To evaluate the efficacy and safety of fosphenytoin (fPHT) for acute trigeminal neuralgia (TN) exacerbations.

Acute TN exacerbations can occur even while taking first-line oral treatments. With no established conservative treatments available, surgery is often the only option. This study is the first to assess the potential of fPHT as a non-surgical approach for alleviating these exacerbations.

A phase 3 multicenter randomized double-blind placebo-controlled clinical trial (jRCT: 2011220043) was conducted between April 2023 and April 2024. Patients with TN were randomized to receive fPHT or placebo in a 1:1. fPHT or placebo was intravenously injected once daily for up to 5 days, the initial and maintenance doses being 18 and 7.5 mg/kg, respectively. Pain was rated on a numerical rating scale (NRS). The primary endpoint was change from baseline in NRS score at 120 minutes after the first dose.

Of the 22 registered patients (mean age 65.2 years), 21 patients with NRS score of ≥ 5 were randomized to receive a study drug. The primary endpoint decreased significantly with the fPHT group compared with the placebo group (p=0.008). The proportion of patients with a ≥ 50% NRS score reduction was 90.9% in the fPHT group and 40.0% in the placebo group (p = 0.040). The number of attacks occurring between the first dose and the next day’s maintenance dose decreased significantly in the fPHT group compared with the placebo group. The adverse events observed in ≥ 2 patients in the fPHT group were mild to moderate somnolence, blood pressure decreased, and nausea; the treatment was well tolerated.

Having a quick pain-relieving effect, with good tolerability, on acute TN exacerbations, intravenous fPHT may provide a new treatment for such patients suffering difficult pain control with oral drugs in emergencies and patients awaiting microvascular decompression, gamma knife radiosurgery, or nerve block treatment.