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Induction and assessment of muscle pain, referred pain, and muscular hyperalgesia

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Abstract

Muscle pain can be induced and assessed experimentally by a variety of methods. Ischemic and exercise-induced muscle pain are typical endogenous pain models; external stimulation with mechanical, electrical, and chemical modalities constitute the exogenous models. These models are a good basis to study the muscle sensitivity, muscle pain responses under normal and pathophysiologic conditions, and drug efficacy on specific muscle pain mechanisms. When evaluating muscle pain in clinical or experimental settings, it is important to assess parameters related to the pain intensity, pain quality, referred and local distribution, and the deep tissue sensitivity in local and referred areas. The experimental test paradigm must include different stimulation modalities (multimodal) to obtain sufficiently advanced and differentiated information about the human nociceptive system under normal and pathophysiologic conditions because the different stimuli activate different receptors, pathways, and mechanisms. This may be a useful approach in future mechanism-based classification and treatment of muscle pain. Similarly, the multimodal approach is important in clinical studies to provide evidence for which specific muscle pain modalities and mechanisms are affected and how they are modulated by pharmacologic approaches.

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References and Recommended Reading

  1. Kellgren JH: Observations on referred pain arising from muscle. Clin Sci 1938, 3:175–190.

    Google Scholar 

  2. Mense S, Simons DG: Muscle Pain: Understanding Its Nature, Diagnosis, and Treatment. Philadelphia: Lippincott Williams & Wilkins; 2001. This book gives a comprehensive review of muscle pain and links data from basic animal studies with clinical manifestations of muscle pain.

    Google Scholar 

  3. Mense S: Nociception from skeletal muscle in relation to clinical muscle pain. Pain 1993, 54:241–289.

    Article  PubMed  CAS  Google Scholar 

  4. Sessle BJ, Hu JW, Yu XM: Brain stem mechanisms of referred pain and hyperalgesia in the orofascial and temporomandibular region. In New Trends in Referred Pain and Hyperalgesia. Edited by Vecchiet L, Albe-Fessard D, Lindblom U, Giamberardino MA. Amsterdam: Elsevier Science Publishers BV; 1993:59–71.

    Google Scholar 

  5. Marchettini P, Simone DA, Caputi G, Ochoa JL: Pain from excitation of identified muscle nociceptors in humans. Brain Res 1996, 740:109–116.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    PubMed  CAS  Google Scholar 

  7. Chapman CR, Casey KL, Dubner R, et al.: Pain measurement: an overview. Pain 1985, 22:1–31.

    Article  PubMed  CAS  Google Scholar 

  8. Gracely RH: Studies of pain in human subjects. In Textbook of Pain, edn 4. Edited by Wall PD, Melzack R. Edinburgh: Churchill Livingstone; 1999:385–407.

    Google Scholar 

  9. Price DD: Psychological Mechanisms of Pain and Analgesia. Seattle: IASP Press; 1999.

    Google Scholar 

  10. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS: Experimental muscle pain: a quantitative study of local and referred pain in humans following injection of hypertonic saline. J Musculoskel Pain 1997, 5:49–69.

    Article  Google Scholar 

  11. Svensson P, Arendt-Nielsen L: Induction and assessment of experimental muscle pain. J Electromyogr Kinesiol 1995, 5:131–140.

    Article  CAS  PubMed  Google Scholar 

  12. Lewis T: Pain in muscular ischemia. Arch Int Med 1932, 49:713–727.

    Google Scholar 

  13. Vecchiet L, Giamberardino MA, Marini I: Immediate muscular pain from physical activity. In Pain and Mobility. Edited by Tiengo M, Eccles J, Cuello AC, Ottoson D. New York: Raven Press; 1987:193–218.

    Google Scholar 

  14. Newham DJ, Mills KR: Muscles, tendons, and ligaments. In Textbook of Pain, edn 4. Edited by Wall PD, Melzack R. Edinburgh: Churchill Livingstone; 1999:517–538.

    Google Scholar 

  15. Graven-Nielsen T, Jansson Y, Segerdahl M, et al.: Experimental pain by ischaemic contractions compared with pain by intramuscular infusions of adenosine and hypertonic saline. Eur J Pain 2003, 7:93–102.

    Article  PubMed  CAS  Google Scholar 

  16. O’Connor PJ, Cook DB: Moderate-intensity muscle pain can be produced and sustained during cycle ergometry. Med Sci Sports Exerc 2001, 33:1046–1051.

    Article  PubMed  CAS  Google Scholar 

  17. Newham DJ: The consequences of eccentric contractions and their relation to delayed onset muscle pain. Eur J Appl Physiol 1988, 57:353–359.

    Article  CAS  Google Scholar 

  18. Howell JN, Chleboun G, Conatser R: Muscle stiffness, strength loss, swelling, and soreness following exercise-induced injury in humans. J Physiol (Lond) 1993, 464:183–196.

    CAS  Google Scholar 

  19. Bajaj P, Graven-Nielsen T, Wright A, et al.: Muscle hyperalgesia in postexercise muscle soreness assessed by single and repetitive ultrasound stimuli. J Pain 2000, 1:111–121.

    Article  Google Scholar 

  20. Slater H, Arendt-Nielsen L, Wright A, Graven-Nielsen T: Experimental deep tissue pain in wrist extensors: a model of lateral epicondylalgia. Eur J Pain 2003, 7:277–288.

    Article  PubMed  Google Scholar 

  21. Svensson P, Houe L, Arendt-Nielsen L: Effect of systemic versus topical nonsteroidal anti-inflammatory drugs on postexercise jaw-muscle soreness: a placebo-controlled study. J Orofac Pain 1997, 11:353–362.

    PubMed  CAS  Google Scholar 

  22. Howell JN, Conatser RR, Chleboun GS, et al.: The effect of nonsteroidal anti-inflammatory drugs on recovery from exercise-induced muscle injury.2: Ibuprofen. J Musculoskel Pain 1998, 6:69–84.

    Article  Google Scholar 

  23. Barlas P, Walsh DM, Baxter GD, Allen JM: Delayed onset muscle soreness: effect of an ischaemic block upon mechanical allodynia in humans. Pain 2000, 87:221–225.

    Article  PubMed  CAS  Google Scholar 

  24. Gomez-Pinilla F, Ying Z, Roy RR, et al.: Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 2002, 88:2187–2195.

    Article  PubMed  CAS  Google Scholar 

  25. Pezet S, Malcangio M, McMahon SB: BDNF: a neuromodulator in nociceptive pathways? Brain Res Brain Res Rev 2002, 40:240–249.

    Article  PubMed  CAS  Google Scholar 

  26. Vecchiet L, Galletti R, Giamberardino MA, et al.: Modifications of cutaneous, subcutaneous, and muscular sensory and pain thresholds after the induction of an experimental allogenic focus in the skeletal muscle. Clin J Pain 1988, 4:55–59.

    Article  Google Scholar 

  27. Sörensen J, Graven-Nielsen T, Henriksson KG, et al.: Hyperexcitability in fibromyalgia. J Rheumatol 1998, 25:152–155.

    PubMed  Google Scholar 

  28. Arendt-Nielsen L, Graven-Nielsen T, Svensson P, Jensen TS: Temporal summation in muscles and referred pain areas: an experimental human study. Muscle Nerve 1997, 20:1311–1313.

    Article  PubMed  CAS  Google Scholar 

  29. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: The effect of differential and complete nerve block on experimental muscle pain in humans. Muscle Nerve 1999, 22:1564–1570.

    Article  PubMed  CAS  Google Scholar 

  30. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: Referred pain is dependent on sensory input from the periphery: a human experimental study. Eur J Pain 1997, 1:261–269.

    Article  PubMed  CAS  Google Scholar 

  31. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: The effect of compression and regional anaesthetic block on referred pain intensity in humans. Pain 1999, 80:257–263. Determined to which degree referred pain is dependent on peripheral or central mechanisms by blocking sensory input from the referred pain area. Despite regional anesthesia of the referred pain area, pain was still present, although the referred pain intensity was decreased. Thus, referred pain is based mainly on a central mechanism and depends partly on peripheral sensory input.

    Article  PubMed  CAS  Google Scholar 

  32. Curatolo M, Petersen-Felix S, Gerber A, Arendt-Nielsen L: Remifentanil inhibits muscular more than cutaneous pain in humans. Br J Anaesth 2000, 85:529–532. Experimental muscle pain induced by intramuscular electrical stimulation was used to assess the efficacy of intravenous remifentanil. Remifentanil inhibited muscle pain more progressively than cutaneous pain.

    Article  PubMed  CAS  Google Scholar 

  33. Schulte H, Graven-Nielsen T, Sollevi A, et al.: Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil, and ketamine in healthy volunteers. Acta Anaesthesiol Scand 2003, 47:1020–1030. This study demonstrates that experimental muscle pain induced by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacologic modulation.

    Article  PubMed  CAS  Google Scholar 

  34. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L: Quantification of local and referred pain in humans induced by intramuscular electrical stimulation. Eur J Pain 1997, 1:105–113.

    Article  PubMed  CAS  Google Scholar 

  35. Jensen K: Quantification of tenderness by palpation and use of pressure algometers. In Advances in Pain Research and Therapy. Edited by Fricton JR, Awad E. New York: Raven Press; 1990:165–181.

    Google Scholar 

  36. Fischer AA: Muscle Pain Syndromes and Fibromyalgia: Pressure Algometry for Quantification of Diagnosis and Treatment Outcome. New York: Haworth Medical Press; 1998.

    Google Scholar 

  37. Kosek E, Ekholm J: Modulation of pressure pain thresholds during and following isometric contraction. Pain 1995, 61:481–486.

    Article  PubMed  CAS  Google Scholar 

  38. Graven-Nielsen T, Babenko V, Svensson P, Arendt-Nielsen L: Experimentally induced muscle pain induces hypoalgesia in heterotropic deep tissues, but not in homotopic deep tissues. Brain Res 1998, 787:203–210.

    Article  PubMed  CAS  Google Scholar 

  39. Jensen K, Andersen H, Olesen J, Lindblom U: Pressure-pain threshold in human temporal region: evaluation of a new pressure algometer. Pain 1986, 25:313–323.

    Article  PubMed  CAS  Google Scholar 

  40. List T, Helkimo M, Karlsson R: Influence of pressure rates on the reliability of a pressure threshold meter. J Craniomandib Disord 1991, 5:173–178.

    PubMed  CAS  Google Scholar 

  41. Ohrbach R, Crow H, Kamer A: Examiner expectancy effects in the measurement of pressure pain thresholds. Pain 1998, 74:163–170.

    Article  PubMed  CAS  Google Scholar 

  42. Wolfe F, Smythe HA, Yunus MB, et al.: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum 1990, 33:160–172.

    Article  PubMed  CAS  Google Scholar 

  43. Vanderweeën L, Oostendorp RA, Vaes P, Duquet W: Pressure algometry in manual therapy. Man Ther 1996, 1:258–265.

    Article  PubMed  Google Scholar 

  44. Carli G, Suman AL, Biasi G, Marcolongo R: Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 2002, 100:259–269. The authors applied quantitative sensory testing of deep and superficial tissue in various groups of patients with chronic musculoskeletal pain. A dysfunction of the nociceptive system was found. In patients with multiregional pain (few tender points), few tests were different from those of healthy control subjects; however, for the patients with widespread pain (high tender point count), several psychophysic tests differed from those of the healthy control subjects.

    Article  PubMed  Google Scholar 

  45. Bendtsen L, Jensen R, Olesen J: Qualitatively altered nociception in chronic myofascial pain. Pain 1996, 65:259–264.

    Article  PubMed  CAS  Google Scholar 

  46. Staud R, Cannon RC, Mauderli AP, et al.: Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003, 102:87–95. Assessed temporal summation to pressure stimulation in patients with fibromyalgia and control subjects. It was concluded that fibromyalgia patients had increased pain responses to repeated pressure stimuli compared with control subjects. This suggests involvement of central sensitization in fibromyalgia.

    Article  PubMed  Google Scholar 

  47. Polianskis R, Graven-Nielsen T, Arendt-Nielsen L: Pressure-pain function in desensitized and hypersensitized muscle and skin assessed by cuff algometry. J Pain 2002, 3:28–37.

    Article  PubMed  Google Scholar 

  48. Polianskis R, Graven-Nielsen T, Arendt-Nielsen L: Modalityspecific facilitation and adaptation to painful tonic stimulation in humans. Eur J Pain 2002, 6:475–484.

    Article  PubMed  Google Scholar 

  49. Graven-Nielsen T, Segerdahl M, Svensson P, Arendt-Nielsen L: Methods for induction and assessment of pain in humans with clinical and pharmacological examples. In Methods in Pain Research. Edited by Kruger L. Boca Raton: CRC Press; 2001:264–304.

    Google Scholar 

  50. 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.

    PubMed  CAS  Google Scholar 

  51. Svendsen O, Edwards CN, Rasmussen AD: Hypertonic saline: study on muscle tissue toxicity in erythrocytes, rat myocyte culture, and in rabbits after intramuscular injection. Proceedings of the 2nd World Institute of Pain Congress. Istanbul: June 27–30, 2001:193.

  52. Witting N, Svensson P, Gottrup H, et al.: Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain. Pain 2000, 84:407–412.

    Article  PubMed  CAS  Google Scholar 

  53. Babenko V, Graven-Nielsen T, Svensson P, et al.: Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and bradykinin. Pain 1999, 82:1–8.

    Article  PubMed  CAS  Google Scholar 

  54. Ernberg M, Lundeberg T, Kopp S: Effect of propranolol and granisetron on experimentally induced pain and allodynia/ hyperalgesia by intramuscular injection of serotonin into the human masseter muscle. Pain 2000, 84:339–346.

    Article  PubMed  CAS  Google Scholar 

  55. Cairns BE, Hu JW, Arendt-Nielsen L, et al.: Sex-related differences in human pain and rat afferent discharge evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2001, 86:782–791. It was found that glutamate evokes afferent activity in rats and muscle pain in humans. The pain induced in humans and afferent responses in rats were higher in women compared with men (this also refers to the rat recordings in which it is inappropriate to refer to women and men, but rather to female and male). This indicates that sex-related differences may be important in peripheral neurobiologic mechanisms involved in chronic musculoskeletal pain.

    PubMed  CAS  Google Scholar 

  56. Svensson P, Cairns BE, Wang K, et al.: Glutamate-evoked pain and mechanical allodynia in the human masseter muscle. Pain 2003, 101:221–227.

    Article  PubMed  CAS  Google Scholar 

  57. Cairns BE, Gambarota G, Svensson P, et al.: Glutamate-induced sensitization of rat masseter muscle fibers. Neuroscience 2002, 109:389–399.

    Article  PubMed  CAS  Google Scholar 

  58. Cairns BE, Svensson P, Wang K, et al.: Activation of peripheral NMDA receptors contributes to human pain and rat afferent discharges evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2003, (in press).

  59. Graven-Nielsen T, Fenger-Grøn LS, Svensson P, et al.: Quantification of deep and superficial sensibility in salineinduced muscle pain: a psychophysical study. Somatosens Mot Res 1998, 15:46–53.

    Article  PubMed  CAS  Google Scholar 

  60. Hu JW, Sessle BJ, Raboisson P, et al.: Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brain stem neurons. Pain 1992, 48:53–60.

    Article  PubMed  CAS  Google Scholar 

  61. Hoheisel U, Mense S, Simons DG, Yu XM: Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle: a model for referral of muscle pain? Neurosci Lett 1993, 153:9–12.

    Article  PubMed  CAS  Google Scholar 

  62. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS: Quantification of local and referred muscle pain in humans after sequential i.m. injections of hypertonic saline. Pain 1997, 69:111–117.

    Article  PubMed  CAS  Google Scholar 

  63. Arendt-Nielsen L, Graven-Nielsen T: Central sensitization in fibromyalgia and other musculoskeletal disorders. Curr Pain Headache Rep 2003, 7:355–361.

    Article  PubMed  Google Scholar 

  64. Arendt-Nielsen L, Svensson P: Referred muscle pain: basic and clinical findings. Clin J Pain 2001, 17:11–19.

    Article  PubMed  CAS  Google Scholar 

  65. 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.

    Article  PubMed  CAS  Google Scholar 

  66. Arendt-Nielsen L, Graven-Nielsen T: Deep tissue hyperalgesia. J Musculoskel Pain 2002, 10:97–119.

    Article  Google Scholar 

  67. Graven-Nielsen T, Arendt-Nielsen L: Peripheral and central sensitization in musculoskeletal pain disorders: an experimental approach. Curr Rheumatol Rep 2002, 4:313–321.

    Article  PubMed  Google Scholar 

  68. Madeleine P, Lundager B, Voigt M, Arendt-Nielsen L: Sensory manifestations in experimental and work-related chronic neck-shoulder pain. Eur J Pain 1998, 2:251–260.

    Article  PubMed  CAS  Google Scholar 

  69. Graven-Nielsen T, Gibson SJ, Laursen RJ, et al.: Opioid-insensitive hypoalgesia to mechanical stimuli at sites ipsilateral and contralateral to experimental muscle pain in human volunteers. Exp Brain Res 2002, 146:213–222. Experimental referred pain was induced by intramuscular injection of capsaicin. Referred hyperalgesia was detected by pressure algometry. Moreover, opioid-insensitive generalized hypoalgesia was found outside of the referred area.

    Article  PubMed  CAS  Google Scholar 

  70. Graven-Nielsen T, Arendt-Nielsen L, Mense S: Thermosensitivity of muscle: high-intensity thermal stimulation of muscle tissue induces muscle pain in humans. J Physiol 2002, 540:647–656. This is the first study to show that high-intensity thermal stimulation of muscle is associated with muscle pain. The data also indicated that the thermosensation from muscle does not exist (ie, subjects cannot differentiate between cold and warm muscle stimuli).

    Article  PubMed  CAS  Google Scholar 

  71. Davies AI, Gavrilov LR, Tsirulnikov EM: Application of focused ultrasound for research on pain. Pain 1996, 67:17–27.

    Article  Google Scholar 

  72. Wright A, Graven-Nielsen T, Davies I, Arendt-Nielsen L: Temporal summation of pain from skin, muscle, and joint following nociceptive ultrasonic stimulation in humans. Exp Brain Res 2002, 144:475–482. Temporal summation of muscle, skin, and joint was assessed with focused ultrasound. It was found that temporal summation is more potent for muscle than skin and joint stimulation.

    Article  PubMed  CAS  Google Scholar 

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Graven-Nielsen, T., Arendt-Nielsen, L. Induction and assessment of muscle pain, referred pain, and muscular hyperalgesia. Current Science Inc 7, 443–451 (2003). https://doi.org/10.1007/s11916-003-0060-y

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