Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception-

Authors
P. Girard, B. Niedergang, Y. Pansart, M.-C. Coppé, M. Verleye.

Lab
Biocodex, Service de Pharmacologie, Compiègne, France.

Journal
Clinical and Experimental Pharmacology and Physiology

Abstract
The objective of this study was to explore the concept of multimodal anaesthesia using a combination of two non-opioid analgesics: nefopam, a centrally acting non-opioid that inhibits monoamines reuptake, and paracetamol, an inhibitor of central cyclo-oxygenases. The antinociceptive characteristics of the combination was evaluated using four different animal models of pain. In the mouse writhing test, antinociceptive properties were observed with ED(50) values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind-paw with ED(50) values of 4.5 ± 1.1 mg/kg for nefopam and 330.7 ± 80.3 mg/kg for paracetamol in the early phase, and ED(50) values of 4.3 ± 0.2 mg/kg for nefopam and 206.1 ± 45.1 mg/kg for paracetamol in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. In a rat incision model of postoperative thermal hyperalgesia, co-administration of nefopam at a non-analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong anti-hyperalgesic effect, maintained during at least three hours. In rat carrageenan-induced tactile allodynia, combination of low analgesic doses of nefopam (10 or 30 mg/kg) with a non-analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with longer duration efficacy. In conclusion, co-administration of nefopam with paracetamol is worthy of clinical evaluation.