The Use of Botulinum Toxin for the Treatment of Chronic Joint Pain: Clinical and Experimental Evidence.

Chronic osteoarthritis pain is an increasing worldwide problem. Treatment for osteoarthritis pain is generally inadequate or fraught with potential toxicities. Botulinum toxins (BoNTs) are potent inhibitors of neuropeptide release. Paralytic toxicity is due to inhibition at the neuromuscular junction, and this effect has been utilized for treatments of painful dystonias. Pain relief following BoNT muscle injection has been noted to be more significant than muscle weakness and hypothesized to occur because of the inhibition of peripheral neuropeptide release and reduction of peripheral sensitization. Because of this observation, BoNT has been studied as an intra-articular (IA) analgesic for chronic joint pain. In clinical trials, BoNT appears to be effective for nociceptive joint pain. No toxicity has been reported. In preclinical models of joint pain, BoNT is similarly effective. Examination of the dorsal root ganglion (DRG) and the central nervous system has shown that catalytically active BoNT is retrogradely transported by neurons and then transcytosed to afferent synapses in the brain. This suggests that pain relief may also be due to the central effects of the drug. In summary, BoNT appears to be safe and effective for the treatment of chronic joint pain. The long-term effects of IA BoNT are still being determined.

Spontaneous and Evoked Measures of Pain in Murine Models of Monoarticular Knee Pain.

Pain is the main cause of disability from arthritis. There is currently an unmet need for adequate treatments for arthritis pain. Pre-clinical models are necessary and useful for studying the mechanisms of pain and for evaluating efficacy of arthritis therapies. Measuring pain in animal models of arthritis is challenging. We have developed methods for measuring evoked and spontaneous pain in three models of murine arthritis. We quantitate the evoked pain responses of mice subjected to firm palpation of a painful knee. We also evaluate spontaneous pain by the proportion of weight and the amount of time placed on each of their 4 limbs after induction of arthritis pain in one knee. Joint pain in these mouse models produces a significant increase in evoked pain responses and an alteration in weight bearing. Since mice are quadrupeds, they offload the painful limb to the contralateral limb, to the forelimbs, or some combination. These methods are simple, require minimal equipment, and are reproducible and sensitive for detecting pain. They are useful for studying both disease-modifying arthritis treatments and analgesics in mice.

The analgesic effect of intraarticular OnabotulinumtoxinA in a female murine model of collagenase induced chronic degenerative monoarthritis.

PURPOSE: We previously reported the efficacy of intraarticular (IA) rimabotulinumtoxinB (BoNT/B) in a murine model of chronic degenerative arthritis pain. This study aimed to measure the analgesic effects of onabotulinumtoxinA (BoNT/A) on collagenase induced chronic degenerative arthritis joint pain. METHODS: Chronic degenerative arthritis was produced by IA injection of 10 µl collagenase (Col) (10 IU) into the left knee of C57BL/6J female mice 4 weeks prior to pain assessment. IA BoNT/A was injected 3 days before testing. Arthritis pain was measured as evoked pain scores (EPS) and spontaneous pain behaviors with an advanced dynamic weight bearing (ADWB) device. EPS was a tally of fights and vocalizations exhibited in one minute with knee palpation. Percent body weight and percent time spent on each limb was quantified. All mice were 12 weeks old at the time of examination. RESULTS: IA Col increased EPS and reduced ADWB measures of percent weight bearing on the left hind limb compared to naïve mice. BoNT/A treatment reduced EPS and increased weight bearing on the left hind limb. The improvements were not significant compared to the Col group. There was no significant difference in time spent on the left hind limb between any treatment groups. Forelimb ADWB measures of percent weight and time in arthritic mice significantly increased compared to nonarthritic animals. Treatment with BoNT/A in the arthritic limb decreased this offloading; however, statistical analysis only showed significance in weightbearing. CONCLUSION: IA Col monoarthritis increased evoked and spontaneous pain behaviors in female mice after four weeks. Treatment with IA BoNT/A decreased pain behaviors but only forelimb weight bearing showed a significant improvement. This led us to conclude that treatment with BoNT/A is not an effective analgesic for the treatment of chronic degenerative knee arthritis in murine models.