Genetics of musculoskeletal (TMD) and neuropathic orofacial pain: a narrative review

Background and Objective: Orofacial pain is a debilitating condition affecting individuals’ quality of
life. Differences in pain perception and analgesia have been reported between individuals, suggesting genetics
as a contributing factor. This genetic component of orofacial pain can be best defined as complex due to
contributions from multiple genes, which interact with each other and additional environmental factors.
The objective of this review was to provide a summary of the progress made in the field of musculoskeletal
[temporomandibular disorders (TMD)] and neuropathic orofacial pain genetics.
Methods: PubMed database was searched using the following Medical Subject Headings: (("Facial
Pain/genetics"[Mesh]) OR ("Trigeminal Neuralgia/genetics"[Mesh]) OR ("Trigeminal Nerve Diseases/
genetics"[Mesh]) OR (“Temporomandibular Joint Disorders/genetics"[Mesh])). The search was limited to
publications in English. No time-frame restriction was used.
Key Content and Findings: In this review, we discuss progress made in the field of orofacial pain
genetics with the focus on non-malignant and non-odontogenic musculoskeletal, i.e., TMDs and forms of
trigeminal neuropathic pain including post-traumatic trigeminal neuropathic pain (PTTN) and trigeminal
neuralgia (TN). Available evidence supports the role of genetics in orofacial pain with variations in voltage
gated ion channels, transient receptor potential channels, and GABA receptor-binding genes possessing the
strongest support.
Conclusion: For most cases, orofacial pain conditions such as TMDs, TN, and PTTN follow a complex
multifactorial pattern of inheritance with multiple compounding environmental and genetic factors. Under
such conditions, the effect of individual genetic variation is modest. Defining the implications of individual
genetic factors would thus require large samples of hundreds or thousands of carefully diagnosed patients
and well-matched controls to provide sufficient statistical power. Rare damaging mutations that have a major
effect on risk probably account for a small portion of cases due to aggregation in families, but nonetheless
may be valuable for identifying pathophysiological mechanisms. Overall, the current evidence strongly
suggests that inherited genetic differences among individuals make an important contribution to the
development and severity of pain in conditions such as TMDs, TN, and PTTN. Future research should be
aimed at identifying both the common variants with modest effects and rare damaging mutations with large
effects on increasing patient risk. Such findings would offer promising avenues for development of novel
therapeutic approaches to improve treatment for patients suffering from these debilitating conditions.