IV Fosphenytoin for Trigeminal Neuralgia
(2026)Objective
To evaluate whether IV fosphenytoin therapy (IFT) is superior to placebo for rapid pain relief in patients with acute trigeminal neuralgia (TN) exacerbations.
Study Summary
• Attack frequency within 24 hours was markedly lower with IFT (2.5 ± 5.3 vs 16.1 ± 19.6 attacks; difference -13.6; 95% CI -26.4 to -0.7)
• ≥50% NRS improvement achieved in 90.9% of IFT vs 40.0% of placebo (difference 50.9%; 95% CI 5.6%-81.6%)
• Adverse events (somnolence, hypotension, nausea) were mild and transient
Intervention
IV fosphenytoin (initial dose 18 mg/kg, maintenance 7.5 mg/kg for 4 days) vs placebo (physiologic saline), administered during hospital admission.
Inclusion Criteria
Adults ≥18 years with classical or idiopathic trigeminal neuralgia (ICHD-3 criteria), experiencing acute exacerbation with baseline NRS pain score ≥5, recruited from emergency and outpatient settings.
Study Design
Arms: IV Fosphenytoin (n=11) vs Placebo/saline (n=10)
Patients per Arm: IFT: 11; Placebo: 10
Outcome
• ≥50% NRS improvement: 90.9% IFT vs 40.0% placebo (difference 50.9%; 95% CI 5.6%-81.6%)
• 24-hour attack frequency: 2.5 ± 5.3 vs 16.1 ± 19.6 (difference -13.6; 95% CI -26.4 to -0.7)
• AEs (somnolence, hypotension, nausea) mild and transient
• Class I evidence that IV fosphenytoin is superior to placebo for acute TN pain at 120 minutes
Bottom Line
In patients with acute trigeminal neuralgia exacerbations, IV fosphenytoin (18 mg/kg load, 7.5 mg/kg maintenance) provided rapid, clinically meaningful pain relief at 120 minutes compared with placebo, with mild and transient adverse events — supporting IFT as a viable short-term rescue/bridging therapy, though findings are preliminary given the small sample.
Major Points
- First RCT to evaluate IV therapy for acute trigeminal neuralgia exacerbations
- IV fosphenytoin produced a between-group NRS reduction of -3.8 at 120 minutes vs placebo (p=0.008)
- 90.9% of IFT participants achieved ≥50% pain reduction vs 40.0% with placebo
- 24-hour attack frequency was lower with IFT (2.5 ± 5.3) than placebo (16.1 ± 19.6); between-group difference -13.6 (95% CI -26.4 to -0.7)
- Adverse events (somnolence, hypotension, nausea) were mild and transient
- Designated Class I evidence by Neurology for acute TN pain reduction at 120 minutes
- Small sample size (n=21 analyzed) limits generalizability; further investigation warranted
Study Design
- Study Type
- Multicenter, parallel-group, randomized, double-blind, placebo-controlled phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators, study coordinators, drug suppliers, and clinical monitors blinded until data fixation)
- Sample Size
- 22
- Follow-up
- 7 days after the final dose (in addition to the up-to-4-day maintenance dosing period with inpatient monitoring)
- Centers
- 6
- Countries
- Japan
Primary Outcome
Definition: Change in NRS pain score from baseline to 120 minutes after the initial dose
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| NRS change -2.4 | NRS change -6.1 | - (-6.4 to -1.1) | 0.008 |
Limitations & Criticisms
- Very small sample size (21 analyzed) limits precision and generalizability
- Single-country (Japan) population — all participants Japanese
- Short observation window for sustained benefit beyond acute exacerbation not fully characterized in abstract
- Most participants were on background carbamazepine, complicating attribution of effect
- Primary endpoint time (120 min) differs from the time point used in the sample-size calculation (1 hour)
Citation
Neurology 2026;106:e218037