Skip to main content

A meta-analytic approach to estimating nocebo effects in neuropathic pain trials

Journal of Neurology volume 259, pages 436–447 (2012)Cite this article

Abstract

The development of non-specific adverse effects following the administration of an active or inert substance is referred to as nocebo phenomenon. We aimed to estimate the frequency and severity of nocebo responses in clinical trials of pharmacological treatments for neuropathic pain. A systematic Medline search for all randomized, placebo-controlled neuropathic pain trials published between 2000 and 2010 was carried out. Meta-analysis of the frequency of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited drug-related adverse events. Nocebo severity was calculated from the percentage of placebo-treated patients that dropped out due to drug-related adverse events. The pooled frequency of nocebo responses in neuropathic pain trials was 52.0% (95% CI: 35.7–67.9) and the pooled nocebo severity was 6.0% (95% CI: 4.5–8.0). Meta-regression analysis revealed an association between the frequency of nocebo responses and the percentage of females in the placebo-treated group (p = 0.0028). Furthermore, nocebo severity displayed a significant association with the study population (p = 0.0386). Our data indicates a powerful nocebo effect in neuropathic pain trials that may be influenced by gender- and population-related factors. A strong nocebo effect may be adversely affecting adherence and efficacy of current treatments for neuropathic pain in clinical practice.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Amanzio M, Corazzini LL, Vase L, Benedetti F (2009) A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146:261–269

    PubMed  Article  CAS  Google Scholar 

  2. Balant LP, Balant-Gorgia EA (2000) Cultural differences: implications on drug therapy and global drug development. Int J Clin Pharmacol Ther 38:47–52

    PubMed  CAS  Google Scholar 

  3. Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287:622–662

    PubMed  Article  Google Scholar 

  4. Berman S, Munakata J, Naliboff BD, Chang L, Mandelkem M, Silverman D, Kovalik E, Mayer EA (2000) Gender differences in regional brain response to visceral pressure in IBS patients. Eur J Pain 4:157–172

    PubMed  Article  CAS  Google Scholar 

  5. Berger A, Dukes EM, Oster G (2004) Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain 5:143–149

    PubMed  Article  Google Scholar 

  6. Bouhassira D, Lantιri-Minet M, Attal N, Laurent B, Touboul C (2008) Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136:380–387

    PubMed  Article  Google Scholar 

  7. Cairns DM, Adkins RH, Scott MD (1996) Pain and depression in acute traumatic spinal cord injury: origins of chronic problematic pain. Arch Phys Med Rehabil 77:329–335

    PubMed  Article  CAS  Google Scholar 

  8. Davis C, Ralevski E, Kennedy SH, Neitzert C (1995) The role of personality factors in the reporting of side effect complaints to moclobemide and placebo: a study of healthy male and female volunteers. J Clin Psychopharmacol 15:347–352

    PubMed  Article  CAS  Google Scholar 

  9. de la Cruz M, Hui D, Parsons HA, Bruera E (2010) Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer. Cancer 116:766–774

    Article  Google Scholar 

  10. Deeks JJ (2001) Systematic reviews in health care: systematic reviews of evaluations of diagnostic and screening tests. BMJ 323:157–162

    PubMed  Article  CAS  Google Scholar 

  11. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    PubMed  Article  CAS  Google Scholar 

  12. Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, Garofalo EA, Poole RM (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 60:1274–1283

    PubMed  CAS  Google Scholar 

  13. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251

    PubMed  Article  CAS  Google Scholar 

  14. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  16. Flaten MA, Simonsen T, Olsen H (1999) Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom Med 61:250–255

    PubMed  CAS  Google Scholar 

  17. Gimbel JS, Richards P, Portenoy RK (2003) Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 60:927–934

    PubMed  CAS  Google Scholar 

  18. Hall GC, Carroll D, Parry D, McQuay HJ (2006) Epidemiology and treatment of neuropathic pain: the UK primary care perspective. Pain 122:156–162

    PubMed  Article  Google Scholar 

  19. Jensen MP, Romano JM, Turner JA, Good AB, Wald LH (1999) Patient beliefs predict patients functioning; further support for a cognitive-behavioural model of chronic pain. Pain 81:95–104

    PubMed  Article  CAS  Google Scholar 

  20. Jensen MP, Chodroff MJ, Dworkin RH (2007) The impact of neuropathic pain on health-related quality of life: review and implications. Neurology 68:1178–1182

    PubMed  Article  Google Scholar 

  21. Kennedy WP (1961) The nocebo reaction. Med Exp Int J Exp Med 95:203–205

    CAS  Google Scholar 

  22. Klosterhalfen S, Kellermann S, Braun S, Kowalski A, Schrauth M, Zipfel S, Enck P (2009) Gender and the nocebo response following conditioning and expectancy. J Psychosom Res 66:323–328

    PubMed  Article  Google Scholar 

  23. Lesser H, Sharma U, LaMoreaux L, Poole RM (2004) Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 63:2104–2110

    PubMed  CAS  Google Scholar 

  24. Liccardi G, Senna G, Russo M, Bonadonna P, Crivellaro M, Dama A, D’Amato M, D’Amato G, Canonica GW, Passalacqua G (2004) Evaluation of the nocebo effect during oral challenge in patients with adverse drug reactions. J Invest Allergol Clin Immunol 14:104–107

    CAS  Google Scholar 

  25. 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 25:124–131

    PubMed  Article  CAS  Google Scholar 

  26. Macedo A, Baños JE, Farré M (2008) Placebo response in the prophylaxis of migraine: a meta-analysis. Eur J Pain 12:68–75

    PubMed  Article  Google Scholar 

  27. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    PubMed  CAS  Google Scholar 

  28. 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 31:550–561

    Google Scholar 

  29. Mitsikostas DD, Thomas AM (1999) Comorbidity of headache and depressive disorders. Cephalalgia 19:211–217

    PubMed  Article  CAS  Google Scholar 

  30. Moher D, Liberati A, Tetzlaff J, Altmann DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:332–336

    Article  Google Scholar 

  31. Connor AB O (2009) Neuropathic pain. Quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics 27:95–112

    Article  Google Scholar 

  32. Otto M, Bach FW, Jensen TS, Sindrup SH (2004) Valproic acid has no effect on pain in polyneuropathy: a randomized, controlled trial. Neurology 62:285–288

    PubMed  CAS  Google Scholar 

  33. Papadopoulos D, Mitsikostas DD (2010) Nocebo effects in multiple sclerosis trials: a meta-analysis. Mult Scler 16:816–828

    PubMed  Article  CAS  Google Scholar 

  34. Paulson PE, Minoshima S, Morrow TJ, Casey KL (1998) Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 76:223–229

    PubMed  Article  CAS  Google Scholar 

  35. Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JN, Tracey I (2001) Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci 21:9896–9903

    PubMed  CAS  Google Scholar 

  36. Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, Royall RM, Max MB (2002) Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 59:1015–1021

    PubMed  CAS  Google Scholar 

  37. Rao RD, Flynn PJ, Sloan JA, Wong GY, Novotny P, Johnson DB, Gross HM, Renno SI, Nashawaty M, Loprinzi CL (2008) Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer 112:2802–2808

    PubMed  Article  CAS  Google Scholar 

  38. Raskin P, Donofrio PD, Rosenthal NR, Hewitt DJ, Jordan DM, Xiang J, Vinik AI, CAPSS-141 Study Group (2004) Topiramate vs. placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology 63:865–873

    PubMed  CAS  Google Scholar 

  39. Rintala DH, Loubser PG, Castro J, Hart KA, Fuhrer MJ (1998) Chronic pain in a community-based sample of men with spinal cord injury: prevalence, severity, and relationship with impairment, disability, handicap, and subjective well-being. Arch Phys Med Rehabil 79:604–614

    PubMed  Article  CAS  Google Scholar 

  40. Rosenzweig P, Brohier S, Zipfel A (1993) The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies. Clin Pharmacol Ther 54:579–583

    Article  Google Scholar 

  41. Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M, Fukuyama H, Konishi J, Shibasaki H (2000) Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci 20:7438–7445

    PubMed  CAS  Google Scholar 

  42. Semenchuk MR, Sherman S, Davis B (2001) Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 57:1583–1588

    PubMed  CAS  Google Scholar 

  43. Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK (2006) Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology 67:1792–1800

    PubMed  Article  CAS  Google Scholar 

  44. Simpson DM, Schifitto G, Murphy TK, Durso-De Cruz E, Glue P, Whalen E, Emir B, Scott GN, Freeman R, HIV Neuropathy Study Group (2010) Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology 74:413–420

    PubMed  Article  CAS  Google Scholar 

  45. Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS (2003) Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology 60:1284–1289

    PubMed  CAS  Google Scholar 

  46. Sindrup SH, Jensen TS (1999) Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389–400

    PubMed  Article  CAS  Google Scholar 

  47. Torrance N, Smith BH, Bennett MI, Lee AJ (2006) The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 7:281–289

    PubMed  Article  Google Scholar 

  48. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635

    PubMed  Article  CAS  Google Scholar 

  49. Uhlenhuth EH, Alexander PE, Dempsey GM, Jones W, Coleman BS, Swiontek AM (1998) Medication side effects in anxious patients: negative placebo responses. J Affect Dis 47:183–190

    PubMed  Article  CAS  Google Scholar 

  50. Wernicke JF, Pritchett YL, D’Souza DN, Waninger A, Tran P, Iyengar S, Raskin J (2006) A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 67:1411–1420

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Mrs. Evie Delicha, MSc for her expert advice on the statistical analysis.

Conflicts of interest

Dr. D. Papadopoulos reports no disclosures. Dr. D.D. Mitsikostas received honoraria for lecturing, traveling and research grants from Bayer-Schering, Merck-Serono, MSD, Novartis, Pfizer, Lilly, and UCB. He is a member of the scientific board of Merck-Serono, Greece, Bayer-Schering, Greece, and Novartis Greece. No funding source had a role in the conception or preparation of this article.

Author information

Affiliations

  1. Department of Neurology, Athens Naval Hospital, 70 Deinokratous Street, 115-21, Athens, Greece

    Dimitrios Papadopoulos & Dimos Dimitrios Mitsikostas

  2. Neurology Section, Evangelismos General Hospital, Athens, Greece

    Dimitrios Papadopoulos

Authors
  1. Dimitrios Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimos Dimitrios Mitsikostas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dimos Dimitrios Mitsikostas.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Papadopoulos, D., Mitsikostas, D.D. A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J Neurol 259, 436–447 (2012). https://doi.org/10.1007/s00415-011-6197-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-011-6197-4

Keywords

  • Nocebo
  • Neuropathic pain
  • Neuralgia
  • Meta-analysis
  • Nocebo
  • Meta-regression