Hyperalgesia induced by cutaneous freeze injury for testing analgesics in healthy volunteers.

Abstract

The early phases of the clinical development of new analgesic agents are severely hindered by a lack of reliable sensitive tests based on experimental pain models. The aim of this study was to assess the ability of a localized hyperalgesia model induced by cutaneous freeze injury to evaluate the pharmacodynamic profile of weak analgesic agents in healthy volunteers. Two groups of 24 healthy volunteers were enrolled in controlled, randomized, double-blind, cross-over studies. After freeze injury, punctate mechanical pain thresholds (MPT) were measured over three consecutive daily sessions to characterize the induced hyperalgesia and compare the effects of (i) oral ibuprofen and acetaminophen and (ii) oral and topical ibuprofen vs. placebo. The freeze injury model provides two types of hyperalgesia, primary and secondary, stable over 72 h. The MPT values (means; 95% confidence interval) in the primary (38.9 g; 34.3, 43.5) and secondary (82.2 g; 81.4, 88.0) areas of hyperalgesia were different from normal skin (107.5 g; 101.5, 115.2). This model clearly showed the antihyperalgesic effect of both systemic and topical ibuprofen (42.1%; 26.6, 61.2 and 33.8%; 16.4, 51.2 of MPT increase, respectively) but not that of acetaminophen. Cutaneous freeze injury coupled with a von Frey electronic device to assess the mechanical pain threshold is a convenient model that causes no discomfort. The improved sensitivity and stability of this experimental model of hyperalgesia over three consecutive days make it a useful tool for evaluating the efficacy and detecting the potential sites of action of analgesic agents such as nonsteroidal anti-inflammatory drugs in healthy human subjects.