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Advances in the pathophysiology of tension-type headache: From stress to central sensitization

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Abstract

Tension-type headache (TTH) is the most common and most socioeconomically costly headache. Yet our knowledge regarding TTH pathophysiological mechanisms is still in its early stages. Psychological stress and weak coping mechanisms may initiate and propagate physiological pain via activation of second messengers in downstream substrates involved in pain. It seems that peripheral mechanisms are predominant in the episodic type (ETTH), whereas central mechanisms are involved in the chronic type (CTTH) of tension headache. The conversion from ETTH to CTTH is most relevant to the clinician and the patient, as CTTH is the most debilitating. This paper focuses and summarizes our current understanding of central sensitization, the process by which this conversion occurs in TTH, and proposes an integrated model to explain how ETTH progresses into CTTH in genetically susceptible individuals.

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References and Recommended Reading

  1. Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, 2nd edn. Cephalalgia 2004, 24(Supp 1):1–150.

    Google Scholar 

  2. Lyngberg AC, Rasmussen BK, Jørgensen T, Jensen R: Has the prevalence of migraine and tension-type headache changed over a 12-year period? A Danish population survey. Eur J Epidemiol 2005, 20:243–249.

    Article  PubMed  Google Scholar 

  3. Rasmussen BK, Jensen R, Schroll M, Olesen J: Epidemiology of headache in a general population. A prevalence study. J Clin Epidemiol 1991, 44:1147–1157.

    Article  CAS  PubMed  Google Scholar 

  4. Jensen R, Symon D: Epidemiology of tension-type headaches. In The Headaches, edn 3. Edited by Olesen J, Goadsby PJ, Ramadan N, et al. Philadelphia: Lippincott Williams & Wilkins; 2005:621–624.

    Google Scholar 

  5. Lyngberg AC, Rasmussen BK, Jørgensen T, Jensen R: Incidence of primary headache: a Danish epidemiologic follow-up study. Am J Epidemiol 2005, 161:1066–1073.

    Article  CAS  PubMed  Google Scholar 

  6. Spierings EL, Ranke AH, Honkoop PC: Precipitating and aggravating factors of migraine versus tension-type headache. Headache 2001, 41:554–558.

    Article  CAS  PubMed  Google Scholar 

  7. Clark GT, Sakai S, Merrill R, et al.: Cross-correlation between stress, pain, physical activity, and temporalis muscle EMG in tension-type headache. Cephalalgia 1995, 15:511–518.

    Article  CAS  PubMed  Google Scholar 

  8. Lyngberg AC, Rasmussen BK, Jørgensen T, Jensen R: Prognosis of migraine and tension-type headache: a population-based follow-up study. Neurology 2005, 65:580–585.

    Article  PubMed  Google Scholar 

  9. Russel MB, Saltyete-Benth J, Levi N: Are infrequent episodic, frequent episodic, and chronic-tension headache inherited? A population based study of 11, 199 twin pairs. J Headache Pain 2006, 7:119–126.

    Article  Google Scholar 

  10. Ostergaard S, Russell MB, Bendtsen L, Olesen J: Comparison of first degree relatives and spouses of people with chronic tension headache. BMJ 1997, 314:1092–1093.

    CAS  PubMed  Google Scholar 

  11. Jensen R, Rasmussen BK, Pedersen B, Olesen J: Muscle tenderness and pressure pain thresholds in headache. A population study. Pain 1993, 52:193–199.

    Article  CAS  PubMed  Google Scholar 

  12. Jensen R, Bendtsen L, Olesen J: Muscular factors are of importance in tension type headache. Headache 1998, 38:10–17.

    Article  CAS  PubMed  Google Scholar 

  13. Jensen R: An analysis of spontaneous tension-type headaches: an analysis of tenderness, pain thresholds and EMG. Pain 1995, 64:251–256.

    Article  Google Scholar 

  14. Mork H, Ashina M, Bendtsen L, et al.: Possible mechanisms of pain perception in patients with episodic tension-type headache: a new experimental model of myofascial pain. Cephalalgia 2004, 24:466–475.

    Article  CAS  PubMed  Google Scholar 

  15. Ashina M, Stallknecht B, Bendtsen L, et al.: Tender points are not sites of ongoing inflammation: in vivo evidence in patients with chronic tension-type headache. Cephalalgia 2003, 23:109–116.

    Article  CAS  PubMed  Google Scholar 

  16. Ashina M, Stallknecht B, Bendtsen L, et al.: In vivo evidence of altered skeletal muscle blood flow in chronic tension-type headache. Brain 2002, 125:320–326.

    Article  CAS  PubMed  Google Scholar 

  17. Schoenen J, Gerard P, De Pasqua V, Juprelle M: EMG activity in pericranial muscles during postural variation and mental activity in healthy volunteers and patients with chronic tension type headache. Headache 1991, 31:321–324.

    Article  CAS  PubMed  Google Scholar 

  18. Rollnik JD, Karst M, Fink M, Dengler R: Botulinum toxin type A and EMG: a key to the understanding of chronic tension-type headaches? Headache 2001, 41:985–989.

    Article  CAS  PubMed  Google Scholar 

  19. Sarkar S, Aziz Q, Woolf CJ, et al.: Contribution of central sensitization to the development of non-cardiac chest pain. Lancet 2000, 356:1154–1159.

    Article  CAS  PubMed  Google Scholar 

  20. Schoenen J, Bottin D, Hardy F, Gerard P: Cephalic and extracephalic pressure pain threshold in chronic tensiontype headache. Pain 1991, 47:145–149.

    Article  CAS  PubMed  Google Scholar 

  21. Bendtsen L, Jensen R, Olesen J: Decreased pain detection and tolerance thresholds in chronic tension-type headache. Arch Neurol 1996, 53:373–376.

    CAS  PubMed  Google Scholar 

  22. Göbel H, Weigle L, Kropp P, Soyka D: Pain sensitivity and pain reactivity of pericranial muscles in migraine and tension type headache. Cephalalgia 1992, 12:142–151.

    Article  PubMed  Google Scholar 

  23. Bigal ME, Ashina S, Burstein, et al.: Prevalence and characteristics of allodynia in headache sufferers. Neurology 2008, 70:1525–1533.

    Article  CAS  PubMed  Google Scholar 

  24. Ashina S, Bendtsen L, Ashina M, et al.: Evidence for generalized muscular and cutaneous hyperalgesia in patients with chronic tension-type headache [abstract]. Presented at the 14th International Headache Research Seminar. Copenhagen, Denmark; March 11–13, 2005.

  25. Langemark M, Jensen K, Jensen TS, Olesen J: Pressure pain thresholds and thermal nociceptive thresholds in chronic tension type headache. Pain 1989, 38:203–210.

    Article  CAS  PubMed  Google Scholar 

  26. Urban MO, Gebhart GF: Supraspinal contributions to hyperalgesia. Proc Natl Acad Sci U S A 1999, 96:7687–7692.

    Article  CAS  PubMed  Google Scholar 

  27. Langemark M, Bach FW, Jensen TS, Olesen J: Decreased nociceptive flexion reflex threshold in chronic tension-type headache. Arch Neurol 1993, 50:1061–1064.

    CAS  PubMed  Google Scholar 

  28. Ji RR, Kohno T, Moore KA, Woolf CJ: Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003, 26:696–705.

    Article  CAS  PubMed  Google Scholar 

  29. Munhoz CD, Garcia-Bueno B, Madrigal JLM, et al.: Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz J Med Biol Res 2008, 41:1038–1046.

    Article  Google Scholar 

  30. Le Doaré K, Akerman S, Holland PR, et al.: Occipital afferent activation of second order neurons in the trigeminocervical complex in rats. Neurosci Lett 2006, 403:73–77.

    Article  PubMed  Google Scholar 

  31. Alam Z, Coombes N, Waring RH, et al.: Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache. J Neurol Sci 1998, 156:102–106.

    Article  CAS  PubMed  Google Scholar 

  32. Mazzotta G, Sarchielli P, Gaggioli A, Gallai V: Study of pressure pain and cellular concentration of neurotransmitters related to nociception in episodic tension-type headache patients. Headache 1997, 37:565–571.

    Article  CAS  PubMed  Google Scholar 

  33. Bendtsen L, Jensen R, Hindberg I, et al.: Serotonin metabolism in chronic tension-type headache. Cephalalgia 1997, 17:843–848.

    Article  CAS  PubMed  Google Scholar 

  34. Olesen J: The role of nitric oxide in migraine, tension-type headache and cluster headache. Pharmacol Ther 2008, 120:157–171.

    Article  CAS  PubMed  Google Scholar 

  35. Ashina M, Lassen LH, Bendtsen L, et al.: Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomized crossover trial. Lancet 1999, 353:287–289.

    Article  CAS  PubMed  Google Scholar 

  36. Ashina M, Simonsen H, Bendtsen L, et al.: Glyceryl trinitrate may trigger endogenous nitric oxide production in patients with chronic tension-type headache. Cephalagia 2004, 24:967–972.

    Article  CAS  Google Scholar 

  37. Holthusen H, Arndt JO: Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans. J Physiol 1995, 487(Pt 1):253–258.

    CAS  PubMed  Google Scholar 

  38. Lambert GA, Hoskin KL, Zagami AS: Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. Neuropharmacology 2004, 47:92–105.

    Article  CAS  PubMed  Google Scholar 

  39. Wu J, Lin Q, Lu Y, et al.: Changes in nitric oxide synthase isoforms in the spinal cord of rat following induction of chronic arthritis. Exp Brain Res 1998, 118:457–465.

    Article  CAS  PubMed  Google Scholar 

  40. Ashina M, Bendtsen L, Jensen R, et al.: Possible mechanisms of action of nitric oxide synthase inhibitors in chronic tension type headache. Brain 1999, 122:1629–1635.

    Article  PubMed  Google Scholar 

  41. Ashina M, Bendtsen L, Jensen R, et al.: Plasma levels of calcitonin gene-related peptide in chronic tension-type headache. Neurology 2000, 55:1335–1340.

    CAS  PubMed  Google Scholar 

  42. Schoenen J: Tension-type headache and fibromyalgia: what’s common, what’s different? Neurol Sci 2004, 25:S157–S159.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Thompson SWN, King AE, Woolf CJ: Activity-dependent changes in rat ventral horn neurons in vitro: summation of prolonged afferent evoked postsynaptic depolarizations produce a D-APV sensitive windup. Eur J Neurosci 1990, 2:638–649.

    Article  CAS  PubMed  Google Scholar 

  45. Tegeder I, Niederberger E, Vetter G, et al.: Effects of selective COX-1 and -2 inhibition on formalin-evoked nociceptive behavior and prostaglandin E2 release in the spinal cord. J Neurochem 2001, 79:777–786.

    Article  CAS  PubMed  Google Scholar 

  46. Classey JD, Knight YE, Goadsby PJ: The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res 2001, 907:117–124.

    Article  CAS  PubMed  Google Scholar 

  47. Bartsch T, Goadsby PJ: Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain 2003, 126:1801–1813.

    Article  CAS  PubMed  Google Scholar 

  48. Hoskin KL, Zagami A, Goadsby PJ: Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. J Anat 1999, 194:579–588.

    Article  CAS  PubMed  Google Scholar 

  49. Neugebauer V, Li W, Bird GC, et al.: Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J Neurosci 2003, 23:52–63.

    CAS  PubMed  Google Scholar 

  50. Wei F, Zhuo M: Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetized rat. J Physiol 2001, 532:823–833.

    Article  CAS  PubMed  Google Scholar 

  51. Schmidt-Wilcke T, Leinisch E, Straube A, et al.: Gray matter decrease in patients with chronic tension type headache. Neurology 2005, 65:1483–1486.

    Article  CAS  PubMed  Google Scholar 

  52. Clark GT, Sakai S, Merrill R, et al.: Cross-correlation between stress, pain, physical activity, and temporalis muscle EMG in tension-type headache. Cephalalgia 1995, 15:511–518.

    Article  CAS  PubMed  Google Scholar 

  53. Madrigal JL, Garcia-Bueno B, Caso JR, et al.: Stressinduced oxidative changes in brain. CNS Neurol Disord Drug Targets 2006, 5:561–568.

    Article  PubMed  Google Scholar 

  54. Madrigal JL, Moro MA, Lizasoain I, et al.: Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. J Neurochem 2001, 76:532–538.

    Article  CAS  PubMed  Google Scholar 

  55. Munhoz CD, Lepsch LB, Kawamoto EM, et al.: Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci 2006, 26:3813–3820.

    Article  CAS  PubMed  Google Scholar 

  56. Holroyd K, O’Donnell F, Stensland M, et al.: Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA 2001, 285:2208–2215.

    Article  CAS  PubMed  Google Scholar 

  57. Spiegel K, Kalb R, Pasternak G: Analgesic activity of tricyclic antidepressants. Ann Neurol 1983, 13:462–465.

    Article  CAS  PubMed  Google Scholar 

  58. Ashina S, Bendtsen L, Jensen R: Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition. Pain 2004, 108:108–114.

    Article  CAS  PubMed  Google Scholar 

  59. Sawynok J, Esser M, Reid A: Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci 2001, 26:21–29.

    CAS  PubMed  Google Scholar 

  60. Watanabe Y, Saito H, Abe K: Tricyclic antidepressants block NMDA receptor-mediated synaptic responses and induction of long-term potentiation in rat hippocampal slices. Neuropharmacology 1993, 32:479–486.

    Article  CAS  PubMed  Google Scholar 

  61. Bendtsen L, Jensen R: Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache. Cephalalgia 2000, 20:603–610.

    Article  CAS  PubMed  Google Scholar 

  62. Bendtsen L, Jensen R: Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 2004, 62:1706–1711.

    CAS  PubMed  Google Scholar 

  63. Westenberg HG: Pharmacology of antidepressants: selectivity or multiplicity? J Clin Psych 1999, 60(Suppl 17):4–8.

    Google Scholar 

  64. Lassen LH, Ashina M, Christiansen I, et al.: Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia 1998, 18:27–32.

    Article  CAS  PubMed  Google Scholar 

  65. Juhasz G, Zsombok T, Modos EA, et al.: NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 2003, 106:461–470.

    Article  CAS  PubMed  Google Scholar 

  66. Goadsby PJ, Edvinsson L: The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993, 33:48–56.

    Article  CAS  PubMed  Google Scholar 

  67. Goadsby PJ: New targets in the acute treatment of headache. Curr Opin Neurol 2005, 18:283–288.

    Article  CAS  PubMed  Google Scholar 

  68. Shields KG, Kaube H, Goadsby PJ: GABA receptors modulate trigeminovascular nociceptive transmission in the ventroposteromedial (VPM) thalamic nucleus of the rat. Cephalalgia 2003, 23:728.

    Google Scholar 

  69. Lindelof K, Bendtsen L: Memantine for prophylaxis of chronic tension-type headache: a double-blind, randomized, crossover clinical trial. Cephalalgia 2008, 29:314–321.

    Article  Google Scholar 

  70. Goadsby PJ, Hoskin KL, Storer RJ, et al.: Adenosine (A1) receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 2002, 125:1392–1401.

    Article  CAS  PubMed  Google Scholar 

  71. Sawynok J, Liu XJ: Adenosine in the spinal cord and periphery: release and regulation of pain. Prog Neurobio 2003, 69:313–340.

    Article  CAS  Google Scholar 

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Chen, Y. Advances in the pathophysiology of tension-type headache: From stress to central sensitization. Current Science Inc 13, 484–494 (2009). https://doi.org/10.1007/s11916-009-0078-x

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