Orally administered tramadol ER 100 mg to 400 mg exhibited dose-proportional pharmacokinetics in healthy human volunteers (Ultram ER PI 2006). Tramadol ER is extensively metabolized through multiple cytochrome P450 pathways (3A4, 2B6, 2D6), of which 2D6 is responsible for formation of the O-demethylated metabolite, M1 (Ultram ER PI 2006). The analgesic activity of tramadol ER is mediated by racemic forms of both tramadol and M1 (Ultram ER PI 2006). However, tramadol has up to a six-fold greater analgesic effect than the M1 metabolite in animal models (Ultram ER PI 2006). Tramadol ER 200 mg once daily (qd) was compared with tramadol IR 50 mg every six hours (q6h) in healthy subjects. Tramadol ER showed a steady and sustained rise in plasma concentration during the 24-hour period after administration, compared with tramadol IR, which exhibited more frequent fluctuations (Figure 3 ) (Ultram ER PI 2006). The M1 metabolite exhibited a pharmacokinetic profile similar to that of the parent drug (Ultram ER PI 2006). Tramadol and its M1 metabolite attained mean peak plasma concentrations at 12-15 hours, reaching steady state at 4 days (Ultram ER PI 2006). Tramadol ER may be taken without food. A high-fat meal slightly decreased tramadol area under the curve (AUC) and maximum concentration (Cmax) 16% and 28%, respectively, and extended its half-life to 17 hours, compared with 14 hours in fasted conditions (Ultram ER PI 2006).