BACKGROUND AND OBJECTIVES: Trigeminal neuralgia (TN) is a debilitating condition characterized by sudden, severe facial pain. IV medications for acute TN exacerbations have not been investigated in randomized controlled trials (RCTs). Oral medications are often insufficient for acute attacks, and surgery is not immediately available. We conducted an RCT to evaluate IV fosphenytoin therapy (IFT) as a rapid-acting rescue treatment for acute TN exacerbations. We hypothesized that, compared with placebo, IFT would reduce acute TN pain.
METHODS: This multicenter, double-blind, placebo-controlled phase 3 trial was conducted at 6 institutions (April 2023-April 2024). Patients with classical or idiopathic TN who were experiencing TN exacerbation (numerical rating scale [NRS] score =5) were recruited from emergency and outpatient settings, and all study drugs were administered during hospital admission. Participants were randomized 1:1 to IFT (initial dose: 18 mg/kg, maintenance: 7.5 mg/kg for 4 days) or placebo. The primary end point was the change in NRS pain scores from baseline to 120 minutes after the initial dose. Secondary end points included attack frequency, the proportion achieving =50% NRS score improvement, and adverse events. Data were collected by blinded personnel and analyzed using repeated-measures mixed-effects models.
RESULTS: Of 31 participants screened, 22 were randomized; 1 placebo-assigned participant did not meet the NRS =5 criterion and was excluded, leaving 21 for analysis (IFT: 11; placebo: 10). Participants had a mean age of 65.2 years (range 42-83; 8 men, 13 women). Compared with placebo, IFT significantly reduced pain (NRS change: -6.1 vs -2.4; between-group difference -3.8; 95% CI -6.4 to -1.1; p = 0.008), decreased attack frequency within 24 hours (2.5 ± 5.3 vs 16.1 ± 19.6, difference -13.6; 95% CI -26.4 to -0.7), and increased the proportion achieving =50% NRS improvement (90.9% vs 40.0%, difference 50.9%; 95% CI 5.6%-81.6%). Adverse events (somnolence, hypotension, and nausea) were mild and transient.
DISCUSSION: IFT provided rapid and well-tolerated pain relief in acute TN exacerbations. Although findings are preliminary because of the small sample size, IFT may be a viable short-term treatment option, meriting further investigation.
TRIAL REGISTRATION INFORMATION: Japan Registry of Clinical Trials, jRCT2011220043. Registered March 3, 2023. First enrollment April 25, 2023. jrct.mhlw.go.jp/en-latest-detail/jRCT2011220043.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with acute TN exacerbations, IV fosphenytoin is superior to placebo in reducing pain intensity at 120 minutes.
| Discipline Area | Score |
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| Physician |  |
Physician rater
An interesting report of fosphenytoin efficacy and reasonable safety for acute trigeminal neuralgia. The findings need to be considered with caution given the small sample size and wide confidence intervals. It may be a platform for further studies with larger numbers.
Physician rater
My main concern is the choice of a placebo comparator. If they are treating acute exacerbations of trigeminal neuralgia presenting to the ED or clinic, then they should use a current treatment for acute episodes as the comparator, e.g., carbamazepine. They also do not tell us the usual preventative treatments used, or what concurrent treatment (e.g., opioids) both arms received during the episode. As a result, this tells us very little about this new agent's effectiveness or role.
, McMaster University