Post‐traumatic headache: A two‐arm parallel‐group, randomized, single‐blind, sham‐controlled clinical superiority trial evaluating repetitive transcranial magnetic stimulation as a novel treatment modality

OBJECTIVE: This study aimed to evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) on persistent post-traumatic headache (pPTH) in adults with pPTH and a high burden of persistent post-concussion symptoms (pPCS) 4-5 months after mild traumatic brain injury (mTBI). BACKGROUND: pPTH is a disabling sequela of mTBI with no established effective treatment. rTMS is a promising treatment modality. METHODS: This two-arm parallel-group, randomized (1:1), single-blind, sham-controlled, clinical superiority trial was conducted at Hammel Neurorehabilitation Centre and University Research Clinic, Hammel, Denmark from August 2023 to August 2024. Participants were randomized to receive five sessions of either active high-frequency rTMS (HF-rTMS; 2000 pulses, 10 Hz) or sham stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) 4-5 months post-trauma. The primary outcome was the monthly mean difference in change in headache days of moderate-to-severe intensity between the active treatment group and the sham group. This was assessed using daily headache diaries before and after intervention. Secondary outcomes included measures of pPCS burden and headache impact, and pain catastrophizing at 1- and 3-month follow-up. RESULTS: A total of 62 participants were randomized (rTMS, n = 30; sham, n = 32). In the intention-to-treat (ITT) population (n = 62), the adjusted monthly mean difference in change (i.e., the treatment effect) between the active treatment group and the sham group was -1.55 (95% confidence interval [CI]: [-3.10; -0.01], p = 0.049) headache days. The treatment effect in a sensitivity analysis of the modified ITT population (n = 61) was -1.08 (95% CI: [-2.60; 0.45]), p = 0.166) headache days. No significant adjusted mean difference in change was observed for any secondary outcome between the active rTMS group and the sham group from baseline to 1 month end of treatment (EOT): it was -0.58 (95% CI: [-1.23; 0.08], p = 0.084) for headache intensity on the Numerical Rating Scale; 0.14 days (95% CI: [-1.01; 1.29], p = 0.816) for acute medication use; -4.07 (95% CI: [-8.81; 0.69], p = 0.093) for total Rivermead Post-Concussion Symptoms Questionnaire score; -1.08 (95% CI: [-4.80; 2.64], p = 0.567) for Headache Impact Test score; -1.36 (95% CI: [-2.91; 0.19], p = 0.085) for Symptom Checklist-6 subscale depression score; 1.74 (95% CI: [-5.22; 1.73], p = 0.324) for Pain Catastrophizing Scale score. The primary outcome and all secondary outcomes, except acute medication use, showed significant reductions over time in both groups (p < 0.001). CONCLUSION: High-frequency rTMS targeting the left DLPFC was associated with a statistically significant reduction in monthly moderate-to-severe headache days compared with sham in adults with pPTH 4-5 months post-trauma; however, the sensitivity analysis did not support the findings. Both groups demonstrated symptom reduction over time, likely reflecting spontaneous recovery and non-specific treatment effects. Further studies are needed to confirm these findings and to further evaluate the role of rTMC in pPTH, including alternative stimulation targets and treatment protocols.