Enhancement of Antihyperalgesia by the Coadministration of N-palmitoylethanolamide and Acetaminophen in Diabetic Rats

Preclinical Research The objective of this study was to evaluate the pharmacological antihyperalgesic interaction between N-palmitoylethanolamide (PEA) and acetaminophen in diabetic rats using the formalin paw test. Streptozotocin (STZ)-induced diabetic rats received subcutaneous injections in the paw of PEA alone (1-100 μg/paw) or acetaminophen alone (3-300 μg/paw) 15 min before formalin (0.5%) injection. The results revealed concentration-dependent responses produced by PEA (EC₅₀ = 7.19 ± 0.7 μg/paw) and acetaminophen (EC₅₀ = 57.9 ± 1.9 μg/paw). Isobolographic analysis was used to evaluate the pharmacological interaction between the PEA + acetaminophen using the EC₅₀ value and a fixed 1:1 ratio combination. The isobologram demonstrated that the combination investigated in this study produced a synergistic interaction; the experimental value (EC₅₀= 23.64 ± 1.9 μg/paw) was significantly smaller than those that resulted from theoretical calculations (EC₅₀ = 32.56 μg/paw). These results provide evidence that PEA in combination with acetaminophen could be useful for pain therapy in neuropathic diabetic patients. Drug Dev Res 76: 228-234, 2015.