Melatonin synergizes with the antinociceptive effect of N-palmitoylethanolamide and paracetamol.

Melatonin has been shown to have an antinociceptive effect and its administration could enhance the antinociceptive effect of other drugs. This study assessed the antinociceptive effects of melatonin in combination with paracetamol and N-palmitoylethanolamide (PEA) using the formalin test in mice. Melatonin, paracetamol, and PEA were administered intraplantarly (paw) alone or combined to mice. A concentration-response curve was generated to determine the concentration needed to reach 30% of the maximal antinociceptive effect (EC₃₀). Melatonin, paracetamol and PEA induced a concentration-dependent antinociceptive effect in both phases of the formalin test, being PEA more potent (EC₃₀ = 7.4±0.2 mg/paw) than melatonin (EC₃₀ = 20.5±3.1 mg/paw) or paracetamol (EC₃₀ = 41.8±2.6 mg/paw). Combinations of melatonin with paracetamol or PEA also induced a concentration-dependent antinociceptive effect in the formalin test. Isobolographic analysis showed that melatonin interacts synergistically with either paracetamol or PEA to reduce formalin-induced inflammatory pain. However, the experimental values of EC₃₀ were significantly smaller than those calculated theoretically.