Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H 3 receptor agonist R-(α)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05–1 µg) in the presence of a fixed dose of R-(α)-methylhistamine (12.5 µg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005–0.1 mg/kg) plus a fixed dose of R-(α)-methylhistamine (0.5 mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(α)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H 3 receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(α)-methylhistamine, and second, thioperamide partially antagonised the combined R-(α)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(α)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.