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Methodological issues in clinical trials of opioids for chronic pain

From the Tufts University School of Medicine, Boston, MA and Inflexxion, Inc., Newton, MA.

Address correspondence and reprint requests to Dr. Nathaniel Katz, MD, MS, 320 Needham Street, Suite 100, Newton, MA 02464; e-mail: NatPaulKatz{at}aol.com

Clinical trials of opioid analgesics for chronic pain are recognized to frequently fail to distinguish the analgesic effect from placebo, despite known efficacy of the drug. This paper reviews the methodologic features of such trials that may be associated with risk of failure. A literature search yielded 23 randomized placebo-controlled studies of opioids with at least one week of continuous treatment; contacting pharmaceutical companies yielded six additional studies. A classification system and standard terminology were developed for describing the methodologic features of these trials. The methodologic features that appeared to augur well for success of the trials were slow titration of medications, flexible dosing, minimizing concomitant and rescue analgesics, homogeneous samples, particularly in terms of opioid use upon entry, fewer study sites (for the same sample size), and including as much data as possible in statistical analyses. Study designs that lead to high dropout rates lack internal validity, unless dropout is the intended endpoint of the trial. Opioid analgesics should be studied in a manner that is clincally relevant, and that supports internal validity. More systematic attention is needed to clinical research methodology.

Publication of this supplement was supported in part by an educational grant from Pfizer Inc to the Office of Professional Education, University of Rochester School of Medicine and Dentistry.

Disclosure: The sponsor has provided the author with an honorarium for his participation in this project as well as honoraria during his professional career.

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