Opportunities for Improving Basic and Translational Pain Research

See Article, page 1128

Pain represents one of the most diverse and heterogeneous human health conditions, and accordingly, the development of therapeutics for treating pain is inherently challenging and risky. A Biotechnology Innovation Organization (BIO) industry analysis in 2018 found that clinical trials for pain therapeutics have only a 2% probability of success, compared to a 10% success rate across all diseases.1 If we exclude the calcitonin gene-related peptide (CGRP) antibodies and small-molecule antagonists for the treatment of migraine, in the last 15 years, there have been very few novel therapeutics that have made it into the hands of clinicians and patients for treating pain, most of which are opioids.1

The review by Eisenach and Rice2 in this issue of Anesthesia & Analgesia, titled “Improving Pre-Clinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results,” identifies shortcomings in preclinical and translational pain research that could have contributed to the failure over the last 40 years of the translation of preclinical pain science to novel therapeutics. In addition, this review suggests changes to the pain research enterprise to increase the likelihood of the translation of that research into novel effective pain therapeutics with minimal or no addictive potential.

The recommendations by Eisenach and Rice2 fall essentially into 2 categories: (1) those related to enhancing the rigor and reproducibility of research in pain science, and (2) the types of animal models used for pain discovery and translational research. The authors rightly note that their comments related to the rigor and reproducibility of research are not specific to the preclinical pain research field. Basic research and drug development efforts in academia and industry, across all areas of biomedical sciences, could benefit from improving experimental and analytical rigor, reducing research bias, and increasing transparency in reporting their results, all of which contribute to enhanced reproducibility.

For at least 10 years, the National Institutes of Health (NIH) Center for Scientific Review (CSR), National Institute of Neurological Disorders and Stroke (NINDS), and many other NIH Institutes have been adapting their review criteria for grant proposals and how funding decisions are made, specifically, based on the quality of the research in the proposal as well as the rigor of previous research that serves as the scientific premise for the grant proposal. In addition, NIH has provided the research community a plethora of educational resources to enhance rigor and reproducibility, which includes transparent reporting of research data and experimental protocols.3,4 The burden for implementing the changes required to increase rigor and transparency in the research enterprise does not lie solely with the federal sponsors of research. The researchers themselves, the institutions where the research is performed, the financial supporters (federal or private foundations), and the editorial staff of scientific journals are all responsible for assuring that data that are generated, reported, and shared are rigorous.

The recommendations by Eisenach and Rice2 in their current review, which are described as internal validity of animal models, should be taken seriously by the preclinical pain research community. Important aspects of rigorous experiments that are critical to the proper interpretation of the generated data include the use of appropriate mathematical methods to determine sample and effect sizes; randomization of animals allocated to experimental groups; preset inclusion/exclusion criteria; blinding of both individuals conducting the experiments and those analyzing the results; and protections against “dropping out” subjects or samples in experiments because their outcomes are outliers, without revealing it. The pain-related funding announcements issued by the NIH Helping to End Addiction Long-term (HEAL) initiative have included specific language requiring applicants to incorporate many of these scientific methods to ensure rigorous experimental designs. Independent replication is also strongly encouraged. For example, the funding announcement, “RFA-NS-22-034 HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment,” asks applicants to include plans to reproduce the findings of the project in another laboratory.5 These techniques for increasing research quality should be taught at the undergraduate and graduate training levels and across all career stages, reinforced through discussions at poster and oral presentations at scientific meetings, and emphasized during the review of grant applications and articles for publication. These concepts for rigorous experimental design should not be an afterthought to conducting the research, only coming up when writing the Methods section of an article.

In January 2019, NIH convened a workshop titled, “A Critical Evaluation of Animal Pain Models.”6 The purpose of this workshop was to discuss the use of animal models of pain and migraine for development of clinical therapeutics. The goals of the workshop were to have a frank discussion on the benefits and shortcomings of the current pain models and to make recommendations for using these models for screening compounds for pain disorders. Participants in the workshop discussed and recommended which animal models should be used for particular pain types and/or conditions, as well as the outcome measures and end points that should be used in those models.

Regarding the use of animal models, Eisenach and Rice2 furthermore provide useful suggestions for increasing the external validity of those used for discovery and translational preclinical pain research. These authors noted that the reflexive behaviors used in the vast majority of rodent pain research studies do not reflect the manifestations of pain in many human pain disorders. Increasing the external validity of these models would require reproducing the disease state(s) and type(s) of pain in the pathological human pain conditions, which, in many instances, according to these authors, would be difficult in rodents.

As a part of the NIH HEAL initiative and in our programs and funding opportunities, we have incorporated these and similar suggestions for increasing the validity of the animal models and end points/outcome measures for translational pain research. Two such recent funding announcements are focused squarely on addressing these needs within the pain research community: “NOT-NS-22-095 HEAL Initiative: Notice of Special Interest (NOSI): Development and Validation of Pain-Related Models and Endpoints to Facilitate Non-Addictive Analgesic Discovery” and “RFA-NS-22-070 HEAL Initiative: Development and Validation of Nonrodent Mammalian Models of Pain.”7,8 Both of these funding opportunities require rigorous internal and external validation studies and stress the importance of models and outcome measures that can recapitulate relevant aspects of human pain pathological phenotypes and etiology, such that end points or markers of disease are similar and measurable in both the model system and in the human pain condition. Applicants are also encouraged to incorporate independent replication studies as a critical component of model validation. RFA-NS-22-070 explicitly encourages the use of objective, nonevoked measures of spontaneous pain8. RFA-NS-22-070 promotes incorporation of preclinical assessments and behavioral outcome measures that are homologous to clinically relevant outcomes in humans, such as restoration of function (eg, species-relevant naturally occurring behaviors) as indication(s) of effective pain management, and central nervous system-dependent responses that include activation of cortical circuits, rather than spinal reflexes alone.8 The ultimate goal of these funding opportunities is to provide the pain research community with a diverse set of well-validated models and measures, which will allow researchers to make well-informed decisions regarding fit for purpose model selection based on specific translational goals and stage of therapeutic development.

These and other NIH funding announcements also call for multidisciplinary teams, which include clinical expertise relevant to specific pain condition(s) that are the focus of the application. Clinical investigators provide an important perspective that should be incorporated into experimental designs to determine how representative a particular model is of the human disease population and to assure that end points are translatable to humans. Eisenach and Rice2 also note that back translating discoveries made in human pain populations into animal models could also increase their ability to be used in translational research.

Along these same lines of thought, the HEAL initiative is encouraging integrated basic and clinical research in pain conducted by interdisciplinary teams, utilizing cross-cutting research approaches to understand the biology of human pain, including pain heterogeneity, susceptibility, and comorbid conditions (NOT-NS-23-009).9 Such an approach will expand our capacity to pursue challenging problems in basic biological understanding, therapeutics development, and effective management of human pain conditions. Furthermore, there is a growing expectation in the HEAL initiative pain funding announcements that the perspectives of clinicians and individuals with lived experience will be included in guiding the preclinical development of the pain therapeutic development projects. This additional perspective is also suggested by Eisenach and Rice2 in their current review. Input from patients and caregivers on the therapeutic goals of the project, even at this early stage, can help researchers develop products that will address the symptoms and needs of these affected individuals.

The need for studies on primary human tissues and cells from subjects, with and without pain, to discover therapeutic targets that are relevant to human pain conditions has been a strong recommendation from multiple stakeholders in the pain research community, including at an NIH-convened workshop in 2020 titled, “Target Validation for Non-Addictive Therapeutics Development for Pain,” as well as both the HEAL Partnership Committee and the HEAL Multidisciplinary Working Group (MDWG).10–12 These latter 2 are external advisory groups for developing and aligning the goals of the NIH HEAL initiative. To address this recommendation, we developed 2 funding announcements (RFA-NS-22-018 and RFA-NS-22-021), that, together, create the Program to Reveal and Evaluate Cells-to-gene Information that Specify Intricacies, Origins, and the Nature of Human Pain (PRECISION) or the PRECISION Human Pain Network.13,14 The PRECISION Human Pain Network aims to capitalize on recent technological advances in high-throughput analyses of molecular, anatomic, and functional measurements for single-cell and tissue-level characterizations and to address the increasing need to enhance data interoperability and harmonization among data producers using human pain-associated tissues.

The PRECISION Human Pain Network will support a group of centers where human tissue will be collected and processed to build comprehensive data sets of molecular signatures, cell types, and cellular function phenotypes that underlie human pain signal transduction, transmission, and processing. In collaboration with these centers, a data coordination and integration center will be responsible for the curation, harmonization, and integration of core data sets to generate digital resources that will be available to the entire pain research community. Thus, the primary goal of the PRECISION Human Pain Network it is to generate a comprehensive data resource for discovery and validation of relevant human genes, proteins, and cellular functional phenotypes that can be used as targets for small molecules and biologics for the treatment of pain, as well as develop, optimize, and cross-validate methods that can be utilized by the broader research community.

In summary, the apt review by Eisenach and Rice2 not only identifies and clearly enumerates many potential problems with historical preclinical pain research, but also provides useful suggestions for how to improve the basic and translational preclinical pain research enterprise. Their review comes at a critical time, as the epidemic of chronic pain, opioid addiction, and overdose deaths are taking a terrible toll. It is our hope that reviews such as this and the new programs and funding opportunities for the NIH HEAL initiative,15 along with many other resources for increasing research rigor and reproducibility at NIH, will break through the logjam of issues and problems that have prevented the development of new treatments for pain.

DISCLOSURES

Name: Michael L. Oshinsky, PhD.

Contribution: This author helped contribute ideas, provide references, organize content, and write and revise the article; and approved the final manuscript.

Name: Julia L. Bachman, PhD.

Contribution: This author helped contribute ideas, provide references, organize content, and write and revise the article.

Name: Durga P. Mohapatra, PhD.

Contribution: This author helped contribute ideas, provide references, organize content, and write and revise the article.

This manuscript was handled by: Thomas R. Vetter, MD, MPH.

REFERENCES 1. Thomas D, Wessel C. The state of innovation in highly prevalent chronic diseases volume II: Pain and addiction therapeutics emerging company trend report, BIO industry analysis. 2018. www.bio.org/iareports or https://go.bio.org/rs/490-EHZ-999/images/BIO_HPCP_Series-Pain_Addiction_2018-02-08.pdf. 2. Eisenach JC, Rice ASC. Improving preclinical development of novel interventions to treat pain: insanity is doing the same thing over and over and expecting different results. Anesth Analg. 2022;135:1128–1136 3. National Institutes of Health. Rigor and Reproducibility. Accessed October 11, 2022. https://www.nih.gov/research-training/rigor-reproducibility 4. National Institute of Neurological Disorders and Stroke. NINDS Office of Research Quality. 2022. Accessed October 11, 2022. https://www.ninds.nih.gov/current-research/trans-agency-activities/ninds-office-research-quality 5. National Institute of Neurological Disorders and Stroke. [Funding Opportunity Announcement] HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed). 2022. Accessed October 11, 2022. https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-22-034.html 6. National Institute of Neurological Disorders and Stroke. NIH Workshop: A Critical Evaluation of Animal Pain Models. January 30-31, 2019. Accessed October 11, 2022. https://www.ninds.nih.gov/news-events/events/nih-workshop-critical-evaluation-animal-pain-models. Day 2 Videocast available at: https://videocast.nih.gov/ 7. National Institute of Neurological Disorders and Stroke. [Funding Opportunity Announcement] HEAL Initiative Notice of Special Interest (NOSI): Development and Validation of Pain-Related Models and Endpoints to Facilitate Non-Addictive Analgesic Discovery. 2022. Accessed October 11, 2022. https://grants.nih.gov/grants/guide/notice-files/NOT-NS-22-095.html 8. National Institute of Neurological Disorders and Stroke. [Funding Opportunity Announcement] HEAL Initiative: Development and Validation of Non-Rodent Mammalian Models of Pain (R01 Clinical Trial Not Allowed). 2022. Accessed October 11, 2022. https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-22-070.html 9. National Institute of Neurological Disorders and Stroke. Notice of Intent to Publish a Funding Opportunity Announcement for HEAL Initiative Integrated Basic and Clinical Team-based Research in Pain (RM1 Clinical Trial Optional). 2022. Accessed October 11, 2022. https://grants.nih.gov/grants/guide/notice-files/NOT-NS-23-009.html 10. National Institutes of Health HEAL Initiative. Target Validation for Non-Addictive Therapeutics Development for Pain - A Virtual Workshop. October 19-20, 2020. Accessed October 11, 2022. https://heal.nih.gov/events/2020-10/target-validation-workshop. Videocast available at: https://videocast.nih.gov/ 11. National Institutes of Health HEAL Initiative. HEAL Partnership Committee. 2022. Accessed October 11, 2022. https://heal.nih.gov/about/partnership-committee 12. National Institutes of Health HEAL Initiative. Multi-Disciplinary Working Group. 2022. Accessed October 11, 2022. https://heal.nih.gov/about/multi-disciplinary-wg 13. National Institute of Neurological Disorders and Stroke. [Funding Opportunity Announcement] HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes & Cells (U19 Clinical Trial Not Allowed). 2022. Accessed October 11, 2022. https://grants.nih.gov/grants/guide/rfa-files/rfa-ns-22-018.html 14. National Institute of Neurological Disorders and Stroke. [Funding Opportunity Announcement] HEAL Initiative: Human Pain-associated Genes & Cells Data Coordination and Integration Center (U24 Clinical Trial Not Allowed). 2022. Accessed October 11, 2022. https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-22-021.html 15. National Institutes of Health HEAL Initiative. Open Funding Opportunities. 2022. Accessed October 11, 2022. https://heal.nih.gov/funding/open

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