Anti-Amitriptyline monoclonal antibody, clone 9.H.20

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.

Background: The pathophysiology behind the subacute but persistent hypercoagulable state after traumatic brain injury (TBI) is poorly understood but contributes to morbidity induced by venous thromboembolism. Because platelets and their microvesicles have been hypothesized to play a role in post-traumatic hypercoagulability, administration of commonly used agents may ameliorate this coagulability. We hypothesized that utilization of aspirin, ketorolac, amitriptyline, unfractionated heparin, or enoxaparin would modulate the platelet aggregation response after TBI. Methods: Concussive TBI was induced by weight drop. Mice were then randomized to receive aspirin, ketorolac, amitriptyline, heparin, enoxaparin, or saline control at 2 and 8 h after TBI. Mice were sacrificed at 6 or 24 h after injury to determine coagulability by rotational thromboelastometry (ROTEM), platelet function testing with impedance aggregometry, and microvesicle enumeration. Platelet sphingolipid metabolites were analyzed by mass spectrometry. Results: ROTEM demonstrated increased platelet contribution to maximum clot firmness at 6 h after TBI in mice that received aspirin or amitriptyline, but this did not persist at 24 h. By contrast, adenosine diphosphate- and arachidonic acid-induced platelet aggregation at 6 h was significantly lower in mice receiving ketorolac, aspirin, and amitriptyline compared with mice receiving saline at 6 h after injury and only arachidonic acid-initiated platelet aggregation was decreased by aspirin at 24 h. There were no differences in microvesicle production at either time point. Platelet sphingosine-1-phosphate levels were decreased at 6 h in the group receiving amitriptyline and increased at 24 h along with platelet ceramide levels at 24 h in the amitriptyline group. Conclusion: After TBI, amitriptyline decreased platelet aggregability and increased contribution to clot in a manner similar to aspirin. The amitriptyline effects on platelet function and sphingolipid metabolites may represent a possible role of the acid sphingomyelinase in the hypercoagulability observed after injury. In addition, inhibition of platelet reactivity may be an underappreciated benefit of low molecular weight heparins, such as enoxaparin. (C) 2019 Elsevier Inc. All rights reserved.