understanding of how pain circuitry changes from a detection system (acute pain) to chronic activation (chronic pain) include detailed characterization of structural and functional changes at the levels of DRG afferents, spinal cord neurons, and supraspinal regions. Progress toward pain biomarkers include component process models of brain activity, connectivity analyses, and molecular markers of inflammatory and neuropathic pain conditions.

Dr. Koroshetz reviewed NIH resources relevant to this area, including the Federal Pain Research Strategy and available Clinical Trial Networks, including:

• The Clinical and Translational Science Awards Program
• The National Drug Abuse Treatment Clinical Trials Network
• The NeuroNEXT Network for Excellence in Clinical Trials
• The Network for Emergency Care Clinical Trials Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN)

In addition, he noted that the June 16 meeting identified the establishment of a clinical trials research network for pain as a priority action item.

In closing, Dr. Koroshetz reviewed the participant responses to the pre-meeting survey on opportunities for pain research (see Appendix A)

Major Themes

• Target-agnostic, unbiased screens could lead to transformative advances.
  • While studies without discrete hypotheses are unpopular in study sections, the NIH Common Fund does support this type of research.
• Research resources don’t reflect the large societal cost of chronic pain and need for improved treatments.
• Current therapies are based on acute analgesic effects, but maladaptive plasticity must be addressed to treat chronic pain.
• In addition to receptor subtype-specific molecules, the field should:
  • Characterize the multiple targets of “dirty” compounds with analgesic efficacy
  • Develop compounds that target the molecular profile of specific neuronal populations involved in pain.
• Stimulation therapies such as direct current stimulation (DCS) can effectively treat pain.
  • Need to determine which treatments will be most effective for individual patients.
  • More research is needed on neuromodulation technologies alone and in combination with drug treatment.
• Biomarkers with translational validity are needed.
• The heterogeneity of pain patients should be factored into clinical trials.
  • Patients with co-morbidities are frequently excluded from clinical trials, which is not reflective of the complex phenotypes of most chronic pain patients.
  • Better control groups may consist of patients with similar underlying vulnerabilities who do not develop chronic pain.
• Interdisciplinary teams of researchers could coordinate efforts for deep phenotyping of common pain circuits and models at molecular, to cellular, and network resolution.

Research Directions

• New technologies such as 3 photon imaging, CLARITY, and CRISPR will enable unprecedented characterization and manipulation of brain circuitry.
  • Create systematic, multiscale pain circuit maps of different pain states.
  • Employ systematic multi-level molecular analysis and informatics.
  • Determine how modification of circuits or molecules impacts interconnected circuits.
• In vitro models could be used to discover new targets.
  • Patient iPSCs could be used to develop population-specific treatments.
  • CRISPR screening could be used to identify genes that specifically impact sensitization but not baseline activity, or genes with selective effects on pain-involved synapses.
• Platform trials involving multimodal treatments could optimize existing (and novel) therapies.
  • Platform trials could include either basket trials, including several indications with the same pain mechanism, to reduce the numbers of separate trials needed for registration, or umbrella trials, including independent parallel testing of different types of treatments, possibly also including an adaptive trial design.
• A deeper understanding of chronic pain mechanisms may allow for the development of treatments that leverage existing tools and technologies.
  • Known methods of plasticity reversal could be leveraged once it’s determined exactly how plasticity needs to be modulated to reverse pain sensitization.
  • Devices are capable of mimicking natural stimulation patterns and could produce a therapeutic stimulation signature if one were identified.
• Studies are needed to define the complexity and trajectories of chronic pain.
  • CMS/payer data could be useful to generate pharmacoepidemiological data sets to subcategorize clinically relevant pain phenotypes.
  • A large patient registry could support longitudinal studies of chronic pain progression.

Target Validation Group

The group was directed to focus on a process to improve means to validate novel targets for pain treatment that might address all stages of target validation from the early molecular, cell screening level through clinical studies. The focus was on broad strategies to improve target development and validation and not to identify specific targets.

Opening discussions focused on topical questions that need to be addressed to improve target validation:

• Do we have the appropriate tools needed to test drugs/treatments in the early stages of development?
• What are the readouts from our current tests? Are they adequate? Consistent?
• How do we do filter the best targets to continue to develop or halt development (i.e. what are current go- no go decision points?)
• Should we target specific pain conditions or narrow a drug target to a specific condition- to facilitate the approval process? Should we target specific pain conditions or modulation of analgesic circuits?
• Do animal behavioral models slow/mislead the validation process? (i.e. do they predict efficacy in human studies?)

Most pharmaceutical companies have their own processes for target validation, but they are likely not consistent across companies and given the number of failures in the discovery process, a more effective and efficient process is needed. Evidence is needed to show that specific validation steps, especially behavioral animal models, are effective tools. We need to systematically test the current models being used and apply new approaches (e.g. objective pain measures/biomarkers) to improve their reliability. Validation steps should leverage the power of human genetics, testing relevant genetic animal models and using new technologies to improve their reliability (with limited use of knockout lines due to compensatory mechanisms).

Potential Research Directions

• Coordinate efforts to validate pain models by evaluating compounds that either succeeded or failed to show efficacy in specific pain disorders.
  • The correlation between molecular effect in a model system and its clinical efficacy can be used quantitatively to judge model validity.
• Develop standardized screening methods to facilitate development of analgesics without abuse liability.
  • Iterative testing in multiple models with go- no-go decision points.
  1. In silico
  2. Human cell based models: Human organoid models, single cell culture model
  3. Systems models
  4. Preclinical in vivo models: develop, improve, and test animal models that are pain condition-specific for reliability. Do this by using known successful drugs and failed drugs at all screening levels.
  5. Human models

• Create a partnership to collect data on validation steps for analgesic development projects for specific pain disorders across companies–and collect them in a centralized portal which can be accessed by those in the partnership. Data for preclinical work would be a priority to help evaluate validation models.
• Create a set of cell lines from patients with complex pain disorders to create screening tools. Must include comprehensive characterization of the disorder.

Possible Opportunities

To accelerate and improve the validation of pain targets in humans:

1. Use existing resources to accelerate testing of current targets in humans with heterogenous pain conditions to reach phase 2 for analgesic efficacy and absence of reward/adverse effects.
2. Use existing compounds that have failed and succeeded in humans to test and improve animal and human cell based models.
   • Evaluate pre-clinical models systematically in the context of human pain-related genotypes. *
3. Create a partnership between NIH, FDA, and industry to develop and test an algorithm for target validation. Then establish a program to test new drugs through the validated algorithm.

*Meeting participants identified this opportunity as holding special promise, although the full work group noted that the 3 action items fit well as short, mid, long term deliverables to achieve the goal.

Circuits Group

The group was directed to focus on circuit-level research priorities with the potential to accelerate pain treatment development. While all agree that circuits are important, the relative focus on afferent vs. efferent signaling differs among the research community, and the complexity of the interactions of these circuits make pain a challenging research area.

Possible Areas for Exploration

• Research the roles of non-nociceptive circuitry in chronic pain, including mesocorticolimbic circuitry and hippocampal circuitry.
• Develop models of functional pain syndromes, such as migraine and fibromyalgia
  • Determine the circuitry that underlies treatment response to migraine medications such as triptans.
• Determine the relationship between phenotype and circuitry, and determine which neurons mediate specific phenotypes.
• Identify the specific activity of mu opioid receptor (MOR) activation within circuits, and the characteristics of MOR-expressing central pain neurons over time and through transition to chronic pain.
  • Is there regional specificity of MOR activation?
  • Can specific elements of circuitry be selectively targeted?
  • Use optogenetics, in vitro recording, transcriptomics to phenotype neurons expressing MOR
  • Understand synaptic level connectivity and temporal changes
  • Look at Ca²⁺ imaging as chronic pain develops
• Understand circuits in specific pain syndromes.
  • On syndromes where we don’t know the afferent signal (e.g. migraine)
  • Understand pain generating mechanisms
  • Leverage available neuroscience tools – promote their use
  • Map cellular specificity onto circuits

Possible Opportunities

To evaluate existing models and accelerate understanding of pain circuitry, both top down and bottom up:

1. Create a coordinated interdisciplinary effort, or a “center without walls,” to enable translation of systems level knowledge to molecular, cellular and circuit level and vice versa. *
2. Foster tool development and repository, including targeted tool development for analyzing the spinal cord and peripheral nerves (e.g. subproject of the BRAIN initiative or SPARC program).
3. Deep phenotyping including molecular phenotype, connectivity, activity, and plasticity in MOR expressing neurons and the changes associated with pain over time.

* Meeting participants identified this opportunity as holding special promise, although the second two could be steps toward achieving the first.

Biomarkers Group

The group was directed to focus on research priorities with the potential to accelerate development of biomarkers for pain. Participants noted that requisite standards for biomarkers as defined by NIH are specific and stringent. The Foundation for NIH manages the Biomarkers Consortium, which has established a framework of evidentiary criteria for biomarkers. While European and Canadian researchers have developed deep phenotyping techniques, including the quantitative sensory task (QST), these are rendered less useful by the amount of time required per patient.

Possible Areas for Exploration

• Biomarkers would be useful to assess many aspects of pain, including:
  • Predicting the transition from acute to chronic pain
  • Differentiation of pain patient populations
  • Predicting the response to treatment
  • Assessing the relative risk of overdose among pain patients
• Develop biomarkers that are flexible enough to reflect pain state transitions
• Combined imaging (PET, fMRI) to develop signature of acute medication effects
  • Develop brain network signatures for a range of pain states as well as therapeutic interventions
• Establish a reward signature as a biomarker of misuse liability
• Behavioral quantification techniques exist that could be adapted as pain biomarkers
• Leverage the increased capacity to collect and analyze large, longitudinal data sets
• The Common Fund is currently supporting a 3000-person cohort to examine molecular response to physical activity; could design a similar study for pain symptom tracking
• Use wearable device tracking data to determine antecedents of overdose, predict heightened risk
• Consider the application of an RDOC-like strategy for pain research to dissociate nociception from emotional and cognitive components of pain (e.g. fear).

Possible Opportunities

The following opportunities discussed for the development of biomarkers that will assist research, clinical trials, and clinical practice:

1. Longitudinal, large prospective trials with multimodality assessments of surgical patients, including patients that are currently excluded from trials (psychiatric comorbidity, etc.). Phenotype, biotype, genotype, and create a biopsychosocial profile- collecting resting state MRI, fitness tracker data, etc. for all. A subset of people would be studied more intensively, e.g. PET scanning and fMRI to create signatures to mine larger dataset. *
2. Develop brain network signatures for a range of therapeutic interventions for pain.
3. Develop standardized measures/biomarkers that address the biopsychosocial characteristics of or pain

* Meeting participants identified this opportunity as holding special promise.

Clinical Trials Group

The group was directed to focus on clinical trial improvements to accelerate pain treatment development.

Possible Areas for Exploration

• Create a pain research network
  • Patient registry/bio-repository to predict factors associated with response to specific treatment modalities.
  • Longitudinal tracking
  • Include various pain conditions including pain associated with specific diseases
  • Phenotyping
  • Sharing data
  • Priorities for the pain research network:

• Explore efficacy of long-term use of opioids for chronic pain.
• Explore risk factors for the transition from acute to chronic pain.
• Evaluate single and multimodal interventions

• Improve the design and conduct of clinical trials for pain research
  • Develop composite, standardized outcome measures
  • Use adaptive trial design
  • Include diverse endpoints: function, mood, sleep, cognition
  • Focus on high-cost, high-impact patients (those with multiple pain conditions and comorbidities)
  • Lower regulatory burden:
    • improve the collection and tracking of informed consent with shorter and more understandable consent forms;
    • lower patient expectations that might contribute to a large placebo response; and
    • identify strategies to decrease time to FDA approval and requirements for the number of patients that must be included in clinical trials.
  • Pragmatic trials
  • Improve clarity of regulatory requirements
  • Patient and provider education to improve recruitment and retention in clinical trials

• Improve patient centeredness of clinical trials
  • Identify what is significant to individuals in pain; develop endpoints of functional relevance to patients for specific pain conditions.
  • Improve informed consent: use shorter, more understandable consent forms that introduce less expectation that may contribute to large placebo response
  • Patient engagement
  • Improve dialogue
  • Greater use of passive monitoring
  • Open access to data—include the patient
  • Lower burden on patients
  • Recruit more broadly, not just at tertiary pain clinics
• Optimize clinical trial design to account for placebo response; explore potential of placebo as intervention

Possible Opportunities

To improve clinical trials for the acceleration of pain treatment development:

1. Establish a federated pain research registry.
2. Develop meaningful outcome measures of pain, including composite measures
3. Establish a database to assist patients with finding and registering for clinical trials

* Meeting participants identified this opportunity as holding special promise.

Reconvened Group Discussion: Future Directions

The group identified the highest priority action item to be the longitudinal study proposed for biomarker development, followed by the target validation goal of using existing compounds to test and improve research models.

When asked for final comments to address any gaps, the group:

• Reiterated the need for all researchers to be able to access unpublished findings
• Emphasized the importance of addiction risk in the treatment of pain
• Suggested focus on developing biased MOR agonists that produce analgesia without tolerance or respiratory depression

Next Steps

NIH will consider strategies to:

1. Promote collaborative cross-sector data and expertise sharing to facilitate more efficient use of resources
2. Develop biomarkers of pain with predictive clinical validity
3. Use existing failed and successful analgesics to evaluate and improve drug screening models and assays (human cell based models, animal models, gene tools to modify targets in cells (CRISPR)) to develop a standardized platform for the validation of drug targets
4. Develop a standardized, composite set of clinically relevant outcome measures to enhance clinical research
5. Facilitate a research collaboratory to explore:
   • Mechanisms of pain, including maladaptive plasticity associated with chronic pain, in the peripheral nervous system, spinal cord, and brain
   • The long-term impact of chronic opioid treatment (e.g. hyperalgesia due to chronic opioid use, mechanism of tolerance)
   • The transition from acute to chronic pain and factors that prevent transition
   • Patients who do and do not respond to treatment and to placebo
   • The impact of co-morbidities on clinical trajectory, treatment response, and long-term outcomes
   • Mechanisms underlying placebo responses