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  • Review Article
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Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain

Nature Reviews Neurology volume 10, pages 694–707 (2014)Cite this article

Subjects

Key Points

  • Chemotherapy-induced peripheral neuropathic pain (CIPNP) affects up to 80% of patients during chemotherapy; it is a severe adverse effect that can limit dose and choice of chemotherapy

  • Many substances already approved for treating neuropathic pain failed to ameliorate CIPNP in clinical trials, underlining the importance of assessing drug efficacy in CIPNP independently of other neuropathic pain states

  • CIPNP has distinctive mechanisms that depend on the causative cytostatic drug; this heterogeneity could explain why results from trials addressing classic neuropathic pain states do not translate to CIPNP

  • Clinical trial designers in academia and industry are encouraged to implement sensory profiling in patient stratification to tailor the analgesic treatment according to the individual underlying mechanisms of CIPNP

  • Mechanisms involved in CIPNP include disruption of axonal transport, altered ion channel and receptor activity, neuronal injury and inflammation, oxidative stress, and mitochondrial damage

  • Suggestions for mechanism-based therapy of CIPNP include duloxetine for oxaliplatin-induced CIPNP, and combination of neuroprotective and anti-inflammatory substances for CIPNP caused by paclitaxel or vincristine

Abstract

Chemotherapy-induced peripheral neuropathic pain (CIPNP)—a severe adverse effect observed in up to 80% of patients during treatment with antineoplastic drugs—limits the tolerable dose of cytostatics, and can lead to discontinuation of chemotherapy. Many drugs that are approved for the treatment of other neuropathic pain states have shown little or no analgesic effect on CIPNP in large randomized, placebo-controlled clinical trials. Here, we review the known mechanisms of CIPNP induced by the three most commonly used cytostatics: paclitaxel, oxaliplatin and vincristine. These substances have distinct neurotoxic and neuroinflammatory properties, but they also have overlapping contributions to pathogenesis of CIPNP that could potentially be targeted for prevention or treatment of CIPNP. We discuss the failure of previously tested antioxidants, neuroprotective agents, anticonvulsants and antidepressants as therapeutic or preventative strategies, and suggest individualized, mechanism-based therapeutic options for CIPNP associated with each of the three main drug groups. We point out the necessity to assess drug efficacy in CIPNP independently of other neuropathic pain states, and emphasize the need for delineation of subpopulations of patients with CIPNP for more-efficient treatment. Finally, we discuss novel therapeutic strategies and recent progress in treatment of CIPNP, and evaluate the potential benefits of these recent proceedings for future therapies.

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Figure 1: Mechanisms of chemotherapy-induced peripheral neuropathic pain.
Figure 2: Distinct and overlapping mechanisms in CIPNP.

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Acknowledgements

M.S., K.S. and G.G. have received funding from the Deutsche Forschungsgemeinschaft (German Research Association; grants SCHO817 and SFB1039 TP A08, A09 and Z01). R.B. and G.G. are part of the Europain Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115007, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and the kind contribution of companies involved in the European Federation of Pharmaceutical Industries and Associations. G.G. has also received funding from the LOEWE-Programme of the State of Hessia (Anwedungsorientierte Arzneimittelforschung).

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, Frankfurt am Main, D-60590, Germany

    Marco Sisignano, Klaus Scholich & Gerd Geisslinger

  2. Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, Haus 41, Kiel, 24105, Germany

    Ralf Baron

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M.S. searched the published work, discussed the content, wrote, edited and revised the article, designed all figures and assembled all tables, R.B. searched the literature, discussed the content, and wrote, edited and revised the article. K.S. and G.G. discussed the content, and wrote, edited and revised the article, figures and tables. All authors read and approved the final draft.

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Correspondence to Gerd Geisslinger.

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Competing interests

R.B. and G.G. are members of the IMI (Innovative Medicine Initiative of the EU) EuroPain collaboration, in which the following industry members are represented: Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Esteve, Gruenenthal, Pfizer, UCB Pharma and Sanofi Aventis. G.G. has received honoraria as a speaker from Gruenenthal, Mundipharma and Pfizer. He is a consultant for Abbvie. He has received research funding in the form of a grant from Mundipharma. R.B. has received honoraria as a speaker from Astellas, Bayer-Schering, Boehringer Ingelheim, Desitin, Eisai, Eli Lilly, Genzyme, Gruenenthal, Medtronic, Mundipharma, MSD, Pfizer, Sanofi Pasteur and Teva Pharma. He is also a consultant for Abbvie, Allergan, Astellas, AstraZeneca, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Genzyme, Gruenenthal, Medtronic, Merck, Mundipharma, Novartis, Pfizer and Sanofi Pasteur. He has received research funding in the form of grants from Genzyme, Gruenenthal and Pfizer. M.S. and K.S. declare no competing interests.

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Sisignano, M., Baron, R., Scholich, K. et al. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol 10, 694–707 (2014). https://doi.org/10.1038/nrneurol.2014.211

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