The synergistic anti-nociceptive effects of nefopam and gabapentinoids in inflammatory, osteoarthritis, and neuropathic pain mouse models

Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (preg...

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Published in:European journal of pharmacology 2024-08, Vol.977, p.176738, Article 176738
Main Authors: Xiao, Xin-Yi, Chen, Yan-Ming, Zhu, Jin, Yin, Ming-Yue, Huang, Chao-Nan, Qin, Hui-Min, Liu, Shu-Xian, Xiao, Yang, Fang, Heng-Wei, Zhuang, Tao, Chen, Yin
Format: Article
Language:English
Subjects:
Chronic pain
Gabapentinoids
Nefopam
Synergistic interaction
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Summary:Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam–pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain. [Display omitted] •Our study indicated nefopam exerted significant anti-allodynic effects in osteoarthritis pain model for the first time.•Nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis and neuropathic pain.•Nefopam–gabapentinoids showed significantly improved anti-inflammatory effects than the equimolar dose of monotherapy.•Nefopam–gabapentinoids can alleviate gabapentinoids-induced sedation or ataxia by lowering their effective doses.
ISSN:0014-2999
1879-0712
1879-0712
DOI:10.1016/j.ejphar.2024.176738