Total hip and knee joint 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 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 replacement is of high clinical value. In this study, patients undergoing primary total hip replacement will be randomized to receive either Suzetrigine or placebo for seven days, with the loading dose administered prior to surgery. The primary outcome is cumulative 48-hour opioid consumption in oral morphine equivalents starting from entry into the post-anesthesia care unit (PACU).

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.

Since FDA approval, Suzetrigine has been incorporated into postoperative pain management at HSS for select patients. Evaluating its role in a controlled, randomized setting among patients undergoing THA will provide important data on its use within multimodal protocols and its potential to reduce opioid requirements [5-9].

Suzetrigine, a selective NaV1.8 sodium channel inhibitor, has shown potential for managing acute postoperative pain. However, its clinical utility in broader surgical contexts, such as total hip arthroplasty, remains to be determined. A comprehensive review of the literature and clinicaltrials.gov indicates no randomized controlled trials (RCTs) evaluating Suzetrigine in this population. As such, its efficacy, safety, and opioid-sparing effects in THA have not yet been established.

The primary efficacy outcome used in existing clinical trials evaluating Suzetrigine-specifically in abdominoplasty and bunionectomy procedures-was SPID48 (Summed Pain Intensity Difference over 48 hours). SPID48 is a time-weighted measure based on the Numerical Rating Scale (NRS) for pain collected at multiple time points during the first 48 hours following surgery. While this metric offers a standardized method of assessing pain reduction, further evaluation in large-joint surgery populations is needed to understand its relevance in recovery and functional outcomes.

Additionally, the use of Suzetrigine as a prophylactic perioperative agent-administered before pain onset-has not been explored. This study will address that gap by administering a loading dose prior to surgery. The potential interaction between Suzetrigine and components of contemporary multimodal analgesia, including regional anesthesia and adjunctive medications, also warrants investigation.

No studies to date have evaluated Suzetrigine's effects on subacute pain, functional recovery, or the risk of long-term opioid use. Independent validation is essential to confirm its safety and effectiveness across diverse surgical populations and clinical settings.

In conclusion, while Suzetrigine has been studied in select surgical procedures, its role in managing pain after total hip arthroplasty remains undefined. This study aims to evaluate its efficacy, safety, and opioid-sparing potential in patients undergoing THA and to inform its potential integration into enhanced recovery pathways.

Inclusion Criteria:

• Patients undergoing primary THA (posterior approach) with participating surgeons
• Age 18 to 80 years old
• Planned discharge to home
• Planned use of neuraxial anesthesia
• American Society of Anesthesiologists (ASA) Physical Status 1 - 3

Exclusion Criteria:

• ASA greater than 3
• Chronic opioid use (daily MME of greater than 30 mg for at least 3 months and within 1 month of surgery)
• History of chronic pain syndromes or uncontrolled pain (i.e. complex regional pain syndrome, fibromyalgia, implanted spinal cord stimulator)
• History of QT prolongation
• Presence of automated implantable cardioverter defibrillator, pacemaker or cardiac resynchronization device
• Evidence of misuse, aberrant use, or addiction to alcohol or an illicitly used drug of abuse, or had a positive test for drugs of abuse
• Inability to comply with any component of the study protocol
• Younger than 18 or greater than 80 years old at the time of enrollment
• Patient already on Suzetrigine
• Allergy or contraindication to Suzetrigine or excipients (eg moderate to severe liver disease/Child Pugh B or C, use of strong CYP3 inhibitors or inducers)
• Contraindications to neuraxial anesthesia or any other part of the study protocol
• Participation in another investigational drug or device study
• Pregnancy