Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctcsusp) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctcsusp exerted synergistic mechanical antiallodynic (experimental ED50 = 2.0 ± 0.5 mg/kg, i.p.; theoretical ED50 = 3.8 ± 0.4 mg/kg, i.p.) and thermal (experimental ED50 = 2.3 ± 0.5 mg/kg, i.p.; theoretical ED50 = 9.8 ± 0.8 mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctcsusp. Overall, rat efficacy and safety data revealed that ctcsusp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctcsusp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctcsusp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids.