Sumatriptan Demonstrates Therapeutic Potential in Post-Traumatic Headache in Phase 2 Pilot Study

Tara Sharma, DO

Preliminary data published from a single-arm, prospective, non-randomized phase 2 trial (NCT01854385) revealed that sumatriptan, a migraine-specific medication, may alleviate the symptom burden for patients with post-traumatic headache (PTH). Investigators concluded that future studies, such as a phase 3 trial with a larger sample size, are needed to better understand the efficacy of sumatriptan in this patient population.

The study, which began in 2013, screened 299 participants, of which 40 were enrolled. Of these, 15 met the criteria for the use of sumatriptan, and completed all assessments. Over a 2-month treatment period, patients used sumatriptan 100 mg at the onset of headache pain and were told to repeat the dose if not pain-free in 2 hours. In the study patients received a maximum of 18 pills over the 2-month period and kept a headache diary documenting headache characteristics and severity.

Led by Tara Sharma, DO, a headache specialist at the University of Washington School of Medicine, results showed that while sumatriptan was used for only 19% (122 of 654) of all reported headaches, 72% (88 of 122) of those headaches resolved within 2 hours of taking the medication. Using a headache diary, the average daily compliance rate for the final month of the study was 80% (372 of 465). Notably, sumatriptan was effective in resolving headaches, regardless of the phenotype (migraine-like: 58% [22 of 38]; probable migraine-like: 83% [24 of 39]; non-migraine-like: 40% [6 of 15]; P = .154).

Among the migraines treated with sumatriptan, around 3% (3 of 122) of headaches had partial resolution. Coming into the study, the median headache frequency was 16.5 (IQR, 8.0–24.5) for days 30–60 and 11 (8.5–24) for days 60–90, while the median headache intensity was 4.1 (3.6–5.1) and 4.1 (3.1–3.6), respectively. Participants reported using acute pain medications for a median of 20% of their headaches during days 30–60, increasing to 50% during days 60–90. Preventative headache medications were used by 13.3% of participants (2 out of 15).

In terms of safety, there were no reported serious adverse events and no deaths in the study. Gastrointestinal disorders, found in 4 of the 17 included patients (23%), were the most common adverse event (AE), followed by numbness/tingling (11%), fatigue (11%), dizziness (11%), and sweating/flushing (11%). Other reported AEs, found in only 1 patient each, included itch/rash, joint pain, dizziness, rebound headaches, restlessness, anxiety, sore throat, and elevated blood pressure.

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With regard to future phase 3 studies testing sumatriptan in PTH, Sharma et al wrote that, "These studies should also include the duration of pain relief with sumatriptan and whether headache reoccurrence occurs. This will help define the treatment of PTH through the development of structured guidelines based on evidence from future controlled clinical trials."¹

This study had several limitations, particularly in its primary data collection via the headache diary. The absence of real-time tracking mechanisms, such as daily reminders, may have led to recall bias, and the pattern of missing data was not statistically assessed. The secondary outcomes were also limited by the study's single-arm design, which did not allow for comparison to a placebo, and by the high placebo response in the TBI population. The study also couldn't assess headache phenotype consistently, and few participants with non-migraine headaches used sumatriptan, making it unclear whether it would be effective for this group.

According to the 2019 Traumatic Brain Injury Guidelines, triptans like sumatriptan may be considered in the treatment of PTH. Specifically, the guidelines state that subcutaneous sumatriptan 6 mg should be regarded for severe migraine or where vomiting precludes effective use of the oral route. Triptans such as sumatriptan, rizatriptan, and zolmitriptan bind to and activate serotonin 1b/1d receptors in the bloodstream, which inhibits the release of vasoactive peptides, promotes the constriction of blood vessels, and inhibits the dural nociception and pain.²

REFERENCES
1. Sharma TL, Lucas S, Barber J, Hoffman JM. Pilot study evaluating treatment with sumatriptan for moderate to severe post-traumatic headache: a phase 2 open-label study. Headache. 2024;64(9):1135-1142. doi:10.1111/head.14807
2. Kiser T, Lindberg R, Davila J, Massey VD. Traumatic brain injury guidelines 2019. https://medicine.uams.edu/pmr/wp-content/uploads/sites/3/2021/02/Guidelines-TBI-Seizures-2019.pdf