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

Abstract

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.