Ja. Desmeules et al., CONTRIBUTION OF MONOAMINERGIC MODULATION TO THE ANALGESIC EFFECT OF TRAMADOL, British journal of clinical pharmacology, 41(1), 1996, pp. 7-12
1 In humans, the central analgesic effect of tramadol 100mg orally is
only partially reversed by the opioid antagonist naloxone (0.8 mg intr
avenously). As suggested by in vitro and animal data tramadol analgesi
a may thus result from an action on opioid as well as monoaminergic pa
thways. 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 intrave
nously) and their respective placebo according to a randomized, double
-blind crossover, placebo (P) controlled design. Analgesia was assesse
d over 8 h by subjective pain threshold (pain intensity numerical scal
e-PINS) and objective pain threshold (RIII nociceptive reflex-RIII) mo
nitoring. 3 Tramadol induced a significant increase in both pain thres
holds. 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 f
or 2.8 h with a maximum decrease of 97 +/- 4% (RIII) and 67 +/- 12% (P
INS), whereas the addition of naloxone abolished tramadol effects thro
ughout 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 modula
tion and the synergy with opioid agonism in tramadol antinociception a
fter a single oral dose.