Spinal neuronal correlates of tapentadol analgesia in cancer pain: A back‐translational approach

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.

Tapentadol in the management of opioid-naïve patients with cancer pain

“…In cancer conditions in preclinical studies, a recent experimental analysis of tapentadol on spinal neuronal signalling in a rat model of metastatic bone pain, has found a marked inhibition 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 (16).…”

The Stage-Specific Plasticity of Descending Modulatory Controls in a Rodent Model of Cancer-Induced Bone Pain

“…Our indication is that stage-specific analgesics, whose mechanism of action accurately reflects the underlying mechanism of central versus peripheral nervous system dysfunction as described in our rodent model of CIBP, could lead to improved analgesic profiles, and therefore should be considered for these patients. Encouragingly, the use of drugs that engage noradrenergic transmission have previously been shown to be effective in preclinical models of CIBP [28][29][30][31]. Interestingly, CIBP is not the only pain state where dynamics in descending controls sub-serving DNIC/CPM have been recorded.…”

Neuropeptide Y is Up-regulated and Induces Antinociception in Cancer-induced Bone Pain

“…Six-week old rats were anesthetized with isoflurane (3.5% for induction, 2.5% for maintenance; Nomeco, DK) and 5 mg/kg Rimadyl or Norodyl (Pfizer, DK) was administered subcutaneously prior to surgery. The surgery for inoculation of cancer cells was performed as previously described (Falk et al, 2015), modifying the method from Medhurst and associates (Medhurst et al, 2002). Briefly, after shaving and disinfecting the area, an incision was performed on the skin of the medial distal side of the right limb, and the tibia was exposed.…”