Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison

Tramadol hydrochloride is a synthetic μ-opioid agonist with additional monoaminergic activity. Tramadol's analgesic effect has been equated with that of pethidine, with a more favourable side-effect profile. Tramadol has been the most-selling prescription analgesic in Germany for several years, and it is now available in many other European countries, but still there is a lack of adequately controlled clinical studies of its analgesic properties. The purpose of this study was to compare the analgesic efficacy of 50 and 100 mg oral tramadol with our standard analgesic for postoperative pain treatment, 1000 mg paracetamol + 60 mg codeine, and placebo. A single-dose, parallel group, double-blind design was used. One hundred forty-four patients were enrolled the day after total hip replacement if they had a pain intensity of 60 mm or more on a 0–100 mm visual analogue scale. Treatments were compared on the basis of pain intensity and derived variables (pain intensity difference, and summed pain intensity differences), the need of rescue medication, and a global evaluation. Serum concentrations confirmed rapid and good absorption comparable with the reported in healthy volunteers. The active drug control, paracetamol + codeine, was significantly superior to placebo for all efficacy variables (P = 0.0002–0.004), confirming good assay sensitivity. Paracetamol + codeine was also significantly superior to both 50 mg tramadol (P = 0.002–0.03) and 100 mg tramadol (P = 0.002–0.02). There was no difference between placebo and 50 and 100 mg tramadol for any of the efficacy variables. Adverse events were more common with tramadol than with the active control (P < 0.02), with significantly more emetic episodes after 50 and 100 mg tramadol (P < 0.05). Thus, this double-blind, placebo- and active drug-controlled study after orthopaedic surgery shows that 50 and 100 mg oral tramadol is well absorbed but has no significant analgesic effect in doses that are tolerable as single doses by mouth. We emphasize the importance of proper study design with documented assay sensitivity and sufficiently high initial pain intensity for differentiation between analgesics of different potencies.