There are several pharmacological treatments available for PTHs. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, are commonly used to manage mild to moderate headaches. Paracetamol can also be effective in managing headaches.

In this way, the association between acute administration of ibuprofen, acetaminophen, or both and the resolution of headache or reduction in headache pain at seven days post-concussion in children and youth was previously investigated [75]. It was found that 74.3% of the individuals aged 5–18 years with acute concussion that were recruited manifested acute headache upon ED presentation; of these, 67.8% received analgesic medication before or during their ED visit. Multivariate analysis pertained to 1707 participants with propensity scores based on personal characteristics and symptoms, and 51.4% reported headache at seven days post-concussion, which was the primary outcome. While using propensity scores and adjusted multivariate regression models, no association between acute administration of ibuprofen, acetaminophen, or both, and headache presence at seven days was obtained, suggesting that the acute treatment with ibuprofen, acetaminophen, or both in the acute phase of TBI could not decrease the risk of headache seven days post-concussion. Despite this, non-opioid analgesics, such as ibuprofen or acetaminophen, could be prescribed for short-term headache relief. However, caution is advised in analgesics long term prescription and use when headache symptoms persist [3].

Other useful medication in PTH could be antiepileptic drugs and tricyclic antidepressants (TCAs). Cushman et al. [76] conducted a retrospective study to examine the correlation between medication (gabapentin and TCAs) and concussion-associated symptoms reduction. While the patients diagnosed with clinical concussion self-reported their symptom scores based on the Post-Concussion Symptom Scale (PCSS), some received prescription for gabapentin or TCAs for headache treatment and were followed-up for over one year post-concussion. The mixed-effects analysis showed a significant decrease in headache and symptom scores over time in each medication group and in those not receiving medication (p  ≤  0.014 for all scenarios, B = −0.005 and −0.08, respectively). Although patients in the medication groups showed significantly higher headache and symptom scores (p  <  0.001), the results showed that medication significantly affected longitudinal improvements in the outcome scores. However, the piecewise regression analysis showed short-term improvements with gabapentin (1.3 points, p  =  0.004) and more sustained improvements with TCAs (3.5 points, p  =  0.006), suggesting the immediate effects of gabapentin and TCAs on improving symptom burden, despite the fact that the long-term outcomes show similar improvement compared with those who are not prescribed medication.

Acute and prophylactic medical therapies efficiency for chronic PTH attributable to mTBI was also evaluated. In a retrospective cohort study that recruited US Army soldiers that were exposed to occupational mild head trauma that were followed for three months after starting headache prophylactic medication, Erickson et al. [77] compared the treatment outcomes by relation to blast and non-blast-related PTH and found that the headache frequency among all PTH subjects decreased from 17.1 days/month at baseline to 14.5 days/month at follow-up (p = 0.009). Additionally, a significant decline in headache frequency occurred in subjects treated with topiramate (n = 29, −23%, p = 0.02), but not among those treated with a low-dose TCAs (n = 48, −12%, p = 0.23). Seventy percent of PTH patients who used triptan class medication experienced reliable headache relief within 2 h compared to 42% of subjects using other headache abortive medications (p = 0.01). Moreover, the results showed that triptan-based medications were effective for both blast PTH and non-blast PTH (66% response rate vs. 86% response rate, respectively; p = 0.20). It was also shown that headache frequency could decrease in 41% of non-blast PTH compared to 9% among blast PTH, and that 57% of non-blast PTH subjects had a 50% or greater decline in headache frequency compared to 29% of blast PTH subjects (p = 0.023). Headache-related disability, as measured by mean Migraine Disability Assessment Scores, declined by 57% among all PTH subjects, with no significant difference between blast PTH (−56%) and non-blast PTH (−61%) suggesting that chronic PTH triggered by a blast injury may be less responsive to commonly prescribed headache prophylactic medications than non-blast PTH. In this context, it was concluded that triptan-class medications are effective for treating headaches due to blast or non-blast-related chronic PTH and that topiramate could be effective in headache prophylaxis in chronic PTH patients.

While no definitive pharmacological treatments exist for persistent PTH, peripheral nerve surgery may be a safe and effective option for some patients. It is crucial to consider an individualized treatment approach, considering the patient’s specific symptoms and medical history and the potential risks and benefits of various treatment options. A multidisciplinary approach involving healthcare providers from different specialties is also beneficial for evaluating and managing persistent PTH.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique that has been investigated as a potential treatment for PTH. In a systematic review of 11 prospective rTMS treatment studies of patients with mild TBI/concussion, Mollica et al. found promising preliminary results for rTMS in treating post-concussion depression and PTH, two symptoms that otherwise have limited effective treatment options [78]. Positive results were found in two out of four studies with depression as a primary outcome and in all three studies that assessed depression as a secondary outcome. All four rTMS studies for PTH reported positive results. Despite the fact that all the studies were based on small pilot samples and the methodological heterogeneity precluded a quantitative meta-analysis, the results suggested that rTMS may be a promising treatment modality for PTH.

Neutralizing prismatic lenses have been investigated as a treatment modality for PTH in patients with vertical heterophoria (VH). Rosner et al. conducted a retrospective study of 38 patients with persistent post-concussive symptoms and VH diagnosed by an optometric binocular vision sub-specialist [79]. The patients were fitted with neutralizing prismatic lenses, and data were collected before and after prism, an application using validated survey instruments for headache, dizziness, anxiety, and BVD symptom burden, as well as subjective ratings of headache, dizziness, and anxiety severity. A sub-analysis of the BVD survey instrument questions that pertain specifically to headache, dizziness, and anxiety was also conducted. The results demonstrated a marked reduction in all measures of headache, dizziness, and anxiety (19.1–60.8%) and an overall subjective improvement of VH symptoms of 80.2%, suggesting that neutralizing prismatic lenses may be an effective treatment for PTH in patients with VH.

Peripheral nerve surgery has been investigated as a safe and effective treatment possibility for PTH in patients with chronic pain that persists despite initial treatments by a neurologist specialized in headache management. Ducic et al. conducted a retrospective review of 28 consecutive patients with PTH who underwent occipital nerve surgery [59]. Preoperative and postoperative headache pain was evaluated on a visual analogue scale (VAS) in 24 patients with at least six months of follow-up. The average VAS headache pain reduced from 6.4 preoperatively to 1.4 (p  <  0.0001), and 21 patients (88%) had a successful outcome of at least a 50% reduction in their VAS following peripheral nerve surgery. Additionally, 12 patients (50%) were pain-free during the final follow-up and no surgical complications occurred.

Maria Lippert-Grüner reported the case of a 62-year-old woman with a history of major TBI who developed chronic tension-type PTHs that were not relieved by oral medication [80]. The patient received local injections of 22 IU Botox^® into the frontalis and corrugator supercilii muscles. Headaches improved after five days and were completely resolved after ten days, even during stressful situations, suggesting that Botulinum toxin injection might be an effective treatment for PTH.

Yerry et al. conducted a retrospective study of onabotulinum toxin A to treat PCS [81] and showed that the patients receiving the toxin manifested significant reduction in headache frequency, intensity, and medication usage. The study also found improvements in cognitive function and quality-of-life measures. However, the study did not include a control group and was limited by its retrospective design.