1. In humans, the central analgesic effect of tramadol 100 mg orally is only partially reversed by the opioid antagonist naloxone (0.8 mg intravenously). As suggested by in vitro and animal data tramadol analgesia may thus result from an action on opioid as well as monoaminergic pathways. We therefore investigated the effect of alpha 2-adrenoceptor antagonism with yohimbine on tramadol analgesia. 2. Healthy volunteers (n = 10) received tramadol (100 mg orally), followed (+3 h) by yohimbine (0.1 mg kg-1 intravenously), and yohimbine + naloxone (0.8 mg intravenously) and their respective placebo according to a randomized, double-blind crossover, placebo (P) controlled design. Analgesia was assessed over 8 h by subjective pain threshold (pain intensity numerical scale--PINS) and objective pain threshold (RIII nociceptive reflex--RIII) monitoring. 3. Tramadol induced a significant increase in both pain thresholds. Peak analgesic effect was observed at 3.7 h (RIII + 39.6 +/- 3.9% and PINS 50.1 +/- s.e.mean 5%) and the analgesia lasted about 6 h. 4. Yohimbine significantly reversed the analgesic effects of tramadol for 2.8 h with a maximum decrease of 97 +/- 4% (RIII) and 67 +/- 12% (PINS), whereas the addition of naloxone abolished tramadol effects throughout the study period with a decrease of 90 +/- 6% (RIII) and 79 +/- 9% (PINS), P < 0.05). 5. Yohimbine alone did not significantly reduce pain thresholds. 6. alpha 2-Adrenoceptor antagonism reverses tramadol effects, thus pointing to the significant role of monoaminergic modulation and the synergy with opioid agonism in tramadol antinociception after a single oral dose.