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There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

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Autoradiography. For autoradiographic localization of [3H]BK receptor binding, guinea pigs were perfused through the heart with 500 ml of a mixture of equal parts of isotonic phosphate-buffered saline (pH 7.4) and 10%o (wt/vol) sucrose. After perfusion, the tissues were removed, embedded in homogenized calf cortex, and frozen on dry ice. Canine tissues were removed without perfusion and immersed in chilled perfusion medium for 20 min, then mounted and frozen as described. Ten-micrometer sections were cut in a cryostat at -12°C, thaw-mounted onto chrome alum/gelatin-coated microscope slides, and stored frozen at -20°C.When ready for use, the slides were warmed to room temperature, incubated for 120 min at 4°C in medium containing 20 mM 2-{[tris(hydroxymethyl)methyl]amino}ethane sulfonic acid (Tes) (pH 6.8), 1 mM 1,10-phenanthroline, 0.2% bovine serum albumin (protease free), 1 mM dithiothreitol, bacitracin (140 ,ug/ml), 0.1 mM SQ20,881, 300 mM sucrose, and 0.5 nM [3H]BK (52 Ci/mmol; 1 Ci = 37 GBq).Blanks were incubated in the same medium with 1 ,uM unlabeled BK or Lys-BK.After incubation, the tissue sections were washed in a solution of 25 mM Tes (pH 6.8) and 10% (vol/vol) sucrose for two 10-min periods at 4°C, dried rapidly under cold dry air, and apposed to either NTB-3 emulsion-coated coverslips or LKB Ultrafilm for 1 month. After exposure, the coverslip/slide or Ultrafilm was developed, and the tissue was stained with cresyl violet.Isolated Tissues. Smooth muscle effects of the BK analogs were determined on the isolated rat uterus and isolated guinea pig ileum by standard methods (10). BK analogs were incubated with the preparation for 30 sec before adding an ED50 dose of BK. BK analogs that decreased BK were then examined in detail to determine pA2 values for antagonism (pA2 is the negative log of the antagonist concentration that causes a 2-fold shift in the agonist dose-response curve) (11). Dose-response curves were determined for analogs that produced contractions at 10 uM.BK-Induced Vascular Pain. Male Sprague-Dawley rats (200-300 g) (Charles River Breeding Laboratories) were housed five per cage with constant access to food and water with a 12-hr light-dark cycle (7 a.m.-7 p.m.). Rats received an indwelling carotid artery cannula routed subcutaneously to exit behind the head. One to 3 days following surgery, the cannula was connected through tubing to a remote syringe allowing intraarterial injections while the rats were conscious and freely moving. In preliminary experiments, BK at 2 nmol/kg caused stereotypic flexion of the right forelimb and dextrorotation of the head in essentially 100% of the rats tested. Rats that displayed this BK response were injected 5 min later, through the same arterial cannula, with BK and a BK antagonist at 2, 20, or 200 nmol/kg.