Comparison of Pain-Generated Functional Outcomes in Experimental Models of Delayed-Onset Muscle Soreness and Nerve Growth Factor Injection of the Masticatory Muscles

Aims: To compare two pain models of myalgic TMD, delayed-onset muscle soreness (DOMS) and injections of nerve growth factor (NGF), in terms of pain-related and motor function outcomes, as well as activity-related temporal summation. Methods: Fifty age- and gender-matched healthy participants were recruited and randomized into one of three groups: to a repeated eccentric contraction task to cause DOMS (n = 20), to receive NGF injections into the masseter muscle (n = 20), or to a control group (n = 10). Mechanical sensitivity of masticatory muscles, chewing parameters, jaw function limitation, maximum bite force, and activity-related temporal summation were assessed at baseline and at days 1, 2, and 7 following the intervention. Results: Compared to baseline, both model groups showed increased mechanical sensitivity, jaw function limitation, pain on chewing, and decreased chewing efficiency, lasting longer in the NGF group than in the DOMS group (P < .05). Furthermore, also compared to baseline, the NGF group showed increased pain on maximum bite and decreased pain-free maximum opening (P < .05). No increases in activity-related temporal summation were shown for any of the model groups when compared to baseline or the control group (P > .05). Conclusion: Both models produced similar pain-related outcomes, with the NGF model having a longer effect. Furthermore, the NGF model showed a more substantial effect on motor function, which was not seen for the DOMS model. Finally, neither of the models were able to provoke activity-related temporal summation of pain.

experimental pain; mechanical sensitivity; myalgia; temporal summation; trigeminal motor physiology

1. Stohler CS. Craniofacial pain and motor function: Pathogenesis, clinical correlates, and implications. Crit Rev Oral Biol Med1999;10:504–518.

2. Svensson P, Graven-Nielsen T. Craniofacial muscle pain: Review of mechanisms and clinical manifestations. J Orofac Pain 2001;15:117–145.

3. Lobbezoo F, van Selms MK, Naeije M. Masticatory muscle pain and disordered jaw motor behaviour: Literature review over the past decade. Arch Oral Biol 2006;51:713–720.

4. Lund JP, Donga R, Widmer CG, Stohler CS. The pain-adaptation model: A discussion of the relationship between chronic musculoskeletal pain and motor activity. Can J PhysiolPharmacol 1991;69:683–694.

5. Peck CC, Murray GM, Gerzina TM. How does pain affect jaw muscle activity? The Integrated Pain Adaptation Model. Aust Dent J 2008;53:201–207.

6. Suzuki S, Arima T, Kitagawa Y, Svensson P, Castrillon E. Influence of glutamate-evoked pain and sustained elevated muscle activity on blood oxygenation in the human masseter muscle. Eur J Oral Sci 2017;125:453–462.

7. Louca S, Christidis N, Ghafouri B, et al. Serotonin, glutamate and glycerol are released after the injection of hypertonic saline into human masseter muscles—A microdialysis study. J Headache Pain 2014;15:89.

8. Arima T, Svensson P, Arendt-Nielsen L. Experimental grinding in healthy subjects: A model for postexercise jaw muscle soreness? J Orofac Pain 1999;13:104–114.

9. Farella M, Bakke M, Michelotti A, Martina R. Effects of prolonged gum chewing on pain and fatigue in human jaw muscles.Eur J Oral Sci 2001;109:81–85.

10. Svensson P, Arendt-Nielsen L. Effect of topical NSAID on post-exercise jaw muscle soreness: A placebo-controlled experimental study. J Musculoskelet Pain 1995;3:41–58.

11. Kumar A, Castrillon E, Svensson KG, Baad-Hansen L, Trulsson M, Svensson P. Effects of experimental craniofacial pain on fine jaw motor control: A placebo-controlled double-blinded study. Exp Brain Res 2015;233:1745–1759.

12. Kumar A, Castrillon E, Svensson P. Can experimentally evoked pain in the jaw muscles or temporomandibular joint affect anterior bite force in humans? J Oral Facial Pain Headache 2015;29:31–40.

13. Sae-Lee D, Whittle T, Peck CC, Forte AR, Klineberg IJ, Murray GM. Experimental jaw-muscle pain has a differential effect on different jaw movement tasks. J Orofac Pain 2008;22:15–29.

14. Svensson P, Arendt-Nielsen L, Houe L. Muscle pain modulates mastication: An experimental study in humans. J Orofac Pain 1998;12:7–16.

15. Svensson P. What can human experimental pain models teach us about clinical TMD? Arch Oral Biol 2007;52:391–394.

16. Koutris M, Lobbezoo F, Sümer NC, Atis ES, Türker KS, Naeije M. Is myofascial pain in temporomandibular disorder patients a manifestation of delayed-onset muscle soreness? Clin J Pain 2013;29:712–716.

17. Koutris M, Turker KS, van Selms MKA, Lobbezoo F. Delayed-onset muscle soreness in human masticatory muscles increases inhibitory jaw reflex responses. J Oral Rehabil 2018;45:430–435.

18. Bucci R, Lobbezoo F, Michelotti A, Orfanou C, Koutris M. Delayed-onset muscle soreness does not influence occlusal sensitivity and position sense of the mandible. J Oral Rehabil 2017;44:655–663.

19. Svensson P, Cairns BE, Wang K, Arendt-Nielsen L. Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain 2003;104:241–247.

20. Svensson P, Castrillon E, Cairns BE. Nerve growth factor-evoked masseter muscle sensitization and perturbation of jaw motor function in healthy women. J Orofac Pain 2008;22:340–348.

21. Stohler CS. Masticatory myalgias. Emphasis on the nerve growth factor–estrogen link. Pain Forum 1997;6:176–180.

22. Deising S, Weinkauf B, Blunk J, Obreja O, Schmelz M, Rukwied R. NGF-evoked sensitization of muscle fascia nociceptors in humans. Pain 2012;153:1673–1679.

23. Rukwied R, Weinkauf B, Main M, Obreja O, Schmelz M. Inflammation meets sensitization—An explanation for sponta-neous nociceptor activity? Pain 2013;154:2707–2714.

24. Dyck PJ, Peroutka S, Rask C, et al. Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology 1997;48:501–505.

25. Petty BG, Cornblath DR, Adornato BT, et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994;36:244–246.

26. Türker KS, Koutris M, Sümer NC, et al. Provocation of delayed-onset muscle soreness in the human jaw-closing muscles. Arch Oral Biol 2010;55:621–626.

27. Proske U, Morgan DL. Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol 2001;537:333–345.

28. Prasartwuth O, Taylor JL, Gandevia SC. Maximal force, voluntary activation and muscle soreness after eccentric damage to human elbow flexor muscles. J Physiol 2005;567:337–348.

29. Mankovsky-Arnold T, Wideman TH, Larivière C, Sullivan MJ. TENS attenuates repetition-induced summation of activity-related pain following experimentally induced muscle soreness. J Pain 2013;14:1416–1424.

30. Sullivan MJ, Thibault P, Andrikonyte J, Butler H, Catchlove R, Larivière C. Psychological influences on repetition-induced summation of activity-related pain in patients with chronic low back pain. Pain 2009;141:70–78.

31. Lambin DI, Thibault P, Simmonds M, Lariviere C, Sullivan MJ. Repetition-induced activity-related summation of pain in patients with fibromyalgia. Pain 2011;152:1424–1430.

32. Zhang Y, Shao S, Zhang J, Wang L, Wang K, Svensson P. Temporal summation and motor function modulation during repeated jaw movements in patients with temporomandibular disorder pain and healthy controls. Pain 2017;158:1272–1279.

33. Logan HL, Baron RS, Kohout F. Sensory focus as therapeutic treatments for acute pain. Psychosom Med 1995;57:475–484.

34. Guo Y, Logan HL, Glueck DH, Muller KE. Selecting a sample size for studies with repeated measures. BMC Med Res Methodol 2013;13:100.

35. Gedney JJ, Logan H, Baron RS. Predictors of short-term and long-term memory of sensory and affective dimensions of pain. J Pain 2003;4:47–55.

36. Schiffman E, Ohrbach R, Truelove E, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for clinical and research applications: Recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache 2014;28:6–27.

37. Slade GD, Spencer AJ. Development and evaluation of the Oral Health Impact Profile. Community Dent Health 1994;11:3–11.

38. Ohrbach R, Larsson P, List T. The jaw functional limitation scale: Development, reliability, and validity of 8-item and 20-item versions. J Orofac Pain 2008;22:219–230.

39. van der Meulen MJ, Lobbezoo F, Aartman IH, Naeije M. Validity of the Oral Behaviours Checklist: Correlations between OBC scores and intensity of facial pain. J Oral Rehabil 2014;41:115–121.

40. Shimada A, Castrillon EE, Svensson P. Revisited relationships between probable sleep bruxism and clinical muscle symptoms. J Dent 2019;82:85–90.

41. Thymi M, Shimada A, Lobbezoo F, Svensson P. Clinical jaw-muscle symptoms in a group of probable sleep bruxers. J Dent 2019;85:81–87.

42. Svensson P, Arendt-Nielsen L, Nielsen H, Larsen JK. Effect of chronic and experimental jaw muscle pain on pain-pressure thresholds and stimulus-response curves. J Orofac Pain 1995;9:347–356.

43. Allen PF, McMillan AS, Locker D. An assessment of sensitivity to change of the Oral Health Impact Profile in a clinical trial. Community Dent Oral Epidemiol 2001;29:175–182.

44. Erkapers M, Ekstrand K, Baer RA, Toljanic JA, Thor A. Patient satisfaction following dental implant treatment with immediate loading in the edentulous atrophic maxilla. Int J Oral Maxillofac Implants 2011;26:356–364.

45. Svensson P, Arendt-Nielsen L. Effects of 5 days of repeated submaximal clenching on masticatory muscle pain and tenderness: An experimental study. J Orofac Pain 1996;10:330–338.

46. Schimmel M, Christou P, Herrmann F, Müller F. A two-colour chewing gum test for masticatory efficiency: Development of different assessment methods. J Oral Rehabil 2007;34:671–678.

47. Schimmel M, Leemann B, Herrmann FR, Kiliaridis S, Schnider A, Müller F. Masticatory function and bite force in stroke patients. J Dent Res 2011;90:230–234.

48. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS. Stimulus-response functions in areas with experimentally induced referred muscle pain—A psychophysical study. Brain Res 1997;744:121–128.

49. Svensson P, Arendt-Nielsen L, Houe L. Sensory-motor interactions of human experimental unilateral jaw muscle pain: A quan-titative analysis. Pain 1996;64:241–249.

50. Exposto FG, Masuda M, Castrillon EE, Svensson P. Effects of nerve growth factor experimentally-induced craniofacial muscle sensitization on referred pain frequency and number of head-ache days: A double-blind, randomized placebo-controlled study. Cephalalgia 2018;38:2006–2016.

51. Dao TT, Lund JP, Lavigne GJ. Pain responses to experimental chewing in myofascial pain patients. J Dent Res 1994;73:1163–1167.

52. Okeson JP (ed). Bell’s Oral and Facial Pain. Chicago: Quintessence, 2014.

53. Wong H, Kang I, Dong XD, et al. NGF-induced mechanical sensitization of the masseter muscle is mediated through peripheral NMDA receptors. Neuroscience 2014;269:232–244.

54. Stauber WT. Eccentric action of muscles: Physiology, injury, and adaptation. Exerc Sport Sci Rev 1989;17:157–185.

55. Cruz-Almeida Y, Fillingim RB. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med 2014;15:61–72.

56. Reynolds WS, Brown ET, Danford J, et al. Temporal summation to thermal stimuli is elevated in women with overactive bladder syndrome. Neurourol Urodyn 2017;36:1108–1112.

57. Price DD, Hull CD, Buchwald NA. Intracellular responses of dorsal horn cells to cutaneous and sural nerve A and C fiber stimuli. Exp Neurol 1971;33:291–309.

58. Dallel R, Duale C, Luccarini P, Molat JL. Stimulus-function, wind-up and modulation by diffuse noxious inhibitory controls of responses of convergent neurons of the spinal trigeminal nucleus oralis. Eur J Neurosci 1999;11:31–40.

59. Raphael KG, Janal MN, Anathan S, Cook DB, Staud R. Temporal summation of heat pain in temporomandibular disorder patients. J Orofac Pain 2009;23:54–64.

60. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001;91:165–175.

61. Edwards RR, Smith MT, Stonerock G, Haythornthwaite JA. Pain-related catastrophizing in healthy women is associated with greater temporal summation of and reduced habituation to thermal pain. Clin J Pain 2006;22:730–737.

62. Simone DA, Marchettini P, Caputi G, Ochoa JL. Identification of muscle afferents subserving sensation of deep pain in humans. J Neurophysiol 1994;72:883–889.

63. Hayashi K, Shiozawa S, Ozaki N, Mizumura K, Graven-Nielsen T. Repeated intramuscular injections of nerve growth factor induced progressive muscle hyperalgesia, facilitated temporal summation, and expanded pain areas. Pain 2013;154:2344–2352.

64. Masuda M, Iida T, Exposto FG, et al. Referred pain and sensations evoked by standardized palpation of the masseter muscle in healthy participants. J Oral Facial Pain Headache 2018;32:159–166.

65. Exposto FG, Udagawa G, Naganawa T, Svensson P. Comparison of masseter muscle referred sensations after mechanical and glutamate stimulation: A randomized, double-blind, controlled, cross-over study. Pain 2018;159:2649–2657.