Comparing the Pharmacokinetics of 2 Novel Intravenous Tramadol Dosing Regimens to Oral Tramadol: A Randomized 3‐Arm Crossover Study

Tramadol is a dual‐mechanism (opiate and monoamine reuptake inhibition) analgesic. Intravenous (IV) tramadol has been widely prescribed outside the United States. However, there have not been studies comparing the pharmacokinetics (PK) of IV dosing regimens to that of oral tramadol. In this phase 1, open‐label, single investigational center, 3‐treatment, 3‐period, multidose crossover study, we compared 2 novel IV dosing regimens (IV tramadol 75 mg and IV tramadol 50 mg) to oral tramadol 100 mg given every 6 hours (the highest approved oral dosage in the United States) Compared to the oral regimen, IV tramadol 50 mg administered at hours 0, 2, and 4 and every 4 hours thereafter reached initial tramadol peak serum concentration (C(max)) more rapidly, while resulting in similar overall steady‐state C(max) and area under the plasma concentration–time curve. IV tramadol 75 mg administered at hours 0, 3, and 6 and every 6 hours thereafter had higher C(max) and greater fluctuation in peak to trough tramadol concentration. The primary metabolite M1 (a potent μ agonist) had lower area under the plasma concentration–time curve and C(max) for both IV regimens than for the oral regimen. IV tramadol at both doses was well tolerated, with adverse event profiles consistent with the known pharmacological effects of tramadol. IV tramadol 50 mg is now in phase 3 development in patients with postsurgical pain.