Is Medication Overuse Drug Specific or Not? Data from a Review of Published Literature and from an Original Study on Italian MOH Patients

  • Licia GrazziEmail author
  • Eleonora Grignani
  • Domenico D’Amico
  • Emanuela Sansone
  • Alberto Raggi
Migraine and Beyond (R Cowan, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Migraine and Beyond


Purpose of Review

The aim is twofold. First, to give an insight on the role exerted by different classes of drugs in favouring migraine chronification. Second, to explore the relationship between type and amount of overused medications and history of previous withdrawal treatment and of frequent relapses.

Recent Findings

All drug classes were found to favour migraine chronification. No data are available for the association with relapses into CM-MOH. Our clinical study shows that patients who underwent previous withdrawal treatments were more likely to be overusers of multiple drug classes and overuse higher amounts of symptomatic medications, particularly, indomethacin, eletriptan and tramadol. Frequent relapsers were more likely to be overusers of opioids or ergotamine and caffeine derivates or of multiple classes, particularly acetylsalicylic acid and ergotamine/caffeine derivates.


The joint results our review and clinical study do not seem to support the idea that MOH is drug-specific: rather, it points out that all drug classes may induce migraine chronification. Those drugs which are at higher risk of overuse are among those preferred by the “worst” patients, i.e. those who needed one or more withdrawal treatments for MOH. Our results reinforce the clinical impression that patients with CM and MOH, and particularly the most difficult to treat for their poor response to withdrawal treatments, are characterised by a particular drive towards the consumption of “whatever is likely to be perceived to provide some relief”, despite these drugs that are perceived as “more powerful”, are often indicated as second- or third-line medications.


Chronic migraine Medication-overuse headache Triptans Anti-inflammatory drugs Opioids Withdrawal 


Compliance with Ethical Standards

The protocol was approved by the Besta Institute Ethical Committee (protocol no. 379/2015).

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

11916_2018_729_MOESM1_ESM.docx (23 kb)
ESM 1 (DOCX 22 kb)


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    International Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd ed. Cephalalgia. 2018;38:1–211.Google Scholar
  2. 2.
    •• Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157–68. This is one of the first and most important studies addressing the risk of chronification connected to the use of acute medications. CrossRefPubMedGoogle Scholar
  3. 3.
    Raggi A, Schiavolin S, Leonardi M, Giovannetti AM, Bussone G, Curone M, et al. Chronic migraine with medication overuse: association between disability and quality of life measures, and impact of disease on patients’ lives. J Neurol Sci. 2015;348(1–2):60–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Andrasik F, Grazzi L, Usai S, Kass S, Bussone G. Disability in chronic migraine with medication overuse: treatment effects through 5 years. Cephalalgia. 2010;30:610–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Raggi A, Leonardi M, Giovannetti AM, Schiavolin S, Bussone G, Grazzi L, et al. A 14-month study of change in disability and mood state in patients with chronic migraine associated to medication overuse. Neurol Sci. 2013;34(Suppl 1):139–40.CrossRefGoogle Scholar
  6. 6.
    Bendtsen L, Munksgaard S, Tassorelli C, Nappi G, Katsarava Z, Lainez M, 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. 2014;34:426–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Lantéri-Minet M, Duru G, Mudge M, Cottrell S. Quality of life impairment, disability and economic burden associated with chronic daily headache, focusing on chronic migraine with or without medication overuse: a systematic review. Cephalalgia. 2011;31:837–50.CrossRefPubMedGoogle Scholar
  8. 8.
    Raggi A, Giovannetti AM, Leonardi M, Schiavolin S, D’Amico D, Curone M, et al. Disability and mood state in patients with episodic and chronic migraine associated to medication overuse. Neurol Sci. 2012;33(Suppl 1):169–71.CrossRefGoogle Scholar
  9. 9.
    Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache. 2008;48(1):7–15.CrossRefPubMedGoogle Scholar
  10. 10.
    Bigal ME, Lipton RB. Migraine chronification. Curr Neurol Neurosci Rep. 2011;11(2):139–48.CrossRefPubMedGoogle Scholar
  11. 11.
    Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L, et al. Global prevalence of chronic migraine: a systematic review. Cephalalgia. 2010;30(5):599–609.CrossRefPubMedGoogle Scholar
  12. 12.
    D’Andrea G, D’Amico D, Bussone G, Bolner A, Aguggia M, Saracco MG, et al. The role of tyrosine metabolism in the pathogenesis of chronic migraine. Cephalalgia. 2013;33:932–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Misra UK, Kalita J, Tripathi GM, Bhoi SK. Is β-endorphin related to migraine headache and its relief? Cephalalgia. 2013;33:316–22.CrossRefPubMedGoogle Scholar
  14. 14.
    Cevoli S, Sancisi E, Grimaldi D, Pierangeli G, Zanigni S, Nicodemo M, et al. Family history for chronic headache and drug overuse as a risk factor for headache chronification. Headache. 2009;49:412–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Evers S, Jensen R. Treatment of medication overuse headache guideline of the EFNS headache panel. Eur J Neurol. 2011;18:1115–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Tassorelli C, Diener HC, Dodick DW, Silberstein SD, Lipton RB, Ashina M, et al. International Headache Society Clinical Trials Standing Committee. Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine in adults. Cephalalgia. 2018;38(5):815–32.CrossRefPubMedGoogle Scholar
  17. 17.
    • Katsarava Z, Muessig M, Dzagnidze A, Fritsche G, Diener HC, Limmroth V. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia. 2005;25:12–5. This is the first study addressing long-term relapse rate and providing data on the "protective" effect of triptans on relapse rate into MOH. CrossRefPubMedGoogle Scholar
  18. 18.
    • Katsarava Z, Limmroth V, Finke M, Diener HC, Fritsche G. Rates and predictors for relapse in medication overuse headache: a 1-year prospective study. Neurology. 2003;60:1682–3. This is one of the the first study addressing medium-term relapse rate and providing data on the "protective" effect of triptans on relapse rate into MOH. CrossRefPubMedGoogle Scholar
  19. 19.
    Rossi P, Faroni JV, Nappi G. Medication overuse headache: predictors and rates of relapse in migraine patients with low medical needs. A 1-year prospective study. Cephalalgia. 2008;28:1196–200.CrossRefPubMedGoogle Scholar
  20. 20.
    Biagianti B, Grazzi L, Usai S, Gambini O. Dependency-like behaviors and pain coping styles in subjects with chronic migraine and medication overuse: results from a 1-year follow-up study. BMC Neurol. 2014;14:181.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cargnin S, Viana M, Ghiotto N, Bianchi M, Sances G, Tassorelli C, et al. Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy. Eur J Neurol. 2014;21:989–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Raggi A, Giovannetti AM, Leonardi M, Sansone E, Schiavolin S, Curone M, et al. Predictors of 12-months relapse after withdrawal treatment in hospitalized patients with chronic migraine associated with medication overuse: a longitudinal observational study. Headache. 2017;57:60–70.CrossRefPubMedGoogle Scholar
  23. 23.
    Raggi A, Grazzi L, Ayadi R, Leonardi M, Proietti A, Schiavolin S, et al. Clinical and psychosocial features of frequent relapsers (FR) among patients with chronic migraine and medication overuse. Neurol Sci. 2017;38(Suppl 1):169–71.CrossRefPubMedGoogle Scholar
  24. 24.
    Raggi A, Leonardi M, Scaratti C, Sansone E, Grazzi L, D’Amico D. Gender and education inequalities in the cost of medication-overuse headache. Neurol Sci. 2018;39(Suppl 1):117–9.CrossRefPubMedGoogle Scholar
  25. 25.
    D’Amico D, Grazzi L, Curone M, Leonardi M, Raggi A. Cost of medication overuse headache in Italian patients at the time-point of withdrawal: a retrospective study based on real data. Neurol Sci. 2017;38(Suppl 1):3–6.CrossRefPubMedGoogle Scholar
  26. 26.
    D’Amico D, Mosconi P, Genco S, Usai S, Prudenzano AM, Grazzi L. Et al. The Migraine Disability Assessment (MIDAS) questionnaire: translation and reliability of the Italian version. Cephalalgia. 2001;21:947–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Federici S, Bracalenti M, Meloni F, Luciano JV. World Health Organization disability assessment schedule 2.0: an international systematic review. Disabil Rehabil. 2017;39:2347–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Scaratti C, Covelli V, Guastafierro E, Leonardi M, Grazzi L, Rizzoli PB, et al. A qualitative study on patients with chronic migraine with medication overuse headache: comparing frequent and non-frequent relapsers. Headache. 2018 ( E-Pub ahead of print.
  29. 29.
    •• Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronification. Curr pain headache rep. 2009;13(4):301–7. This is one of the first and most important studies addressing the risk of chronification connected to the use of acute medications. CrossRefPubMedGoogle Scholar
  30. 30.
    •• Lipton RB, Serrano D, Nicholson RA, Buse DC, Runken MC, Reed ML. Impact of NSAID and Triptan use on developing chronic migraine: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013;53(10):1548–63. This is a population study that addressed the risk of chronification connected to the use of triptans. CrossRefPubMedGoogle Scholar
  31. 31.
    Bigal ME, Lipton RB. Excessive opioid use and the development of chronic migraine. Pain. 2009;142(3):179–82.CrossRefPubMedGoogle Scholar
  32. 32.
    Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. AMPP advisory group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Biondi DM. Opioid resistance in chronic daily headache: a synthesis of ideas from the bench and bedside. Curr Pain Headache Rep. 2003;7(1):67–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Wilkinson SM, Becker WJ, Heine JA. Opiate use to control bowel motility may induce chronic daily headache in patients with migraine. Headache. 2001;41(3):303–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Rothrock JF. The case for opiate/opioid therapy in the management of headache. Headache. 2012;52(Suppl 1):35–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Sarchielli P, Granella F, Prudenzano MP, Pini LA, Guidetti V, Bono G, et al. Italian guidelines for primary headaches: 2012 revised version. J Headache Pain. 2012;13(Suppl 2):31–70.CrossRefPubMedCentralGoogle Scholar
  37. 37.
    Dodick DW. Review of comorbidities and risk factors for the development of migraine complications (infarct and chronic migraine). Cephalalgia. 2009;29(Suppl 3):7–14.PubMedGoogle Scholar
  38. 38.
    Sandrini G, Cerbo R, Del Bene E, Ferrari A, Genco S, Grazioli I, et al. Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomized, parallel group, multicentre study. Int J Clin Pract. 2007;61(8):1256–69.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    • Scher AI1, Lipton RB, Stewart WF, Bigal M. Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia. 2010;30(3):321–8. This is one of the most important population studies investigating the pattern of consumption of acute medications among CDH sufferers. CrossRefPubMedGoogle Scholar
  40. 40.
    Ferrari A, Savino G, Gallesi D, Pinetti D, Bertolini A, Sances G, et al. Effect of overuse of the antimigraine combination of indomethacin, prochlorperazine and caffeine (IPC) on the disposition of its components in chronic headache patients. Pharmacol Res. 2006;54(2):142–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Jonsson P, Jakobsson A, Hensing G, Linde M, Moore CD, Hedenrud T. Holding on to the indispensable medication--a grounded theory on medication use from the perspective of persons with medication overuse headache. J Headache Pain. 2013;14:43.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nichols VP, Ellard DR, Griffiths FE, Kamal A, Underwood M, SJC T. CHESS team. The lived experience of chronic headache: a systematic review and synthesis of the qualitative literature. BMJ Open. 2017;7(12):e019929.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Engstrom M, Hagen K, Bjork MH, Stovner LJ, Gravdahl GB, Stjern M, et al. Sleep quality, arousal and pain thresholds in migraineurs: a blinded controlled polysomnographic study. J Headache Pain. 2013;14:1–12.CrossRefGoogle Scholar
  44. 44.
    Florencio LL, Giantomassi MC, Carvalho GF, Gonçalves MC, Dach F, Fernández-de-Las-Peñas C, et al. Generalized pressure pain hypersensitivity in the cervical muscles in women with migraine. Pain Med. 2015;16:1629–34.CrossRefPubMedGoogle Scholar
  45. 45.
    Weissman-Fogel I, Sprecher E, Granovsky Y, Yarnitsky M. Repeated noxious stimulation of the skin enhances cutaneous pain perception of migraine patients in-between attacks: clinical evidence for continuous sub-threshold increase in membrane excitability of central trigeminovascular neurons. Pain. 2003;104:693–700.CrossRefPubMedGoogle Scholar
  46. 46.
    Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous allodynia in the migraine population. Ann Neurol. 2008;63:148–58.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Baykan B, Ekizoglu E, Karli N, Kocasoy-Orhan E, Zarifoglu M, Saip S, et al. Characterization of migraineurs having allodynia: results of a large population-based study. Clin J Pain. 2016;32:631–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Mathur VA, Moayedi M, Keaser ML, Khan SA, Hubbard CS, Goyal M, et al. High frequency migraine is associated with lower acute pain sensitivity and abnormal insula activity related to migraine pain intensity, attack frequency, and pain catastrophizing. Front Hum Neurosci. 2016;10:489.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Hubbard CS, Khan SA, Keaser ML, Mathur VA, Goyal M, Seminowicz DA. Altered brain structure and function correlate with disease severity and pain catastrophizing in migraine patients. eNeuro. 2014;1(1):e20.14.CrossRefPubMedGoogle Scholar
  50. 50.
    Schwedt TJ, Alam A, Reed ML, Fanning KM, Munjal S, Buse DC, 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. 2018;19(1):38.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Louter MA, Bosker JE, van Oosterhout WP, van Zwet EW, Zitman FG, Ferrari MD, et al. Cutaneous allodynia as a predictor of migraine chronification. Brain. 2013;136(Pt 11):3489–96.CrossRefPubMedGoogle Scholar
  52. 52.
    Bigal ME, Lipton RB. What predicts the change from episodic to chronic migraine? Curr Opin Neurol. 2009;22(3):269–76.CrossRefPubMedGoogle Scholar
  53. 53.
    Leonardi M, Raggi A, Bussone G, D’Amico D. Health-related quality of life, disability and severity of disease in patients with migraine attending to a specialty headache center. Headache. 2010;50:1576–86.CrossRefPubMedGoogle Scholar
  54. 54.
    Raggi A, Grazzi L, Grignani E, Leonardi M, Sansone E, Scaratti C, et al. The use of MIDAS in patients with chronic migraine and medication-overuse headache: should we trust it? Neurol Sci. 2018;39(Suppl 1):125–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):1668–75.CrossRefPubMedGoogle Scholar
  56. 56.
    Cameron C, Kelly S, Hsieh SC, Murphy M, Chen L, Kotb A, et al. Triptans in the acute treatment of migraine: a systematic review and network meta-analysis. Headache. 2015;55(Suppl 4):221–35.CrossRefPubMedGoogle Scholar
  57. 57.
    Thorlund K, Mills EJ, Wu P, Ramos E, Chatterjee A, Druyts E, et al. Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis. Cephalalgia. 2014;34(4):258–67.CrossRefPubMedGoogle Scholar
  58. 58.
    Ashaye T, Hounsome N, Carnes D, Taylor SJC, Homer K, Eldridge S, et al. COPERS Study Team (ISRCTN 24426731). Opioid prescribing for chronic musculoskeletal pain in UK primary care: results from a cohort analysis of the COPERS trial. BMJ Open. 2018;8(6):e019491.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Hakkarainen H, Gustafsson B, Stockman O. A comparative trail of ergotamine tartrate, acetyl salicylic acid and a dextropropoxyphene compound in acute migraine attacks. Headache. 1978;18(1):35–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Anneken K, Evers S, Husstedt IW. Efficacy of fixed combinations of acetylsalicyclic acid, acetaminophen and caffeine in the treatment of idiopathic headache: a review. Eur J Neurol. 2010;17(4):534–e25.CrossRefPubMedGoogle Scholar
  61. 61.
    Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22):1821–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Lipton RB. Ergotamine tartrate and dihydroergotamine mesylate: safety profiles. Headache. 1997;37(Suppl 1):33–41.Google Scholar
  63. 63.
    Raggi A, Grignani E, Leonardi M, Andrasik F, Sansone E, Grazzi L, et al. Behavioral approaches for primary headaches: recent advances. Headache. 2018;58(6):913–25.CrossRefPubMedGoogle Scholar
  64. 64.
    Andrasik F, Grazzi L, D’Amico D, Sansone E, Leonardi M, Raggi A, et al. Mindfulness and headache: a "new" old treatment, with new findings. Cephalalgia. 2016;36(12):1192–205.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Licia Grazzi
    • 1
    Email author
  • Eleonora Grignani
    • 2
  • Domenico D’Amico
    • 1
  • Emanuela Sansone
    • 1
  • Alberto Raggi
    • 2
  1. 1.Division of NeuroalgologyFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
  2. 2.Neurology, Public Health and Disability UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly

Personalised recommendations