Tramadol Hydrochloride at Steady State Lacks Clinically Relevant QTc Interval Increases in Healthy Adults

We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18‐55 years) in a randomized, phase I, double‐blind, placebo‐ and positive‐controlled, multiple‐dose, 4‐way crossover study. Participants were randomized to receive 1 of 4 treatments (A‐D), 1 each in 4 treatment periods (1‐4), separated by a washout period (7‐15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin‐matched placebo on day 4, and placebo on all 4 days. Treatment B comprised tramadol 600 mg (supratherapeutic dose) on days 1 through 3, and tramadol 150 mg and moxifloxacin‐matched placebo on day 4. Treatment C comprised placebo on days 1 through 4 and moxifloxacin‐matched placebo on day 4. Treatment D comprised placebo on days 1 through 4 and moxifloxacin 400 mg on day 4. Of 68 participants enrolled, 57 (83.8%) completed the study. Both therapeutic and supratherapeutic doses of tramadol were shown to be noninferior to placebo regarding their effect on QTc prolongation. Sixty‐one of 68 (89.7%) participants reported at least 1 treatment‐emergent adverse event (mild); nausea was the most frequently reported treatment‐emergent adverse event. Summarizing, tramadol at doses up to 600 mg/day did not cause clinically relevant QTc interval prolongation in healthy adults.