Future Direction and Conclusion

Future Direction and Conclusion 12 Jean-Paul Goulet and Ana Miriam Velly Our understanding of many aspects of chronic pain and more specifically of trigeminal pain has advanced substantially over the past 25 years (see Chap. 3). Among others are the processing of afferent inputs along the trigeminal path and at the brainstem trigeminal sensory complex, the peripheral as well as central mechanisms involved in sensitization that can contribute to the transition from acute to chronic pain, and the role played by non-neuronal cells and genetic and environmental factors. These progresses in our understanding of chronic pain also apply to chronic orofacial pain conditions even though physiologic studies on trigeminal pain point to several unique characteristics compared with the spinal nociceptive system in terms of differences in response patterns to tissue injury [1]. Despite the accumulation of new knowledge and insights into orofacial pain mechanisms, the advancement in management strategies has not kept the pace. That is reflected by the lack of significant changes seen in the treatment response for most chronic orofacial pain conditions over the past decade. J.-P. Goulet, DDS, MSD, FRCD (*) Faculty of Dental Medicine, Université Laval, 2420 Rue de la Terrasse, G1V 0A6, QC, Québec, Canada e-mail: [email protected] A.M. Velly, DDS, MSc, PhD Faculty of Dentistry, McGill University, Montréal, QC, Canada The main alleged difference among the most common chronic orofacial pain conditions is that the predominant symptoms and physical manifestations arise from distinct anatomical location and target organs [2, 3]. For example, the masticatory muscles, temporomandibular joints, dentoalveolar process, tongue, and branches of the trigeminal nerve are all different structures or systems involved that push patients to seek care. When we dismiss the body region and target organ to focus on similarities, the most common chronic pain conditions share a number of important features. For one, clinical examination findings are less deviant than expected considering the number and extent of reported symptoms and associated suffering. In addition, the presence of comorbid conditions is more the norm than the exception, and most notably the etiology and pathogenesis of the pain remain unclear or at best speculative. This should make us wonder if we are really dealing with conditions that are unrelated and pain mechanisms that need different treatment strategies. As new findings in orofacial pain unfold, our operationalized concept of chronic orofacial pain based on specific end organs is more than ever challenged [4]. At least for TMDs that feature persistent pain in the absence of organic substrate, the target organ identified as the source of the pain might not be where all the answers lie. While the view that peripheral inputs play a major role in chronic pain state and ongoing pathological processes occur within the end © Springer-Verlag GmbH Germany 2017 J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI 10.1007/978-3-662-53994-1_12 [email protected] 147 J.-P. Goulet and A.M. Velly 148 organ is frequently emphasized, the evidence remains equivocal for the cluster of chronic orofacial pain disorders that are commonly seen in clinic and more specifically for joint (arthralgia) and muscle pain (myalgia and its subtypes) related to TMD. Recent studies have greatly advanced our understanding of biomarkers in orofacial pain, and so far, some putative biomarkers have been identified. The overview on masticatory muscle pain biomarkers in Chap. 6 indicates that glutamate and serotonin are implicated in jaw myalgia, although the exact pathological process is yet to be elucidated. Chapter 7 on molecular temporomandibular joint biomarkers underscores that a number of peripheral pain mediators are indeed elevated in the synovial fluid of TMJ arthritis patients with joint pain on mandibular movements. Significant correlation is reported for higher level of tumor necrosis factor, interleukin 6, serotonin, and prostaglandin E2. Synovial fluid of arthritic TMJ with high level of interleukin-1β is associated with resting joint pain and tenderness to palpation. In addition, interleukin 6 is more frequently found in synovial fluid of patients with TMJ pain associated with cartilage destruction. These potential biomarkers are therefore good candidates for distinguishing TMJ arthritis from TMJ arthralgia, knowing that this distinction impacts on treatment decision and prognosis. Arthralgia with masticatory muscle myalgia and its different subtypes are the most common TMDs featuring persistent pain in the absence of organic substrate. There is accumulating evidence that these conditions can be defined and understood through the appraisal of other painful symptoms and psychosocial factors as well (Chap. 2). This would be in line with the proposed hypotheses that biopsychosocial risk factors are appropriate predictors of distinct clusters of people with pain-related TMD in the absence of end-organ pathobiological substrate and that some manifestations result from the interplay of central and peripheral nociceptive mechanisms influenced by genes that regulate biological systems relevant to pain perception [5–7]. As pointed out in Chap. 8 (Seltzer and Diehl), a number of genes harboring single nucleotide polymorphisms (SNPs) can alter regulatory mechanisms of neurotransmitters involved in processing nociceptive input and contribute to the onset or put subjects at risk of developing chronic orofacial pain. Of particular interest is the catecholamine-O-methyltransferase (COMT) gene located on chromosome 22 that encodes the enzyme COMT responsible for the inactivation and catabolism of neurotransmitters such as dopamine and norepinephrine and the HTR2A gene that encodes one of the serotonin receptors (5-hydroxytryptamine receptor 2A). Dopamine and 5-hydroxytryptamine (5-HT) are neurotransmitters involved, respectively, in pain perception and pain transmission. Altered dopaminergic neurotransmission in the central nervous system has been reported in patients with burning mouth syndrome (BMS) and persistent idiopathic face pain (PIFP) [8, 9]. Moreover, patients with chronic masticatory muscle pain have elevated interstitial concentrations of 5-HT compared to healthy controls, and 5-HT levels are correlated with muscle pain and allodynia [10, 11]. More recently it has been shown that plasma dopamine level was elevated in muscle pain-related TMD and correlated with present pain intensity and perceived mental stress [12]. What is emphasized and discussed in Chap. 2 about the presence of other painful and nonpainful comorbid symptoms that coexist with a chronic orofacial pain condition is the norm rather than the exception. Other comorbid pain disorders such as fibromyalgia, low back pain, and irritable bowel syndrome show similar patterns of clinical manifestations. This substantial overlap of physical symptoms related and unrelated to the endorgan conditions among different comorbid pain disorders raises the possibility of a common underlying substrate that needs full attention. Thus, it is legitimate to consider unexplained chronic orofacial pain conditions as potential manifestations of general central nervous system dysregulation [7, 13]. Knowing the temporal relationship of these different clinical manifestations could uncover whether nonspecific symptoms [email protected] 12 Future Direction and Conclusion 149 that occur frequently strongly influence and predict the onset of pain-related TMD [14]. The combined effect of genetic determinants and gene-environment interaction with psychosocial stress could represent a pathway giving rise not only to pain-related TMD but also to other chronic orofacial pain conditions such as burning mouth syndrome (BMS) and persistent idiopathic face pain (PIFP) that are unexplained by pathological processes involving the peripheral end organs. This is conceivable as evidenced by data presented in Chap. 5 on neurophysiologic markers of orofacial pain attributed to a dysregulation or dysfunction of the trigeminal sensory system. Thermal hypoesthesia, a feature of small fiber system hypofunction as well as increased excitability within the trigeminal system evocative of a deficient top-down inhibition, has been reported in BMS and PIFP. Gain of function on the other hand was observed in subgroups of BMS, PIFP, and atypical odontalgia (AO) that represent three distinct end-organ chronic orofacial pain conditions commonly categorized as trigeminal neuropathic pain disorders. From Chap. 9, saliva appears to represent an attractive biofluid for the analysis of potential biomarkers. The technique for the collection of saliva is noninvasive and can be done at specific time intervals in different environments with rather simple equipment. This offers the possibility of conducting longitudinal studies targeting the onset and temporal dimensions of somatic complaints related to comorbidities in unexplained chronic orofacial pain disorders while focusing on biomarkers of chronic activation of the body’s stress system, the hypothalamicpituitary-adrenal axis (HPA axis), and, more importantly, the sympathetic adrenomedullary (SAM) system. Further advancement will only come with the improvement of our study protocols, and the need to better define prospectively the specific aims and the target population when studying biomarkers is well emphasized in Chaps. 10 and 11. Dismissing the importance of other subthreshold symptoms, the top-down influences of regulatory mechanisms, as well as the impact of psychosocial factors, represent a serious barrier to the future identification of meaningful orofacial pain biomarkers. Revisiting the conceptual framework of unexplained chronic orofacial pain disorders, and searching for biomarkers of autonomically mediated dysregulation as a generator of nonspecific symptoms in an apparent endorgan disorder, may provide answers regarding the natural history and the possibility of a common underlying substrate shared by the most common disorders. Therefore, it is crucial to identify a series of biomarkers indicative of diagnosis, classification, pain mechanism, prognosis, and orofacial pain management (Chap. 10). References 1. Hargreaves KM. Orofacial pain. Pain. 2011;152(3 Suppl):S25–32. 2. Woda A, Pionchon P. A unified concept of idiopathic orofacial pain: clinical features. J Orofac Pain 1999;13(3):172–184; discussion 85–95. 3. Woda A, Tubert-Jeannin S, Bouhassira D, Attal N, Fleiter B, Goulet JP, et al. Towards a new taxonomy of idiopathic orofacial pain. Pain. 2005;116(3):396–406. 4. Slade GD, Ohrbach R, Greenspan JD, Fillingim RB, Bair E, Sanders AE, et al. 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