Evaluation of the Antinociceptive Effects of Combining Serratiopeptidase and Ibuprofen in Acute and Chronic Nociceptive Models in Rats.

Pain is a major symptom of many medical conditions with diverse etiologies. World Health Organization (WHO) indicates that 1 in 5 adults globally suffers from pain. Thus, there is a great demand on finding alternative interventions whether to be used alone or in combination with opioids or NSAIDs. In this preclinical study, we evaluated the antinociceptive effect of serratiopeptidase; a well-known proteolytic enzyme with proven anti-inflammatory effect and questionable analgesic effect; in the presence and absence of ibuprofen. Isobolographic analysis for drug combination was used to determine whether combination effects were synergistic. Intraperitoneal injection of 1.8 % of lactic acid and intraplantar injection of Complete Freund's Adjuvant (CFA) were used to assess acute and chronic inflammatory pain in adult male Sprague-Dawley rats. Both ibuprofen (10-32 mg/kg) and serratiopeptidase (1-3.2 mg/kg) showed a significant antinociceptive effect on lactic acid-induced stretching. Also, only ibuprofen (32 mg/kg) showed significant increase in the number of reward bottle activations using Orofacial Pain Assessment Device (OPAD) for the assessment of acid-depressed feeding behavior. Moreover, only ibuprofen (32 mg/kg) increased paw withdrawal threshold significantly in CFA-induced mechanical allodynia using von Frey filaments. Combination treatments of ibuprofen and serratiopeptidase resulted in a subadditive (antagonistic) interaction on lactic acid-stimulated body stretching behavior. However, synergistic interaction resulted by drug combination on lactic acid-depressed feeding behavior and on CFA-induced mechanical allodynia. In addition, the coadministration of serratiopeptidase with ibuprofen in showed a significant decrease in the duration of CFA-induced mechanical allodynia. These data suggest that the administration of serratiopeptidase with ibuprofen may produce synergistic antinociceptive effect in chronic inflammatory conditions and pain-depressed behaviors such as food consumption. Further clinical tests may be needed to assess this synergistic effect in human subjects.