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

Abstract

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 AUC 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 C 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.

Acute pain and side effects after tramadol in breast cancer patients: results of a prospective double-blind randomized study

“…The occurrence and severity of side effects is related to the dose of opioids 10 , 16 . DeLemos et al 16 , in a randomized, double-blind, placebo-controlled multiple-ascending-dose study, administered 200, 400, or 600 mg/day tramadol to 21 healthy adults. Their participants reported ≥ 1 treatment-emergent adverse event in 87.5% of cases, and the most frequent were nausea (71%) and vomiting (29%) 16 .…”

“…DeLemos et al 16 , in a randomized, double-blind, placebo-controlled multiple-ascending-dose study, administered 200, 400, or 600 mg/day tramadol to 21 healthy adults. Their participants reported ≥ 1 treatment-emergent adverse event in 87.5% of cases, and the most frequent were nausea (71%) and vomiting (29%) 16 . Vomiting increased with an increasing dose from 200 to 600 mg/day, but was only mild (5 of 24 cases) or moderate (2 of 24 cases) in severity 16 .…”

“…Their participants reported ≥ 1 treatment-emergent adverse event in 87.5% of cases, and the most frequent were nausea (71%) and vomiting (29%) 16 . Vomiting increased with an increasing dose from 200 to 600 mg/day, but was only mild (5 of 24 cases) or moderate (2 of 24 cases) in severity 16 . DeLemos et al 16 concluded that all tested dosage regimens of tramadol showed an acceptable safety and tolerability profile.…”

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

“…23 The selection of a supratherapeutic dose of tramadol as a 1.5-fold higher dose than its therapeutic dose was based on an acceptable safety data profile observed with this dose (600 mg) in a previous multiple ascending dose study. 24 Also, a dose higher than 600 mg/day could not be used because of safety concerns associated with high doses of tramadol, such as seizures and respiratory depression. 25 The assay sensitivity was established using moxifloxacin 400 mg as the positive control.…”

“…Samples were analyzed using liquid chromatography-tandem mass spectrometry to determine plasma concentrations of the (+) and (−) enantiomers of tramadol and its metabolite M1 as mentioned earlier. 24 The concentration range of the calibrator samples used for the assay was 1 to 250 ng/mL, and the lower limit of quantitation was 1 ng/mL. Samples from moxifloxacin treatment were collected at 2, 2.5, 3, and 4 hours postdose.…”