Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double‐Blind, Placebo‐Controlled Multiple‐Ascending‐Dose Study

This randomized, double‐blind, parallel‐group multiple‐ascending‐dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2‐ and 3.6‐fold for the (+) enantiomer and 2.0‐ and 3.5‐fold for the (‐) enantiomer with increasing dose from 200 to 400 and 600 mg/day, whereas the Cmax,ss increased 2.1‐ and 3.3‐fold for the (+) enantiomer and 2.0‐ and 3.2‐fold for the (‐) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment‐emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.