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

Max Hurwitz, Sylvia Lucas, Kathleen R. Bell, Nancy Temkin, Sureyya Dikmen, Jeanne Hoffman

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)713-723
Number of pages11
Issue number4
StatePublished - Apr 1 2020


  • amitriptyline
  • chronic headache
  • headache prevention
  • headache prophylaxis
  • mild traumatic brain injury
  • posttraumatic headache

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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