Acta Neurologica Belgica

, Volume 119, Issue 2, pp 257–264 | Cite as

Nocebo effect in myasthenia gravis: systematic review and meta-analysis of placebo-controlled clinical trials

  • Adithya Varma
  • Panagiotis ZisEmail author
Original article


Nocebo refers to the adverse events (AEs) experienced when taking a placebo drug and is believed to be a centrally mediated process. We sought to examine the AEs following placebo administration in Randomised Controlled Trials (RCTs) for Myasthenia Gravis (MG) patients. A systematic literature search was performed on Medline and Web of Science for RCTs for MG pharmacological treatments. We assessed the number of placebo-treated patients reporting at least one AE and the number of dropouts because of AEs. Data were extracted from six RCTs fulfilling the search criteria. Four out of five placebo-treated participants (80.1%) reported at least one AE and one in 40 (2.4%) discontinued placebo treatment because of AE. All patients participating in the MG trials reported similar AEs independent of the study arm to which they belonged (placebo or active treatment). This meta-analysis demonstrates a low nocebo dropout rate in MG compared to central nervous system disorders.


Adverse events Myasthenia gravis Nocebo Placebo Systematic review 



Adverse events


Chronic inflammatory demyelinating polyneuropathy




Medical subject headings


Myasthenia gravis


Peripheral nervous system


Preferred reporting items for systematic reviews and meta-analyses


Randomised controlled trials



We are sincerely thankful to Stamatina Iliodromiti for her contribution to the statistical analysis.

Author contribution

Study concept and supervision: PZ. Study design: AV, PZ. Data acquisition: AV. Data analysis: AV, PZ. Drafting and revision the manuscript: AV, PZ. Both authors edited and approved the final manuscript.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest



  1. 1.
    Colloca L, Miller FG (2011) The nocebo effect and its relevance for clinical practice. Psychosom Med 73(7):598–603CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha EM, Sfikakis PP (2012) Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 19(5):672–680CrossRefPubMedGoogle Scholar
  3. 3.
    Benedetti F, Lanotte M, Lopiano L, Colloca L (2007) When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 147(2):260–271CrossRefPubMedGoogle Scholar
  4. 4.
    Tracey I (2010) Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat Med 16(11):1277–1283CrossRefPubMedGoogle Scholar
  5. 5.
    Manchikanti L, Giordano J, Fellows B, Hirsch JA (2011) Placebo and nocebo in interventional pain management: a friend or a foe–or simply foes? Pain Physician 14(2):E157–E175PubMedGoogle Scholar
  6. 6.
    Elsenbruch S (2014) How positive and negative expectations shape the experience of visceral pain. Handb Exp Pharmacol 225:97–119CrossRefPubMedGoogle Scholar
  7. 7.
    Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287(5):622–627CrossRefPubMedGoogle Scholar
  8. 8.
    Enck P, Benedetti F, Schedlowski M (2008) New insights into the placebo and nocebo responses. Neuron 59(2):195–206CrossRefPubMedGoogle Scholar
  9. 9.
    Zis P, Mitsikostas DD (2015) Nocebo in Alzheimer’s disease; meta-analysis of placebo-controlled clinical trials. J Neurol Sci 355(1–2):94–100CrossRefPubMedGoogle Scholar
  10. 10.
    Stathis P, Smpiliris M, Konitsiotis S, Mitsikostas DD (2013) Nocebo as a potential confounding factor in clinical trials for Parkinson’s disease treatment: a meta-analysis. Eur J Neurol 20(3):527–533CrossRefPubMedGoogle Scholar
  11. 11.
    Papadopoulos D, Mitsikostas DD (2010) Nocebo effects in multiple sclerosis trials: a meta-analysis. Mult Scler (Houndmills, Basingstoke, England). 16(7):816–828CrossRefGoogle Scholar
  12. 12.
    Shafiq F, Mitsikostas DD, Zis P (2017) Nocebo in motor neuron disease: systematic review and meta-analysis of placebo-controlled clinical trials. Amyotroph Lateral Scler Frontotemporal Degener 18(7–8):576–582CrossRefPubMedGoogle Scholar
  13. 13.
    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(5):550–561CrossRefPubMedGoogle Scholar
  14. 14.
    Mitsikostas DD (2012) Nocebo in headaches: implications for clinical practice and trial design. Curr Neurol Neurosci Rep 12(2):132–137CrossRefPubMedGoogle Scholar
  15. 15.
    Hauser W, Bartram C, Bartram-Wunn E, Tolle T (2012) Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: systematic review. Clin J Pain 28(5):437–451CrossRefPubMedGoogle Scholar
  16. 16.
    Papadopoulos D, Mitsikostas DD (2012) A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J Neurol 259(3):436–447CrossRefPubMedGoogle Scholar
  17. 17.
    Silva MA, Duarte GS, Camara R, Rodrigues FB, Fernandes RM, Abreu D et al (2017) Placebo and nocebo responses in restless legs syndrome: a systematic review and meta-analysis. Neurology 88(23):2216–2224CrossRefPubMedGoogle Scholar
  18. 18.
    Mitsikostas DD, Mantonakis L, Chalarakis N (2014) Nocebo in clinical trials for depression: a meta-analysis. Psychiatry Res 215(1):82–86CrossRefPubMedGoogle Scholar
  19. 19.
    Rutherford BR, Wall MM, Glass A, Stewart JW (2014) The role of patient expectancy in placebo and nocebo effects in antidepressant trials. J Clin Psychiatry 75(10):1040–1046CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zis P, Shafiq F, Mitsikostas DD (2017) Nocebo effect in refractory partial epilepsy during pre-surgical monitoring: systematic review and meta-analysis of placebo-controlled clinical trials. Seizure 45:95–99CrossRefPubMedGoogle Scholar
  21. 21.
    Dimitriadis PA, Zis P (2017) Nocebo effect in Meniere’s disease: a meta-analysis of placebo-controlled randomized controlled trials. Otol Neurotol 38(9):1370–1375CrossRefPubMedGoogle Scholar
  22. 22.
    Zis P, Hadjivassiliou M, Sarrigiannis PG, Jenkins TM, Mitsikostas DD (2018) Nocebo in chronic inflammatory demyelinating polyneuropathy; a systematic review and meta-analysis of placebo-controlled clinical trials. J Neurol Sci 388:79–83CrossRefPubMedGoogle Scholar
  23. 23.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12CrossRefPubMedGoogle Scholar
  25. 25.
    Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I et al (2017) Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol 16(12):976–986CrossRefPubMedGoogle Scholar
  26. 26.
    Zhou L, Liu W, Li W, Li H, Zhang X, Shang H et al (2017) Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China. Ther Adv Neurol Disord 10(9):315–325CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pasnoor M, He J, Herbelin L, Burns TM, Nations S, Bril V et al (2016) A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology 87(1):57–64CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sanders DB, Rosenfeld J, Dimachkie MM, Meng L, Malik FI (2015) A double-blinded, randomized, placebo-controlled trial to evaluate efficacy, safety, and tolerability of single doses of tirasemtiv in patients with acetylcholine receptor-binding antibody-positive myasthenia gravis. Neurotherapeutics 12(2):455–460CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yoshikawa H, Kiuchi T, Saida T, Takamori M (2011) Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 82(9):970–977CrossRefPubMedGoogle Scholar
  30. 30.
    Sanders DB, Hart IK, Mantegazza R, Shukla SS, Siddiqi ZA, De Baets MH et al (2008) An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 71(6):400–406CrossRefPubMedGoogle Scholar
  31. 31.
    Benedetti F, Amanzio M, Vighetti S, Asteggiano G (2006) The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 26(46):12014–12022CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Planes S, Villier C, Mallaret M (2016) The nocebo effect of drugs. Pharmacol Res Perspect 4(2):e00208CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Zis P, Sykioti P (2019) Adverse events and nocebo phenomena: treatment or disease specific? BMC Med 17(1):30CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zis P, Shafique F, Hadjivassiliou M, Blackburn D, Venneri A, Iliodromiti S, Mitsikostas DD, Sarrigiannis PG (2019) Safety, tolerability, and nocebo phenomena during transcranial magnetic stimulation: a systematic review and meta-analysis of placebo-controlled clinical trials. Neuromodulation. (Epub ahead of print) CrossRefPubMedGoogle Scholar
  35. 35.
    Zis P, Mitsikostas DD (2018) Nocebo responses in brain diseases: a systematic review of the current literature. Int Rev Neurobiol 139:443–462CrossRefPubMedGoogle Scholar
  36. 36.
    Petrisor BA, Bhandari M (2007) The hierarchy of evidence: levels and grades of recommendation. Indian J Orthop 41(1):11–15CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Wells RE, Kaptchuk TJ (2012) To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am J Bioeth 12(3):22–29CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Belgian Neurological Society 2019

Authors and Affiliations

  1. 1.Sheffield Institute for Translational NeuroscienceSheffieldUK
  2. 2.Academic Department of NeurosciencesSheffield Teaching Hospitals, NHS TrustSheffieldUK
  3. 3.Medical SchoolUniversity of CyprusNicosiaCyprus

Personalised recommendations