Background and aims
The placebo response has been identified as one factor responsible for the lack of therapeutic trials with positive outcomes in neuropathic pain. Reviews have suggested that certain neuropathic pain conditions, including HIV-associated sensory neuropathy (HIV-SN), exhibit a greater placebo response than other neuropathic aetiologies. If true, such a finding could substantially affect clinical trial design and therapeutic developments for these conditions. This study aimed to identify any difference in placebo response between trials of systemic pharmacological intervention in HIV-SN and a comparable neuropathic condition, diabetic polyneuropathy (DPN) and to identify factors influencing the placebo response.
A systematic review search to identify randomised, double-blind studies of systemic pharmacological interventions for painful HIV-SN and DPN published between January 1966 and June 2019 was performed. A meta-analysis of the magnitude of placebo response and the proportion of placebo responders was conducted and compared between the two disease conditions. A meta-regression was used to assess for any study and participant characteristics that were associated with the placebo response. Only studies meeting a methodological quality threshold were included.
Seventy-five trials were identified. There was no statistically significant difference in the proportion of placebo responders (HIV-SN = 0.35; versus DPN = 0.27, p = 0.129). The difference observed in the magnitude of the placebo response [pain reduction of 1.68 (1.47–1.88) DPN; 2.38 (1.87–2.98) in HIV-SN] was based on only 2 trials of HIV-SN and 35 of DPN. Potential factors influencing the placebo response such as psychological measures, were reported inconsistently.
We found no statistically significant difference in the placebo response rate between painful HIV-SN and DPN. Too few studies were available that reported the necessary information to clarify potential differences in the magnitude of placebo response or to elucidate parameters that could be contributing such differences.
The placebo response is one factor that may contribute to a lack of positive trials in neuropathic pain; some etiologies may display larger responses than others. This meta-analysis found no significant difference in placebo response between trials of HIV-associated sensory neuropathy and painful diabetic polyneuropathy, although limited data were available.
Research funding: HIK was funded by a European Commission, NeuroPain FP7 Grant EC (#2013-602891). The funder provided financial support for the conduct and reporting of this research, they did not contribute to study design; nor collection, analysis or interpretation of data; in the writing of this report; nor in the decision to submit the article for publication.
Conflict of interest: NBF has received fees for serving on advisory boards from Grünenthal, Mitsubishi Tanabe, Novartis, Teva Pharmaceuticals, and Merck Selbstmedikation, lecture fees from Astellas, and grant support from Innovative Medicines Initiative. ASCR undertakes consultancy and advisory board work for Imperial College Consultants- in the last 12 months this has included remunerated work for: Merck, Galapagos, Toray, Quartet, Lateral, Novartis and Orion. ASCR was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued upon the acquisition of Spinifex by Novartis in July 2015 and from which future milestone payments may occur. ASCR is named as an inventor on patents: Rice A.S.C., Vandevoorde S. and Lambert D.M Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain. WO 2005/079771; Okuse K. et al. Methods of treating pain by inhibition of vgf activity EP13702262.0/WO2013 110945. SH reports receiving research support from Pfizer Inc. and Disarm Therapeutics, and personal fees from Medoc Ltd. SH reports no conflicts of interest. HIK, LV, JE, ABA, SN report no conflicts of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.
 Dworkin RH, Katz J, Gitlin M. Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain. Neurology 2005;65:S7–19.10.1212/WNL.65.12_suppl_4.S7Search in Google Scholar PubMed
 Tuttle AH, Tohyama S, Ramsay T, Kimmelman J, Schweindhardt P, Bennett GJ, Mogil JS. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain 2015;156:2616–26.10.1097/j.pain.0000000000000333Search in Google Scholar PubMed
 Cragg JJ, Warner FM, Finnerup NB, Jensen MP, Mercier C, Richards JS, Wrigley P, Soler D, Kramer JL. Meta-analysis of placebo responses in central neuropathic pain. Pain 2016;157:530–40.10.1097/j.pain.0000000000000431Search in Google Scholar PubMed
 Häuser W, Bartram-Wunn E, Bartram C, Reinecke H, Tölle T. Systematic review: placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy – Magnitude and patient-related predictors. Pain 2011;152:1709–17.10.1016/j.pain.2011.01.050Search in Google Scholar PubMed
 Arakawa A, Kaneko M, Narukawa M. An investigation of factors contributing to higher levels of placebo response in clinical trials in neuropathic pain: a systematic review and meta-analysis. Clin Drug Investig 2015;35:67–81.10.1007/s40261-014-0259-1Search in Google Scholar PubMed
 Cepeda MS, Berlin JA, Gao CY, Wiegand F, Wada DR. Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis. Pain Med 2012;13:575–95.10.1111/j.1526-4637.2012.01340.xSearch in Google Scholar PubMed
 Irizarry MC, Webb DJ, Ali Z, Chizh BA, Gold M, Kinrade FJ, Meisner PD, Blum D, Silver MT, Weil JG. Predictors of placebo response in pooled lamotrigine neuropathic pain clinical trials. Clin J Pain 2009;25:469–76.10.1097/AJP.0b013e31819dddedSearch in Google Scholar PubMed
 Menezes P, Miller WC, Wohl DA, Adimora AA, Leone PA, Miller WC, Eron JJ. Does HAART efficacy translate to effectiveness? Evidence for a trial effect. PLoS One 2011;6:1–9.10.1371/journal.pone.0021824Search in Google Scholar PubMed PubMed Central
 Dworkin RH, Turk DC, Peirce-Sandner S, Baron R, Bellamy N, Burke LB, Chappell A, Chartier K, Cleeland CS, Costello A, Cowan P, Dimitrova R, Ellenberg S, Farrar JT, French JA, Gilron I, Hertz S, Jadad AR, Jay GW, Kalliomaki J, et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010;149:177–93.10.1016/j.pain.2010.02.018Search in Google Scholar
 Katz J, Finnerup NB, Dworkin RH. Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology 2008;70:263–72.10.1212/01.wnl.0000275528.01263.6cSearch in Google Scholar
 Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbatham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet 2015;14:162–73.10.1016/S1474-4422(14)70251-0Search in Google Scholar
 Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.10.1016/0197-2456(95)00134-4Search in Google Scholar
 Gracely R, McGrath P, Dubner R. Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: manipulation of affect by diazepam. Pain 1978;5:19–29.10.1016/0304-3959(78)90021-0Search in Google Scholar
 Higgins J, Green S. Chapter 16 Special topics in statistics. In: Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0.; 2011:16.1.13 Missing standard deviations.Search in Google Scholar
 Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9:105–21.10.1016/j.jpain.2007.09.005Search in Google Scholar
 Farrar JT, Young JJ, LaMoreaux L, Werth J, Poole R. Clinical importance of changes in chronic pain intensity measured on an 11 point numerical pain rating scale. Pain 2001;94:149–58.10.1016/S0304-3959(01)00349-9Search in Google Scholar
 Vase L, Vollert J, Finnerup NB, Miao X, Atkinson G, Marshall S, Nemeth R, Lange B, Liss C, Price DD, Maier C, Jensen TS, Segerdahl M. Predictors of the placebo analgesia response in randomized controlled trials of chronic pain: a meta-analysis of the individual data from nine industrially sponsored trials. Pain 2015;156:1795–802.10.1097/j.pain.0000000000000217Search in Google Scholar PubMed
 Hess K, Johnson AS, Hu X, Li J, Wu B, Yu C, Zhu H, Jin C, Chen M, Gerstle J, Morgan M, Friend M, Siddiqi A, Hernandez A. Diagnoses of HIV Infection in the United States and Dependent Areas, 2016. HIV Surveill Rep. 2016;28.Search in Google Scholar
 Kirwan PD, Chau C, Brown AE, Gill ON, Delpech VC and contributors. HIV in the UK – 2016 report. December 2016. Public Health England, London.Search in Google Scholar
 Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67:1716–23.10.1136/ard.2008.092015Search in Google Scholar
 Dworkin RH, Turk DC, Peirce-Sandner S, He H, McDErmott MP, Farrar JT, Katz NP, Lin AH, Rappaport BA, Rowbotham MC. Assay sensitivity and study features in neuropathic pain trials: an ACTTION meta-Analysis. Neurology 2013;81:67–75.10.1212/WNL.0b013e318297ee69Search in Google Scholar
 Higgins JPT, Altman D, Sterne J, Cochrane Statistical Methods Group, Cochrane Bias Methods Group. Assessing risk of bias in included studies. In: Higgins J, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. 5.1.0. The Cochrane Collaboration; 2011:3.3.Search in Google Scholar
 Moher D, Jadad A, Nichol G, Penman M, Tugwell P, Walsh S. Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials 1995;16:62–73.10.1016/0197-2456(94)00031-WSearch in Google Scholar
 Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9–19.10.1016/j.pain.2004.09.012Search in Google Scholar PubMed
The online version of this article offers supplementary material (https://doi.org/10.1515/sjpain-2019-0152).
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