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Br J Anaesth. 2013 Jul;111(1):38-45. doi: 10.1093/bja/aet126.

Challenges in design and interpretation of chronic pain trials.

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Pain Research and Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, The Churchill, Oxford OX3 7LE, UK.


The process of systematic review has shone a light on the methodology of randomized controlled trials. Notably, a range of potential biases hinders the interpretation of chronic pain trials. These include a consistent bias favouring active over placebo in trials that are small and of short duration. The use of the 'last observation carried forward' imputation method is known to inflate results, often generating statistically significance when adverse event withdrawals are high; in clinical practice terms, this is the wrong answer. Patients want outcomes of low pain scores, large reductions in pain and relief from associated symptoms, with improvements in ability to function and in quality of life. Some patients achieve this, but many do not. The distribution of benefit is skewed and the use of average pain scores, or change in pain, can be misleading compared with responder analysis in which withdrawal is regarded as non-response. Historically, chronic pain trials have had a simple classic or a crossover design. They have been small and short, and used inappropriate imputation and outcomes unconnected to the experiences of most patients. While these designs are useful for answering some questions, they may be insensitive for many interventions. Newer designs, like enriched enrolment randomized withdrawal (EERW) trials or clinical effectiveness trials, are potentially more interesting and informative.


bias; chronic pain; clinical trial

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