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Medication overuse headache

Abstract

Medication overuse headache (MOH) is a secondary headache disorder attributed to overuse of acute headache medications by a person with an underlying headache disorder, usually migraine or tension-type headache. MOH is common among individuals with 15 or more headache days per month. Although MOH is associated with substantial disability and reductions in quality of life, this condition is often under-recognized. As MOH is both preventable and treatable, it warrants greater attention and awareness. The diagnosis of MOH is based on the history and an unremarkable neurological examination, and is made according to the diagnostic criteria of the International Classification of Headache Disorders third edition (ICHD-3). Pathophysiological mechanisms of MOH include altered descending pain modulation, central sensitization and biobehavioural factors. Treatment of MOH includes the use of headache preventive therapies, but essential to success is eliminating the cause, by reducing the frequency of use of acute headache medication, and perhaps withdrawing the overused medication altogether. Appropriate treatment is usually highly effective, leading to reduced headache burden and acute medication consumption.

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Fig. 1: Proposed neuroanatomical circuits relevant to pathophysiology of medication overuse headache and medication overuse.
Fig. 2: Putative cellular and molecular mechanisms of medication overuse headache.
Fig. 3: Example of an electronic headache diary of a patient with chronic migraine and medication overuse headache.
Fig. 4: Proposed prevention and treatment algorithm of medication overuse headache.

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References

  1. Peters, G. A. & Horton, B. T. Headache: with special reference to the excessive use of ergotamine preparations and withdrawal effects. Proc. Staff. Meet. Mayo Clin. 26, 153–161 (1951).

    CAS  Google Scholar 

  2. Westergaard, M. L., Hansen, E. H., Glümer, C., Olesen, J. & Jensen, R. H. Definitions of medication-overuse headache in population-based studies and their implications on prevalence estimates: a systematic review. Cephalalgia 34, 409–425 (2014).

    Article  Google Scholar 

  3. Headache Classification Committee of the International Headache Society (IHS). Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8, 1–96 (1988).

    Google Scholar 

  4. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38, 1–211 (2018).

    Article  Google Scholar 

  5. Schwedt, T. J. et al. Factors associated with acute medication overuse in people with migraine: results from the 2017 migraine in America symptoms and treatment (MAST) study. J. Headache Pain 19, 38 (2018).

    Article  Google Scholar 

  6. Bigal, M. E. et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 48, 1157–1168 (2008).

    Article  Google Scholar 

  7. Bigal, M. E., Rapoport, A. M., Sheftell, F. D., Tepper, S. J. & Lipton, R. B. Transformed migraine and medication overuse in a tertiary headache centre-clinical characteristics and treatment outcomes. Cephalalgia 24, 483–490 (2004).

    Article  CAS  Google Scholar 

  8. Buse, D. C., Greisman, J. D., Baigi, K. & Lipton, R. B. Migraine progression: a systematic review. Headache 59, 306–338 (2019).

    Article  Google Scholar 

  9. Hagen, K., Linde, M., Steiner, T. J., Stovner, L. J. & Zwart, J. A. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trøndelag health studies. Pain 153, 56–61 (2012).

    Article  Google Scholar 

  10. Ashina, H. & Dodick, D. W. Medication-overuse headache in patients with secondary headache disorders: need for revision? Headache 61, 790–791 (2021).

    Article  Google Scholar 

  11. Zwart, J. A. et al. Analgesic overuse among subjects with headache, neck, and low-back pain. Neurology 62, 1540–1544 (2004).

    Article  Google Scholar 

  12. Young, W. B. De-stigmatizing migraine - with words. Headache 58, 319–321 (2018).

    Article  Google Scholar 

  13. Institute for Health Metrics and Evaluation. Global Burden of Disease (GBD). Institute for Health Metrics and Evaluation https://www.healthdata.org/gbd/2019 (2019).

  14. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1545–1602 (2016).

    Article  Google Scholar 

  15. Population Pyramid. Population pyramids of the World from 1950 to 2100. Population Pyramid https://www.populationpyramid.net (2019).

  16. Luvsannorov, O. et al. Primary headache disorders among the adult population of Mongolia: prevalences and associations from a population-based survey. J. Headache Pain 20, 114 (2019).

    Article  CAS  Google Scholar 

  17. Yu, S. et al. The prevalence and burden of primary headaches in China: a population-based door-to-door survey. Headache 52, 582–591 (2012).

    Article  Google Scholar 

  18. Manandhar, K., Risal, A., Steiner, T. J., Holen, A. & Linde, M. The prevalence of primary headache disorders in Nepal: a nationwide population-based study. J. Headache Pain 16, 95 (2015).

    Article  Google Scholar 

  19. Kulkarni, G. B., Rao, G. N., Gururaj, G., Stovner, L. J. & Steiner, T. J. Headache disorders and public ill-health in India: prevalence estimates in Karnataka State. J. Headache Pain 16, 67 (2015).

    Article  Google Scholar 

  20. Ayzenberg, I. et al. The prevalence of primary headache disorders in Russia: a countrywide survey. Cephalalgia 32, 373–381 (2012).

    Article  CAS  Google Scholar 

  21. Rastenytė, D. et al. Prevalence and burden of headache disorders in Lithuania and their public-health and policy implications: a population-based study within the Eurolight Project. J. Headache Pain 18, 53 (2017).

    Article  Google Scholar 

  22. Al Jumah, M. et al. The prevalence of primary headache disorders in Saudi Arabia: a cross-sectional population-based study. J. Headache Pain 21, 11 (2020).

    Article  Google Scholar 

  23. Herekar, A. A. et al. Primary headache disorders in the adult general population of Pakistan - a cross sectional nationwide prevalence survey. J. Headache Pain 18, 28 (2017).

    Article  CAS  Google Scholar 

  24. Mbewe, E. et al. The epidemiology of primary headache disorders in Zambia: a population-based door-to-door survey. J. Headache Pain 16, 515 (2015).

    Google Scholar 

  25. Zebenigus, M., Tekle-Haimanot, R., Worku, D. K., Thomas, H. & Steiner, T. J. The prevalence of primary headache disorders in Ethiopia. J. Headache Pain 17, 110 (2016).

    Article  Google Scholar 

  26. Stovner, L. J., Hagen, K., Linde, M. & Steiner, T. J. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J. Headache Pain 23, 34 (2022).

    Article  Google Scholar 

  27. Zewde, Y. Z. et al. The prevalence of headache disorders in children and adolescents in Ethiopia: a schools-based study. J. Headache Pain 21, 108 (2020).

    Article  Google Scholar 

  28. Togha, M. et al. The prevalence of headache disorders in children and adolescents in Iran: a schools-based study. Cephalalgia 42, 1246–1254 (2022).

    Article  Google Scholar 

  29. Genc, D. et al. The prevalence of headache disorders in children and adolescents in Lithuania: a schools-based study. J. Headache Pain 21, 73 (2020).

    Article  Google Scholar 

  30. Luvsannorov, O. et al. The prevalence of headache disorders in children and adolescents in Mongolia: a nationwide schools-based study. J. Headache Pain 21, 107 (2020).

    Article  Google Scholar 

  31. Kawatu, N. et al. The prevalence of primary headache disorders in children and adolescents in Zambia: a schools-based study. J. Headache Pain 23, 118 (2022).

    Article  Google Scholar 

  32. Wöber-Bingöl, Ç. et al. The global burden of headache in children and adolescents-developing a questionnaire and methodology for a global study. J. Headache Pain 15, 86 (2014).

    Article  Google Scholar 

  33. Westergaard, M. L., Glümer, C., Hansen, E. H. & Jensen, R. H. Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. Pain 155, 2005–2013 (2014).

    Article  Google Scholar 

  34. Westergaard, M. L., Lau, C. J., Allesøe, K., Gjendal, S. T. & Jensen, R. H. Monitoring chronic headache and medication-overuse headache prevalence in Denmark. Cephalalgia 40, 6–18 (2020).

    Article  Google Scholar 

  35. Jonsson, P., Hedenrud, T. & Linde, M. Epidemiology of medication overuse headache in the general Swedish population. Cephalalgia 31, 1015–1022 (2011).

    Article  Google Scholar 

  36. Aaseth, K. et al. Prevalence of secondary chronic headaches in a population-based sample of 30-44-year-old persons. The Akershus study of chronic headache. Cephalalgia 28, 705–713 (2008).

    Article  CAS  Google Scholar 

  37. Lampl, C. et al. Headache, depression and anxiety: associations in the Eurolight project. J. Headache Pain 17, 59 (2016).

    Article  Google Scholar 

  38. Bendtsen, L. et al. Disability, anxiety and depression associated with medication-overuse headache can be considerably reduced by detoxification and prophylactic treatment. Results from a multicentre, multinational study (COMOESTAS project). Cephalalgia 34, 426–433 (2014).

    Article  CAS  Google Scholar 

  39. Kristoffersen, E. S., Straand, J., Russell, M. B. & Lundqvist, C. Disability, anxiety and depression in patients with medication-overuse headache in primary care - the BIMOH study. Eur. J. Neurol. 23, 28–35 (2016).

    Article  Google Scholar 

  40. Sarchielli, P. et al. Psychopathological comorbidities in medication-overuse headache: a multicentre clinical study. Eur. J. Neurol. 23, 85–91 (2016).

    Article  CAS  Google Scholar 

  41. Vandenbussche, N. et al. Medication-overuse headache: a widely recognized entity amidst ongoing debate. J. Headache Pain 19, 50 (2018).

    Article  Google Scholar 

  42. Wang, Y.-F., Yu, C.-C., Kuan, A. S., Chen, S.-P. & Wang, S.-J. Association between suicidal risks and medication-overuse headache in chronic migraine: a cross-sectional study. J. Headache Pain 22, 36 (2021).

    Article  Google Scholar 

  43. Pakalnis, A., Butz, C., Splaingard, D., Kring, D. & Fong, J. Emotional problems and prevalence of medication overuse in pediatric chronic daily headache. J. Child Neurol. 22, 1356–1359 (2007).

    Article  Google Scholar 

  44. Pompili, M. et al. Psychiatric comorbidity and suicide risk in patients with chronic migraine. Neuropsychiatr. Dis. Treat. 6, 81–91 (2010).

    Article  Google Scholar 

  45. Bottiroli, S. et al. Psychological, clinical, and therapeutic predictors of the outcome of detoxification in a large clinical population of medication-overuse headache: a six-month follow-up of the COMOESTAS Project. Cephalalgia 39, 135–147 (2018).

    Article  Google Scholar 

  46. Schwedt, T. J. et al. Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: results from the MOTS trial. Cephalalgia 41, 1053–1064 (2021).

    Article  Google Scholar 

  47. Diener, H. C., Holle, D., Solbach, K. & Gaul, C. Medication-overuse headache: risk factors, pathophysiology and management. Nat. Rev. Neurol. 12, 575–583 (2016).

    Article  Google Scholar 

  48. Viana, M. et al. Clinical subtypes of medication overuse headache - findings from a large cohort. Headache 59, 1481–1491 (2019).

    Article  Google Scholar 

  49. Schwedt, T. J. et al. Headache characteristics and burden from chronic migraine with medication overuse headache: Cross-sectional observations from the Medication Overuse Treatment Strategy trial. Headache 61, 351–362 (2021).

    Article  Google Scholar 

  50. Wang, S. J., Juang, K. D., Fuh, J. L. & Lu, S. R. Psychiatric comorbidity and suicide risk in adolescents with chronic daily headache. Neurology 68, 1468–1473 (2007).

    Article  Google Scholar 

  51. Saylor, D. & Steiner, T. J. The global burden of headache. Semin. Neurol. 38, 182–190 (2018).

    Article  Google Scholar 

  52. He, Z. et al. Metabolic syndrome in female migraine patients is associated with medication overuse headache: a clinic-based study in China. Eur. J. Neurol. 22, 1228–1234 (2015).

    Article  CAS  Google Scholar 

  53. Togha, M. et al. Characteristics and comorbidities of headache in patients over 50 years of age: a cross-sectional study. BMC Geriatrics 22, 313 (2022).

    Article  Google Scholar 

  54. Sancisi, E. et al. Increased prevalence of sleep disorders in chronic headache: a case–control study. Headache 50, 1464–1472 (2010).

    Article  Google Scholar 

  55. Westergaard, M. L., Glümer, C., Hansen, E. H. & Jensen, R. H. Medication overuse, healthy lifestyle behaviour and stress in chronic headache: results from a population-based representative survey. Cephalalgia 36, 15–28 (2016).

    Article  Google Scholar 

  56. World Health Organization. WHO methods and data sources for global burden of disease estimates 2000-2019. WHO https://cdn.who.int/media/docs/default-source/gho-documents/global-health-estimates/ghe2019_daly-methods.pdf (2020).

  57. Mathers, C. D., Vos, T., Lopez, A. D., Salomon, J. & Ezzatti, M. (ed.) National Burden of Disease Studies: A Practical Guide. Edition 2.0. Global Program on Evidence for Health Policy (World Health Organization, 2001).

  58. Grosse, S. D., Lollar, D. J., Campbell, V. A. & Chamie, M. Disability and disability-adjusted life years: not the same. Public Health Rep. 124, 197–202 (2009).

    Article  Google Scholar 

  59. Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386, 743–800 (2015).

    Article  Google Scholar 

  60. Linde, M. et al. The cost of headache disorders in Europe: the Eurolight project. Eur. J. Neurol. 19, 703–711 (2012).

    Article  CAS  Google Scholar 

  61. Loder, E. W. & Scher, A. I. Medication overuse headache: the trouble with prevalence estimates. Cephalalgia 40, 3–5 (2020).

    Article  Google Scholar 

  62. Steiner, T. Can we know the prevalence of MOH? Cephalalgia 34, 403–404 (2014).

    Article  Google Scholar 

  63. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33, 629–808 (2013).

    Article  Google Scholar 

  64. Silberstein, S. D. et al. The International Classification of Headache Disorders, 2nd edition (ICHD-II)–revision of criteria for 8.2 Medication-overuse headache. Cephalalgia 25, 460–465 (2005).

    Article  CAS  Google Scholar 

  65. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24, 9–160 (2004).

    Google Scholar 

  66. Siberstein, S. D., Lipton, R. B., Solomon, S. & Mathew, N. T. Classification of daily and near-daily headaches: proposed revisions to the IHS criteria. Headache 34, 1–7 (1994).

    Article  CAS  Google Scholar 

  67. World Health Organization. ICD-10: international statistical classification of diseases and related health problems: tenth revision, 2nd ed. WHO https://apps.who.int/iris/handle/10665/42980 (2004).

  68. Steiner, T. J. et al. The Global Campaign turns 18: a brief review of its activities and achievements. J. Headache Pain 23, 49 (2022).

    Article  Google Scholar 

  69. Stovner, L. J. et al. The methodology of population surveys of headache prevalence, burden and cost: principles and recommendations from the Global Campaign against Headache. J. Headache Pain 15, 5 (2014).

    Article  Google Scholar 

  70. Steiner, T. J. et al. Diagnosis, prevalence estimation and burden measurement in population surveys of headache: presenting the HARDSHIP questionnaire. J. Headache Pain 15, 3 (2014).

    Article  Google Scholar 

  71. Diener, H. C. et al. Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol. 18, 891–902 (2019).

    Article  Google Scholar 

  72. Sun-Edelstein, C., Rapoport, A. M., Rattanawong, W. & Srikiatkhachorn, A. The evolution of medication overuse headache: history, pathophysiology and clinical update. CNS Drugs 35, 545–565 (2021).

    Article  Google Scholar 

  73. Lance, F., Parkes, C. & Wilkinson, M. Does analgesic abuse cause headaches de novo? Headache 28, 61–62 (1988).

    Article  CAS  Google Scholar 

  74. Bahra, A., Walsh, M., Menon, S. & Goadsby, P. J. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache 43, 179–190 (2003).

    Article  Google Scholar 

  75. Rosignoli, C. et al. Applying a biopsychosocial model to migraine: rationale and clinical implications. J. Headache Pain 23, 100 (2022).

    Article  Google Scholar 

  76. Da Silva, A. N. & Lake, A. E. III Clinical aspects of medication overuse headaches. Headache 54, 211–217 (2014).

    Article  Google Scholar 

  77. Hautakangas, H. et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat. Genet. 54, 152–160 (2022).

    Article  CAS  Google Scholar 

  78. Di Lorenzo, C. et al. Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism. Cephalalgia 32, 1189–1197 (2012).

    Article  Google Scholar 

  79. Di Lorenzo, C. et al. Drug consumption in medication overuse headache is influenced by brain-derived neurotrophic factor Val66Met polymorphism. J. Headache Pain 10, 349–355 (2009).

    Article  Google Scholar 

  80. Cargnin, S. et al. Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy. Eur. J. Neurol. 21, 989–995 (2014).

    Article  CAS  Google Scholar 

  81. Cargnin, S., Viana, M., Sances, G., Tassorelli, C. & Terrazzino, S. A systematic review and critical appraisal of gene polymorphism association studies in medication-overuse headache. Cephalalgia 38, 1361–1373 (2018).

    Article  Google Scholar 

  82. Phillips, M. I. Functions of angiotensin in the central nervous system. Annu. Rev. Physiol. 49, 413–435 (1987).

    Article  CAS  Google Scholar 

  83. Lau, C. I., Liu, M.-N., Chen, W.-H., Walsh, V. & Wang, S.-J. in Progress in Brain Research: Update on Emerging Treatments for Migraine Vol. 255 (eds Wang, S.-J. & Lau, C. I.) 371–402 (Elsevier, 2020).

  84. Haulică, I., Petrescu, G., Uluitu, M., Roşca, V. & Slătineanu, S. Influence of angiotensin II on dog pineal serotonin content. Neurosci. Lett. 18, 329–332 (1980).

    Article  Google Scholar 

  85. Fuxe, K. et al. Neuropeptides and central catecholamine systems: interactions in neuroendocrine and central cardiovascular regulation. Adv. Biochem. Psychopharmacol. 22, 37–50 (1980).

    CAS  Google Scholar 

  86. Yang, Y. et al. Molecular genetic overlap between migraine and major depressive disorder. Eur. J. Hum. Genet. 26, 1202–1216 (2018).

    Article  CAS  Google Scholar 

  87. Anttila, V. et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).

    Article  Google Scholar 

  88. Takahashi, T. T. et al. Medication overuse and drug addiction: a narrative review from addiction perspective. J. Headache Pain 22, 32 (2021).

    Article  Google Scholar 

  89. Lundqvist, C., Gossop, M., Russell, M. B., Straand, J. & Kristoffersen, E. S. Severity of analgesic dependence and medication-overuse headache. J. Addict. Med. 13, 346–353 (2019).

    Article  Google Scholar 

  90. Radat, F., Chanraud, S., Di Scala, G., Dousset, V. & Allard, M. Psychological and neuropsychological correlates of dependence-related behaviour in medication overuse headaches: a one year follow-up study. J. Headache Pain 14, 59 (2013).

    Article  Google Scholar 

  91. Radat, F. et al. Behavioral dependence in patients with medication overuse headache: a cross-sectional study in consulting patients using the DSM-IV criteria. Headache 48, 1026–1036 (2008).

    Article  Google Scholar 

  92. Lundqvist, C., Grande, R. B., Aaseth, K. & Russell, M. B. Dependence scores predict prognosis of medication overuse headache: a prospective cohort from the Akershus study of chronic headache. Pain 153, 682–686 (2012).

    Article  Google Scholar 

  93. Fuh, J. L. & Wang, S. J. Dependent behavior in patients with medication-overuse headache. Curr. Pain Headache Rep. 16, 73–79 (2012).

    Article  Google Scholar 

  94. Buse, D. C. et al. Opioid use and dependence among persons with migraine: results of the AMPP study. Headache 52, 18–36 (2012).

    Article  Google Scholar 

  95. Saper, J. R., Hamel, R. L. & Lake, A. E. III Medication overuse headache (MOH) is a biobehavioural disorder. Cephalalgia 25, 545–546 (2005).

    Article  CAS  Google Scholar 

  96. Cevoli, S. et al. Family history for chronic headache and drug overuse as a risk factor for headache chronification. Headache 49, 412–418 (2009).

    Article  Google Scholar 

  97. Barbanti, P. et al. Dopamine-beta-hydroxylase 19-bp insertion/deletion polymorphism affects medication overuse in patients with chronic migraine. Neurol. Sci. 40, 1717–1724 (2019).

    Article  Google Scholar 

  98. Lake, A. E. III Medication overuse headache: biobehavioral issues and solutions. Headache 46, S88–S97 (2006).

    Article  Google Scholar 

  99. GBD 2016 Alcohol and Drug Use Collaborators. The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Psychiatry 5, 987–1012 (2018).

    Article  Google Scholar 

  100. Popescu, A., Marian, M., Drăgoi, A. M. & Costea, R. V. Understanding the genetics and neurobiological pathways behind addiction (review). Exp. Ther. Med. 21, 544 (2021).

    Article  CAS  Google Scholar 

  101. Peres, M. F. et al. Cephalalgiaphobia: a possible specific phobia of illness. J. Headache Pain 8, 56–59 (2007).

    Article  Google Scholar 

  102. van Casteren, D. S., Verhagen, I. E., Onderwater, G. L., MaassenVanDenBrink, A. & Terwindt, G. M. Sex differences in prevalence of migraine trigger factors: a cross-sectional study. Cephalalgia 41, 643–648 (2021).

    Article  Google Scholar 

  103. Verhagen, I. E. et al. Validation of diagnostic ICHD-3 criteria for menstrual migraine. Cephalalgia 42, 1184–1193 (2022).

    Article  Google Scholar 

  104. Martin, V. T. & Behbehani, M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis–part I. Headache 46, 3–23 (2006).

    Article  Google Scholar 

  105. Dussor, G., Boyd, J. T. & Akopian, A. N. Pituitary hormones and orofacial pain. Front. Integr. Neurosci. 12, 42 (2018).

    Article  CAS  Google Scholar 

  106. Chen, Y., Navratilova, E., Dodick, D. W. & Porreca, F. An emerging role for prolactin in female-selective pain. Trends Neurosci. 43, 635–648 (2020).

    Article  CAS  Google Scholar 

  107. van Casteren, D. S. et al. Comparing perimenstrual and nonperimenstrual migraine attacks using an e-Diary. Neurology 97, e1661–e1671 (2021).

    Article  Google Scholar 

  108. van Casteren, D. S., Kurth, T., Danser, A. H. J., Terwindt, G. M. & MaassenVanDenBrink, A. Sex differences in response to triptans: a systematic review and meta-analysis. Neurology 96, 162–170 (2021).

    Article  Google Scholar 

  109. MacGregor, E. A. Migraine headache in perimenopausal and menopausal women. Curr. Pain Headache Rep. 13, 399–403 (2009).

    Article  Google Scholar 

  110. Schwedt, T. J. & Chong, C. D. Medication overuse headache: pathophysiological insights from structural and functional brain MRI research. Headache 57, 1173–1178 (2017).

    Article  Google Scholar 

  111. Lai, T. H. et al. Gray matter changes related to medication overuse in patients with chronic migraine. Cephalalgia 36, 1324–1333 (2016).

    Article  Google Scholar 

  112. Riederer, F. et al. Grey matter changes associated with medication-overuse headache: correlations with disease related disability and anxiety. World J. Biol. Psychiatry 13, 517–525 (2012).

    Article  Google Scholar 

  113. Chong, C. D. Brain structural and functional imaging findings in medication-overuse headache. Front. Neurol. 10, 1336–1336 (2020).

    Article  Google Scholar 

  114. Fumal, A. et al. Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine. Brain 129, 543–550 (2006).

    Article  Google Scholar 

  115. Liu, H. et al. Medication overuse headache associated with decreased dopamine transporter availability in the medial but not in the lateral orbitofrontal cortex: a (11)CFT PET/MR study. Int. J. Neurosci. https://doi.org/10.1080/00207454.2022.2126773 (2022).

    Article  Google Scholar 

  116. Grazzi, L. et al. Chronic migraine with medication overuse pre-post withdrawal of symptomatic medication: clinical results and FMRI correlations. Headache 50, 998–1004 (2010).

    Article  Google Scholar 

  117. Ferraro, S. et al. Pain processing in medication overuse headache: a functional magnetic resonance imaging (fMRI) study. Pain Med. 13, 255–262 (2012).

    Article  Google Scholar 

  118. Xu, J., Kong, F. & Buse, D. C. Predictors of episodic migraine transformation to chronic migraine: a systematic review and meta-analysis of observational cohort studies. Cephalalgia 40, 503–516 (2019).

    Article  Google Scholar 

  119. Ashina, M. Migraine. N. Engl. J. Med. 383, 1866–1876 (2020).

    Article  CAS  Google Scholar 

  120. Burstein, R. Deconstructing migraine headache into peripheral and central sensitization. Pain 89, 107–110 (2001).

    Article  CAS  Google Scholar 

  121. De Felice, M., Ossipov, M. H. & Porreca, F. Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache. Curr. Opin. Neurol. 24, 193–196 (2011).

    Article  Google Scholar 

  122. Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).

    Article  Google Scholar 

  123. Ossipov, M. H., Dussor, G. O. & Porreca, F. Central modulation of pain. J. Clin. Invest. 120, 3779–3787 (2010).

    Article  CAS  Google Scholar 

  124. Le Bars, D., Villanueva, L., Bouhassira, D. & Willer, J. C. Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patol. Fiziol. Eksp. Ter. 4, 55–65 (1992).

    Google Scholar 

  125. Ramaswamy, S. & Wodehouse, T. Conditioned pain modulation — a comprehensive review. Neurophysiol. Clin. 51, 197–208 (2021).

    Article  Google Scholar 

  126. Xie, J. Y. et al. Kappa opioid receptor antagonists: a possible new class of therapeutics for migraine prevention. Cephalalgia 37, 780–794 (2017).

    Article  Google Scholar 

  127. Hein, M. et al. Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors. Neuropharmacology 185, 108456 (2021).

    Article  CAS  Google Scholar 

  128. Marmura, M. J. Triggers, protectors, and predictors in episodic migraine. Curr. Pain Headache Rep. 22, 81 (2018).

    Article  Google Scholar 

  129. Hoffmann, J. & Recober, A. Migraine and triggers: post hoc ergo propter hoc. Curr. Pain Headache Rep. 17, 370 (2013).

    Article  Google Scholar 

  130. Nation, K. M., Dodick, D. W., Navratilova, E. & Porreca, F. Sustained exposure to acute migraine medications combined with repeated noxious stimulation dysregulates descending pain modulatory circuits: relevance to medication overuse headache. Cephalalgia 39, 617–625 (2019).

    Article  Google Scholar 

  131. Meng, I. D., Dodick, D., Ossipov, M. H. & Porreca, F. Pathophysiology of medication overuse headache: insights and hypotheses from preclinical studies. Cephalalgia 31, 851–860 (2011).

    Article  Google Scholar 

  132. Ikegami, D. et al. A prolactin-dependent sexually dimorphic mechanism of migraine chronification. Cephalalgia 42, 197–208 (2022).

    Article  Google Scholar 

  133. Nassini, R. et al. The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system. Brain 135, 376–390 (2012).

    Article  Google Scholar 

  134. Munksgaard, S. B., Bendtsen, L. & Jensen, R. H. Modulation of central sensitisation by detoxification in MOH: results of a 12-month detoxification study. Cephalalgia 33, 444–453 (2013).

    Article  Google Scholar 

  135. Filatova, E., Latysheva, N. & Kurenkov, A. Evidence of persistent central sensitization in chronic headaches: a multi-method study. J. Headache Pain 9, 295–300 (2008).

    Article  Google Scholar 

  136. Zappaterra, M., Guerzoni, S., Cainazzo, M. M., Ferrari, A. & Pini, L. A. Basal cutaneous pain threshold in headache patients. J. Headache Pain 12, 303–310 (2011).

    Article  Google Scholar 

  137. Perrotta, A. et al. Acute reduction of anandamide-hydrolase (FAAH) activity is coupled with a reduction of nociceptive pathways facilitation in medication-overuse headache subjects after withdrawal treatment. Headache 52, 1350–1361 (2012).

    Article  Google Scholar 

  138. Perrotta, A. et al. Sensitisation of spinal cord pain processing in medication overuse headache involves supraspinal pain control. Cephalalgia 30, 272–284 (2010).

    Article  CAS  Google Scholar 

  139. Schou, W. S., Ashina, S., Amin, F. M., Goadsby, P. J. & Ashina, M. Calcitonin gene-related peptide and pain: a systematic review. J. Headache Pain 18, 34 (2017).

    Article  Google Scholar 

  140. Messlinger, K. The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system. J. Headache Pain 19, 22 (2018).

    Article  Google Scholar 

  141. Belanger, S., Ma, W., Chabot, J. G. & Quirion, R. Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates. Neuroscience 115, 441–453 (2002).

    Article  CAS  Google Scholar 

  142. Ma, W., Zheng, W. H., Kar, S. & Quirion, R. Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons. Neuroscience 99, 529–539 (2000).

    Article  CAS  Google Scholar 

  143. Yisarakun, W. et al. Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model. Neuropeptides 51, 9–16 (2015).

    Article  CAS  Google Scholar 

  144. Ménard, D. P. et al. Tolerance to the antinociceptive properties of morphine in the rat spinal cord: alteration of calcitonin gene-related peptide-like immunostaining and receptor binding sites. J. Pharmacol. Exp. Ther. 273, 887–894 (1995).

    Google Scholar 

  145. De Felice, M. et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann. Neurol. 67, 325–337 (2010).

    Google Scholar 

  146. De Felice, M. et al. Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 133, 2475–2488 (2010).

    Article  Google Scholar 

  147. Calabresi, P. & Cupini, L. M. Medication-overuse headache: similarities with drug addiction. Trends Pharmacol. Sci. 26, 62–68 (2005).

    Article  CAS  Google Scholar 

  148. Supornsilpchai, W., le Grand, S. M. & Srikiatkhachorn, A. Cortical hyperexcitability and mechanism of medication-overuse headache. Cephalalgia 30, 1101–1109 (2010).

    Article  Google Scholar 

  149. Green, A. L. et al. Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache. Cephalalgia 34, 594–604 (2014).

    Article  Google Scholar 

  150. Becerra, L. et al. Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas. J. Neurophysiol. 115, 208–217 (2016).

    Article  CAS  Google Scholar 

  151. Ayzenberg, I. et al. Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures. Cephalalgia 26, 1106–1114 (2006).

    Article  CAS  Google Scholar 

  152. Coppola, G. et al. Abnormal cortical responses to somatosensory stimulation in medication-overuse headache. BMC Neurol. 10, 126 (2010).

    Article  Google Scholar 

  153. Ashina, S. et al. Tension-type headache. Nat. Rev. Dis. Primers 7, 24 (2021).

    Article  Google Scholar 

  154. Deen, M. et al. Serotonergic mechanisms in the migraine brain - a systematic review. Cephalalgia 37, 251–264 (2017).

    Article  Google Scholar 

  155. Srikiatkhachorn, A., Tarasub, N. & Govitrapong, P. Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Headache 40, 343–350 (2000).

    Article  CAS  Google Scholar 

  156. Pini, L. A., Vitale, G., Ottani, A. & Sandrini, M. Naloxone-reversible antinociception by paracetamol in the rat. J. Pharmacol. Exp. Ther. 280, 934–940 (1997).

    CAS  Google Scholar 

  157. Björkman, R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol. Scand. Suppl. 103, 1–44 (1995).

    Google Scholar 

  158. Darmani, N. A., Martin, B. R. & Glennon, R. A. Behavioral evidence for differential adaptation of the serotonergic system after acute and chronic treatment with (+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or ketanserin. J. Pharmacol. Exp. Ther. 262, 692–698 (1992).

    CAS  Google Scholar 

  159. Eikermann-Haerter, K. et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J. Clin. Invest. 119, 99–109 (2009).

    CAS  Google Scholar 

  160. Rossi, P., Faroni, J. V., Tassorelli, C. & Nappi, G. Advice alone versus structured detoxification programmes for complicated medication overuse headache (MOH): a prospective, randomized, open-label trial. J. Headache Pain 14, 10 (2013).

    Article  Google Scholar 

  161. Tassorelli, C. et al. The added value of an electronic monitoring and alerting system in the management of medication-overuse headache: a controlled multicentre study. Cephalalgia 37, 1115–1125 (2017).

    Article  Google Scholar 

  162. Pijpers, J. A., Kies, D. A., van Zwet, E. W., Rosendaal, F. R. & Terwindt, G. M. Behavioural intervention in medication overuse headache: a concealed double-blind randomized controlled trial. Eur. J. Neurol. 29, 1496–1504 (2022).

    Article  Google Scholar 

  163. Pijpers, J. A. et al. Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: a double-blind randomized controlled trial. Brain 142, 1203–1214 (2019).

    Article  Google Scholar 

  164. Carlsen, L. N. et al. Comparison of 3 treatment strategies for medication overuse headache: a randomized clinical trial. JAMA Neurol. 77, 1069–1078 (2020).

    Article  Google Scholar 

  165. Munksgaard, S. B. & Jensen, R. H. Medication overuse headache. Headache 54, 1251–1257 (2014).

    Article  Google Scholar 

  166. Eide, P. K. Wind-up and the NMDA receptor complex from a clinical perspective. Eur. J. Pain 4, 5–15 (2000).

    Article  CAS  Google Scholar 

  167. Dodick, D. W. et al. Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Cephalalgia 41, 340–352 (2021).

    Article  Google Scholar 

  168. Silberstein, S. D. et al. The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study. J. Headache Pain 21, 114 (2020).

    Article  CAS  Google Scholar 

  169. Tepper, S. J. et al. Erenumab in chronic migraine with medication overuse: subgroup analysis of a randomized trial. Neurology 92, e2309–e2320 (2019).

    Article  CAS  Google Scholar 

  170. Diener, H. C. et al. Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: subgroup analysis of PROMISE-2. Headache 61, 125–136 (2021).

    Article  Google Scholar 

  171. Navratilova, E. et al. Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache. Cephalalgia 40, 892–902 (2020).

    Article  Google Scholar 

  172. Croop, R. et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet 394, 737–745 (2019).

    Article  CAS  Google Scholar 

  173. McGinley, J. S. et al. Rimegepant 75 mg results in reductions in monthly migraine days: secondary analysis of a multicenter, open label long-term safety study of rimegepant for the acute treatment of migraine. Neurology 94 (Suppl. 15), 1793 (2020).

    Google Scholar 

  174. Ailani, J., Burch, R. C. & Robbins, M. S. The American Headache Society Consensus Statement: update on integrating new migraine treatments into clinical practice Headache 61, 1021–1039 (2021).

    Article  Google Scholar 

  175. Limmroth, V., Katsarava, Z., Fritsche, G., Przywara, S. & Diener, H. C. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 59, 1011–1014 (2002).

    Article  CAS  Google Scholar 

  176. Lipton, R. B. et al. Burden of increasing opioid use in the treatment of migraine: results from the Migraine in America Symptoms and Treatment study. Headache 61, 103–116 (2021).

    Article  Google Scholar 

  177. Willer, L., Jensen, R. H. & Juhler, M. Medication overuse as a cause of chronic headache in shunted hydrocephalus patients. J. Neurol. Neurosurg. Psychiatry 81, 1261–1264 (2010).

    Article  CAS  Google Scholar 

  178. deSouza, R. M., Toma, A. & Watkins, L. Medication overuse headache–an under-diagnosed problem in shunted idiopathic intracranial hypertension patients. Br. J. Neurosurg. 29, 30–34 (2015).

    Article  Google Scholar 

  179. Heyer, G. L. & Idris, S. A. Does analgesic overuse contribute to chronic post-traumatic headaches in adolescent concussion patients? Pediatr. Neurol. 50, 464–468 (2014).

    Article  Google Scholar 

  180. Diener, H. C. & Dahlöf, C. in The Headaches (eds Olesen, J., Tfelt-Hansen, P. & Welch, K. M.) Ch. 115, 871–878 (Lippincott Williams & Wilkins, 2000).

  181. Oh, S. Y. et al. Clinical characteristics of medication-overuse headache according to the class of acute medication: a cross-sectional multicenter study. Headache 62, 890–902 (2022).

    Article  Google Scholar 

  182. Thorlund, K. et al. Risk of medication overuse headache across classes of treatments for acute migraine. J. Headache Pain 17, 107 (2016).

    Article  Google Scholar 

  183. Jellestad, P. L. et al. Economic benefits of treating medication-overuse headache–results from the multicenter COMOESTAS project. Cephalalgia 39, 274–285 (2019).

    Article  Google Scholar 

  184. Do, T. P. et al. Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list. Neurology 92, 134–144 (2019).

    Article  Google Scholar 

  185. Dodick, D. W. Clinical clues and clinical rules: primary vs secondary headache. Adv. Stud. Med. 3, S550–S555 (2003).

    Google Scholar 

  186. van Casteren, D. S. et al. E-diary use in clinical headache practice: a prospective observational study. Cephalalgia 41, 1161–1171 (2021).

    Article  Google Scholar 

  187. Lai, J. T. F. et al. Should we educate about the risks of medication overuse headache. J. Headache Pain 15, 10 (2014).

    Article  Google Scholar 

  188. Carlsen, L. N., Westergaard, M. L., Bisgaard, M., Schytz, J. B. & Jensen, R. H. National awareness campaign to prevent medication-overuse headache in Denmark. Cephalalgia 38, 1316–1325 (2018).

    Article  Google Scholar 

  189. Hedenrud, T., Babic, N. & Jonsson, P. Medication overuse headache: self-perceived and actual knowledge among pharmacy staff. Headache 54, 1019–1025 (2014).

    Article  Google Scholar 

  190. Lagman-Bartolome, A. M., Lawler, V. & Lay, C. Headache education active-waiting directive: a program to enhance well-being during long referral wait times. Headache 58, 109–117 (2018).

    Article  Google Scholar 

  191. FDA. Treating migraines: more ways to fight the pain. FDA https://www.fda.gov/consumers/consumer-updates/treating-migraines-more-ways-fight-pain (2017).

  192. Ashina, S., Lyngberg, A. & Jensen, R. Headache characteristics and chronification of migraine and tension-type headache: a population-based study. Cephalalgia 30, 943–952 (2010).

    Article  Google Scholar 

  193. Scher, A. I. et al. Comorbid pain and migraine chronicity: the chronic migraine epidemiology and outcomes study. Neurology 89, 461–468 (2017).

    Article  Google Scholar 

  194. Scher, A. I., Stewart, W. F., Ricci, J. A. & Lipton, R. B. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 106, 81–89 (2003).

    Article  CAS  Google Scholar 

  195. Hagen, K., Jensen, R., Bøe, M. G. & Stovner, L. J. Medication overuse headache: a critical review of end points in recent follow-up studies. J. Headache Pain 11, 373–377 (2010).

    Article  Google Scholar 

  196. Scher, A. I., Rizzoli, P. B. & Loder, E. W. Medication overuse headache: an entrenched idea in need of scrutiny. Neurology 89, 1296–1304 (2017).

    Article  Google Scholar 

  197. Chen, P. K. & Wang, S. J. Medication overuse and medication overuse headache: risk factors, comorbidities, associated burdens and nonpharmacologic and pharmacologic treatment approaches. Curr. Pain Headache Rep. 23, 60 (2019).

    Article  CAS  Google Scholar 

  198. Diener, H. C. et al. European Academy of Neurology guideline on the management of medication-overuse headache. Eur. J. Neurol. 27, 1102–1116 (2020).

    Article  CAS  Google Scholar 

  199. Rossi, P., Di Lorenzo, C., Faroni, J., Cesarino, F. & Nappi, G. Advice alone vs. structured detoxification programmes for medication overuse headache: a prospective, randomized, open-label trial in transformed migraine patients with low medical needs. Cephalalgia 26, 1097–1105 (2006).

    Article  CAS  Google Scholar 

  200. Kristoffersen, E. S. et al. Brief intervention for medication-overuse headache in primary care. The BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial. J. Neurol. Neurosurg. Psychiatry 86, 505–512 (2015).

    Article  Google Scholar 

  201. Hagen, K. et al. Management of medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia 29, 221–232 (2009).

    Article  CAS  Google Scholar 

  202. Chiang, C. C., Schwedt, T. J., Wang, S. J. & Dodick, D. W. Treatment of medication-overuse headache: a systematic review. Cephalalgia 36, 371–386 (2016).

    Article  Google Scholar 

  203. Schwedt, T. J. et al. Patient-centered treatment of chronic migraine with medication overuse: a prospective, randomized, pragmatic clinical trial. Neurology 98, e1409–e1421 (2022).

    Article  Google Scholar 

  204. Carlsen, L. N., Munksgaard, S. B., Jensen, R. H. & Bendtsen, L. Complete detoxification is the most effective treatment of medication-overuse headache: a randomized controlled open-label trial. Cephalalgia 38, 225–236 (2018).

    Article  Google Scholar 

  205. Engelstoft, I. M. S. et al. Complete withdrawal is the most feasible treatment for medication-overuse headache: a randomized controlled open-label trial. Eur. J. Pain 23, 1162–1170 (2019).

    Article  Google Scholar 

  206. Bottiroli, S. et al. Negative short-term outcome of detoxification therapy in chronic migraine with medication overuse headache: role for early life traumatic experiences and recent stressful events. Front. Neurol. 10, 173 (2019).

    Article  Google Scholar 

  207. Tassorelli, C. et al. A consensus protocol for the management of medication-overuse headache: evaluation in a multicentric, multinational study. Cephalalgia 34, 645–655 (2014).

    Article  Google Scholar 

  208. Schytz, H. W. et al. Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 3rd edition, 2020. J. Headache Pain 22, 22 (2021).

    Article  Google Scholar 

  209. Krymchantowski, A. V. & Moreira, P. F. Out-patient detoxification in chronic migraine: comparison of strategies. Cephalalgia 23, 982–993 (2003).

    Article  CAS  Google Scholar 

  210. Boe, M. G., Mygland, A. & Salvesen, R. Prednisolone does not reduce withdrawal headache: a randomized, double-blind study. Neurology 69, 26–31 (2007).

    Article  Google Scholar 

  211. Rabe, K. et al. Prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind, placebo-controlled study. Cephalalgia 33, 202–207 (2013).

    Article  Google Scholar 

  212. Cevoli, S. et al. Treatment of withdrawal headache in patients with medication overuse headache: a pilot study. J. Headache Pain 18, 56 (2017).

    Article  Google Scholar 

  213. Taghdiri, F., Togha, M., Razeghi Jahromi, S. & Paknejad, S. M. Celecoxib vs prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind clinical trial. Headache 55, 128–135 (2015).

    Article  Google Scholar 

  214. Diener, H. C. et al. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 27, 814–823 (2007).

    Article  Google Scholar 

  215. Sarchielli, P. et al. Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial. Eur. Neuropsychopharmacol. 24, 1289–1297 (2014).

    Article  CAS  Google Scholar 

  216. Silberstein, S. D. et al. OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J. Neurol. Sci. 331, 48–56 (2013).

    Article  CAS  Google Scholar 

  217. Silberstein, S. D. et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 47, 170–180 (2007).

    Article  Google Scholar 

  218. Diener, H. C. et al. Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse. Cephalalgia 29, 1021–1027 (2009).

    Article  Google Scholar 

  219. Goadsby, P. J. et al. Efficacy of oral atogepant in people with chronic migraine with and without acute medication overuse: results from the PROGRESS trial. Cephalalgia 42 (Suppl. 1) 34–35 (2022).

    Google Scholar 

  220. Croop, R. et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet 397, 51–60 (2021).

    Article  CAS  Google Scholar 

  221. Karadas, O., Ozon, A. O., Ozcelik, F. & Ozge, A. Greater occipital nerve block in the treatment of triptan-overuse headache: a randomized comparative study. Acta Neurol. Scand. 135, 426–433 (2017).

    Article  CAS  Google Scholar 

  222. Andrasik, F., Grazzi, L., Usai, S., Buse, D. C. & Bussone, G. Non-pharmacological approaches to treating chronic migraine with medication overuse. Neurol. Sci. 30, S89–S93 (2009).

    Article  Google Scholar 

  223. Pijpers, J. A. et al. Detoxification in medication-overuse headache, a retrospective controlled follow-up study: does care by a headache nurse lead to cure. Cephalalgia 36, 122–130 (2016).

    Article  CAS  Google Scholar 

  224. Munksgaard, S. B., Bendtsen, L. & Jensen, R. H. Detoxification of medication-overuse headache by a multidisciplinary treatment programme is highly effective: a comparison of two consecutive treatment methods in an open-label design. Cephalalgia 32, 834–844 (2012).

    Article  Google Scholar 

  225. Rausa, M. et al. Biofeedback in the prophylactic treatment of medication overuse headache: a pilot randomized controlled trial. J. Headache Pain 17, 87 (2016).

    Article  Google Scholar 

  226. Grazzi, L. et al. A preliminary analysis on the feasibility and short-term efficacy of a phase-III RCT on mindfulness added to treatment as usual for patients with chronic migraine and medication overuse headache. Int. J. Environ. Res. Public Health 19, 14116 (2022).

    Article  Google Scholar 

  227. Yang, C. P. et al. Acupuncture versus topiramate in chronic migraine prophylaxis: a randomized clinical trial. Cephalalgia 31, 1510–1521 (2011).

    Article  Google Scholar 

  228. Serra, G. & Marchioretto, F. Occipital nerve stimulation for chronic migraine: a randomized trial. Pain Physician 15, 245–253 (2012).

    Article  Google Scholar 

  229. Paemeleire, K. et al. Phenotype of patients responsive to occipital nerve stimulation for refractory head pain. Cephalalgia 30, 662–673 (2010).

    CAS  Google Scholar 

  230. Grazzi, L. et al. No efficacy of transcranial direct current stimulation on chronic migraine with medication overuse: a double blind, randomised clinical trial. Cephalalgia 40, 1202–1211 (2020).

    Article  Google Scholar 

  231. De Icco, R. et al. Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: a pilot double-blind randomized sham-controlled trial. Clin. Neurophysiol. 132, 126–136 (2021).

    Article  Google Scholar 

  232. Schoenen, J. et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 80, 697–704 (2013).

    Article  Google Scholar 

  233. Najib, U. et al. Non-invasive vagus nerve stimulation for prevention of migraine: the multicenter, randomized, double-blind, sham-controlled PREMIUM II trial. Cephalalgia 42, 560–569 (2022).

    Article  Google Scholar 

  234. Wilkinson, D. et al. Preventing episodic migraine with caloric vestibular stimulation: a randomized controlled trial. Headache 57, 1065–1087 (2017).

    Article  Google Scholar 

  235. Lipton, R. B. et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 9, 373–380 (2010).

    Article  Google Scholar 

  236. Starling, A. J. et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE study). Cephalalgia 38, 1038–1048 (2018).

    Article  Google Scholar 

  237. Tassorelli, C. et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology 91, e364–e373 (2018).

    Article  Google Scholar 

  238. Yarnitsky, D. et al. Nonpainful remote electrical stimulation alleviates episodic migraine pain. Neurology 88, 1250–1255 (2017).

    Article  Google Scholar 

  239. Marmura, M. J., Lin, T., Harris, D., Ironi, A. & Rosen, N. L. Incorporating remote electrical neuromodulation (REN) into usual care reduces acute migraine medication use: an open-label extension study. Front. Neurol. 11, 226 (2020).

    Article  Google Scholar 

  240. Vacca, A. et al. Noninvasive vagal nerve stimulation in chronic migraine with medication overuse headache. Pain Med. 19, 2575–2577 (2018).

    Article  Google Scholar 

  241. Zidverc-Trajkovic, J. J. et al. Long-term predictors of remission in patients treated for medication-overuse headache at a specialized headache center: a prospective cohort study. Cephalalgia 38, 265–273 (2018).

    Article  Google Scholar 

  242. Bøe, M. G., Thortveit, E., Vatne, A. & Mygland, Å. Chronic headache with medication overuse: long-term prognosis after withdrawal therapy. Cephalalgia 37, 1215–1221 (2017).

    Article  Google Scholar 

  243. Grazzi, L., Andrasik, F., Usai, S. & Bussone, G. Headache with medication overuse: treatment strategies and proposals of relapse prevention. Neurol. Sci. 29, 93–98 (2008).

    Article  Google Scholar 

  244. Katsarava, Z. et al. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia 25, 12–15 (2005).

    Article  CAS  Google Scholar 

  245. Pini, L. A., Cicero, A. F. & Sandrini, M. Long-term follow-up of patients treated for chronic headache with analgesic overuse. Cephalalgia 21, 878–883 (2001).

    Article  CAS  Google Scholar 

  246. Sances, G. et al. Risk factors in medication-overuse headache: a 1-year follow-up study (care II protocol). Cephalalgia 30, 329–336 (2010).

    Article  CAS  Google Scholar 

  247. Hershey, A. D., Burdine, D., Kabbouche, M. A. & Powers, S. W. Genomic expression patterns in medication overuse headaches. Cephalalgia 31, 161–171 (2011).

    Article  Google Scholar 

  248. Gelfand, A. A. & Goadsby, P. J. Medication overuse in children and adolescents. Curr. Pain Headache Rep. 18, 428 (2014).

    Article  Google Scholar 

  249. Shah, A. M., Bendtsen, L., Zeeberg, P. & Jensen, R. H. Reduction of medication costs after detoxification for medication-overuse headache. Headache 53, 665–672 (2013).

    Article  Google Scholar 

  250. Ljubisavljevic, M., Ignjatovic, A., Djordjevic, V., Pesic, M. H. & Ljubisavljevic, S. Depression, anxiety, stress, and health-related quality of life among patients with medication overuse headache in a tertiary headache center: a cross-sectional study. J. Neuropsychiatry Clin. Neurosci. 33, 132–143 (2021).

    Article  Google Scholar 

  251. Zebenholzer, K., Thamer, M. & Wöber, C. Quality of life, depression, and anxiety 6 months after inpatient withdrawal in patients with medication overuse headache: an observational study. Clin. J. Pain 28, 284–290 (2012).

    Article  Google Scholar 

  252. Hagen, K. et al. A 4-year follow-up of patients with medication-overuse headache previously included in a randomized multicentre study. J. Headache Pain 12, 315–322 (2011).

    Article  Google Scholar 

  253. Altintaş, E., Karakurum Göksel, B., Taşkintuna, N. & Saritürk, Ç. Correlation between life events and quality of life in patients with medication-overuse headache. Noro Psikiyatr. Ars. 52, 233–239 (2015).

    Article  Google Scholar 

  254. Benz, T. et al. Health and quality of life in patients with medication overuse headache syndrome after standardized inpatient rehabilitation: a cross-sectional pilot study. Medicine 96, e8493 (2017).

    Article  Google Scholar 

  255. Mao, J., Sung, B., Ji, R. R. & Lim, G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J. Neurosci. 22, 8312–8323 (2002).

    Article  CAS  Google Scholar 

  256. Schwedt, T. J. et al. Medication overuse and headache burden: results from the CaMEO study. Neurol. Clin. Pract. 11, 216–226 (2021).

    Article  Google Scholar 

  257. Ailani, J. et al. Atogepant for the preventive treatment of migraine. N. Engl. J. Med. 385, 695–706 (2021).

    Article  CAS  Google Scholar 

  258. Dodick, D. W. et al. Ubrogepant for the treatment of migraine. N. Engl. J. Med. 381, 2230–2241 (2019).

    Article  CAS  Google Scholar 

  259. Lipton, R. B. et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N. Engl. J. Med. 381, 142–149 (2019).

    Article  CAS  Google Scholar 

  260. Rau, J. C. et al. Evaluation of LY573144 (lasmiditan) in a preclinical model of medication overuse headache. Cephalalgia 40, 903–912 (2020).

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank T. P. Do for skilful assistance and for providing the initial sketches for Fig. 1.

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Authors and Affiliations

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Contributions

Introduction (S.A., R.B.L. and T. J. Steiner); Epidemiology (S.A., T. J. Steiner and R.B.L.); Mechanisms/pathophysiology (S.A., G.M.T., F.P. and C.T.); Diagnosis, screening and prevention (S.A., G.M.T., T. J. Schwedt and R.H.J.); Management (S.A., M.J.L., R.H.J. and H.-C.D.); Quality of life (S.A., T. J. Steiner, T. J. Schwedt and R.B.L.); Outlook (S.A., F.P., R.H.J., H.-C.D. and R.B.L.); Overview of Primer (S.A.).

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Correspondence to Sait Ashina.

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Competing interests

S.A. received honoraria for consulting from Allergan/AbbVie, Amgen, Biohaven, Eli Lilly, Impel NeuroPharma, Linpharma, Lundbeck, Novartis, Satsuma, Supernus, Teva, Theranica, Percept. S.A. is an associate editor for Neurology Reviews, Frontiers in Neurology and BMC Neurology, serves on the advisory board for the Journal of Headache and Pain, and is a member of the Education Committee of the International Headache Society. G.M.T. reports consultancy support from Novartis, Allergan, Lilly, Teva, Lundbeck, and independent support from the Dutch Organization for Scientific Research, the Dutch Heart and Brain Foundations, IRRF and Dioraphte. M.J.L. received honoraria as a consultant and/or speaker for Eli Lilly, Teva, Sanofi-Aventis, SK Pharma and YuYu Pharma; has been the principal investigator or co-investigator in trials sponsored by Eli Lilly, Novartis, Teva (Otsuka), Allergan, Biohaven, Yuhan Company, Samjin Pharm, and DongA ST; received research support from National Research Foundation of Korea. M.J.L. is an associate editor of Cephalalgia. F.P. has served as a consultant or received research funding from Amgen, Acadia, Teva, Eli Lilly, Lundbeck, Allergan, AbbVie, AstraZeneca, Ipsen and PeptideLogic and is a founder of Catalina Pharma and Axon Therapeutics. C.T. has received personal fees from AbbVie, Allergan, Biohaven, Eli Lilly, Lundbeck, Novartis and Teva. C.T. has received research funding from the European Commission, the Italian Ministry of Health and Migraine Research Foundation. T. J. Schwedt has received personal income from AbbVie, Allergan, Biohaven, Click Therapeutics, Eli Lilly, Equinox, Lundbeck, Novartis, Tonix and Weber & Weber. T. J. Schwedt holds stock options in Aural Analytics and Nocira and has received royalties from UpToDate. T. J. Schwedt has received research funding from the American Migraine Foundation, Amgen, Henry Jackson Foundation, NIH, Patient Centered Outcomes Research Institute, SPARK Neuro and the US Department of Defense. R.H.J. has received honoraria for lectures and/or patient leaflets from MSD, Berlin-Chemie Menarini, ATI, Novartis, Teva, Allergan, Lundbeck and Pfizer, and has been principal investigator in studies sponsored by Eli Lilly, Lundbeck and ATI. H.-C.D. received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Ipsen, Lilly, Novartis, Pfizer and Teva. The German Research Council (DFG), the German Ministry of Education and Research (BMBF) and the European Union support his headache research. H.-C.D. serves on the editorial boards of Cephalalgia and Lancet Neurology. H.-C.D. is member of the Clinical Trials Committee of the IHS. R.B.L. is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He receives research support from the NIH and FDA. R.B.L. also receives support from the National Headache Foundation and the Marx Foundation. R.B.L. serves on the editorial board of Neurology, is senior adviser to Headache, and associate editor to Cephalalgia and has reviewed for the NIA and NINDS, holds stock options in Biohaven Holdings, Manistee and CntrlM; serves as consultant, advisory board member, or has received honoraria or conducted research funded by Allergan/AbbVie, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Dr Reddy’s (Promius), Electrocore, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Pernix, Pfizer, Teva, Trigemina, Vector, Vedanta. R.B.L. receives royalties from Wolff’s Headache 7th and 8th Edition, Oxford University Press, 2009, Wiley and Informa. T. J. Steiner declares no competing interests.

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Ashina, S., Terwindt, G.M., Steiner, T.J. et al. Medication overuse headache. Nat Rev Dis Primers 9, 5 (2023). https://doi.org/10.1038/s41572-022-00415-0

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