ORIGINAL ARTICLE Spinal neuronal correlates of tapentadol analgesia in cancer pain: A back-translational approach S. Falk 1 , R. Patel 2 , A. Heegaard 1 , S. Mercadante 3 , A.H. Dickenson 2 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark 2 Departments of Neuroscience, Physiology and Pharmacology, University College London, UK 3 Department of Anesthesia and Intensive Care & Pain Relief and Palliative Care, La Maddalena Cancer Center, Palermo, Italy Correspondence Sarah Falk E-mail: falk@sund.ku.dk Funding sources Supported by the University of Copenhagen, The Danish Cancer Society and the Wellcome Trust–funded London Pain Consortium. Conflicts of interest AHD has received research funding and Speaker fees from Grünenthal. Tapentadol was a gift from Grünenthal but the design, execution and analysis of the study, as well as the preparation and submission of the manuscript were entirely independent of this support. Accepted for publication 27 March 2014 doi:10.1002/ejp.530 Abstract Background: Pain is a common and highly debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of multiple mechanisms including both inflammatory and neuropathic processes and also some unique changes. Strong opioids are a mainstay of treatments but side effects are problematic and can compromise optimal pain control. Tapentadol is a novel dual-action drug, both stimulating inhibitory μ-opioid receptors (MOR) and mediating noradrenaline reuptake inhibition (NRI) leading to activation of the inhibitory α-2 adrenoceptor. It has been demonstrated to treat effectively both acute and chronic pain. We here demonstrate the efficacy in a model of cancer-induced bone pain. Methods: MRMT-1 mammary carcinoma cells were inoculated into the tibia of 6-week-old rats and 2 weeks after, the neuronal responses to a wide range of peripheral stimulation were evaluated. The recordings were made from wide-dynamic range neurons in lamina V of the dorsal horn before and after administration of tapentadol as well as antagonists of the two mechanisms, naloxone or atipamezole. Results: We found marked inhibitions of the neuronal activity with efficacy against mechanical, thermal and electrically evoked activity following tapentadol administration. In addition, the effects of the drug were fully reversible by naloxone and partly by atipamezole, supporting the idea of MOR-NRI dual actions. Conclusions: These findings add to the mechanistic understanding of cancer-induced bone pain and support the sparse clinical data indicating a possible use of the drug as a therapeutic alternative for cancer patients with metastatic pain complication. 1. Introduction The number of people living with cancer has increased over the last decade (Office for National Statistics, 2011) leading to new challenges in dealing with the secondary complications of cancer survivors including pain and depression (Velikova et al., 2004; Barsevick et al., 2006; Stromgren et al., 2006; Johnsen et al., 2009). These patients often experience moderate to severe pain that compromises quality of life (Svendsen et al., 2005; Coleman, 2006; Stromgren et al., 2006). Cancer-related pain includes components of both neu- ropathic and inflammatory pain, but has additional unique features (Falk and Dickenson, 2014). Cancer pains are challenging to manage since efficacy of most analgesic drugs is assessed in noncancerous conditions that may not necessarily relate to the mixed mecha- nisms of cancer pain. Patients can develop metastatic spread to the bone causing relatively stable levels of background pain and © 2014 European Pain Federation - EFIC ® Eur J Pain •• (2014) ••–•• 1