Skip to main content

Part of the book series: Headache ((HEAD))

  • 1973 Accesses

Abstract

Placebo refers to the positive expectation that a treatment will help patients, and nocebo refers to adverse events related to patient’s negative expectations that a medical treatment will likely harm instead of healing. Both conditions illustrate the power of human brain and are strongly related to treatment outcome and adherence. Placebos and nocebos display particular role in pain conditions, such as headache. There is evidence that placebo analgesia and hyperhedonia associated with pain relief are mediated by activation of shared emotion appraisal neurocircuitry, which regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure. It has been suggested that dopaminergic, cyclooxygenase/prostaglandins and opioid brain pathways reward circuitries, and decision-making processes play a crucial role in the mechanisms that underlie nocebo. For migraine prophylaxis, the mean placebo effect for responders (those who report at least 50 % reduction in headache days after treatment) has been estimated at 23.5 ± 8 % (95 % CI 18.3–28.8 %) vs. 45.5 ± 15.5 % (95 % CI 37.4–53.6 %) in the active groups. Correspondently, a reduction in migraine attacks of 16.8 ± 12.7 % (95 % CI 10.9–22.6 %) was observed in the placebo groups and 41.8 ± 11.7 % (95 % CI 36.9–46.6 %) in the active groups. In preventive treatments for migraine, dropout ratio due to adverse events in placebo-treated patients has been estimated up to 5 %, showing that 1 out of 20 patients treated for migraine prophylaxis discontinues treatment due to nocebo. Placebos and nocebos therefore affect migraine treatment outcomes significantly.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Antonaci F, Chimento P, Diener H-C, Sances G, Bono G (2007) Lessons from placebo effects in migraine treatment. J Headache Pain 8:63–6

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shapiro AK (1964) A historic and heuristic definition of the placebo. Psychiatry 27:52–8

    CAS  PubMed  Google Scholar 

  3. de Craen AJM (1999) Placebos and placebo effects in medicine: historical overview. J R Soc Med 92:511–5

    PubMed  PubMed Central  Google Scholar 

  4. Motherby G (1795) A new medical dictionary or general repository of physics, 4th edn. J. Johnson, London

    Google Scholar 

  5. Taber CW (1937) Taber’s digest of medical terms. F.A. Davis, Philadelphia

    Google Scholar 

  6. Ellingsen D-M, Wessberg J, Eikemo M, Liljencrantz J, Endestad T, Olausson H, Leknes S (2013) Placebo improves pleasure and pain through opposite modulation of sensory processing. Proc Natl Acad Sci U S A 110(44):17993–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 6:545–52

    Article  CAS  PubMed  Google Scholar 

  8. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubeita JK (2005) Neurobiological mechanisms of the placebo effect. J Neurosci 25:10390–402

    Article  CAS  PubMed  Google Scholar 

  9. Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7(6):587–8

    Article  CAS  PubMed  Google Scholar 

  10. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010) Placebo effects: biological, clinical and ethical advances. Lancet 375(9715):686–95

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bendtsen L, Mattsson P, Zwart JA, Lipton RB (2003) Placebo response in clinical randomized trials of analgesics in migraine. Cephalalgia 23:487–90

    Article  CAS  PubMed  Google Scholar 

  12. Loder E, Goldstein R, Biondi D (2005) Placebo effects in oral triptan trials: the scientific and ethical rationale for continued use of placebo controls. Cephalalgia 25:124–31

    Article  CAS  PubMed  Google Scholar 

  13. Lewis DW, Winner P, Wasiewski W (2005) The placebo responder rate in children and adolescents. Headache 45:232–9

    Article  PubMed  Google Scholar 

  14. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ (2014) BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34(2):114–25

    Article  PubMed  Google Scholar 

  15. Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J (2011) BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 31(5):573–84

    Article  PubMed  Google Scholar 

  16. Färkkilä M, Diener HC, Géraud G, Láinez M, Schoenen J, Harner N, Pilgrim A, Reuter U, COL MIG-202 study group (2012) Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 11(5):405–13

    Article  PubMed  Google Scholar 

  17. Goldstein DJ, Roon KI, Offen WW, Ramadan NM, Phebus LA, Johnson KW, Schaus JM, Ferrari MD (2001) Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet 358(9289):1230–4

    Article  CAS  PubMed  Google Scholar 

  18. Gomez-Mancilla B, Brand R, Jürgens TP, Göbel H, Sommer C, Straube A, Evers S, Sommer M, Campos V, Kalkman HO, Hariry S, Pezous N, Johns D, Diener HC, BGG492 Study Group (2014) Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks. Cephalalgia 34(2):103–13

    Article  PubMed  Google Scholar 

  19. Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, Fischell RE, Ruppel PL, Goadsby PJ (2010) Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 9(4):373–80

    Article  PubMed  Google Scholar 

  20. van der Kuy P-HM, Lohman JJHM (2002) A quantification of the placebo response in migraine prophylaxis. Cephalalgia 22:265–70

    Article  PubMed  Google Scholar 

  21. Linde M, Mulleners WM, Chronicle EP, McCrory DC (2013) Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev (6):CD010610

    Google Scholar 

  22. Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, Diener HC, Brin MF, PREEMPT Chronic Migraine Study Group (2010) Onabotulinumtoxin A for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache 50(6):921–36

    Article  PubMed  Google Scholar 

  23. Meissner K, Fässler M, Rücker G, Kleijnen J, Hróbjartsson A, Schneider A, Antes G, Linde K (2013) Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern Med 173(21):1941–51

    Article  PubMed  Google Scholar 

  24. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J, ALD403 study investigators (2014) Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13(11):1100–7

    Article  CAS  PubMed  Google Scholar 

  25. Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS (2014) Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 13(9):885–92

    Article  CAS  PubMed  Google Scholar 

  26. Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gérard P, Magis D (2013) Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 80(8):697–704

    Article  PubMed  Google Scholar 

  27. Silberstein SD, Dodick DW, Saper J, Huh B, Slavin KV, Sharan A, Reed K, Narouze S, Mogilner A, Goldstein J, Trentman T, Vaisman J, Ordia J, Weber P, Deer T, Levy R, Diaz RL, Washburn SN, Mekhail N (2012) Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 32(16):1165–79

    Article  PubMed  Google Scholar 

  28. Moore RA, Derry S, Wiffen PJ, Straube S, Bendtsen L (2014) Evidence for efficacy of acute treatment of episodic tension-type headache: Methodological critique of randomised trials for oral treatments. Pain 155(11):2220–8

    Article  PubMed  Google Scholar 

  29. Zissis NP, Harmoussi S, Vlaikidis N, Mitsikostas D, Thomaidis T, Georgiadis G, Karageorgiou K (2007) A randomized, double-blind, placebo-controlled study of venlafaxine XR in out-patients with tension-type headache. Cephalalgia 27(4):315–24

    Article  CAS  PubMed  Google Scholar 

  30. Bendtsen L, Jensen R (2004) Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 62(10):1706–11

    Article  CAS  PubMed  Google Scholar 

  31. Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White AR (2009) Acupuncture for tension-type headache. Cochrane Database Syst Rev (1):CD007587

    Google Scholar 

  32. Law S, Derry S, Moore RA (2013) Triptans for acute cluster headache. Cochrane Database Syst Rev (7):CD008042

    Google Scholar 

  33. Cohen AS, Burns B, Goadsby PJ (2009) High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA 302(22):2451–7

    Article  CAS  PubMed  Google Scholar 

  34. Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, Bussone G (2000) Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 54(6):1382–5

    Article  CAS  PubMed  Google Scholar 

  35. Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, Ducros A (2011) Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 10(10):891–7

    Article  CAS  PubMed  Google Scholar 

  36. Mitsikostas DD, Mantonakis LI, Chalarakis NG (2011) Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia 31:550–61

    Article  PubMed  Google Scholar 

  37. Amanzion M, Corazzini LL, Vase L, Benedetti F (2009) A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146:261–9

    Article  Google Scholar 

  38. Kennedy WP (1961) The nocebo reaction. Med World 95:203–5

    CAS  PubMed  Google Scholar 

  39. Barsky AJ, Saintfort R, Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287:622–7

    Article  PubMed  Google Scholar 

  40. Enck P, Benedetti F, Schedlowski M (2008) New insights into the placebo and nocebo responces. Neuron 59:195–206

    Article  CAS  PubMed  Google Scholar 

  41. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2008) Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 65:220–31

    Article  PubMed  Google Scholar 

  42. Benedetti F, Lanotte M, Lopiano L, Colloca L (2007) When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 147(2):260–71

    Article  CAS  PubMed  Google Scholar 

  43. Benedetti F, Durando J, Vighetti S (2014) Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway. Pain 155(5):921–8

    Article  CAS  PubMed  Google Scholar 

  44. Evans WR (2003) Headaches and the nocebo effect. Headache 43:1111–5

    Google Scholar 

  45. Colloca L, Miller FG (2011) The nocebo effect and its relevance for clinical practice. Psychosom Med 73(7):598–603

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mitsikostas DD (2012) Nocebo in headaches: implications for clinical practice and trial design. Curr Neurol Neurosci Rep 12(2):132–7

    Article  PubMed  Google Scholar 

  47. Reuter U, Sanchez del Rio M, Carpay JA et al (2003) GSK headache masters program: placebo adverse events in headache trials: headache as an adverse event of placebo. Cephalalgia 23:496–503

    Article  CAS  PubMed  Google Scholar 

  48. Amanzio M (2011) Do we need a new procedure for the assessment of adverse events in anti-migraine clinical trials? Recent Pat CNS Drug Discov 6:41–7

    Article  CAS  PubMed  Google Scholar 

  49. Manzoni GC, Torelli P (2010) Epidemiological classification and social impact of chronic headache. Intern Emerg Med 5(Suppl 1):S1–5

    Article  PubMed  Google Scholar 

  50. Stovner LJ, Andree C (2010) Prevalence of headache in Europe: a review for the Eurolight project. J Headache Pain 11:289–99

    Article  PubMed  PubMed Central  Google Scholar 

  51. Howick J, Friedemann C, Tsakok M, Watson R, Tsakok T, Thomas J, Perera R, Fleming S, Heneghan C (2013) Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One 8(5), e62599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Benedetti F (2014) Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84(3):623–37

    Article  CAS  PubMed  Google Scholar 

  53. Deligianni CI, Vikelis M, Mitsikostas DD (2012) Depression in headaches: chronification. Curr Opin Neurol 25(3):277–83

    Article  PubMed  Google Scholar 

  54. Mitsikostas DD, Deligianni CI (2014) Q-No: a questionnaire to predict nocebo in outpatients seeking neurological consultation. Neurol Sci 2015;36(3):379–81

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dimos D. Mitsikostas MD, PhD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Mitsikostas, D.D., Deligianni, C.I. (2016). Placebo and Nocebo Effects. In: Mitsikostas, D., Paemeleire, K. (eds) Pharmacological Management of Headaches. Headache. Springer, Cham. https://doi.org/10.1007/978-3-319-19911-5_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-19911-5_4

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-19910-8

  • Online ISBN: 978-3-319-19911-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics