Nocebo in Headache Treatment

  • Christina Deligianni
  • Dimos D. MitsikostasEmail author
Part of the Headache book series (HEAD)


Nocebo refers to adverse events (AEs) related to negative expectations that medical treatment will likely harm instead of heal and affects significantly adherence and treatment outcome. It varies considerably among neurological conditions but can be assessed in placebo-controlled clinical trials (RCTs) by investigating the AEs observed in patients treated with placebo. In clinical practice nocebo can be predicted by applying the Q-No questionnaire. Clinically relevant outcomes for nocebo in RCTs include the percentage of patients treated with placebo who experienced any AE (nocebo AE) and the percentage of patients who discontinued treatment due to AEs although treated with placebo (nocebo withdrawal). Meta-analyses of RCTs for migraine prevention estimated that nocebo AE and withdrawal rise up to 42.78% (95% CI 34.73–51.36%) and 4.75% (95% CI 3.28–6.45%) of placebo-treated patients. In studies for symptomatic treatment for migraine, the nocebo AE and withdrawal frequencies were 18.45% (95% CI 14.90–22.23%) and 0.33% (95% CI 0.19–0.53%), respectively. In trials for prevention of tension-type headache (TTH), nocebo and dropout frequencies were 23.99% (95% CI 4.61–52.20%) and 5.44% (95% CI 1.32–12.12%). For symptomatic treatment of cluster headache, the nocebo AE frequency was 18.67% (95% CI 10.65–28.33%; insufficient data were gathered to calculate the nocebo withdrawal). In clinical practice nocebo can be predicted by using the Q-No questionnaire, a four-item (rating range 4–20) self-fulfilled questionnaire. Using a cutoff at score 15, the Q-No predicts nocebo with 71.7% specificity, 67.5% sensitivity, and 42.5% positive predictive value. Almost 57% of headache sufferers score more than 15 indicating potential nocebo behaviors that contributed significantly in their therapy choices, as well as in treatment adherence. These data indicate that nocebo plays a severe role in headache therapeutics requiring major attention and appropriate management, although it remains largely unknown and underappreciated.


Migraine Tension-type headache Cluster headache Nocebo Treatment Adverse events 


  1. 1.
    Amanzio M, Corazzini LL, Vase L, Benedetti F. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain. 2009;146(3):261–9.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Bartels DJP, van Laarhoven AIM, Stroo M, Hijne K, Peerdeman KJ, Donders ART, van de Kerkhof PCM, Evers AWM. Minimizing nocebo effects by conditioning with verbal suggestion: a randomized clinical trial in healthy humans. PLoS One. 2017;12(9):e0182959.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Blassini M, Corsi N, Klinger R, Colloca L. Nocebo and pain: an overview of the psychoneurobiological mechanisms. Pain Rep. 2017;2(2). pii: e585.Google Scholar
  4. 4.
    Benedetti F, Amanzio M. The placebo response: how words and rituals change the patient’s brain. Patient Educ Couns. 2011;84(3):413–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Benedetti F, Lanotte M, Lopiano L, Colloca L. When word are painful: unraveling the mechanisms of the nocebo effect. Neuroscience. 2007;147:260–71.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bingel U. Avoiding nocebo effects to optimize treatment outcome. JAMA. 2014;312:693–4.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Colloca L. Placebo, nocebo, and learning mechanisms. Handb Exp Pharmacol. 2014;225:17–35.PubMedCrossRefGoogle Scholar
  8. 8.
    Colloca L, Grillon C. Understanding placebo and nocebo responses for pain management. Curr Pain Headache Rep. 2014;18:419.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Colloca L, Finniss D. Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012;307:567–8.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, Malhi GS, Berk M. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015;76(6):702–11.PubMedCrossRefGoogle Scholar
  11. 11.
    GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211–59.CrossRefGoogle Scholar
  12. 12.
    Greville-Harris M, Dieppe P. Bad is more powerful than good: the nocebo response in medical consultations. Am J Med. 2015;128:126–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Gracia-Naya M, Santos-Lasaosa S, Ríos-Gómez C, Sánchez-Valiente S, García-Gomara MJ, Latorre-Jiménez AM, Artal-Roy J, Mauri-Llerda JA. Predisposing factors affecting drop-out rates in preventive treatment in a series of patients with migraine. Rev Neurol. 2011;53:201–8.PubMedGoogle Scholar
  14. 14.
    Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, Collins R, Sever P, ASCOT Investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomized double blind placebo-controlled trial and its non-randomized non-blind extension phase. Lancet. 2017;389(10088):2473–81.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35:478–88.CrossRefGoogle Scholar
  16. 16.
    Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. J Manag Care Pharm. 2014;20:22–33.Google Scholar
  17. 17.
    Klosterhalfen S, Kellermann S, Braun S, Kowalski A, Schrauth M, Zipfel S, Enck P. Gender and the nocebo response following conditioning and expectancy. J Psychosom Res. 2009;66(4):323–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Loder E, Goldstein R, Biondi D. Placebo effects in oral triptan trials: the scientific and ethical rationale for continued use of placebo controls. Cephalalgia. 2005;25:124–31.PubMedCrossRefGoogle Scholar
  19. 19.
    McCormack JP, Allan GM, Virani AS. Is bigger better? An argument for very low starting doses. CMAJ. 2011;183:65–9.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Meister R, Jansen A, Härter M, Nestoriuc Y, Kriston L. Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis. J Affect Disord. 2017;215:288–98.PubMedCrossRefGoogle Scholar
  21. 21.
    Mitsikostas DD. Nocebo in headaches: implications for clinical practice and trial design. Curr Neurol Neurosci Rep. 2012;12:132–7.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Mitsikostas DD. Nocebo in headache. Curr Opin Neurol. 2016;29(3):331–6.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Mitsikostas DD, Deligianni CI. Q-No: a questionnaire to predict nocebo in & outpatients seeking neurological consultation. Neurol Sci. 2015;36:379–81.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Mitsikostas DD, Belesioti I, Arvaniti C, Mitropoulou E, Deligianni C, Kasioti E, Constantinidis T, Dermitzakis M, Vikelis M. Hellenic Headache Society. Patients’ preferences for headache acute and preventive treatment. J Headache Pain. 2017;18(1):102.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha EM, Sfikakis PP. Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol. 2012;19(5):672–80.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Mitsikostas DD, Mantonakis LI, Chalarakis NG. Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia. 2011;31:550–61.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Mitsikostas DD, Mantonakis L, Chalarakis N. Nocebo in clinical trials for depression: a meta-analysis. Psychiatry Res. 2014;215(1):82–6.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Petersen GL, Finnerup NB, Colloca L, Amanzio M, Price DD, Jensen TS, Vase L. The magnitude of nocebo effects in pain: a meta-analysis. Pain. 2014;155(8):1426–34.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Papadopoulos D, Mitsikostas DD. A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J Neurol. 2012;259:436–47.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Papadopoulos D, Mitsikostas DD. Nocebo effects in multiple sclerosis trials: a meta-analysis. Mult Scler. 2010;16:816–28.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Reuter U, Sanchez del Rio M, Carpay JA, Boes CJ, Silberstein SD. GSK headache masters program: placebo adverse events in headache trials: headache as an adverse event of placebo. Cephalalgia. 2003;23:496–503.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52:99–113.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Silva MA, Duarte GS, Camara R, Rodrigues FB, Fernandes RM, Abreu D, Mestre T, Costa J, Trenkwalder C, Ferreira JJ. Placebo and nocebo responses in restless legs syndrome: a systematic review and meta-analysis. Neurology. 2017;88(23):2216–24.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Silvestri A, Galetta P, Cerquetani E, Marazzi G, Patrizi R, Fini M, Rosano GM. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo. Eur Heart J. 2003;24(21):1928–32.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Stathis P, Smpiliris M, Konitsiotis S, Mitsikostas DD. Nocebo as a potential confounding factor in clinical trials for Parkinson’s disease treatment: a meta-analysis. Eur J Neurol. 2013;20:527–33.CrossRefGoogle Scholar
  36. 36.
    Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lantéri-Minet M, Rastenyte D, Ruiz de la Torre E, Tassorelli C, Barré J, Andrée C. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain. 2014;15:31.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Tinnermann A, Geuter S, Sprenger C, Finsterbusch J, Büchel C. Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia. Science. 2017;358(6359):105–8.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Webster RK, Weinman J, Rubin GJ. A systematic review of factors that contribute to nocebo effects. Health Psychol. 2016;35(12):1334–55.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Zaccara G, Giovannelli F, Giorgi FS, Franco V, Gasparini S. Analysis of nocebo effects of antiepileptic drugs across different conditions. J Neurol. 2016;263(7):1274–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Zis P, Shafiq F, Mitsikostas DD. Nocebo effect in refractory partial epilepsy during pre-surgical monitoring: systematic review and meta-analysis of placebo-controlled clinical trials. Seizure. 2017;45:95–9.PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.1st Neurology DepartmentAeginition Hospital, National and Kapodistrian University of AthensAthensGreece

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