Flupirtine Enhances the Anti-Hyperalgesic Effects of Morphine in a Rat Model of Prostate Bone Metastasis

Authors

  • Anton Kolosov PhD,

    Corresponding author
    1. Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
    • Laboratory for Pain Medicine and Palliative Care, Monash University, Clayton, Victoria, Australia
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  • Colin S. Goodchild MA, MB, BChir, PhD, FRCA, FANZCA, FFPMANZCA,

    1. Laboratory for Pain Medicine and Palliative Care, Monash University, Clayton, Victoria, Australia
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  • Elizabeth D. Williams PhD,

    1. Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
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  • Ian Cooke PhD

    1. Asia Pacific Centre for Science and Wealth Creation, Monash University, Clayton, Victoria, Australia
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  • Disclosure: Dr Colin S Goodchild and Dr Ian Cooke have shares in Relevare Inc, which holds the rights to commercialize new intellectual property arising from the research described in this article.

Reprint requests to: Anton Kolosov, PhD, Centre for Cancer Research, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Vic. 3168, Australia. Tel: +61-3-9527-9246; Fax: +61-3-9670-4116; E-mail: anton.kolosov@gmail.com.

Abstract

Objective

Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain.

Design

Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis.

Results

Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia.

Conclusions

These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

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