• W-Z Zhou, T-Y Zhao, Z-Y Wang, G-Y Lu, S-Z Zhang, C Zhang, N Wu, and J Li.
• Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, China.
• Eur J Pain. 2019 Jan 1; 23 (1): 46-56.

BackgroundA combination of analgesic agents with different mechanisms can induce additive or synergistic analgesia. The N-type voltage-dependent calcium channel (N-VDCC) is a novel therapeutic target for pain control. In addition to providing effective pain relief when used alone, N-VDCC blockers produce synergistic analgesia when used in combination with opiates. However, the interaction between N-VDCC blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) remains unclear.MethodsUsing isobolographic analysis and composite additive curve analysis, the antinociceptive interaction between ZC88, a selective N-VDCC blocker and ibuprofen, a classical NSAID, was investigated in two mouse models of visceral and somatic inflammatory pain.ResultsIn the acetic acid writhing test, both ZC88 (10.5-42 mg/kg, intraperitoneally) and ibuprofen (50-200 mg/kg, orally) produced dose-dependent antinociception, with ED50 values of 27.2 and 100.5 mg/kg, respectively. ZC88 in combination with ibuprofen (ZC88 + ibuprofen) also induced significant antinociception, and isobolographic analysis revealed a synergistic interaction at 50% effect level. The experimental ED50 (ED50 mix ) of this combination (34.5 mg/kg) was significantly lower than the theoretical ED50 (ED50 add ; 63.8 mg/kg). Additionally, composite additive curve analysis displayed synergistic interaction at other effect levels. In the formalin test, ZC88 or ibuprofen alone significantly reduced late-phase rather than early-phase pain, with ED50 values of 31.3 and 123.9 mg/kg, respectively. Similarly, both isobolographic analysis and composite additive curve analysis revealed synergistic antinociception of ZC88 + ibuprofen (40.6 mg/kg of ED50 mix vs. 77.6 mg/kg of ED50 add ).ConclusionZC88 in combination with ibuprofen produces synergistic antinociception in mouse models of somatic and visceral inflammatory pain.SignificanceBecause ZC88 + ibuprofen achieves the same antinociceptive effect at lower doses, the use of this combination could result in fewer dose-related untoward effects. The potentiation of ZC88 on ibuprofen-induced antinociception indicates that N-VDCC blocker has potential benefit to treat severe inflammatory pain.© 2018 European Pain Federation - EFIC®.

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