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Cryotherapy and Duration of Inflammatory Pain in Mice. BACKGROUND: Cryotherapy, or icing, is ubiquitously employed and recommended for managing acute inflammation and the pain that accompanies it. Recently published data have suggested that pharmacologic reduction of inflammation, despite the short-term benefit of pain relief, has a longer-term risk of delaying the resolution of pain and increasing the risk of pain chronification. METHODS: Whether cryotherapy would similarly lead to delayed pain resolution was tested in mice either given complete Freund's adjuvant into the hind paw or subjected to an exercise-enhanced pain assay whereby hypotonic saline was injected into the gastrocnemius muscle before and after wheel running. The mice were tested for tactile pain thresholds before and at multiple time points after injury. RESULTS: Cryotherapy, applied over 3 days using different timing protocols, was observed to prolong the duration of pain behavior by approximately two-fold, from approximately 15 days to more than 30 days. Neutrophil injection into the hind paw was found to prevent the pain chronification caused by cryotherapy. Alternate therapies, including heat, menthol, and contrast therapy (alternating heat and cold) did not affect pain resolution. CONCLUSIONS: The results of this study show that, similar to steroid and nonsteroidal anti-inflammatory drugs, the use of cryotherapy should be reconsidered for the management of acute inflammatory injury.