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

Abstract

1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non-opioid analgesics, namely nefopam, a centrally acting non-opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo-oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED50 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 ED50 values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration 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 antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan-induced tactile allodynia, the 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 a longer duration of efficacy. 4. In conclusion, coadministration of nefopam with paracetamol is worthy of clinical evaluation.

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

“…The median effective dose (ED50) of the two drug's coadministration was significantly lowered compared with that of nefopam alone, and it was suggested that the nefopam and ketoprofen interaction may be additive, with a possible tendency toward synergy (3). Another study also illustrated the enhanced antinociceptive properties of combined administration of nefopam and acetaminophen in a writhing test, in which a 36.3±5.5 mg/kg ED50 value was observed on coadministration compared with 1.5±0.2 and 120.9±14.8 mg/kg for nefopam and acetaminophen, respectively (25). Meanwhile, Miranda et al (36) confirmed a synergistic interaction between paracetamol and tramadol on their coadministration via i.p.…”

“…It has been demonstrated that nefopam has synergistic analgesic effects in humans and rodent animals when administered concomitantly with nonsteroidal anti-inflammatory drugs (3,(23)(24)(25). A previous clinical trial indicated that a combination of nefopam and ketoprofen produced effective analgesia with synergistic interaction in humans (23).…”

“…Elstraete and Sitbon (24) reported that the combination of nefopam and acetaminophen produced effective analgesia with a synergistic interaction allowing a dose reduction of each drug. Furthermore, it has been observed that coadministration of nefopam with ketoprofen or paracetamol has synergistic effects in rats with carrageenan-induced tactile allodynia, in the inflammatory phase of the mouse formalin test, in thermal hyperalgesia in an incision model of postoperative pain, and in the abdominal writhing response in the AA test (3,25). The present study verified an additive potentiation of acetaminophen and nefopam at the tested doses when compared to their per se effect in rodents, and this positive combination allowed dose reduction of each drug.…”

“…A primary hypothesis on the mechanism of analgesic action of nefopam focuses on the inhibition of monoamine uptake in synapses, which would lead to an increase in noradrenaline, dopamine and serotonin (25). The analgesic action of nefopam may involve the serotonergic or noradrenergic descending pathways; a previous study demonstrated that depletion of spinal noradrenaline attenuated the analgesic action of i.t.…”

A New Class of Antidepressant Drugs in the Treatment of Psychiatric Disorders: The Triple Reuptake Inhibitors

“…It was reported that DA played a critical role in nefopam analgesia as indicated by the observation that rats with selective loss of DA neurons, have a marked reduction in nefopam-induced analgesia. In a marked contrast, the lesion of the serotonergic or noradrenergic systems induced by 5,7-duhydroxytryptamine (5,7-DHT) or DSP4, respectively, failed to affect nefopam-induced analgesia in rats (Esposito et al, 1986;Girard et al, 2006;Girard et al, 2011). The potential interest of TRIs in the relief of pain has been corroborated by a recent publication characterizing the antinociceptive effects of the TRI bicifadine in acute, www.intechopen.com persistent and chronic models of pain (Basile et al, 2007).…”