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.