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SAN DIEGO — Intravenous (IV) administration of the anticonvulsant fosphenytoin is effective as a fast-acting treatment for acute trigeminal neuralgia (TN) exacerbation, new research suggested.

TN is a severe, disabling facial pain disorder that has often been described as feeling like “an electric shock.”

In a small phase 3 trial of patients with acute TN, the group randomly assigned to receive IV fosphenytoin had a significantly greater reduction in pain scores 2 hours after administration than the placebo group, meeting the primary endpoint.

Those receiving the active drug also had significantly fewer TN attacks between treatment and a maintenance dose the following day.

Fosphenytoin “allows patients to remain comfortable while awaiting definitive treatments,” lead investigator Shusaku Noro, MD, chief of the Department of Neurosurgery and director of the Microvascular Decompression (MVD) Center at Nakamura Memorial Hospital, Sapporo, Japan, told Medscape Medical News.

In addition, if a patient experiences a sudden severe attack because of medication discontinuation or interruption, this agent “offers rapid relief, allowing them to resume regular oral medications and return to their daily lives swiftly,” Noro said.

“As a neurosurgeon, seeing a patient’s smile after successful surgery is incredibly rewarding, but witnessing immediate relief provided by fosphenytoin brings equal joy,” he added.

The findings were presented on April 7 at the American Academy of Neurology (AAN) 2025 Annual Meeting.

Need for a Fast-Acting Option

TN consists of sudden unilateral pain along trigeminal nerve branches. For typical TN, antiepileptic medications, especially carbamazepine or oxcarbazepine, are usually recommended as first-line treatment.

However, some patients experience persistent pain attacks up to days later even after mono or combined therapy with oral medications — and there are currently no established treatments for these acute exacerbations of TN outside of surgical procedures, Noro noted.

Although MVD or other surgical treatments are effective, they often cannot be provided immediately, especially during weekends or holidays. So a need remains for a fast-acting option for acute exacerbations, Noro noted.

“This topic is very close to my heart. Many patients around the world are still suffering without access to rapid relief for trigeminal neuralgia attacks,” he said.

Fosphenytoin is marketed in Japan (as Fostoin) and in several other countries including the United States to treat epilepsy. Noro reported that his center has used the agent off-label for patients with exacerbation of TN who could not receive procedures such as MVD.

In January, results from an observational study from him and his colleagues were published in Frontiers in Neurology. Results showed that in 41 patients with acute TN, the mean numerical rating scale (NRS) score dropped significantly from 9.85 at baseline to 0.69 (P < .001) 2 hours after administration of IV fosphenytoin and remained significant at 12 and 24 hours afterwards.

Using that study as a foundation, the current phase 3 IFT study was created and conducted across five medical centers in Japan. It included 21 adult patients with acute TN who had a score of at least 5 on the NRS at baseline (mean score, 7). The scale ranges from 0, signifying no pain, to 10, signifying “most severe pain experienced.”

Those randomly assigned to receive active treatment (n = 11; mean age, 63.2 years; 55% women) were administered 18 mg/kg of fosphenytoin on day 1, which was lowered to 7.5 mg/kg once daily on days 2-5. The other group received matching placebo (n = 10; mean age, 67.4 years; 70% women).

Reducing Severe Pain

The primary outcome was change in baseline NRS score 2 hours after initial dose. Results showed that score improvement was significantly greater in the active drug group than in the placebo group (0.8 vs 4.6; least square mean difference, −6.1 vs −2.4; P = .008).

In addition, the reduction in the number of TN attacks from initial dose to right before the first maintenance dose on the following day were significantly lower for those receiving the active drug (2.5 vs 16.1; P = .04).

The most common adverse events were somnolence (affecting five members of the fosphenytoin group and one member of the placebo group), decreased blood pressure (affecting two members of each group), and nausea (affecting two and one member, respectively).

These events resolved quickly and the active treatment was “generally well tolerated,” Noro reported. There were no deaths reported in either group.

The investigators noted that most countries currently lack approved medications specifically designed for the rapid relief of TN pain.

“Having a quick pain-relieving effect, with good tolerability on acute TN exacerbations, [IV fosphenytoin] 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,” they wrote.

Noro said the most important message he wants to convey to clinicians worldwide is that rapid, effective treatment for acute TN attacks does exist.

“Knowledge truly can save lives and ease suffering. Too many patients globally endure unbearable pain, losing hope due to the lack of immediately available, effective treatment options,” he said.

“Through this research, I want to emphasize that clinicians no longer need to watch helplessly — there is something they can do, right now, to alleviate their patients’ severe pain,” Noro added.

Effective Bridging Therapy

Commenting for Medscape Medical News, Amaal Starling, MD, associate professor of neurology at Mayo Clinic in Arizona, Phoenix, and program director of the Headache Medicine Fellowship Program at the Mayo Clinic College of Medicine and Science, agreed with the investigators that currently available treatment options for acute TN may not be effective or may be poorly tolerated for a cohort of patients.

She noted that although IV fosphenytoin has been described as effective in the literature, there had been no previously conducted randomized clinical trials (RCTs) to determine its efficacy.

The current study is a “novel” RCT showing “significant reduction in pain and attacks” in the active treatment group vs in the placebo group — at least over the short term, said Starling, who was not involved with the research.

She added that although it showed a robust effect, the study only evaluated short-term efficacy and had a small sample size, so the main findings do not provide evidence for a treatment effect beyond the first 24 hours after the first infusion.

Still, based on the study results and her own experience, “I do think this is generalizable to patients in the US with trigeminal neuralgia,” she said.

“Larger, more robust studies are need for label expansion, but in the absence of FDA [US Food and Drug Administration] approval, this study suggests that fosphenytoin is an effective off-label therapy for acute exacerbations of trigeminal neuralgia — likely as a bridging therapy to oral treatment efficacy or surgical intervention,” Starling said.

Noro reported receiving personal compensation for serving as a consultant for Nobelpharma. Starling reported receiving consulting fees from numerous pharmaceutical companies, but none is relevant to this study.