Interagency Pain Research Coordinating Committee

November 2, 2022

Virtual Meeting

Meeting Summary

On November 2, 2022, at 10:00 a.m., the Interagency Pain Research Coordinating Committee (IPRCC) convened for a virtual meeting. In accordance with Public Law 92-463, the meeting was open to the public. Helene Langevin, MD, Director of the National Center for Complementary and Integrative Health, presided as IPRCC Chair.

The following IPRCC members were in attendance:

• Federal Members: Elisabeth Kato, MD; Walter Koroshetz, MD; Rigoberto Roca, MD; Friedhelm Sandbrink, MD
• Scientific Members: Jose Moron-Concepcion, PhD; Christine Nai-Mei Sang, MD, MPH; David A. Williams, PhD; Todd Vanderah, PhD
• Public Members: Maggie Buckley, MBA; Julie Eller; Sue Pinkham; Irma Rodriguez, MD
• Ex-Officio Members: Lindsey Criswell, MD, MPH, DSc; Melissa Ghim, PhD (on behalf of Rena D’Souza, DDS, PhD); Helene Langevin, MD; Shannon Zenk, PhD, MPH, RN, FAAN
• Designated Federal Official: Linda L. Porter, PhD

Dr. Langevin introduced several individuals who may join the Committee as full members in 2023: Kate Nicholson, JD; Monica Mallampalli, PhD; and Renee Manworren, PhD, RN.

IPRCC members voted to approve the minutes from the IPRCC meeting on June 7, 2022.

Federal Updates

On November 1, 2022, the Centers for Medicare & Medicaid Services (CMS) released a new set of final rules, which includes information regarding how to facilitate interdisciplinary pain care strategies, use billing codes, and develop reimbursement strategies. In collaboration with the National Institutes of Health (NIH), CMS also developed a list of relevant, efficacious screening tools for assessing both general and specific pain conditions. This list, which will be regularly updated, is a valuable resource to support clinicians when treating pain conditions.

The VA/DOD Clinical Practice Guideline: Management of Opioid Therapy for Chronic Pain

Friedhelm Sandbrink, MD, Acting National Program Director for Pain Management, VA

The Department of Veterans Affairs (VA) in collaboration with the Department of Defense (DOD) issued 20 new Clinical Practice Guidelines (CPGs) regarding opioid therapy for patients with chronic pain. These CPGs rely on systematic evidence review and are intended to support clinicians as they make patient-centered decisions to help minimize preventable complications and optimize health outcomes. Notably, CPGs are in effect immediately upon publication, and VA and DOD educate clinicians regarding new CPGs in order to accelerate their rollout.

CPGs include not initiating opioid therapy for chronic non-cancer pain and not using long-term opioid therapy, especially for younger patients and patients with substance use disorder (SUD). In addition, CPGs state that insufficient evidence exists to recommend for or against the selection of methadone, buprenorphine, or naltrexone for patients being treated for opioid use disorder (OUD). VA and DOD further recommend against the concurrent use of benzodiazepines and opioids for chronic pain. CPGs subsequently describe recommended dose, duration, and tapering strategies for opioid prescription, as well as screening, patient assessment, and evaluation of individual risk considerations.

In addition, CPGs 18 through 20 provide recommendations surrounding risk mitigation strategies. Dr. Sandbrink specifically highlighted Recommendation 5, which suggests prescribing buprenorphine to patients receiving daily opioids for chronic pain. The working group that developed the 2022 CPGs determined that insufficient evidence exists comparing the effectiveness of buprenorphine to full agonist opioids for chronic pain. In contrast, other studies identified buprenorphine as having a superior safety profile and lower risk of abuse compared to full agonist. To balance these risks and benefits, VA and DOD recommend using buprenorphine instead of full agonist opioids as a first-line agent in adults with chronic pain in order to reduce the chances of overdose and misuse (i.e., buprenorphine should not be used only as a backup therapy after the failure of a full agonist opioid).

Discussion

Evidence Limitations

Exclusion criteria (e.g., patients with current or former SUD, behavioral health disorders, use of psychotropic medications) limit the strength of recommendations surrounding behavioral health screening tools prior to prescription of opioids for chronic pain management. No VA-specific data exist that investigate the risk for abuse of buprenorphine by chronic pain patients. Nonetheless, behavioral screening tools can help mitigate or prevent opioid overdoses and suicides. VA and DOD aim to gather stronger evidence advancing the implementation of CPGs.

Partial Mu and Kappa Opioid Receptor Agonism

Multiple animal studies have demonstrated that buprenorphine is a partial agonist for mu opioid receptors and for kappa opioid receptors. Moreover, partial kappa opioid agonism may reduce the negative behavioral health effects (e.g., anhedonia, depression, anxiety) observed in chronic pain patients. However, clinical trial results have not robustly shown that buprenorphine serves as a partial kappa opioid receptor agonist. VA and DOD do not consider evidence from animal studies when drafting CPGs; thus, they did not consider partial kappa opioid receptor agonism in the new CPGs.

Full mu opioid receptor agonists may accelerate bone loss in cancer patients. As a partial mu opioid receptor agonist, buprenorphine likely avoids many long-term side effects (e.g., severe bone loss) associated with other opioids. The VA and DOD relied on this likelihood of reduced long-term negative outcomes when recommending prescription of a higher dose of buprenorphine instead of full agonist opioids. However, long-term buprenorphine use may not be completely free of side effects. Patients who take long-term, high-dose buprenorphine may experience reduced analgesic effect from full mu opioid receptor agonists used for acute pain (e.g., postsurgical pain management).

Buprenorphine Access

State regulatory policies that restrict the number of buprenorphine prescriptions that a health care professional can provide or fill for treatment of OUD impinges on access to buprenorphine. However, these policies do not limit the prescription of buprenorphine for pain patients. Many patients have both OUD and chronic pain. Although earlier guidelines generally discouraged treating those patients with any opioids—including buprenorphine—VA and DOD have reversed this guidance and concluded that buprenorphine may be beneficial for patients with both OUD and chronic pain. To increase access to buprenorphine, VA and DOD aim to revise these state regulatory policies. Furthermore, they plan to provide a comprehensive education for health care providers on the importance and impact of adhering to these CPGs.

FDA Efforts to Foster Development of Non-Opioid Medications for Acute Pain Management

Rigoberto Roca, MD, Director, Center for Drug Evaluation and Research, FDA

In February 2022, the Food and Drug Administration (FDA) released Development of Non-Opioid Analgesics for Acute Pain; Draft Guidance for Industry. Although this document primarily addresses the pharmaceutical industry, it may also be beneficial for clinicians because it outlines requirements for clinical trials prior to an investigational new drug (IND) submission, such as outcome measures. This document focuses on Phase 3 trials, rather than preclinical or early clinical trials.

The pharmaceutical industry should highlight the specific impact of products on opioid use (e.g., reduction, elimination), focusing on the clinical benefit to patients. Non-opioid medication development may reduce severe adverse events associated with opioids (e.g., respiratory depression). FDA does not emphasize reducing minor adverse events (e.g., nausea, constipation).

Pharmaceutical developers may use four programs focused on expediting drug approval for non-opioid acute pain treatment. These programs are the Fast Track designation, Breakthrough Therapy designation, priority review, and accelerated approval programs. Fast Track designation can be acquired at any point in the IND process and requires showing that the indication is a serious condition, other therapies for that indication are minimal or nonexistent, and that the product may provide major benefits. With this designation, the company increases the number of its interactions with FDA, and submissions from the company can be applied to the application on a rolling basis. Breakthrough Therapy designation requires clinical trial data, but is otherwise comparable to Fast Track designation. Priority review occurs after application submission and ensures that an IND submission is reviewed earlier than the typical 10-month process. Accelerated approval involves evaluating therapies based on biomarker evidence, often because no effective clinical evaluation tool exists; thus, accelerated approval is rare for analgesics.

AHRQ Updates

Elizabeth Kato, MD, Medical Officer, Center for Evidence and Practice Improvement, AHRQ

In recent years, the Agency for Healthcare Research and Quality (AHRQ) has completed a suite of systematic reviews concerning treatments for chronic and acute pain. AHRQ’s reviews do not provide clinical guidance, but instead focus on collecting scientific evidence to support clinical guidelines from public-facing organizations (e.g., the Centers for Disease Control and Prevention). One ongoing review is updated each quarter with new evidence concerning plant-based treatments (e.g., kratom and cannabinoids). In addition, AHRQ also releases annual statistical briefs on opioid prescribing. In March 2023, AHRQ will release a draft review that describes Strategies for Integrating Behavioral Health and Primary Care, which will highlight research gaps.

AHRQ offers several grants relevant to IPRCC’s work. These grants support research on (1) drug interactions (especially selective serotonin receptor inhibitor [SSRI] interactions) and opioid-related emergency room visits and (2) the prescribing of opioids at hospital discharge and associated adverse patient outcomes. Two additional grants target improving postsurgical pain management using health information technology. One grant involves pairing a provider-facing decision support tool with a patient-facing smartphone app to reduce postsurgical opioid prescription; the other grant addresses using an algorithm in electronic health records to tailor a discharge prescription to each patient’s individual needs. Furthermore, AHRQ also supports a qualitative study describing patient perspectives on opioid prescription discontinuation, and a cluster randomized controlled trial of a novel community-based biobehavioral chronic pain team training program.

Federal Pain Research Strategy Overview and Progress

Progress on FPRS Research Priorities and Gaps to Consider

Linda Porter, PhD, FPRS Co-Chair

IPRCC was formed through the Affordable Care Act in 2010. In the pain care and pain research fields, the act emphasized a pain care bill, Section 4305: Advancing Research and Treatment for Pain Care Management. As part of the bill, the Secretary of the U.S. Department of Health and Human Services (HHS) convened an Institute of Medicine (IOM) Conference on Pain to recognize pain as a significant health problem. The HHS Secretary established IPRCC to coordinate all efforts across federal agencies and other departments that support pain-related research.

Shortly after the pain health care bill was passed, IOM published Relieving Pain in America, which recommended that the HHS Secretary develop a comprehensive, population health–level strategy for pain prevention, pain treatment, pain management, education, reimbursement, and research that includes specific goals, actions, timeframes, and resources. This recommendation prompted HHS to request IPRCC to oversee the creation of the National Pain Strategy (NPS) in 2016. The Federal Pain Research Strategy (FPRS), a component of the NPS, created working groups to examine research gaps in (1) pain prevention, (2) acute pain and acute pain management, (3) the transition from acute to chronic pain, (4) chronic pain and pain management, and (5) disparities in pain and pain care. These working groups began to address the most impactful research within each pain domain. FPRS will be used to support a high-quality, robust research agenda across federal agencies and departments that support pain research.

In 2019, the working groups created a list of research gaps that continue to guide the pain research field, and established programs to support these research endeavors. These programs included NINDS (Institute and Center mechanisms, SBIR); BRAIN Initiative (trans-NIH); HEAL (Re-join); NCATS (human tissues model of circuitry of pain); NIH HEAL Initiative (myofascial pain measures research, back pain consortium, pain biomarkers research, trials examining chronic pain); and NIH Common Fund (acute to chronic pain signatures program).

Discussion of Gaps in Remaining Priority Areas

Led by Linda Porter, PhD, FPRS Co-Chair

Dr. Buckley noted that comorbidities generally associated with pain are often difficult to attribute to one specific type of pain; therefore, diversity in research approaches to study pain-associated comorbidities would be helpful. She stressed the importance of an integrative approach to pain management, because some mental health–related comorbidities (e.g., depression and anxiety) manifest as direct physiological reactions to pain, as opposed to psychological stressors. Dr. Porter added that the HEAL Initiative has released supplementary funding to track comorbid pain conditions in ongoing studies.

The HEAL Initiative has also released two funding opportunities focused on examining health equity, discrimination, and pain management. The first funding opportunity focuses on interventions in populations that may not receive adequate levels of high-quality health care, while the second funding opportunity focuses on comorbidities associated with pain. These two funding opportunities will enable researchers to examine aspects of intersectionality by establishing community boards and creating resources for investigators to capture lived experiences of patients.

Dr. Moron-Concepcion noted the need for products that support the clinical testing of basic research findings. Dr. Baker agreed, adding that the HEAL Initiative has identified categories of research that explicitly integrate basic and clinical science, as well as developed programs in which research scientists can become involved in clinical fields.

Dr. Langevin emphasized the importance of implementation science and effective strategies to embed clinical trials in the health care system. For example, implementation science might explain why opioid drugs are often prescribed as first-line treatment, despite warnings to clinicians about unnecessary prescription of addictive narcotics. She added that embedding clinical trials in the health care system may spur rapid change in health care practices.

IPRCC members discussed the need to investigate pain in overlooked populations, such as older adults, children, and people with disabilities. Engagement from older adults during clinical trials has been limited; developing strategies to increase compliance with treatment plans may help to mitigate this issue. Clinical trials involving pediatric patients could be carried out with sufficient funding. However, legislation introduced during the past decade has presented many challenges to successful conduct of clinical trials in this population.

Finally, NIH Institutes and Centers employ different communication strategies to contact outside organizations about potential partnerships, such as email notices, webcasts, and workshops. Researchers can sign up on the HEAL website to receive frequent communications about open funding opportunities. In addition, Dr. Williams has established a platform for interactive networking, which includes bringing together basic clinical researchers for active collaborations.

New Findings from the Pain Research Community: NSAIDS, Benefit or Harm

Impact of NSAIDS for Chronic Pain in Animal Models

Mary Barbe, PhD, Professor, Lewis Katz School of Medicine, Temple University

Work-related musculoskeletal disorders (WMSDs) have a multifactorial etiology, including physical, individual, job, and social factors, and are associated with increased absence from work, sickness, depression, and chronic pain. Although non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are the most commonly used drugs among workers, biobehavioral mechanisms underlying work-related depression and chronic pain changes are not well understood. To research these mechanisms, Dr. Barbe’s team developed a rat model of WMSD by training rats to perform a repetitive handle pulling task, which resulted in a food reward. To test the efficacy of NSAIDs in the WMSD rat models, Dr. Barbe’s team administered ibuprofen, TNF alpha, IL-1 beta, or control vehicles at three time points, forming three distinct study groups—naïve control rats (i.e., no food restriction or task training), food restricted (FR) control rats, and rats trained to high force tasks (TRHF). Dr. Barbe’s team found that during the high force task training period, prophylactic administration of NSAIDs significantly reduced hypersensitivity and changes in grip strength in TRHF rats compared to FR rats. In addition, nerve inflammatory cytokine levels in tissue decreased in TRHF rats given NSAIDs compared to TRHF rats without NSAIDS.

Although prophylactic treatment with NSAIDs reduced pain behaviors in rats, this outcome may not be feasible in humans because high doses or continual dosing of NSAIDs can negatively impact the gastrointestinal tract and muscle healing. Because of these risks, Dr. Barbe’s team also studied NSAID use as an intervention in rats at week 5 of the 12-week HRHF task. In addition, some rats underwent an ergonomic task reduction, in which they were switched from the HRHF task to a low repeat low force (LRLF) task at week 5. Both HRHF rats given ibuprofen and LRLF rats without ibuprofen showed less nerve inflammatory cytokines than TRHF rats without ibuprofen. In addition, ibuprofen treatment in HRHF rats rescued grip strength decline, nerve conduction velocity, and the number of macrophages in the nerve.

Because the handle pulling tasks were voluntary and based on a food reward system, Dr. Barbe’s team also conducted a reflexive, involuntary grip strength test. In this test, ibuprofen only partially rescued declines in grip strength in HRHF rats, in which grip strength improved compared to HRHF rats without ibuprofen, but not to the levels of naïve control rats. In addition, ibuprofen rescued the duration in which HRHF rats pulled the handle, as well as voluntary reach force (i.e., the force the rat applied to the handle on each pull), compared to HRHF rats without ibuprofen. However, the percentage of successful reaches (i.e., reach attempts to the handle that result in a food reward) for HRHF rats given ibuprofen was significantly lower than HRHF rats without ibuprofen. Similarly, HRHF rats showed no improvement in mechanical allodynia throughout the 12 weeks compared to week 1. Based on reduced nociceptor neuropeptide expression in the dorsal horn of HRHF rats, Dr. Barbe concluded that ibuprofen is failing to cross the blood–brain barrier and dampen the nociceptive sensitization that occurs in the spinal cord.

Dr. Barbe concluded that NSAIDs effectively prevented the development of pain behaviors in WMSD rat models; however, the feasibility of prophylactic use in humans is questionable. Secondary ibuprofen treatment, after the onset of inflammation and pain behaviors, reduced inflammation and fibrosis, improved grasp duration, and improved reach force; however, the treatment only partially rescued reflexive grip strength and failed to improve successful reaches and mechanical sensitivity. Although NSAIDs did show some effectiveness in reducing the onset of brain sensitization changes, failures to rescue reflexive grip strength, successful reaches, and sensitivity are likely because of spinal cord sensitization. Long-term studies are likely needed to determine the full scope of benefits in NSAID treatment of WMSDs.

Increased Risk of Pain Persistence Driven by Anti-inflammatory Treatment for Acute Pain

Luda Diatchenko, MD, PhD, Professor, Alan Edwards Centre for Research on Pain, McGill University

Dr. Diatchenko has conducted multiple studies on lower back pain (LBP) in both the clinical setting and with animal models to identify genetic pathways and mechanisms of pain. In a clinical study, Dr. Diatchenko’s team collected whole blood from a cohort of 100 Caucasian patients for RNA analysis within 6 weeks of acute LBP episodes. Three months after enrollment, one-half of patients no longer experienced LBP while the other half experienced persistent LBP. Transcriptome analysis found that patients with non-persistent LBP showed high differential gene expression between the initial and 3-month blood samples, while those with persistent LBP showed no significant differential gene expression. Dr. Diatchenko’s team then analyzed the differential gene expression by functional pathways, in which inflammatory, neuroinflammatory, and acute response pathways were elevated in non-persistent LBP patients compared to persistent LBP patients. However, these functional pathways were correlated between non-persistent and persistent LBP patients, with persistent LBP patients showing 30-fold less expression of genes within those pathways. Non-persistent LBP patients also had decreased transcript levels of neutrophils and mast cells, as well as increased levels of T cells and NK cells. Dr. Diatchenko concluded that persistent LBP patients produce the same immunological response as non-persistent LBP patients, but at a significantly less efficient rate.

To further investigate inflammatory responses, Dr. Diatchenko’s team conducted a collaborative study in which researchers induced hyperalgesia in mice using complete Freund’s adjuvant (CFA) injection into the paw. Researchers then injected the mice with dexamethasone, which provides both analgesic and immunosuppressive effects. Dr. Diatchenko hypothesized that mice given dexamethasone would show similar persistent pain to humans because of a lowered inflammatory response. Over the course of 35 days, researchers measured the sensitivity threshold of the mice using a paw withdrawal test and found that mice given dexamethasone showed a higher threshold than controls because of dexamethasone’s analgesic effects. However, controls recovered to baseline sensitivity by day 15, where mice given dexamethasone showed decreased thresholds from baseline. Researchers found similar results in sensitivity thresholds in controlled cortical impact (CCI) and nerve growth factor (NGF)-injured mouse models, with both models also showing lower allodynia effects during dexamethasone injection periods. In addition, another research group found that applying ice to CFA-injected mice showed similar sensitivity results to Dr. Diatchenko’s mice given dexamethasone.

To confirm that reduced inflammatory response was causing persistent hyperalgesia in CFA- injected mice, Dr. Diatchenko’s team repeated the CFA experiment, giving mice either an NSAID or a pain reducer instead of dexamethasone. The team found that only mice given an NSAID experienced persistent hyperalgesia compared to baseline sensitivity thresholds. Dr. Diatchenko concluded that persistent hyperalgesia in mice occurs independently from analgesia. Dr. Diatchenko next hypothesized that within the inflammatory response, neutrophil suppression specifically caused persistent hyperalgesia in mice. To test this hypothesis, the team gave mice anti-Ly6G antibodies to reduce neutrophil levels and found similar results in sensitivity thresholds of mice given dexamethasone. In addition, mice given both dexamethasone and neutrophils did not show persistent hyperalgesia. Dr. Diatchenko concluded that dexamethasone causes persistent hyperalgesia by directly affecting neutrophils.

Using data from the UK Biobank, Dr. Diatchenko’s team surveyed a cohort consisting of more than 500,000 patients on whether patients experienced interference pain on chronic pain lasting more than 3 months. The team found that patients using NSAIDs and patients with high neutrophil levels had an increased risk of chronic pain. From both clinical and animal model findings, Dr. Diatchenko concluded that there is an active adaptive component of the immune system in the acute to chronic pain transition in LBP patients, and inhibiting this immune response may lead to chronic pain. Dr. Diatchenko suggested that animal models for drug development target pain resolution rather than analgesic effect and active immune responses, where the inhibition of immune responses may be counterproductive for long-term outcomes of LBP patients.

Discussion of the Potential Impact of These Studies

Led by Christine Goertz, PhD and Sue Pinkham

Dr. Barbe suggested that researchers expand the scope of pain behavior assays beyond commonly used assays. In addition, Dr. Barbe clarified methods and protocols for her own pain behavior experiments in rats, including (1) implementing locomotion and behavior assays that can delineate between motivation and nociception; (2) altering the force threshold of the handle to observe how rats change their approach to pulling the handle; and (3) minimizing the influence of fatigue by allowing rats to pull the handle for 30-minute intervals with hour-long breaks, which occurs 3 days per week for 2 hours per day.

The IRPCC discussed analgesic and non-pharmaceutical approaches to preventing acute pain from transitioning into chronic pain, including (1) utilizing the innate adaptability of the immune system and enhancing the restorative response of tissues; (2) conducting longitudinal research to find resolutions to pain, as opposed to suppressing pain with analgesics at the acute phase; and (3) implementing integrative approaches to treating acute pain, which combines analgesics, drugs that support adaptability restorative responses, and whole-person health interventions.

Topics for the Next Meeting and Action Items for the Committee

Nominations are open for three IPRCC memberships: two public members and one scientific or care provider member. In addition, a written public comment by Elizabeth Brewer on behalf of the company Haleon was circulated prior to the meeting. IPRCC members should submit any responses to that public comment to IPRCC leadership.

The IPRCC discussed additional research topics that should be considered for a future meeting: (1) neural circuitry of pain (including peripheral inputs) and (2) adaptive neuroplasticity both impacting and resulting from pain.

The IPRCC identified the following action items:

• Ms. Eller, Dr. Goertz, and Dr. Williams will expand IPRCC’s cataloguing of pain research projects beyond research conducted in or funded by NIH to include research conducted in other settings (e.g., pharmaceutical industry, DOD research programs), which will facilitate better identification of existing research gaps.
• Dr. Moron-Concepcion will begin organizing a series of workshops to determine future directions for pain research incorporating circuit work.
• IPRCC members should submit any responses to the written public comment to IPRCC leadership.

Adjourn

The IPRCC will begin to schedule future meetings in early 2023. The meeting was adjourned.

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We certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.

 

Linda Porter, PhD
Designated Federal Official
Interagency Pain Research Coordinating Committee
Director, Office of Pain Policy, National Institute of Neurological Disorders and Stroke
 
Helene Langevin, MD
Chair Interagency Pain Research Coordinating Committee
Director, National Center for Complementary and Integrative Health
 
These minutes have been formally approved by the committee.

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This meeting summary was prepared by Rose Li and Associates, Inc., under contract to the National Institute for Neurological Disorders and Stroke (NINDS). The views expressed in this document reflect both individual and collective opinions of the meeting participants and not necessarily those of NINDS. Review of earlier versions of this meeting summary by the following individuals is gratefully acknowledged: Christina Tricou, Cooper Roache, Urmi Roy, Martin Sabandal, Nancy Tuvesson.