Skip to main content
Log in

An Investigation of Factors Contributing to Higher Levels of Placebo Response in Clinical Trials in Neuropathic Pain: A Systematic Review and Meta-Analysis

  • Systematic Review
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background

In new drug development in neuropathic pain (NeP), randomized, double-blind, placebo-controlled trials (PCTs) with long treatment durations in a parallel-group design are recommended for confirmatory trials.

Objective

This study was conducted to identify potential factors contributing to elevated placebo response in parallel-group PCTs for oral drugs with at least a 4-week treatment duration.

Methods

A literature search was conducted through MEDLINE and EMBASE, and was supplemented with data from ClinicalTrials.gov and US/Japanese regulatory approval review information. Using the 30 or 50 % responder rate (RR), logistic regression analyses were performed to investigate the relationship between the degree of placebo response and several potential influencing factors.

Results

The search identified 71 trials (n = 6,126). The estimated 50 % RRs (95 % confidence intervals) in the placebo group were as follows: peripheral neuropathic pain (P-NeP) 23 % (21, 26 %); central neuropathic pain (C-NeP) 14 % (10, 19 %); postherpetic neuralgia (PHN) 19 % (15, 24 %); painful diabetic peripheral neuropathy (pDPN) 26 % (23, 29 %); posttraumatic peripheral neuropathic pain (PT) 15 % (10, 20 %). From the logistic regression analyses, it was found that there was a significant association between placebo response (50 % RR and 30 % RR) and NeP classification (P < 0.05). Associations between placebo response and several factors were seen in univariate logistic regression analyses of 50 % RR. Multivariate analyses showed that age and baseline pain intensity in PHN, and treatment duration, trial design (fixed-dose/flexible-dose) and baseline pain intensity in pDPN, were associated with placebo response, suggesting that a reduced placebo response correlated with increasing age and baseline pain intensity, and a higher placebo response correlated with a longer treatment period and flexible dosing regimen. A similar pattern observed in the analysis of 50 % RR was suggested in the analysis of 30 % RR, with the exception of treatment duration. In addition, investigations of trials with at least a 12-week treatment duration in pDPN found associations with the number of patients per site, patient enrolment rate, proportion of male patients and baseline pain intensity, suggesting that a higher placebo response correlated with an increasing number of patients per site, and a reduced placebo response correlated with increasing patient enrolment rate and proportion of male patients and baseline pain intensity.

Conclusion

The results of this study suggest that NeP condition, trial design, and demographic and baseline characteristics may contribute to elevated placebo response in clinical trials in patients with NeP. In addition, the magnitude of placebo response and the effect of treatment duration are greater in pDPN than in PHN. These facts should be considered when planning and conducting confirmatory trials in NeP.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. European Medical Agency. Guideline on clinical medical products intended for the treatment of neuropathic pain. 2007. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000425.jsp&mid=WC0b01ac0580034cf5. Accessed 22 Aug 2014.

  2. U.S. Food and Drug Administration. Guidance for Industry–Analgesic Indications: Developing Drug and Biological Products [Draft guidance]. February 2014. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Accessed 22 Aug 2014.

  3. Dworkin RH, Turk DC, Peirce-Sandner S, et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain. 2010;149:177–93.

    Article  PubMed  Google Scholar 

  4. Dworkin RH, Turk DC, Peirce-Sandner S, et al. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain. 2010;150:12–6.

    Article  PubMed  Google Scholar 

  5. Cepeda MS, Berlin JA, Gao CY, et al. Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis. Pain Med. 2012;13:575–95.

    Article  PubMed  Google Scholar 

  6. Quessy SN, Rowbotham MC. Placebo response in neuropathic pain trials. Pain. 2008;138:479–83.

    Article  PubMed  Google Scholar 

  7. Irizarry MC, Webb DJ, Ali Z, et al. Predictors of placebo response in pooled lamotrigine neuropathic pain clinical trials. Clin J Pain. 2009;25:469–76.

    Article  PubMed  Google Scholar 

  8. Ziegler D, Pritchett YL, Wang F, et al. Impact of disease characteristics on the efficacy of duloxetine in diabetic peripheral neuropathic pain. Diabetes Care. 2007;30:664–9.

    Article  CAS  PubMed  Google Scholar 

  9. Häuser W, Bartram-Wunn E, Bartram C, et al. 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.

    Article  PubMed  Google Scholar 

  10. Katz J, Finnerup NB, Dworkin RH. Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology. 2008;70:263–72.

    Article  PubMed  Google Scholar 

  11. Dworkin DH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524–34.

    Article  PubMed  Google Scholar 

  12. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105–21.

    Article  PubMed  Google Scholar 

  13. Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94:149–58.

    Article  CAS  PubMed  Google Scholar 

  14. Jensen TS, Baron R, Haanpää M, et al. A new definition of neuropathic pain. Pain. 2011;152:2204–5.

    Article  PubMed  Google Scholar 

  15. Stacey BR, Barrett JA, Whalen E, et al. Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain. 2008;9:1006–17.

    Article  CAS  PubMed  Google Scholar 

  16. Irving G, Jensen M, Cramer M, et al. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial. Clin J Pain. 2009;25:185–92.

    Article  PubMed  Google Scholar 

  17. Pharmaceutical and Medical Devices Agency [in Japanese]. Pregabalin CTD Study 1008-030. http://www.info.pmda.go.jp/shinyaku/P201000025/index.html. Accessed 1 Feb 2014.

  18. U.S. Food and Drug Administration. Lyrica NDA #021723 Study 1008-030. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LYRICA. Accessed 1 Feb 2014.

  19. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003;104:323–31.

    Article  CAS  PubMed  Google Scholar 

  20. Rice AS, Maton S. Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–24.

    Article  CAS  PubMed  Google Scholar 

  21. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837–42.

    Article  CAS  PubMed  Google Scholar 

  22. U.S. Food and Drug Administration. Neurontin NDA #021397 Study 945-211. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=NEURONTIN. Accessed 1 Feb 2014.

  23. Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2003;60:1274–83.

    Article  CAS  PubMed  Google Scholar 

  24. U.S. Food and Drug Administration. Lyrica NDA #021446 Study 1008-127. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LYRICA. Accessed 1 Feb 2014.

  25. Sabatowski R, Galvez R, Cherry DA, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004;109:26–35.

    Article  CAS  PubMed  Google Scholar 

  26. U.S. Food and Drug Administration. Lyrica NDA #021446 Study 1008-045. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LYRICA. Accessed 1 Feb 2014.

  27. Kochar DK, Garg P, Bumb RA, et al. Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study. Q J Med. 2005;98:29–34.

    Article  CAS  Google Scholar 

  28. Wallace MS, Irving G, Cowles VE. Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicentre study. Clin Drug Invest. 2010;30:765–76.

    Article  CAS  Google Scholar 

  29. NCT00612105. Retigabine Study VRX-RET-E22-NP201. http://www.clinicaltrials.gov/ct2/show/study/NCT00612105?term=NCT00612105&rank=1. Accessed 1 Feb 2014.

  30. Sang CN, Sathyanarayana R, Sweeney M, et al. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281–8.

    Article  PubMed  Google Scholar 

  31. van Seventer R, Feister HA, Young JP Jr, et al. Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin. 2006;22:375–84.

    Article  PubMed  Google Scholar 

  32. NCT00394901. Pregabalin Study A0081120. http://www.clinicaltrials.gov/ct2/show/NCT00394901?term=NCT00394901&rank=1. Accessed 1 Feb 2014.

  33. Ogawa S, Suzuki M, Arakawa A, et al. Efficacy and tolerability of pregabalin for postherpetic neuralgia: a multicenter, randomized, double-blind, placebo-controlled clinical trial[in Japanese]. Journal of the Japan Society of Pain Clinicians. 2010;17:141–52.

    Google Scholar 

  34. Zhang L, Rainka M, Freeman R, et al. A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of gabapentin enacarbil in subjects with neuropathic pain associated with postherpetic neuralgia (PXN110748). J Pain. 2013;14:590–603.

    Article  CAS  PubMed  Google Scholar 

  35. NCT00592774. Perampanel Study E2007-A001-218. http://www.clinicaltrials.gov/ct2/show/NCT00592774?term=NCT00592774&rank=1. Accessed 1 Feb 2014.

  36. Sandercock D, Cramer M, Biton V, et al. A gastroretentive gabapentin formulation for the treatment of painful diabetic peripheral neuropathy: efficacy and tolerability in a double-blind, randomized, controlled clinical trial. Diabetes Res Clin Pract. 2012;97:438–45.

    Article  CAS  PubMed  Google Scholar 

  37. NCT00857623. AZD2066 Study D0475C00009. http://www.clinicaltrials.gov/ct2/show/NCT00857623?term=NCT00857623&rank=1. Accessed 1 Feb 2014.

  38. NCT01201317. AZD2423 Study D2600C00005. http://www.clinicaltrials.gov/ct2/show/NCT01201317?term=NCT01201317&rank=1. Accessed 1 Feb 2014.

  39. Lesser H, Sharma U, LaMoreaux L, et al. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63:2104–10.

    Article  CAS  PubMed  Google Scholar 

  40. U.S. Food and Drug Administration. Lyrica NDA #021446 Study 1008-029. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LYRICA. Accessed 1 Feb 2014.

  41. NCT00785577. LY545694 Study 11977/ H8C-MC-LQBF. http://www.clinicaltrials.gov/ct2/show/NCT00785577?term=NCT00785577&rank=1. Accessed 1 Feb 2014.

  42. Rowbotham MC, Goli V, Kunz NR, et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706.

    Article  CAS  PubMed  Google Scholar 

  43. Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain. 2005;6:253–60.

    Article  CAS  PubMed  Google Scholar 

  44. Rowbotham MC, Duan WR, Thomas J, et al. A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain. Pain. 2009;146:245–52.

    Article  CAS  PubMed  Google Scholar 

  45. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology. 2001;57:505–9.

    Article  CAS  PubMed  Google Scholar 

  46. Rosenstock J, Tuchman M, LaMoreaux L, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004;110:628–38.

    Article  CAS  PubMed  Google Scholar 

  47. U.S. Food and Drug Administration. Lyrica NDA #021446 study 1008-131. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LYRICA. Accessed 1 Feb 2014.

  48. Rowbotham MC, Arslanian A, Nothaft W, et al. Efficacy and safety of the a4b2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain. Pain. 2012;153:862–8.

    Article  CAS  PubMed  Google Scholar 

  49. Pharmaceutical and Medical Devices Agency [in Japanese]. Pregabalin CTD Study 1008-040. http://www.info.pmda.go.jp/shinyaku/P201000025/index.html. Accessed 1 Feb 2014.

  50. Freeman R, Raskin P, Hewitt DJ, et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy. Curr Med Res Opin. 2007;23:147–61.

    Article  CAS  PubMed  Google Scholar 

  51. Rauck RL, Shaibani A, Biton V, et al. Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study. Clin J Pain. 2007;23:150–8.

    Article  PubMed  Google Scholar 

  52. Raskin P, Donofrio PD, Rosenthal NR, et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004;63:865–73.

    Article  CAS  PubMed  Google Scholar 

  53. Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116:109–18.

    Article  CAS  PubMed  Google Scholar 

  54. Skljarevski V, Frakes EP, Sagman D. Review of efficacy and safety of duloxetine 40 to 60 mg once daily in patients with diabetic peripheral neuropathic pain. Pain Res Treat. 2012;. doi:10.1155/2012/898347.

    Google Scholar 

  55. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6:346–56.

    Article  PubMed  Google Scholar 

  56. Atli A, Dogra S. Zonisamide in the treatment of painful diabetic neuropathy: a randomized, double-blind, placebo-controlled pilot study. Pain Med. 2005;6:225–34.

    Article  PubMed  Google Scholar 

  57. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67:1411–20.

    Article  CAS  PubMed  Google Scholar 

  58. Tolle T, Freynhagen R, Versavel M, et al. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain. 2008;12:203–13.

    Article  PubMed  Google Scholar 

  59. Gao Y, Ning G, Jia WP, et al. Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China. Chin Med J. 2010;123:3184–92.

    CAS  PubMed  Google Scholar 

  60. Yasuda H, Hotta N, Nakao K, et al. Superiority of duloxetine to placebo in improving diabetic neuropathic pain: results of a randomized controlled trial in Japan. J Diabetes Invest. 2011;2:132–9.

    Article  CAS  Google Scholar 

  61. Pharmaceutical and Medical Devices Agency [in Japanese]. Pregabalin CTD Study A0081030. http://www.info.pmda.go.jp/shinyaku/P201000025/index.html. Accessed 1 Feb 2014.

  62. Arezzo JC, Rosenstock J, LaMoreaux L, et al. Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial. BMC Neurol. 2008;8:33–46.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Satoh J, Yagihashi S, Baba M, et al. Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial. Diabet Med. 2011;28:109–16.

    Article  CAS  PubMed  Google Scholar 

  64. Shaibani AI, Pope LE, Thisted R, et al. Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study. Pain Med. 2012;13:243–54.

    Article  PubMed  Google Scholar 

  65. Rauck R, Makumi CW, Schwartz S, et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13:485–96.

    Article  PubMed  Google Scholar 

  66. Pharmaceutical and Medical Devices Agency [in Japanese]. Pregabalin CTD Study A0081071. http://www.info.pmda.go.jp/shinyaku/P201000025/index.html. Accessed 1 Feb 2014.

  67. NCT00283842. Desvenlafaxine Study 3151A5-322. http://www.clinicaltrials.gov/ct2/show/NCT00283842?term=NCT00283842&rank=1. Accessed 1 Feb 2014.

  68. Smith T, DiBernardo A, Shi Y, et al. Efficacy and safety of carisbamate in patients with diabetic neuropathy or postherpetic neuralgia: results from 3 randomized, double-blind placebo-controlled trials. Pain Pract. 2014;14:332–42.

    Article  PubMed  Google Scholar 

  69. NCT00505284. Perampanel Study E2007-G000-227/2006-006488-22. http://www.clinicaltrials.gov/ct2/show/NCT00505284?term=NCT00505284&rank=1. Accessed 1 Feb 2014.

  70. Dogra S, Beydoun S, Mazzola J, et al. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain. 2005;9:543–54.

    Article  CAS  PubMed  Google Scholar 

  71. Shaibani A, Fares S, Selam JL, et al. Lacosamide in painful diabetic neuropathy: an 18-week double-blind placebo-controlled trial. J Pain. 2009;10:818–28.

    Article  CAS  PubMed  Google Scholar 

  72. Wymer JP, Simpson J, Sen D, et al. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clin J Pain. 2009;25:376–85.

    Article  PubMed  Google Scholar 

  73. Ziegler D, Hidvegi T, Gurieva I, et al. Efficacy and safety of lacosamide in painful diabetic neuropathy. Diabetes Care. 2010;33:839–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Vinik AI, Tuchman M, Safirstein B, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain. 2007;128:169–79.

    Article  CAS  PubMed  Google Scholar 

  75. Kalliomaki J, Attal N, Jonzon B, et al. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain. 2013;154:761–7.

    Article  PubMed  Google Scholar 

  76. Ostenfeld T, Krishen A, Lai RY, et al. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2013;17:844–57.

    Article  CAS  PubMed  Google Scholar 

  77. van Seventer R, Bach FW, Toth CC, et al. Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial. Eur J Neurol. 2010;17:1082–9.

    Article  PubMed  Google Scholar 

  78. Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology. 2010;74:413–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. NCT00109772. Lenalidomide Study CC-5013-CRPS-002. http://www.clinicaltrials.gov/ct2/show/NCT00109772?term=NCT00109772&rank=1. Accessed 1 Feb 2014.

  80. Maier C, Dertwinkel R, Mansourian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain-results of a randomized double-blinded, placebo-controlled trial. Pain. 2003;103:277–83.

    Article  CAS  PubMed  Google Scholar 

  81. Moon DE, Lee DI, Lee SC, et al. Efficacy and tolerability of pregabalin using a flexible, optimized dose schedule in Korean patients with peripheral neuropathic pain: a 10-week, randomized, double-blind, placebo-controlled, multicenter study. Clin Ther. 2010;32:2370–85.

    Article  CAS  PubMed  Google Scholar 

  82. Guan Y, Ding X, Cheng Y, et al. Efficacy of pregabalin for peripheral neuropathic pain: results of an 8-week, flexible-dose, double-blind, placebo-controlled study conducted in China. Clin Ther. 2011;33:159–66.

    Article  CAS  PubMed  Google Scholar 

  83. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005;115:254–63.

    Article  CAS  PubMed  Google Scholar 

  84. NCT01124617. Tapentadol Study CR017002/JNS024ER-JPN-N22. http://www.clinicaltrials.gov/ct2/show/NCT01124617?term=NCT01124617&rank=1. Accessed 1 Feb 2014.

  85. Siddall PJ, Cousins MJ, Otte A, et al. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67:1792–800.

    Article  CAS  PubMed  Google Scholar 

  86. U.S. Food and Drug Administration. Lyrica NDA #021446 Study 1008-125. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LYRICA. Accessed 1 Feb 2014.

  87. Cardenas DD, Nieshoff EC, Suda K, et al. A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology. 2013;80:533–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Kim JS, Bashford G, Murphy TK, et al. Safety and efficacy of pregabalin in patients with central post-stroke pain. Pain. 2011;152:1018–23.

    Article  CAS  PubMed  Google Scholar 

  89. Vollmer TL, Robinson MJ, Risser RC, et al. A randomised, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patient with multiple sclerosis. Pain Practice. 2013; doi:10.1111/papr.12127

  90. Vranken JH, Dijkgraaf MG, Kruis MR, et al. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain. 2008;136:150–7.

    Article  CAS  PubMed  Google Scholar 

  91. Serpell MG. Neuropathic pain study group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99:557–66.

    Article  CAS  PubMed  Google Scholar 

  92. Kost RG, Straus SE. Postherpetic neuralgia – pathogenesis, treatment, and prevention. N Engl J Med. 1996;335:32–42.

    Article  CAS  PubMed  Google Scholar 

  93. Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol. 2008;59:565–90.

    Article  PubMed  Google Scholar 

  94. Linde K, Witt CM, Streng A, et al. The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain. 2007;128:264–71.

    Article  PubMed  Google Scholar 

  95. Katz N. Methodological issues in clinical trials of opioids for chronic pain. Neurology. 2005;65:S32–49.

    Article  PubMed  Google Scholar 

  96. Dworkin RH, Katz J, Gitlin MJ, et al. Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain. Neurology. 2005;65:S7–19.

    Article  PubMed  Google Scholar 

  97. Sakai F, Diener HC, Ryan R, et al. Eletriptan for the acute treatment of migraine: results of bridging a Japanese study to Western clinical trials. Curr Med Res Opin. 2004;20:269–77.

    Article  CAS  PubMed  Google Scholar 

  98. Wang SJ, Fuh JL, Wu ZA. Intranasal sumatriptan study with high placebo response in Taiwanese patients with migraine. J Chin Med Assoc. 2007;70:39–46.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors have no conflicts of interest that are directly relevant to this research. Akio Arakawa is an employee of Pfizer Japan Inc. The preparation of this manuscript was not supported by any external funding.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Akio Arakawa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 255 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 35, 67–81 (2015). https://doi.org/10.1007/s40261-014-0259-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-014-0259-1

Keywords

Navigation