There is a growing need for novel treatments of refractory arthritis joint pain as the aging population is expanding with many patients who are unable to undergo joint replacement surgery. We are studying the efficacy and safety of intra-articular injection of Botulinum Toxin Type A (IA-BoNT/A) into joints with arthritis pain. In several small open label studies, initial effects for IA-BoNT/A were encouraging because two thirds of the patients had more than 50% reduction in joint pain severity that was associated with a significant improvement in function. Importantly no serious adverse effects of IA-BoN/A were noted. Based on these initial results, we have completed two pilot randomized controlled trials in painful shoulder joints and painful knee joints. In the shoulder study, IA-BoNT/A produced a significant decrease in shoulder pain severity at one month (6.8-4.4 on VAS, p=.002) that was also significantly better than the non-significant change after IA-Saline placebo (1.6 unit difference favoring IA-BoNT/A, p=.014). In the knee study IA-BoNT/A produced a significant 48% decrease in McGill Total Pain Score at one month (p=.01 1) that was still significant at 3 mo after injection (p=.002). There was a strong placebo response in one third of those but the decrease in pain severity was not significant. We are currently conducting a RCT of IA-BoNT/A for painful prosthetic knee joints. Based on these initial studies of IA-BoNT/A we have gone 'back to the bench' to standardize a menu of pain behaviors for mice with acute inflammatory arthritis pain and chronic inflammatory arthritis pain. IA-BoNT/A significantly reduced arthritis joint tenderness (evoked pain score) in acute and chronic inflammatory arthritis and normalized impaired spontaneous wheel running in mice with chronic inflammatory arthritis but not in those with acute inflammatory arthritis. With these models of arthritis and pain behavior methods we will be able to screen potential intra-articular analgesics, define dose response curves and injection schedule, and study the relationships of articular pain and loss of function.