Placebo Response in Human Models of Headache

  • Jakob Møller Hansen
  • Messoud AshinaEmail author
Part of the Headache book series (HEAD)


Human models of migraine are important to better understand the underlying mechanisms of action of potential anti-migraine compounds as well as to explore the pathophysiology of the condition. Like in other interventions, participant expectations, content and delivery of information, and unspecific effects of the intervention may exert a placebo or nocebo effect on the outcomes. However, the recorded placebo responses are modest in human studies for migraine. With the use of an appropriate control intervention, this effect may be mitigated and taken into account. In this chapter all human models of migraine are summarized in relation to the placebo response.


  1. 1.
    Antonova M, Wienecke T, Olesen J, Ashina M. Prostaglandin E(2) induces immediate migraine-like attack in migraine patients without aura. Cephalalgia. 2012;32:822–33.CrossRefGoogle Scholar
  2. 2.
    Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de Koning PJ, Olsen KS, Secher NH, Larsson HB, Olesen J, Ashina M. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain. 2016;139:723–37.CrossRefGoogle Scholar
  3. 3.
    Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2010;75:1520–6.CrossRefGoogle Scholar
  4. 4.
    Ashina M. Human models—screening models. Oxford: Oxford University Press; 2008.CrossRefGoogle Scholar
  5. 5.
    Ashina M, Bendtsen L, Jensen R, Olesen J. Nitric oxide-induced headache in patients with chronic tension-type headache. Brain. 2000;123(Pt 9):1830–7.CrossRefGoogle Scholar
  6. 6.
    Ashina M, Hansen JM, Bo AD, Olesen J. Human models of migraine—short-term pain for long-term gain. Nat Rev Neurol. 2017;13:713–24.CrossRefGoogle Scholar
  7. 7.
    Birk S, Kruuse C, Petersen KA, Tfelt-Hansen P, Olesen J. The headache-inducing effect of cilostazol in human volunteers. Cephalalgia. 2006;26:1304–9.CrossRefGoogle Scholar
  8. 8.
    Diener HC, Dowson AJ, Ferrari M, Nappi G, Tfelt-Hansen P. Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia. 1999;19:699–700.CrossRefGoogle Scholar
  9. 9.
    Guo S, Olesen J, Ashina M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain. 2014;137:2951–9.CrossRefGoogle Scholar
  10. 10.
    Hansen EK, Olesen J. Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals. Cephalalgia. 2017;37(1):11–9.CrossRefGoogle Scholar
  11. 11.
    Hansen JM, Sitarz J, Birk S, Rahmann AM, Oturai PS, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers. Cephalalgia. 2006;26:992–1003.CrossRefGoogle Scholar
  12. 12.
    Hansen JM, Pedersen D, Larsen VA, Sanchez-del-Rio M, Alvarez Linera JR, Olesen J, Ashina M. Magnetic resonance angiography shows dilatation of the middle cerebral artery after infusion of glyceryl trinitrate in healthy volunteers. Cephalalgia. 2007;27:118–27.CrossRefGoogle Scholar
  13. 13.
    Hrobjartsson A, Gotzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;(1):CD003974.Google Scholar
  14. 14.
    IHS. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629–808.CrossRefGoogle Scholar
  15. 15.
    Jensen K, Tfelt-Hansen P, Hansen EW, Krois EH, Pedersen OS. Introduction of a novel self-injector for sumatriptan. A controlled clinical trial in general practice. Cephalalgia. 1995;15:423–9.CrossRefGoogle Scholar
  16. 16.
    Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC, Kaptchuk TJ, Burstein R. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med. 2014;6:218ra5.CrossRefGoogle Scholar
  17. 17.
    Kruuse C, Frandsen E, Schifter S, Thomsen LL, Birk S, Olesen J. Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache. Cephalalgia. 2004;24:547–53.CrossRefGoogle Scholar
  18. 18.
    Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 2003;126:241–7.CrossRefGoogle Scholar
  19. 19.
    Kruuse C, Thomsen LL, Jacobsen TB, Olesen J. The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab. 2002;22:1124–31.CrossRefGoogle Scholar
  20. 20.
    Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54–61.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    Macedo A, Farre M, Banos JE. A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials. Eur J Clin Pharmacol. 2006;62:161–72.CrossRefGoogle Scholar
  23. 23.
    Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basanez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabe E, Bhalla K, Bhandari B, Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2197–223.CrossRefGoogle Scholar
  24. 24.
    Nichols FT 3rd, Mawad M, Mohr JP, Stein B, Hilal S, Michelsen WJ. Focal headache during balloon inflation in the internal carotid and middle cerebral arteries. Stroke. 1990;21:555–9.CrossRefGoogle Scholar
  25. 25.
    Olesen J, Tfelt-Hansen P, Ashina M. Finding new drug targets for the treatment of migraine attacks. Cephalalgia. 2009;29:909–20.CrossRefGoogle Scholar
  26. 26.
    Perrotta A, Serrao M, Tassorelli C, Arce-Leal N, Guaschino E, Sances G, Rossi P, Bartolo M, Pierelli F, Sandrini G, Nappi G. Oral nitric-oxide donor glyceryl-trinitrate induces sensitization in spinal cord pain processing in migraineurs: a double-blind, placebo-controlled, cross-over study. Eur J Pain. 2011;15:482–90.CrossRefGoogle Scholar
  27. 27.
    Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28:226–36.CrossRefGoogle Scholar
  28. 28.
    Russell MB, Rasmussen BK, Brennum J, Iversen HK, Jensen RA, Olesen J. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia. 1992;12:369–74.CrossRefGoogle Scholar
  29. 29.
    Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25.CrossRefGoogle Scholar
  30. 30.
    Schytz HW, Wienecke T, Olesen J, Ashina M. Carbachol induces headache, but not migraine-like attacks, in patients with migraine without aura. Cephalalgia. 2010;30:337–45.CrossRefGoogle Scholar
  31. 31.
    Schytz HW, Wienecke T, Oturai PS, Olesen J, Ashina M. The cholinomimetic agent carbachol induces headache in healthy subjects. Cephalalgia. 2009;29:258–68.CrossRefGoogle Scholar
  32. 32.
    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. 2016;388:1545–602.Google Scholar
  33. 33.
    Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia. 1993;13:395–9; discussion 376.CrossRefGoogle Scholar
  34. 34.
    Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol. 1994;1:73–80.CrossRefGoogle Scholar
  35. 35.
    Tvedskov JF, Thomsen LL, Iversen HK, Gibson A, Wiliams P, Olesen J. The prophylactic effect of valproate on glyceryltrinitrate induced migraine. Cephalalgia. 2004;24:576–85.CrossRefGoogle Scholar
  36. 36.
    Tvedskov JF, Thomsen LL, Iversen HK, Williams P, Gibson A, Jenkins K, Peck R, Olesen J. The effect of propranolol on glyceryltrinitrate-induced headache and arterial response. Cephalalgia. 2004;24:1076–87.CrossRefGoogle Scholar
  37. 37.
    Wienecke T, Olesen J, Ashina M. Prostaglandin I2 (epoprostenol) triggers migraine-like attacks in migraineurs. Cephalalgia. 2010;30:179–90.CrossRefGoogle Scholar
  38. 38.
    Wienecke T, Olesen J, Oturai PS, Ashina M. Prostacyclin (epoprostenol) induces headache in healthy subjects. Pain. 2008;139:106–16.CrossRefGoogle Scholar
  39. 39.
    Wienecke T, Olesen J, Oturai PS, Ashina M. Prostaglandin E2(PGE2) induces headache in healthy subjects. Cephalalgia. 2009;29:509–19.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of NeurologyDanish Headache Center, RigshospitaletGlostrupDenmark
  2. 2.Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations