Molecular and Cellular Neuroscience Program, Integrative Biology and Infectious Diseases Branch, DER, NIDCR
Objective
The goal of this initiative is to encourage research on the genetic basis of variability in therapeutic drug responses and adverse events in individuals with painful conditions of the orofacial region. Objectives of this initiative are to determine the role of genetic variability in pharmacokinetics, pharmacodynamics, and drug toxicities 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 such as receptors and enzymes, 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 a second objective of this initiative. Clinical and basic science researchers will be encouraged to form multidisciplinary teams to effectively address the goals of this initiative. The ability to categorize individuals who differ in their responses to analgesic therapy will aid health care givers in their ability to prescribe the best treatments for acute and chronic pain patients. Although this initiative is focused on orofacial pain, it also may serve as a catalyst for the pain research community to explore new pharmacogenomics studies.
Background
Chronic pain conditions affect approximately 100 million Americans and lead to large economic and personal costs. Chronic pain is a complex condition influenced by biological, psychological, environmental and social factors. Recent studies suggest that genetics plays an important role in pain sensitivity and susceptibility to development of chronic pain conditions. There is great variability in how individuals cope with chronic pain; some are little affected, while others suffer debilitating dysfunction. Individuals also vary substantially in their responses to therapeutic interventions; for some, pharmacological treatment is highly efficacious and in others only modest reductions in pain occur. Likewise, individuals have varying adverse responses to drug treatment and for some, these adverse effects preclude continued therapeutic treatment.
The prevalence and incidence of some chronic pain conditions are reported to be higher in women than in men. However, the literature is less clear on the existence of differences in pain sensitivity (Hashmi JA and Davis KD, 2014) and analgesic responses (Niesters M, et al. 2010) between women and men. (Bartley EJ and Fillingim RB, 2013) This lack of clarity in sex differences may be due to the disorders studied, the many different methods used to measure pain sensitivity, sociocultural differences in the experience of pain, and the various pharmacological and non-pharmacological treatments employed. (Mogil JS, 2012) Effective treatment of chronic pain conditions and development of precision medicine will necessitate a better understanding of the biological, psychological, and genetic mechanisms underlying pain sensitivity and analgesic responses.
Pharmacogenomics is playing an increasingly important role in the treatment of complex diseases such as diabetes, cardiovascular disorders and cancer. (Jablonski KA, et al. 2010; Maruthur NM, et al. 2014; Siest G, et al. 2007; Low SK, et al. 2014). For example, the FDA has placed warnings on the labels of two drugs, 6-mercaptopurine and camptothecin used in the treatment of pediatric leukemias and colorectal and lung cancers respectively. Their warning suggests that the genotypes of two genes involved in metabolism of the two drugs, TPMT and UGT1A1, are risk factors for, and would be helpful in predicting toxic side effects of these drugs. This action was prompted by careful pharmacogenomics studies of candidate genes involved in drug metabolism. Genome-wide association studies and whole genome sequencing now provide an agnostic approach to identifying new genes and their variants that will facilitate pharmacogenomics studies and potentially lead to a mechanistic understanding of genotype-phenotype interactions. While much work has been done on the pharmacogenomics of these complex diseases, more rigorous studies are needed to validate previous results, overcome the currently small percentage of known genetic contributions to disease and treatment variability, and understand mechanistically, the interactions of genetic variation and patient responses (i.e. phenotypes).
The pharmacogenomics of opioid analgesia has been studied and much is known about the role of genetic variation in the metabolism (cytochrome P450 genes; ex. CYP2D6) receptor interactions (m-opioid receptor; ex. OPRM1), and abuse potential of several opioids (Hajj A, et al. 2013). However, the pharmacogenomics of other treatments for pain have been less well studied. Although many discoveries of the genetic variability that produces differences in pain sensitivity in rodents and humans have provided clues about possible drug targets, little is known about specific pharmacogenomics of analgesic treatments beyond opioids. Some but limited information is available for monoamine neurotransmitter metabolism and transport (COMT, GCH1, MAO, NET, SERT, MDR1/ABCB1), proinflammatory cytokines, and ion channel receptors (TRP family members, Na+, Ca++, and K+ channels).
Recent research has identified a growing number of new targets for pharmacological treatment of neuropathic and inflammatory pain conditions (Lötsch J, et al. 2013; Smith MT and Muralidharan A, 2012). New compounds are being evaluated for these targets. Other drug targets in development include cannabinoid and NMDA receptors, SNRIs, and steroid hormone receptors. Much less research on the pharmacogenomics of temporomandibular joint disorder (TMD) treatments has been done. An NIDCR funded research group at UNC has examined pain sensitivity, risk of development of chronic TMD, and other phenotypes for two candidate genes, COMT and the beta-2 adrenergic receptor, but not drug efficacy or toxicity. They discovered three variant haplotypes of the COMT gene and found that several combinations of these haplotypes are associated with variation in sensitivity to experimental pain. Also, they found that the presence of a low pain sensitivity phenotype reduced the risk for developing myogenous TMD (Diatchenko L, et al. 2005). In another study, this research team found that different haplotypes of the beta-2 adrenergic receptor also determine different risk levels for developing chronic TMD and variation in blood pressure and positive psychological traits (Diatchenko L, et al. 2006). A study by Herken et al. (Herken H, et al. 2001) examined polymorphisms in a serotonin transporter gene and their relationship to temporomandibular joint pain. A promoter variant (44bp indel) and variable number tandem repeat (VNTR) variant in the second intron of the gene were examined for association with TMD. Only the variants at the VNTR were strongly associated with development of TMD.
It is necessary to identify the genetic variance responsible for predicting drug efficacy and toxicity and for the sometimes disparate patient responses to analgesic drugs that are currently on the market and that will be available in the near term. This information will be critical for the incorporation of precision medicine into clinical practice to treat a problem affecting a large proportion of our population. Unbiased genomic and proteomic scans are now identifying large numbers of new targets to treat chronic and acute pain. Molecular modeling of the interactions of pharmacophores with receptors in the context of known familial mutations and altered receptor activity/function can be utilized to predict activity changes in other genetic variants of these proteins. The emergence of these targets as viable pharmacological treatment goals will likely propel the pain therapeutics field forward. A more personalized approach to treatment can be achieved by a comprehensive understanding of the role of genetic variability in the human response to these pharmacological treatments of chronic pain conditions.
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. There are no grants centered on pain pharmacogenomics. NIDCR funds several groups who are assessing the role of genetic variation in the development of chronic pain conditions and in variation in sensitivity of subjects to experimental pain, but no projects focused on pharmacogenomics of analgesic therapies. There are several patient cohorts with chronic pain conditions that may be useful for pharmacogenomic studies. The assembly of these and new cohorts will be necessary for achieving the goals of this initiative.
Alignment with Institute Goals and Strategic Plan
This initiative is aligned with NIDCR Strategic Plan 2014-2019: Goal 1, Objective 1-2: Promote development and use of comprehensive, interoperable databases and informatics resources to advance prevention, diagnosis, and treatment of dental, oral, and craniofacial diseases; Goal 2, Objective 2-1: Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease; and Goal 3, Objective 3-1: Support multidisciplinary, multilevel research and research training to overcome oral health disparities.
The goals and objectives of this initiative are consistent with the mission of the NIH Pain Consortium. NIDCR will partner with member Institutes of the Pain Consortium in developing FOAs that address the research encouraged by this initiative.
References
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Diatchenko L, Anderson AD, Slade GD, Fillingim RB, Shabalina SA, Higgins TJ, Sama S, Belfer I, Goldman D, Max MB, Weir BS, Maixner W. Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am J Med Genet B Neuropsychiatr Genet. 2006 Jul 5; 141B (5):449-62.
Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1; 14(1):135-43.
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Herken H, Erdal E, Mutlu N, Barlas O, Cataloluk O, Oz F, Güray E. Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. Am J Orthod Dentofacial Orthop. 2001 Sep; 120(3):308-13.
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