Use of Amitriptyline in the Treatment of Headache After Traumatic Brain Injury: Lessons Learned From a Clinical Trial

Abstract

Objectives The primary outcome of this study was to assess the efficacy and safety of preventive treatment with amitriptyline on headache frequency and severity after mild traumatic brain injury (mTBI). Background Despite the fact that headache is the most common and persistent physical symptom after TBI, there has been little research on the longitudinal course or pharmacologic treatment of this disorder. Of those who have headache after injury, about 60% continue to complain of headache at 3 months post injury, with higher levels of disability than those without headache. There have been no prospective, randomized, controlled trials of a pharmacologic agent for headache after TBI. Additionally, a brain‐injured population may be more susceptible to side effects of medication. Design This is a single‐center phase II trial of amitriptyline to prevent persistent headache after an mTBI. Medication dose was gradually increased from 10 to 50 mg daily. Results Fifty participants were enrolled and 33 who completed the 90‐day assessment were included in the final analysis. In order to detect a possible cognitive impact of the study drug, 24 participants were randomly assigned to start amitriptyline immediately after study enrollment and 26 were assigned to start 30 days after enrollment. Forty‐nine percent (18/37) of those assigned to take medication took none throughout the study period, with less compliance in younger participants with mean ages of 32.7 in those who did not take any medication, 33.4 who were less than 80% compliant, and 42.3 who were compliant (P = .013). Compliance in keeping a daily headache diary was low, with 29/50 participants (58%) meeting daily entry completion, and only 10 participants maintaining 100% diary completion. No differences were found between those who started medication immediately vs at day 30 in headache frequency or severity. Conclusions While headache is the most common symptom following mTBI, current evidence does not support a specific treatment. No differences were noted in headache frequency compared to our prior study. However, the current sample had significantly lower headache severity (15% vs 36% with pain rating of 6 or above, P = .015) compared to our prior study. Our current study was not able to determine whether there is any benefit for the use of amitriptyline as a headache preventive because of difficulty with study recruitment and compliance. The challenges with recruitment and retention in the mTBI population were instructive, and future research in this area will need to identify strategies to improve recruitment, diary compliance, and medication adherence in this population.

Persistent Post-Traumatic Headache and Migraine: Pre-Clinical Comparisons

“…Only 33 subjects arrived at the end of 90 days of the therapy management. The results did not show a clarity preventive effect of amitriptyline for PTH disease [59].…”

Headache Diary Mobile Application for Monitoring and Characterizing Posttraumatic Headaches

“…Future research may also warrant exploration of what aspects of mobile headache diaries, such as daily reminders through the application, positively impact patient engagement or patient satisfaction, especially in the context of rapid transition to telemedicine options during the COVID-19 pandemic 27. Finally, identification of patient characteristics, such as headache pain severity or TBI severity, that influence compliance with a mobile headache diary will be important in determining the feasibility of using mobile headache diaries with specific populations 17…”

“…27 Finally, identification of patient characteristics, such as headache pain severity or TBI severity, that influence compliance with a mobile headache diary will be important in determining the feasibility of using mobile headache diaries with specific populations. 17…”

“…For example, at least one study has concluded that a headache diary was successful in differentiating migraine from tension-type headaches 15. In addition, past studies have successfully used headache diaries to collect information on headaches following TBI 16,17…”

“…15 In addition, past studies have successfully used headache diaries to collect information on headaches following TBI. 16,17 Recently, studies have shown electronic headache diaries to elicit higher patient compliance and satisfaction than handwritten diaries. One study found significantly higher compliance with an e-diary (94%) than with a paper diary (11%), as well as significantly higher daily usage with an e-diary (90% of days) than with a paper diary (68% of days).…”