Retrospective Study Suggests Suzetrigine May Benefit Patients With Refractory Headache Disorders

A retrospective review conducted at the University of California, Los Angeles showed that patients with refractory headache and facial pain disorders experienced symptom improvement after off-label treatment with suzetrigine. Overall, the data suggest that recently approved NaV1.8 sodium channel blocker may have broader neurologic applications beyond acute pain.¹

“Our results indicate that suzetrigine shows potential benefit for patients with a variety of headache disorders who demonstrate inadequate efficacy or poor tolerability to currently available standard therapies,” study authors wrote in the study.¹ “Some patients with marked improvements had headache diagnoses, such as short-lasting unilateral neuralgiform headache and nummular headache, for which established therapeutic options are limited. It was encouraging that some patients with MOH responded to suzetrigine. Whereas the potential for MOH with suzetrigineremains unknown, its mechanism as an ion channel blocker is highly distinct from other therapies that cause MOH, such as receptor agonists like opioids, triptans, or barbiturates.”

Study Overview

Molly Fensterwald, MD, lead author and assistant professor of neurology at the University of Colorado Anschutz Medical Campus, and colleagues retrospectively reviewed electronic health records of patients treated within the UCLA Goldberg Migraine Program between December 2024 and February 2026. Although more than 1300 patients had been prescribed suzetrigine during the study period, the final analysis included 80 patients with documented off-label use for headache or facial pain disorders and documented treatment response.

The cohort represented a diverse population of refractory headache disorders, including chronic migraine, medication-overuse headache, trigeminal autonomic cephalalgias, occipital neuralgia, nummular headache, persistent idiopathic facial pain, and several patients whose symptoms did not fit established diagnostic criteria. Nearly all patients had previously failed or were unable to tolerate multiple standard acute and preventive therapies.

Results

Overall, 54 of 80 patients (67.5%) reported improvement on the Patient Global Impression of Change (PGIC) scale after receiving treatment. Notably, 21 patients (26.3%) reported no change, and 5 (6.3%) reported worsening symptoms (P < .001).

Although subgroup analyses were limited by small sample sizes, patients with trigeminal autonomic cephalalgias demonstrated the highest observed improvement rate (83.3%), whereas those with medication-overuse headache showed lower response rates (40%). Because of the limited number of patients within each diagnostic category, investigators did not perform comparative statistical analyses between headache disorders.

All told, the treatment was generally well tolerated, and no serious adverse events (AEs) were reported. Mild AEs occurred in 15 patients and most commonly included pruritus, lightheadedness, and constipation.

Clinical Context

Suzetrigine is a selective NaV1.8 voltage-gated sodium channel inhibitor that received FDA approval in 2025 for the treatment of acute moderate-to-severe pain following positive postoperative pain trials.¹ Unlike traditional sodium channel blockers, NaV1.8 inhibition is largely restricted to peripheral sensory neurons, potentially limiting cardiac and central nervous system adverse effects associated with less selective agents.²

Sodium channel blockade has long been implicated in headache management through therapies such as intravenous lidocaine, carbamazepine, lamotrigine, lacosamide, and topiramate. However, these treatments often have limited efficacy, poor tolerability, or logistical challenges, creating an unmet need for better-targeted approaches.¹

Limitations

The authors emphasized that the findings should be interpreted cautiously because of the retrospective design, lack of placebo control, relatively small sample size, and heterogeneous patient population. In addition, treatment response was based on patient-reported global improvement rather than standardized efficacy endpoints.¹

Nevertheless, investigators concluded that the consistency of improvement across multiple refractory headache disorders supports further prospective clinical studies evaluating suzetrigine for headache and facial pain conditions.¹

REFERENCES
1. Fensterwald M, Johnson J, Moreno A, et al. Suzetrigine as a novel treatment for headache disorders: A case series. Headache. 2026;66(7):1644-1649. doi:10.1111/head.70147
2.Jones J, Correll DJ, Lechner SM, et al. Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. N Engl J Med. 2023;389(5):393-405. doi:10.1056/NEJMoa2209870