Pharmacogenomics and Pharmacomicrobiomics of Pain Management Across Pain States

Integrative Biology and Infectious Diseases Branch, DER, NIDCR

OBJECTIVE 

The primary objective of this initiative is to determine the role of genetic and microbiome variability in pharmacokinetics, pharmacodynamics, drug toxicity, and vulnerability to opioid use disorder (OUD) that contribute to and predict the clinical outcomes of analgesic treatment of individuals with acute and chronic pain conditions. Delineation of genetic variation in drug metabolizing enzymes, transporters, drug target molecules, and associated intracellular signaling pathway molecules is an important outcome of this initiative. Identification of key molecular signatures that are predictive of a therapeutic response is the second objective of this initiative.

  1. Pain conditions represent a complex set of disorders that often exhibit heterogeneity within a condition but can exhibit commonalities across conditions. Studies suggest that genetics plays an important role in pain sensitivity and susceptibility that contributes to chronic pain conditions. There is great variability in how individual patients cope with pain, respond to therapeutic interventions, and are vulnerable to OUD; for some, pharmacological treatment is highly efficacious and in others only modest reduction in pain occur 1. Increasing evidence suggests that in addition to genetic elements, microbiota plays an important role in conferring additional metabolic capacities to their host as well as to its phenotypic heterogeneity. These adaptations in turn influence the efficacy and toxicity of a broad range of drugs 2. A greater understanding of how genetic variation and microbiota modulation influence drug efficacy and toxicity, differential patient responses to interventions, and phenotypic heterogeneity will allow for precision medicine approaches to manage various pain states and elucidate commonalities that may exist across painful conditions.

While discovery of genetic variability leading to differences in pain sensitivity in rodents and humans has provided clues about possible drug targets, little is known about specific pharmacogenomics of analgesic treatments beyond opioids. Although it is well recognized that CYP2D6 genetic variation allows for phenotypic characterization, such as poor, intermediate, normal and ultra-rapid opioid metabolizers, current pharmacogenetic evidence is insufficient to identify populations at increased risk for OUD 3. Even less is known about the impact of the microbiota which expands the human-associated gene pool by orders of magnitude and is more plastic than the human genome; with compositional variations over time, space, health, and physiological states 2. Recent studies indicate that the microbiota should be taken into consideration when establishing analgesic pharmacological therapies. For example, gut microbiota have been shown to promote development of chemotherapy-induced mechanical hyperalgesia 4, and epidemiological studies in humans and experiments in mouse models indicate that gut microbiota determines the effectiveness of anticancer immunotherapies that involve blockade of programmed cell death protein 1 (PD1) or PD1 ligand (PDL1) in patients with melanoma, non-small cell lung cancer or renal cell cancer 5. 

CURRENT PORTFOLIO OVERVIEW

The NIH currently funds research projects that focus on the pharmacogenomics of several types of cancer treatments and on treatments for a few neurological disorders. An examination of research project grants from FY2015-FY2017 indicates that the NIH has funded ten research project grants centered on pain pharmacogenomics and none addressing pharmacomicrobiomics and pain.

GAPS AND OPPORTUNITIES

Precision medicine approaches for pain management and prevention of OUD will necessitate delineation of mechanisms underlying the considerable variability in patient responses to analgesic therapy, adverse events, and susceptibility to OUD. It is estimated that patients’ genomes account for 20-95% of the variation in drug disposition 6-8. While likely true, the genetic basis of variability is probably even more complex and multi-factorial with at least two contributing components: 1) a relatively stable, inheritable human gene pool and 2) a changeable, evolvable gene pool supplied by a resident microbiota that adds another layer of biotransformative metabolic capacity2. Little is known about the diverse and complicated interactions among the microbiota, drugs, and the human host that mediate pharmacotherapy outcomes.

Specific Areas of Interest

Strategies to address sex-based differences/influences are considered cross-cutting and expected to be incorporated into projects. This initiative will support research projects that may include, but are not limited to the following:

  • Genetic predictors of therapeutic response and poor outcomes to drug treatments
  • Development of novel pharmacogenomic and/or pharmacomicrobiomic analytical genomic methods
  • Pharmacogenomics and/or pharmacomicrobiomics of pain treatment in special populations
  • Genomic variability influencing behaviors such as somatization, reward seeking, anxiety, depression, self-awareness that may directly affect therapeutic responses
  • Drug-microbial gene and drug-microbe interactions and their correlation with drug-human gene interactions
  • The role of microbiota in delivery, disposition, and co-metabolism of drugs

INDIVIDUALS AND GROUPS WHOSE INPUT WAS SOLICITED FOR THIS
INITIATIVE 

Program Officers fromNCCIH, NIDA, NCI, NINDS, NHLBI, NIAAA, NEI, NIAID, NIA, ORWH, and NIBIB.

ALIGNMENT WITH INSTITUTE GOALS AND STRATEGIC PLAN

This initiative is aligned with the NIDCR Strategic Plan 2014-2019, Goals I and II, “Support the best science to improve dental, oral, and craniofacial health” and “Enable precise and personalized oral health care through research” respectively. Specifically, the initiative aligns with objectives I-1, I-2, II-1, and III-1 that include “Enable basic research to advance knowledge of dental, oral, and craniofacial health”, “Promote development and use of comprehensive, interoperable databases and informatics resources to advance prevention, diagnosis, and treatment of dental, oral, and craniofacial diseases”, “Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease”, and “Support multidisciplinary, multilevel research and research training to overcome oral health disparities”. It is also aligned with the following NIDCR 2030goal areas: “Oral Health + Overall Health” and “Precision Health”.

This initiative is also aligned with the Federal Pain Research Strategypublished in 2017, that lists the following as research priorities: “Develop Approaches Incorporating the Principles of Precision Medicine to Prevent and Effectively Treat Chronic Pain, “Determine Similarities and Differences across Chronic Pain States, and “Explore novel biological targets”.

References

1 Owusu Obeng, A., Hamadeh, I. & Smith, M. Review of Opioid Pharmacogenetics and Considerations for Pain Management. Pharmacotherapy 37, 1105-1121, doi:10.1002/phar.1986 (2017).

2 ElRakaiby, M.et al. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics. OMICS 18, 402-414, doi:10.1089/omi.2014.0018 (2014).

3 Smith, D. M., Weitzel, K. W., Cavallari, L. H., Elsey, A. R. & Schmidt, S. O. Clinical application of pharmacogenetics in pain management. Per Med 15, 117-126, doi:10.2217/pme-2017-0032 (2018).

4 Shen, S.et al.Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci 20, 1213-1216, doi:10.1038/nn.4606 (2017).

5 Kroemer, G. & Zitvogel, L. Cancer immunotherapy in 2017: The breakthrough of the microbiota. Nat Rev Immune 18, 87-88, doi:10.1038/nri.2018.4 (2018).

6 Crews, K. R., Hicks, J. K., Pui, C. H., Relling, M. V. & Evans, W. E. Pharmacogenomics and individualized medicine: translating science into practice. Clin Pharmacy Ther 92, 467-475, doi:10.1038/clpt.2012.120 (2012).

7 Kalow, W., Tang, B. K. & Endrenyi, L. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics 8, 283-289 (1998).

8 Godman, B.et al.Personalizing health care: feasibility and future implications. BMC Med 11, 179, doi:10.1186/1741-7015-11-179 (2013).