Doxepin prevents the Expression and Development of Paclitaxel-Induced Neuropathic Pain

Background: Peripheral neurotoxicity is a common side effect of many anticancer chemotherapy drugs, including paclitaxel. Peripheral neurotoxicity may present as changes in sensory function and mild paresthesia that, in turn, can lead to alleviation of the prescribed dose of the medication. The aim of this study was to evaluate the effectiveness of acute and chronic doxepin administration on development and expression of neuropathic pain during the treatment of cancer with paclitaxel. Materials and Methods: Neuropathic pain was induced in mice by paclitaxel (2 mg/kg, intraperitoneally [i.p.,] once daily from day 1 to day 5) that caused mechanical and cold allodynia. Doxepin was administrated every day from day 6 to 10 (10 and 15 mg/kg i.p.). Mechanical and cold allodynia was evaluated on day 11 of the experiment in both the test and the control group. Results: Daily administration of doxepin (2.5, 5, and 10 mg/kg i.p.) from day 1 to 5 significantly inhibited the development of cold and mechanical allodynia. As well doxepin administration (5 and 10 mg/kg i.p.) from the 6 th day, to 10 th day significantly inhibited cold and mechanical allodynia expression. To address the concerns associated with the effectiveness of chemotherapy agents on the tumor, we evaluated paclitaxel cytotoxicity effect in combination with doxepin. Our observations indicate that doxepin even at high concentrations (1 and 10 μg/ml) does not interfere with the cytotoxic effect of paclitaxel (0.05 μg/ml). Conclusions: These results indicate that doxepin, when administered during chemotherapy, can prevent the development and expression of paclitaxel-induced neuropathic pain.