High-Dose Tramadol Enhances the Proliferative and Invasive Potential of Pancreatic Ductal Adenocarcinoma in Mice...

Opioids are known to have various effects on cancer depending on the type and dose. Tramadol, a weak opioid used for mild cancer pain, exhibits antitumor effects, whereas strong opioids demonstrate protumor effects. We previously reported that 10 mg/kg/day of tramadol (low dose) improves cancer pain and exerts antitumor effects in mice with pancreatic cancer. However, the effects of high-dose tramadol on pancreatic cancer remain unknown. Therefore, the effect of high-dose tramadol on pancreatic cancer was investigated in mice using the pancreatic cancer model mouse KPPC (LSL - Kras^G12D/+;  Trp53^flox/flox;  Pdx - 1^cre/+).

High-dose tramadol (50 mg/kg/day) was orally administered to 6-week-old KPPC mice bearing pancreatic ductal adenocarcinoma until a humane endpoint (n = 10). Cancer-related pain was assessed using the mouse grimace scale, and tumor status was determined histopathologically. Plasma cytokine concentrations were assessed using a cytokine array. The effects of tramadol on the invasive potential of murine pancreatic ductal adenocarcinoma cell lines were investigated in vitro.

High-dose tramadol improved mouse grimace scale scores but increased tumor size (1734.2 vs. 907.1 mm²; P  <  0.01). High-dose tramadol stimulated proliferative Ki-67 labeling index and inhibited local infiltration of CD8⁺ cytotoxic T cells and M2-like tumor-associated macrophages. Similar to alterations in local immunoinflammatory cells and relief of cancer pain, plasma tumor necrosis factor-α, interleukin (IL)-6, IL-2, IL-12, and interferon-γ decreased following high-dose tramadol administration. The invasive potential of mouse pancreatic ductal adenocarcinoma cell lines was suppressed by adding high-dose tramadol.

These results suggest that high-dose tramadol improves cancer-associated pain but enhances the tumor volume of pancreatic ductal adenocarcinoma by decreasing anti-tumor CD8⁺ T lymphocytes.