Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models, and thus it has potential utility as a preemptive analgesic. We investigated the adverse effects of preoperative intravenous amitriptyline in a phase 1A trial, after obtaining FDA IND and hospital IRB approval.

In subjects undergoing thorascopic surgery for wedge resection or shoulder arthoscopy, we used a single blinded, placebo controlled, dose-escalating design in 2 centers. We administered IV amitriptyline preoperatively over 1 hour (saline placebo (n=5), 25 mg (n=10), 50mg (n=5), and 100 mg (n=3)). We recorded plasma levels of amitriptyline/nortriptyline over 3 hours, EKG changes, and side effects. We assessed pain during the recovery room (RR) admission and the usage of opioids intraoperatively and immediately postoperatively.

N=23 (15 male, 8 female), average age=53 years. Side effects were dose dependent, with 2 subjects in the 25 and 50 mg reporting moderate drowsiness and dizziness. The 100 mg dose was unsafe, with 1 subject having severe bradycardia (HR=30), another with severe drowsiness and difficulty speaking, and a third with agitation. This arm was discontinued after 3 subjects. On EKG monitoring, there was no significant difference in QTc interval compared to baseline in any group. TCA levels were well below toxicity in all groups. There was no significant difference in drug arms in the amount of intraoperative opioid or RR opioid used. Upon admission to the RR, the 50 mg group had significantly lower pain scores than the 25 mg group (4.1 vs. 8.7, p<.05)

IV infusion of 25 and 50 mg amitriptyline was safe and well tolerated in this small study sample. The safety profile and the suggestion that 50 mg may have preemptive analgesic properties justifies an appropriately powered future trial to determine a potential role of amitriptyline in decreasing postoperative pain.