Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies

BACKGROUND: Magnesium ions (Mg(2+)) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg(2+) alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination. METHODS: Tramadol was administered to healthy Caucasian subjects with and without Mg(2+) as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg(2+) was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured. RESULTS: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for C(max) and AUC(0-t) geometric mean ratios for tramadol were 91.95–102.40% and 93.22–102.76%. The 90% confidence intervals for C(max,ss) and AUC(0-τ) geometric mean ratios for tramadol were 93.85–103.31% and 99.04–105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg(2+). CONCLUSIONS: The absence of Mg(2+) interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain. GRAPHIC ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-021-00239-x.