A Randomized, Placebo-controlled, Double-blind Trial of Suzetrigine in Total Hip Arthroplasty

Hip and knee replacements are among the most common and painful orthopedic procedures performed worldwide, often requiring intensive analgesia to support early ambulation and recovery. Despite widespread use of multimodal regimens, many patients still rely on opioids, which can cause sedation, nausea, constipation, and long-term dependency. Evaluating Suzetrigine in this high-need population may help inform strategies to improve recovery trajectories, reduce opioid consumption, and support enhanced recovery protocols. Given the growing surgical volume and the emphasis on opioid-sparing strategies, rigorous investigation of Suzetrigine's efficacy in joint arthroplasty is of high clinical value. In this study, patients undergoing primary total hip arthroplasty will be randomized to receive Suzetrigine or placebo for seven days, with the loading dose administered prior to surgery. The primary outcome is cumulative 48-hour opioid consumption in morphine milligram equivalents starting from entry into the post-anesthesia care unit (PACU).

Suzetrigine (VX-548, marketed as Journavx™) is a first-in-class, non-opioid analgesic approved by the U.S. Food and Drug Administration (FDA) in January 2025 for the treatment of moderate-to-severe acute pain in adults [1,2]. It acts through potent and selective inhibition of the voltage-gated sodium channel NaV1.8, which is expressed primarily in peripheral nociceptive neurons (Figure 1) and minimally in the central nervous system [2]. By allosteric stabilization of the channel's closed state (Figure 2), Suzetrigine suppresses nociceptive signaling without impairing cognitive or motor function, offering a novel analgesic mechanism with a low risk of abuse or sedation [3].

Phase III randomized controlled trials have evaluated Suzetrigine for postoperative pain management in procedures such as abdominoplasty and bunionectomy, using the time-weighted sum of the pain intensity difference (SPID) over 48 hours as the primary endpoint [2,4,5]. In these studies, Suzetrigine was compared with placebo and standard opioid regimens. Rescue medications, such as ibuprofen, were permitted.

A supportive phase III safety and effectiveness study (SASE) also assessed Suzetrigine in a broad population that included postoperative surgical and non-surgical patients [6,7]. A subset of these participants underwent orthopedic procedures. In this study, Suzetrigine was administered as a 100 mg loading dose followed by 50 mg every 12 hours for up to 14 days, with acetaminophen and ibuprofen allowed as rescue medications. The most commonly reported adverse events were mild and transient [6,7].

At HSS, multimodal strategies for primary total hip arthroplasty currently include regional anesthesia, acetaminophen, and NSAIDs. Despite these approaches, a proportion of patients still require postoperative opioid prescriptions or refills, suggesting that additional options for acute pain management could be valuable.