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Randomized Controlled Trial Multicenter Study
OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients.
- Chi T Viet, Dongmin Dang, Bradley E Aouizerat, Christine Miaskowski, Yi Ye, Dan T Viet, Kentaro Ono, and Brian L Schmidt.
- Department of Oral Maxillofacial Surgery, New York University, New York, New York; Bluestone Center for Clinical Research, New York University, New York, New York.
- J Pain. 2017 Sep 1; 18 (9): 1046-1059.
AbstractCancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.
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