Skip to main content

Advertisement

SpringerLink
Log in

Advances in clinical research methodology for pain clinical trials

  • Review Article
  • Published:

From Nature Medicine

View current issue Submit your manuscript

Abstract

Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2: Normal density curves of simulated data for a single normal distribution control group and a combined (bimodal) treatment group.
Figure 3: Cumulative distribution function curve for a simulated analysis of two groups, placebo and combined treatment created from data used for the graph in Figure 2.

Similar content being viewed by others

References

  1. Merskey, H. & Bogduk, N. Part III: Pain terms—a current list with definitions and notes on usage. in Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy 209–214 (IASP, Seattle, 1994).

    Google Scholar 

  2. Treede, R.D. et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635 (2008).

    Article  CAS  Google Scholar 

  3. Hill, A.B. The Clinical Trial. N. Engl. J. Med. 247, 113–119 (1952).

    Article  CAS  Google Scholar 

  4. Lasagna, L. & Beecher, H.K. Analgesic effectiveness of nalorphine and nalorphine–morphine combinations in man. J. Pharmacol. Exp. Ther. 112, 356–363 (1954).

    CAS  PubMed  Google Scholar 

  5. Houde, R.W. & Wallenstein, S.L. Clinical studies of morphine–nalorphine combinations. Fed. Proc. 15, 440–441 (1956).

    Google Scholar 

  6. Beecher, H.K. Measurement of Subjective Responses: Quantitative Effects of Drugs (Oxford University Press, Oxford, 1959).

    Google Scholar 

  7. Melzack, R. & Wall, P.D. Pain mechanisms: a new theory. Science 150, 971–979 (1965).

    Article  CAS  Google Scholar 

  8. Dworkin, R.H. et al. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain 150, 12–16 (2010).

    Article  Google Scholar 

  9. Basbaum, A.I. et al. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    Article  CAS  Google Scholar 

  10. Bouhassira, D. et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136, 380–387 (2008).

    Article  Google Scholar 

  11. Torrance, N. et al. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J. Pain 7, 281–289 (2006).

    Article  Google Scholar 

  12. Deng, W., Aimone, J.B. & Gage, F.H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350 (2010).

    Article  CAS  Google Scholar 

  13. Woolf, C.J. & Mannion, R.J. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353, 1959–1964 (1999).

    Article  CAS  Google Scholar 

  14. Shavit, Y. et al. Postoperative pain management and proinflammatory cytokines: animal and human studies. J. Neuroimmune Pharmacol. 1, 443–451 (2006).

    Article  Google Scholar 

  15. Moiniche, S. et al. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 96, 725–741 (2002).

    Article  Google Scholar 

  16. Woolf, C.J., American College of Physicians & American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann. Intern. Med. 140, 441–451 (2004).

    Article  Google Scholar 

  17. Lee, S., Walker, J.R., Jakul, L. & Sexton, K. Does elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A meta-analytic evaluation. Depress. Anxiety 19, 10–19 (2004).

    Article  Google Scholar 

  18. Dworkin, R.H. et al. Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain. Neurology 65, S7–S19 (2005).

    Article  Google Scholar 

  19. Kundt, G. & Kundt, G. Comparative evaluation of balancing properties of stratified randomization procedures. Methods Inf. Med. 48, 129–134 (2009).

    Article  Google Scholar 

  20. Temple, R.J., Meyer, R., Temple, R.J. & Meyer, R. Continued need for placebo in many cases, even when there is effective therapy. Arch. Intern. Med. 163, 371–373 (2003).

    Article  Google Scholar 

  21. Boutron, I. et al. Reporting methods of blinding in randomized trials assessing nonpharmacological treatments. PLoS Med. 4, e61 (2007).

    Article  Google Scholar 

  22. Turner, J.A. et al. Blinding effectiveness and association of pretreatment expectations with pain improvement in a double-blind randomized controlled trial. Pain 99, 91–99 (2002).

    Article  CAS  Google Scholar 

  23. Irizarry, M.C. et al. Predictors of placebo response in pooled lamotrigine neuropathic pain clinical trials. Clin. J. Pain 25, 469–476 (2009).

    Article  Google Scholar 

  24. Boutron, I. et al. Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review. PLoS Med. 3, e425 (2006).

    Article  Google Scholar 

  25. Bingel, U., Tracey, I., Bingel, U. & Tracey, I. Imaging CNS modulation of pain in humans. Physiology (Bethesda) 23, 371–380 (2008).

    Google Scholar 

  26. Tracey, I. Imaging pain. Br. J. Anaesth. 101, 32–39 (2008).

    Article  CAS  Google Scholar 

  27. Bouhassira, D. et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114, 29–36 (2005).

    Article  Google Scholar 

  28. Bennett, M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 92, 147–157 (2001).

    Article  CAS  Google Scholar 

  29. Galer, B.S. & Jensen, M.P. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology 48, 332–338 (1997).

    Article  CAS  Google Scholar 

  30. Krause, S.J. & Backonja, M.M. Development of a neuropathic pain questionnaire. Clin. J. Pain 19, 306–314 (2003).

    Article  Google Scholar 

  31. Cleeland, C.S. & Ryan, K.M. Pain assessment: global use of the Brief Pain Inventory. Ann. Acad. Med. Singapore 23, 129–138 (1994).

    CAS  PubMed  Google Scholar 

  32. Hurny, C.B.J. et al. Responsiveness of a single-item indicator versus a multi-item scale: assessment of emotional well-being in an international adjuvant breast cancer trial. Med. Care 34, 234–248 (1996).

    Article  CAS  Google Scholar 

  33. Breivik, E.K., Bjornsson, G.A. & Skovlund, E. A comparison of pain rating scales by sampling from clinical trial data. Clin. J. Pain 16, 22–28 (2000).

    Article  CAS  Google Scholar 

  34. McDowell, I. & Newell, C. Pain measurements. in Measuring Health: A Guide to Rating Scales and Questionnaires Ch. 8 (Oxford University Press, Oxford, 1996).

    Google Scholar 

  35. Farrar, J.T., Portenoy, R.K., Berlin, J.A., Kinman, J. & Strom, B.L. Defining the Clinically Important Difference in Pain Outcome Measures. Pain 88, 287–294 (2000).

    Article  CAS  Google Scholar 

  36. Farrar, J.T., Young, J.P. Jr., LaMoreaux, L., Werth, J.L. & Poole, R.M. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94, 149–158 (2001).

    Article  CAS  Google Scholar 

  37. Kerns, R.D., Turk, D.C. & Rudy, T.E. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 23, 345–356 (1985).

    Article  CAS  Google Scholar 

  38. Bellamy, N. et al. Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III. J. Rheumatol. 24, 799–802 (1997).

    CAS  PubMed  Google Scholar 

  39. Dworkin, R.H. et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 113, 9–19 (2005).

    Article  Google Scholar 

  40. Turk, D.C. et al. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain 106, 337–345 (2003).

    Article  Google Scholar 

  41. Moore, A., McQuay, H. & Gavaghan, D. Deriving dichotomous outcome measures from continuous data in randomised controlled trials of analgesics. Pain 66, 229–237 (1996).

    Article  CAS  Google Scholar 

  42. Cook, R.J. & Sackett, D.L. The number needed to treat: a clinically useful measure of treatment effect. Br. Med. J. 310, 452–454 (1995).

    Article  CAS  Google Scholar 

  43. Edelsberg, J., Oster, G., Edelsberg, J. & Oster, G. Summary measures of number needed to treat: how much clinical guidance do they provide in neuropathic pain? Eur. J. Pain 13, 11–16 (2009).

    Article  Google Scholar 

  44. Committee on National Statistics. The prevention and treatment of missing data. in Clinical Trials: Panel on Handling Missing Data in Clinical Trials Ch. 2 and Ch. 5 (The National Academies Press, Washington, DC, 2010).

  45. Katz, N. Methodological issues in clinical trials of opioids for chronic pain. Neurology 65, S32–S49 (2005).

    Article  Google Scholar 

  46. Keller, S. et al. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin. J. Pain 20, 309–318 (2004).

    Article  Google Scholar 

  47. Melzack, R. The short-form McGill Pain Questionnaire. Pain 30, 191–197 (1987).

    Article  CAS  Google Scholar 

  48. Heft, M.W., Gracely, R.H., Dubner, R. & McGrath, P.A. A validation model for verbal description scaling of human clinical pain. Pain 9, 363–373 (1980).

    Article  CAS  Google Scholar 

  49. Portenoy, R.K., Thaler, H.T. & Kornblith, A.B. The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptom prevalence, characteristics, and distress. Eur. J. Cancer 30A, 1326–1336 (1994).

    Article  CAS  Google Scholar 

  50. Serlin, R.C., Mendoza, T.R., Nakamura, Y., Edwards, K.R. & Cleeland, C.S. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 61, 277–284 (1995).

    Article  CAS  Google Scholar 

  51. Farrar, J.T. et al. A comparison of change in the 0–10 numeric rating scale to a pain relief scale and global medication performance scale in a short-term clinical trial of breakthrough pain intensity. Anesthesiology 112, 1464–1472 (2010).

    Article  Google Scholar 

  52. Fishman, B., Houde, R.W., Wallenstein, S. & Foley, K.M. Appraisal of pain relief mediates the relationship between pain intensity and emotional distress in cancer pain. Pain 30, S415 (1987).

    Article  Google Scholar 

  53. Sloan, J.A. et al. Assessing the clinical significance of single items relative to summated scores. Mayo Clin. Proc. 77, 479–487 (2002).

    Article  Google Scholar 

  54. Farrar, J.T. et al. The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: analyses of data from clinical trials of duloxetine in pain disorders. J. Pain 11, 109–118 (2010).

    Article  CAS  Google Scholar 

  55. Guy, W. Clinical Global Impressions. in ECDEU assessment manual for psychopharmacology. 217–222 (US Department of Health and Human Services, Public Health Service, Alcohol Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch, Rockville, Maryland, 1976).

    Google Scholar 

  56. Bergh, I., Sjostrom, B., Oden, A. & Steen, B. An application of pain rating scales in geriatric patients. Aging Clin. Exp. Res. 12, 380–387 (2000).

    Article  CAS  Google Scholar 

  57. Flaherty, S.A. Pain measurement tools for clinical practice and research. AANA J. 64, 133–140 (1996).

    CAS  PubMed  Google Scholar 

  58. Gracely, R.H., Dubner, R., McGrath, P. & Heft, H. New methods of pain measurement and their application to pain control. Int. Dent. J. 28, 52–65 (1978).

    CAS  PubMed  Google Scholar 

  59. Baker, R. Measuring change in health in general practice: a comparison of a simple transition question with the Nottingham Health Profile. Int. J. Qual. Health Care 10, 207–212 (1998).

    Article  CAS  Google Scholar 

  60. Fitzpatrick, R., Ziebland, S., Jenkinson, C. & Mowat, A. Transition questions to assess outcomes in rheumatoid arthritis. Br. J. Rheumatol. 32, 807–811 (1993).

    Article  CAS  Google Scholar 

  61. Jenkinson, C. & Ziebland, S. Interpretation of data from health status measures: What do the numbers mean? in Individual quality of life: Approaches to conceptualisation and assessment. (eds. Joyce, C.R.B. & McGee, H.M.) 75–86 (Harwood Academic Publishers, Amsterdam, 1999).

    Google Scholar 

  62. Jensen, M.P., Turner, J.A. & Romano, J.M. What is the maximum number of levels needed in pain intensity measurement? Pain 58, 387–392 (1994).

    Article  CAS  Google Scholar 

  63. Cepeda, M.S., Africano, J.M., Polo, R., Alcala, R. & Carr, D.B. Agreement between percentage pain reductions calculated from numeric rating scores of pain intensity and those reported by patients with acute or cancer pain. Pain 106, 439–442 (2003).

    Article  Google Scholar 

  64. Angst, M.S., Brose, W.G. & Dyck, J.B. The relationship between the visual analog pain intensity and pain relief scale changes during analgesic drug studies in chronic pain patients. Anesthesiology 91, 34–41 (1999).

    Article  CAS  Google Scholar 

  65. de Tovar, C. et al. Postoperative self-report of pain in children: interscale agreement, response to analgesic, and preference for a faces scale and a visual analogue scale. Pain Res. Manag. 15, 163–168 (2010).

    Article  Google Scholar 

  66. Decruynaere, C. et al. How many response levels do children distinguish on faces scales for pain assessment? Eur. J. Pain 13, 641–648 (2009).

    Article  Google Scholar 

  67. Tesler, M.D. et al. The word-graphic rating scale as a measure of children's and adolescents' pain intensity. Res. Nurs. Health 14, 361–371 (1991).

    Article  CAS  Google Scholar 

  68. Huskisson, E.C. Measurement of pain. Lancet 2, 1127–1131 (1974).

    Article  CAS  Google Scholar 

  69. Price, D.D., McGrath, P.A., Rafii, A. & Buckingham, B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 17, 45–56 (1983).

    Article  CAS  Google Scholar 

  70. Jamison, R.N. et al. Comparative study of electronic vs. paper VAS ratings: a randomized, crossover trial using healthy volunteers. Pain 99, 341–347 (2002).

    Article  Google Scholar 

  71. Marceau, L.D. et al. Electronic diaries as a tool to improve pain management: is there any evidence? Pain Med. 8 Suppl 3, S101–S109 (2007).

    Article  Google Scholar 

  72. Jensen, M.P. & McFarland, C.A. Increasing the reliability and validity of pain intensity measurement in chronic pain patients. Pain [see comments] 55, 195–203 (1993).

    Article  CAS  Google Scholar 

  73. Guyatt, G.H. et al. Methods to explain the clinical significance of health status measures. Mayo Clin. Proc. 77, 371–383 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

I would like to acknowledge R.H. Dworkin, N. Katz, B.A. Rappaport, D.C. Turk and the late M.B. Max for their roles in educating me on the subject matter of this article over many years, and E. Weisberg for his editorial help.

Author information

Authors and Affiliations

  1. Associate Professor of Epidemiology and Anesthesia, Clinical Associate in Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

    John T Farrar

Authors
  1. John T Farrar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John T Farrar.

Ethics declarations

Competing interests

The author declares competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farrar, J. Advances in clinical research methodology for pain clinical trials. Nat Med 16, 1284–1293 (2010). https://doi.org/10.1038/nm.2249

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2249

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation