Introduction: 4975 is a novel, long-acting, non-opioid analgesic for moderate-to-severe pain that specifically targets TRPV1 receptors. In clinical trials, a single, local administration of 4975 provided prolonged analgesia for postsurgical pain, osteoarthritis, intermetatarsal neuroma, and tendonitis.^1-3

Purpose: To evaluate the safety and tolerability and explore the efficacy of 4975 for postsurgical pain after total knee arthroplasty (TKA).

Methods: Fifty patients undergoing unilateral TKA were randomized to receive a single intra-operative instillation of 60mL 4975 (5mg; n=25) or placebo (n=25). Concomitant analgesics included preoperative femoral nerve block with ropivacaine (0.5%, 10–30mL), intra-operative bupivacaine (0.25%, up to 40mL via wound instillation), pre-, intra-, and postoperative ketorolac (15–90mg, IV), and postoperative morphine (up to 10mg, IV bolus). Postoperative opioid rescue medications included IV PCA morphine with lockout (up to 40mg every 4 hours) and hydrocodone/acetaminophen (7.5mg/500mg). Safety and tolerability were evaluated by adverse events and wound healing. Efficacy evaluation included pain on first ambulation (0–10 Numerical Rating Scale on days 1–14), rescue opioid use, and Brief Pain Inventory (BPI) scores (2, 6, and 12 weeks).

Results: Overall adverse event profiles were similar in the two treatment groups. Both exhibited normal wound healing. Average pain on first ambulation was lower on days 1–2, 3–7, and 8–14 in the 4975 group; the difference was significant on day 1 (5.4±2.48 vs. 7.1±2.47; P=0.027). The 4975 group had lower median IV morphine PCA use, but the difference was not statistically significant. At week 2, the 4975 group had significantly lower mean scores for “pain right now” using BPI (2.5±2.02 vs. 3.8±2.45; P=0.049) and “worst pain over the last 24 hours” (3.9±2.32 vs. 5.9±2.64; P=0.007).

Conclusion: When used in a multi-modal analgesic protocol for TKA, a single, intra-operative instillation of 4975 produced additional analgesic effects on the day after surgery that were sustained up to two weeks.