Suzetrigine (Journavx) as Multimodal Therapy for Pain Management in Adults Undergoing Surgery for Hip Fracture

Hip fracture surgery is frequently associated with substantial acute perioperative pain and a continued need for opioid analgesics. This is particularly important in the predominantly older population affected by hip fracture, in whom opioid exposure may contribute to delirium, respiratory depression, constipation, falls, cognitive impairment, and prolonged opioid use. Although contemporary multimodal analgesic pathways incorporate acetaminophen, nonsteroidal anti-inflammatory drugs when clinically appropriate, regional anesthesia, and opioid rescue medication, there remains a need for effective non-opioid analgesic strategies that can reduce opioid exposure without compromising pain control or rehabilitation.

Suzetrigine (Journavx®) is a selective inhibitor of the Nav1.8 voltage-gated sodium channel expressed predominantly in peripheral nociceptive neurons. It is FDA approved for the treatment of moderate-to-severe acute pain in adults. The biological rationale for evaluating suzetrigine after hip fracture surgery is based on the prominent nociceptive innervation of bone and periosteum by C-fiber and Aδ sensory neurons and the involvement of Nav1.8 signaling in acute skeletal pain. Existing clinical studies of suzetrigine have largely evaluated elective surgical pain models; prospective evidence in an acute hip-fracture trauma population, particularly an older and medically complex population undergoing urgent surgery, is limited.

STRIDE-HIP is a single-center, open-label, nonrandomized prospective clinical trial conducted at Beth Israel Deaconess Medical Center. The prospective cohort will receive suzetrigine in addition to the institution's established multimodal analgesic pathway for operative hip-fracture care. The study is designed to determine whether incorporation of suzetrigine can reduce postoperative opioid requirements while maintaining acceptable pain control and tolerability in this clinical setting. The prospective cohort will be compared with a matched historical-control cohort from the institution, treated at BIDMC before the availability of suzetrigine.

Prospective Treatment Strategy Suzetrigine is administered as an adjunct to, rather than a replacement for, standard multimodal pain therapy. Study treatment uses the approved oral dosing approach, beginning with a loading dose, followed by maintenance therapy for no more than 14 days from the first dose, or until pain has resolved or therapy is discontinued earlier for clinical or safety reasons. Participants discharged while still receiving study medication may complete the planned treatment course outside the hospital. Day 28 is a post-treatment follow-up assessment and does not involve continued study-drug administration.

Background analgesic care remains under the direction of the clinical orthopedic and anesthesia teams and may include scheduled acetaminophen, regional anesthesia, NSAID therapy when clinically appropriate, and rescue opioid analgesia. Clinically necessary rescue medication is not withheld for research purposes. This design is intended to evaluate suzetrigine as an additive component of real-world multimodal hip-fracture pain management rather than as an isolated analgesic monotherapy.

The protocol uses the FDA-approved oral route, labeled loading and maintenance doses, and a treatment duration not exceeding 14 days. The protocol states that the study is not intended to support a new indication or significant labeling or promotional change; if uncertainty regarding IND-exemption requirements remains before enrollment, FDA guidance will be sought.

Historical-Control Framework Because this is a nonrandomized prospective study, comparative effectiveness will be assessed using a contemporaneously relevant institutional historical-control cohort derived from BIDMC clinical records for hip-fracture surgery performed during 2020-2025. Historical patients will have received the established institutional multimodal analgesic pathway without suzetrigine.

The external-control strategy is designed to reduce confounding through prespecified matching. Historical controls will be matched approximately 2:1 to prospective participants using clinically relevant baseline and perioperative characteristics, including age, sex, fracture type, surgical procedure, surgeon, ASA physical-status class, opioid-naïve status, comorbidity burden, baseline pain when available, time to surgery, regional-anesthesia exposure, and relevant components of multimodal analgesia. Additional variables available for assessment include body mass index, preexisting pain conditions, psychiatric and centrally acting medications, smoking and alcohol history, and other medical and social factors.

The institutional hip-fracture multimodal analgesic pathway has remained materially stable during the historical-control period with respect to its principal components. Nevertheless, changes in specific medications, dosing thresholds, or regional-anesthesia practice will be characterized. If a temporal change is identified that could independently influence opioid use, a sensitivity analysis restricted to a more contemporary historical-control period will be performed.

Propensity scores will be estimated using logistic regression incorporating prespecified demographic, fracture, operative, medical, and analgesic covariates. Covariate balance following matching will be evaluated using standardized mean differences, with an absolute standardized mean difference below 0.10 used as the target for adequate balance. Inverse probability of treatment weighting will provide an additional sensitivity analysis. These methods are intended to address measured confounding inherent in the externally controlled design while acknowledging that residual unmeasured confounding cannot be completely eliminated.

Clinical Assessments and Data Collection Study data will be collected prospectively from participants, the medical record, treating clinicians, medication-administration records, study-drug accountability records, and participant medication diaries. Baseline characterization includes demographic and medical factors, frailty and functional information, comorbidity burden, preinjury mobility, prior pain and analgesic exposure, fracture characteristics, and relevant clinical history. Operative data include time from injury and admission to surgery, anesthetic technique, surgical procedure, operative duration, and estimated blood loss. Postoperative information includes mobilization, weight-bearing status, physical-therapy participation, discharge timing and destination, ambulation status, medication use, and clinically documented complications.

Pain assessments are obtained repeatedly during the perioperative hospitalization and during post-discharge follow-up. The Numeric Rating Scale is used when participants can reliably self-report pain. When cognitive impairment makes standard self-report unreliable, the protocol permits use of the Pain Assessment in Advanced Dementia observational scale. The prospective study additionally captures patient-reported measures of pain interference and global assessment that are not routinely available in the historical-control cohort and therefore will be analyzed descriptively rather than used for historical comparative inference.

Opioid administration is converted to morphine milligram equivalents using a standardized approach. Because hospitalization length may differ among participants, the primary analytical framework incorporates opioid exposure normalized to observation time in addition to total opioid burden. Prespecified interval analyses separate preoperative fracture-related analgesic exposure, intraoperative and post-anesthesia exposure, early postoperative inpatient use, later inpatient use, and post-discharge opioid consumption so that analgesia associated with the initial fracture can be distinguished from postoperative surgical pain.

Post-discharge assessments occur during the first month after surgery. The clinical study does not replace or alter routine orthopedic follow-up. Participants who continue suzetrigine after discharge maintain a medication diary documenting study-drug doses, missed or late doses, early discontinuation, rescue analgesic use, relevant symptoms, and medication changes. Medication adherence is assessed through diary review and reconciliation of remaining tablets.

Safety Monitoring A structured medication-safety program is incorporated because patients with hip fractures frequently have multimorbidity and polypharmacy. Before study-drug administration, the research and clinical teams perform medication reconciliation and review prescription medications, over-the-counter products, supplements, anticoagulants, antiplatelet agents, and medications affecting CYP3A metabolism. Clinically necessary medications take precedence over continuation of the study drug. The research team will not request withholding or delaying necessary therapy solely to maintain study eligibility.

Medication reconciliation is repeated before discharge and during post-discharge follow-up while participants remain on suzetrigine. If a newly required medication creates a potentially important interaction, suzetrigine may be held or discontinued after study-physician review. Participants transferred to rehabilitation or skilled-nursing facilities receive a medication and safety handoff describing the dosing schedule, interaction precautions, and study contact procedures.

Participants who remain on suzetrigine after hospital discharge receive structured safety contacts approximately every three days, with study-physician backup, until study treatment is completed or discontinued. These contacts assess adherence, rescue analgesic use, newly prescribed medications, potential drug-related symptoms, falls, confusion, breathing difficulties, wound concerns, emergency-department visits, rehospitalization, and other clinically important events. Participants who cannot initially be reached undergo repeated contact attempts and, when applicable, coordination with receiving rehabilitation or nursing facilities. Findings suggesting an adverse drug reaction, clinically significant medication interaction, uncontrolled pain, emergency visit, or hospitalization are escalated to the study physician.

Statistical Framework The principal comparative analysis will evaluate opioid exposure in the prospective suzetrigine cohort relative to matched historical controls. Distributional assumptions will be evaluated before formal testing; Welch-adjusted parametric testing or permutation methods will be used as appropriate. A prespecified covariate-adjusted model will account for important prognostic factors, including age, fracture type, ASA class, regional-anesthesia exposure, time from admission to surgery, baseline pain, and relevant components of multimodal analgesia.

Repeated pain measurements will be evaluated using longitudinal mixed-effects models incorporating treatment group, time, treatment-by-time interaction, and relevant covariates. Binary clinical endpoints will use appropriate exact or regression-based approaches, and time-dependent outcomes may be evaluated using survival-analysis methods. Safety events will primarily be summarized descriptively with confidence intervals because the trial is not designed or powered to establish differences in uncommon adverse events.

The principal analysis population includes participants who receive at least one dose of suzetrigine. A per-protocol sensitivity population will include participants with adequate postoperative study-drug exposure and no major protocol deviations. Prespecified sensitivity analyses include alternative approaches to missing data, analyses according to regional-anesthesia exposure, fracture type and age group, inverse-probability weighting, and quantitative assessment of the potential influence of unmeasured confounding.

The sample-size framework was developed using simulation based on published and institutional estimates of postoperative opioid exposure and was designed to provide robust power for the principal opioid-consumption comparison. A larger number of prospective participants may be enrolled than are ultimately required for the evaluable analysis population to allow for withdrawal, early discontinuation, or unavailable primary-endpoint data. Approximately two matched historical controls will be selected per evaluable prospective participant.

Because the study uses an externally controlled rather than randomized design, results will be interpreted in the context of the potential for residual confounding despite matching, covariate adjustment, weighting, and sensitivity analyses. The trial is intended to generate prospective effectiveness, safety, tolerability, adherence, and implementation data for suzetrigine used within contemporary multimodal care for acute hip-fracture surgery and to determine whether subsequent randomized or multicenter evaluation is warranted.