Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-848d4c4894-nr4z6 Total loading time: 0 Render date: 2024-05-26T01:19:04.700Z Has data issue: false hasContentIssue false

31 - Understanding clinical trials in pain research

from SECTION X - SYSTEMS OF CARE

Published online by Cambridge University Press:  06 July 2010

By
JOHN T. FARRAR  and
SCOTT D. HALPERN
Edited by
Eduardo D. Bruera  and
Russell K. Portenoy
JOHN T. FARRAR
Affiliation:
The University of Pennsylvania
SCOTT D. HALPERN
Affiliation:
The University of Pennsylvania
Eduardo D. Bruera
Affiliation:
University of Texas, Houston
Russell K. Portenoy
Affiliation:
Albert Einstein College of Medicine, New York
Get access

Summary

Introduction

The randomized controlled trial (RCT) is a modern innovation; the first RCT – the British Medical Research Council's trial of streptomycin for pulmonary tuberculosis – was published in 1948. Despite this relatively brief history, the RCT now represents the “gold standard” for evaluating the efficacy of new medical interventions and new applications for existing interventions. Unfortunately, the marked increase in the use of RCTs during the past 50 years has not been accompanied by corresponding advances in overcoming the method's several limitations. Indeed, a number of potential scientific and ethical difficulties continue to limit the use of RCTs in some clinical contexts and hinder the interpretation of their results in others.

In this chapter, we discuss the various strengths and limitations common to all RCTs, making special reference to trials of pain management interventions when appropriate. We describe the structure of an RCT, consider how several decisions regarding trial design can influence the trial's results, discuss basic issues in the analysis of trial data, and attempt to guide readers in interpreting a trial's results. Because no research experiment can ever be perfect, we hope this chapter will provide clinicians with sufficient understanding of the proper structure of, and inherent problems with, RCTs to be able to ascertain whether the results of published trials are likely 1) to be valid, 2) clinically important, and 3) apply to their patients.

Anatomy of a trial

Designing and conducting an RCT requires investigators to carefully consider several design issues.

Type
Chapter
Information
Cancer Pain
Assessment and Management
 , pp. 568 - 582
Publisher: Cambridge University Press
Print publication year: 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

,Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. Brit Med J 2:769–82, 1948.CrossRefGoogle Scholar
,Anonymous. Fifty years of randomised controlled trials. BMJ 317(7167):0, 1998.CrossRefGoogle Scholar
Peto, R, Baigent, C. Trials: the next 50 years. Large scale randomised evidence of moderate benefits. [see comment]. BMJ 317(7167):1170–1, 1998.CrossRefGoogle Scholar
Freedman, B, Freedman, B. Scientific value and validity as ethical requirements for research: a proposed explication. Irb: a Review of Human Subjects Research 9(6):7–10, 1987.CrossRefGoogle ScholarPubMed
Rutstein, DD. The ethical design of human experiments. In: PA, F, ed. Experimentation with human subjects. New York: George Braziller; 1970, pp 383–401.Google Scholar
Emanuel, EJ, Wendler, D, Grady, C. What makes clinical research ethical?JAMA 283(20):2701–11, 2000.CrossRefGoogle ScholarPubMed
Chaput de Saintonge, DM, Herxheimer, A. Harnessing placebo effects in health care. [see comments]. Lancet 344(8928):995–8, 1994.CrossRefGoogle Scholar
Kleijnen, J, de Craen, AJ, Everdingen, J, Krol, L. Placebo effect in double-blind clinical trials: a review of interactions with medications. Lancet 344(8933):1347–9, 1994.CrossRefGoogle ScholarPubMed
Hrobjartsson, A, Gotzsche, PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 344:1594–602, 2001.CrossRefGoogle ScholarPubMed
Temple, R, Ellenberg, SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med 133(6):455–63, 2000.CrossRefGoogle ScholarPubMed
Freedman, B, Glass, KC, Weijer, C. Placebo orthodoxy in clinical research. II: Ethical, legal, and regulatory myths. J Law, Med Ethics 24(3):252–9, 1996.CrossRefGoogle ScholarPubMed
Freedman, B, Glass, KC, Weijer, C. Placebo orthodoxy in clinical research. II: Ethical, legal, and regulatory myths. J Law, Med Ethics 24:243–51, 1996.CrossRefGoogle ScholarPubMed
Rothman, KJ, Michels, KB. The continuing unethical use of placebo controls. [see comment]. N Engl J Med 331(6):394–8, 1994.CrossRefGoogle ScholarPubMed
Halpern, SD, Karlawish, JH. Placebo-controlled trials are unethical in clinical hypertension research. [comment]. Arch Intern Med 160(20):3167–9, 2000.CrossRefGoogle ScholarPubMed
Macklin, R. The ethical problems with sham surgery in clinical research. [see comment]. N Engl J Med 341(13):992–6, 1999.CrossRefGoogle Scholar
Cobb, , Thomas, GI, Dillard, DH, Merendino, KA, Bruce, RA. An evaluation of internal-mammary-artery ligation by a double-blind technic. N Engl J Med 260(22):1115–18, 1959.CrossRefGoogle ScholarPubMed
Freeman, TB, Vawter, , Leaverton, PE, et al. Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson's disease. [see comment]. N Engl J Med 341(13):988–92, 1999.CrossRefGoogle Scholar
Morin, CM, Colecchi, C, Brink, D, Astruc, M, Mercer, J, Remsberg, S. How “blind” are double-blind placebo-controlled trials of benzodiazepine hypnotics?Sleep 18(4):240–5, 1995.CrossRefGoogle ScholarPubMed
Karlowski, TR, Chalmers, TC, Frenkel, LD, Kapikian, AZ, Lewis, TL, Lynch, JM. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. JAMA 231(10):1038–42, 1975.CrossRefGoogle ScholarPubMed
Howard, J, Whittemore, AS, Hoover, JJ, Panos, M. How blind was the patient blind in AMIS?Clin Pharma Ther 32(5):543–53, 1982.CrossRefGoogle ScholarPubMed
Brownell, KD, Stunkard, AJ. The double-blind in danger: untoward consequences of informed consent. Amer J Psychiatry 139(11):1487–9, 1982.Google ScholarPubMed
Byington, RP, Curb, JD, Mattson, ME. Assessment of double-blindness at the conclusion of the Beta-Blocker Heart Attack Trial. JAMA 253(12):1733–6, 1985.CrossRefGoogle ScholarPubMed
Rabkin, JG, Markowitz, JS, Stewart, J, et al. How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine. Psychiatry Research 19(1):75–86, 1986.CrossRefGoogle Scholar
Moscucci, M, Byrne, L, Weintraub, M, Cox, C. Blinding, unblinding, and the placebo effect: an analysis of patients' guesses of treatment assignment in a double-blind clinical trial. Clin Pharmacol Ther 41(3):259–65, 1987.CrossRefGoogle Scholar
Fisher, S, Greenberg, RP. How sound is the double-blind design for evaluating psychotropic drugs?J Nerv Ment Dis 181(6):345–50, 1993.CrossRefGoogle ScholarPubMed
Basoglu, M, Marks, I, Livanou, M, Swinson, R. Double-blindness procedures, rater blindness, and ratings of outcome. Observations from a controlled trial. Arch Gen Psychiatry 54(8):744–8, 1997.CrossRefGoogle ScholarPubMed
Miller, FG, Kaptchuk, TJ, Miller, FG, Kaptchuk, TJ. The power of context: reconceptualizing the placebo effect. J R Soc Med 101(5):222–5, 2008.CrossRefGoogle ScholarPubMed
Streiner, DL, Norman, GR. Health measurement scales: a practical guide to their development and use, 2nd ed. New York: Oxford University Press, 1995.Google Scholar
Jensen, MP, Turner, JA, Romano, JM, Fisher, LD. Comparative reliability and validity of chronic pain intensity measures. Pain 83(2):157–62, 1999.CrossRefGoogle ScholarPubMed
Guy, W. ,Clinical Global Impressions (CGI). ECDEU assessment manual for psychopharmacology. Rockville, MD: US Department of Health and Human Services, Public Health Service, Alcohol Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch, 1976, pp 218–22.Google Scholar
Farrar, JT, Young, JP, LaMoreaux, L, Werth, JL, Poole, RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94(2):149–58, 2001.CrossRefGoogle ScholarPubMed
Dworkin, RH, Turk, DC, Farrar, JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. [see comment]. Pain 113(1–2):9–19, 2005.CrossRefGoogle Scholar
Farrar, JT, Dworkin, RH, Max, MB. Use of the Cumulative Proportion of Responders Analysis (CPRA) graph to present pain data over a range of cut-off points: making clinical trial data more understandable. J Pain Symptom Manage 30(4):369–77, 2006.CrossRefGoogle Scholar
Gerber, WD, Diener, HC, Scholz, E, Niederberger, U. Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 11(1):37–45, 1991.CrossRefGoogle ScholarPubMed
Leijon, G, Boivie, J. Central post-stroke pain—a controlled trial of amitriptyline and carbamazepine. Pain 36(1):27–36, 1989.CrossRefGoogle ScholarPubMed
Davis, CP, Torre, PR, Williams, C, et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. Am J Emerg Med 13(2):146–50, 1995.CrossRefGoogle ScholarPubMed
Fromm, GH, Terrence, CF, Maroon, JC. Trigeminal neuralgia. Current concepts regarding etiology and pathogenesis. Arch Neurol 41(11):1204–7, 1984.CrossRefGoogle ScholarPubMed
Max, MB. Combining opioids with other drugs: challenges in clinical trial design. In: Gebhart, GF, Hammond, DL, Jensen, TS, eds. Progress in pain research and management, vol. 2. Seattle: IASP Press, 1994, pp 569–85.Google Scholar
Jaeschke, R, Singer, J, Guyatt, GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 10(4):407–15, 1989.CrossRefGoogle ScholarPubMed
Jaeschke, R, Guyatt, GH, Keller, J, Singer, J. Interpreting changes in quality-of-life score in N of 1 randomized trials. Control Clin Trials 12(4 Suppl):226S–33S, 1991.CrossRefGoogle ScholarPubMed
Todd, KH. Clinical versus statistical significance in the assessment of pain relief. Ann Emerg Med 27(4):439–41, 1996.CrossRefGoogle ScholarPubMed
Farrar, JT, Portenoy, RK, Berlin, JA, Kinman, JL, Strom, BL. Defining the clinically important difference in pain outcome measures. Pain 88(3):287–94, 2000.CrossRefGoogle ScholarPubMed
Polansky, AM, Polansky, AM. Selecting the best treatment in designed experiments. Stat Med 22(22):3461–71, 2003.CrossRefGoogle ScholarPubMed
,Anonymous. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators. [see comment]. N Engl J Med 337(16):1124–30, 1997.CrossRefGoogle Scholar
,Anonymous. A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. [see comment]. N Engl J Med 337(16):1118–23, 1997.CrossRefGoogle Scholar
,Anonymous. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Lancet 354:716–22, 1999.CrossRefGoogle Scholar
Temple, RJ. When are clinical trials of a given agent vs. placebo no longer appropriate or feasible?Control Clin Trials 18(6):613–20; discussion 661–6, 1997.CrossRefGoogle ScholarPubMed
Temple, R, Temple, R. Problems in interpreting active control equivalence trials. Account Res 4(3–4):267–75, 1996.CrossRefGoogle ScholarPubMed
Jones, B, Jarvis, P, Lewis, JA, Ebbutt, AF. Trials to assess equivalence: the importance of rigorous methods. [see comment] [erratum appears in BMJ 313(7056):550, 1996]. BMJ 313(7048):36–9, 1996.CrossRefGoogle Scholar
Fleming, TR. Design and interpretation of equivalence trials. Am Heart J 139(4):S171–6, 2000.CrossRefGoogle ScholarPubMed
Ellenberg, SS, Temple, R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and specific cases. [see comment]. Ann Intern Med 133(6):464–70, 2000.CrossRefGoogle Scholar
,Food and Drug Administration. E 10: choice of control group and related issues in clinical trials. Guidance for IndustryRockville, MD: Department of Health and Human Services, 2001.Google Scholar
Begg, CB, Berlin, JA. Publication bias: a problem in interpreting medical data. J R Statistical Soc A 151:419–63, 1988.CrossRefGoogle Scholar
Reidenberg, MM. Decreasing publication bias. Clin Pharmacol Thera 63(1):1–3, 1998.CrossRefGoogle ScholarPubMed
Turner, EH, Matthews, AM, Linardatos, E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. [see comment]. N Engl J Med 358(3):252–60, 2008.CrossRefGoogle Scholar
Feinstein, AR. An additional basic science for clinical medicine: II. The limitations of randomized trials. Ann Intern Med 99(4):544–50, 1983.CrossRefGoogle ScholarPubMed
Kramer, MS, Shapiro, SH. Scientific challenges in the application of randomized trials. JAMA 252(19):2739–45, 1984.CrossRefGoogle ScholarPubMed
Freiman, JA, Chalmers, TC, Smith, H., Kuebler, RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. Survey of 71 “negative” trials. N Engl J Med 299(13):690–4, 1978.CrossRefGoogle ScholarPubMed
Altman, DG. Statistics and ethics in medical research: III How large a sample?Br Med J 281 (6251):1336–8, 1980.CrossRefGoogle Scholar
Collins, JF, Bingham, SF, Weiss, DG, Williford, WO, Kuhn, RM. Some adaptive strategies for inadequate sample acquisition in Veterans Administration cooperative clinical trials. Control Clin Trials 1(3):227–48, 1980.CrossRefGoogle ScholarPubMed
Hunninghake, DB, Darby, CA, Probstfield, JL. Recruitment experience in clinical trials: literature summary and annotated bibliography. Control Clin Trials 8(4 Suppl):6S–30S, 1987.CrossRefGoogle ScholarPubMed
Meinert, CL. Patient recruitment and enrollment. Clinical trials: design, conduct, and analysis. New York: Oxford University Press, 1986, pp 149–58.CrossRefGoogle Scholar
Nathan, RA. How important is patient recruitment in performing clinical trials?[comment]. J Asthma 36(3):213–16, 1999.CrossRefGoogle Scholar
Taylor, KM, Margolese, RG, Soskolne, CL. Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 310(21):1363–7, 1984.CrossRefGoogle ScholarPubMed
Taylor, KM. Physician participation in a randomized clinical trial for ocular melanoma. Ann Ophthalmol 24(9):337–44, 1992.Google Scholar
Taylor, KM, Feldstein, ML, Skeel, RT, Pandya, KJ, Ng, P, Carbone, PP. Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators. [see comment]. J Clin Oncol 12(9):1796–805, 1994.CrossRefGoogle Scholar
Greenlick, MR, Bailey, JW, Wild, J, Grover, J. Characteristics of men most likely to respond to an invitation to be screened. Am J Public Health 69(10):1011–15, 1979.CrossRefGoogle Scholar
Barofsky, I, Sugarbaker, PH. Determinants of patient nonparticipation in randmized clinical trials for the treatment of sarcomas. Cancer Clin Trials 2:137–46, 1979.Google Scholar
Collins, JF, Williford, WO, Weiss, DG, Bingham, SF, Klett, CJ. Planning patient recruitment: fantasy and reality. Stat Med 3(4):435–43, 1984.CrossRefGoogle Scholar
Begg, CB, Carbone, PP, Elson, PJ, Zelen, M. Participation of community hospitals in clinical trials: analysis of five years of experience in the Eastern Cooperative Oncology Group. N Engl J Med 306(18):1076–80, 1982.CrossRefGoogle ScholarPubMed
Shea, S, Bigger, JT., Campion, J, et al. Enrollment in clinical trials: institutional factors affecting enrollment in the cardiac arrhythmia suppression trial (CAST). Control Clin Trials 13(6):466–86, 1992.CrossRefGoogle Scholar
Mant, D. Can randomised trials inform clinical decisions about individual patients? [see comment]. Lancet 353(9154):743–6, 1999.CrossRefGoogle Scholar
Halpern, SD, Metzger, DS, Berlin, JA, Ubel, PA. Who will enroll? Predicting participation in a phase II AIDS vaccine trial. Journal of Acquired Immune Deficiency Syndromes: JAIDS 27(3):281–8, 2001.CrossRefGoogle Scholar
Guyatt, GH. Methodologic problems in clinical trials in heart failure. Journal of Chronic Diseases 38(4):353–63, 1985.CrossRefGoogle ScholarPubMed
Ellenberg, JH. Selection bias in observational and experimental studies. Stat Med 13(5–7):557–67, 1994.CrossRefGoogle ScholarPubMed
Fischl, MA, Richman, DD, Grieco, MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317(4):185–91, 1987.CrossRefGoogle ScholarPubMed
Sano, M, Ernesto, C, Thomas, RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. [see comment]. N Engl J Med 336(17):1216–22, 1997.CrossRefGoogle Scholar
Kodish, E, Lantos, JD, Siegler, M. Ethical considerations in randomized controlled clinical trials. Cancer 65(10 Suppl):2400–4, 1990.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
Epstein, S. Impure science: AIDS, activism, and the politics of knowledge. Berkeley: University of California Press, 1996.Google ScholarPubMed
Karlawish, JH, Whitehouse, PJ. Is the placebo control obsolete in a world after donepezil and vitamin E? [see comment]. Arch Neurol 55(11):1420–4, 1998.CrossRefGoogle Scholar
Volberding, PA, Lagakos, SW, Koch, MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. [see comment]. N Engl J Med 322(14):941–9, 1990.CrossRefGoogle Scholar
Merigan, TC. You can teach an old dog new tricks. How AIDS trials are pioneering new strategies. N Engl J Med 323(19):1341–3, 1990.CrossRefGoogle ScholarPubMed
Peto, R, Collins, R, Gray, R. Large-scale randomized evidence: large, simple trials and overviews of trials. [see comment]. J Clin Epidemiol 48(1):23–40, 1995.CrossRefGoogle Scholar
,National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Ethical principles and guidelines for the protection of human subjects of research. Washington, DC: US Government Printing Office, 1979.Google Scholar
,World Medical Association. Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA 277:925–6, 1997.CrossRefGoogle Scholar
Casarett, D, Karlawish, J, Sankar, P, Hirschman, KB, Asch, DA. Obtaining informed consent for clinical pain research: patients' concerns and information needs. Pain 92(1–2):71–9, 2001.CrossRefGoogle ScholarPubMed
,World Medical Association. International Declaration of Helsinki, 1964. 2000.

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×