Puin, 62(1995) 111-118 0 1995 Elsevier Science B.V. Al1 rights reserved 0304-3959/95/$09.50 111 PAIN 2846 Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison Audun Stubhaug *, Jens Grimstad and Harald Breivik Department of Anaesthesiology, The National Hospital, University of Oslo, N-0027 Oslo (Norway) (Received 18 November 1994, accepted 2 March 1995) Summary Tramadol hydrochloride is a synthetic CL-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 stil1 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 intens@ 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 differente, and summed pain intensity differences), the need of rescue medication, and a global evaluation. Serum concentrations confirmed rapid and good absorption comparable with that reported in healthy volunteers. The active drug control, paracetamol + codeine, was significantly superior to placebo for al1 efficacy variables CP = 0.0002-0.004), confirming good assay sensitivity. Paracetamol + codeine was also significantly superior to both 50 mg tramadol CP = 0.002-0.03) and 100 mg tramadol (P = 0.002-0.02). There was no differente 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 CP < 0.021, 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 wel1 absorbed but has no significant analgesic effect in doses that are tolerable as single doses by mouth. We emphasize the importante of proper study design with documented assay sensitivity and sufficiently high initial pain intensity for differentiation between analgesics of different potenties. Key words: Postoperative analgesia; Tramadol; Codeine; Paracetamol; Randomized clinical trial Introduction Tramadol hydrochloride (tramadol) is a synthetic CL-receptor opioid agonist with an analgesic effect that has been equated with that of pethidine. Tramadol also has effects on noradrenaline and serotonin (Raffa et al. 1992). Tramadol and its main metabolite both exist as isomers with different opioid and monoaminergic * Corresponding authoc Audun Stubhaug, M.D., Department of Anaesthesiology, The National Hospital, University of Oslo, N- 0027 Oslo, Norway. Tel.: (47) 22-86-71-10; FAX: (47) 22-36-03-55. potency. Synergy between its opioid and non-opioid effects has been demonstrated in analgesic tests in mice (Raffa et al. 1993). The monoaminergic effects may contribute to the unusual side-effect profile of tramadol with low abuse potential and slow develop- ment of tolerante compared with traditional opioids (Preston et al. 1991). Thus, tramadol appeared as an interesting new analgesic for treatment of both acute and chronic pain. A basic requirement for a new analgesic must be a documented analgesic efficacy in realistic clinical set- tings, comparable to that of a standard analgesic. A SSDI 0304-3959(95)00056-9