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Effects of tramadol via a µ-opioid receptor on pancreatic ductal adenocarcinoma in vitro and in vivo
  1. Tomoya Kuramochi1,
  2. Makoto Sano1,
  3. Ichie Kajiwara1,
  4. Yukino Oshima1,
  5. Tomoaki Itaya1,
  6. Jinsuk Kim1,
  7. Yoshimi Ichimaru2,
  8. Osamu Kitajima1,
  9. Atsushi Masamune3,
  10. Hideaki Ijichi4,5 and
  11. Takahiro Suzuki1
  1. 1 Department of Anesthesiology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
  2. 2 School of Pharmacy, Shonan University of Medical Sciences, Yokohama, Kanagawa, Japan
  3. 3 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  4. 4 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  5. 5 Clinical Nutrition Center, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
  1. Correspondence to Dr Makoto Sano, Department of Anesthesiology, Nihon University School of Medicine, Itabashi-ku 173-8610, Tokyo, Japan; sano.makoto{at}


Introduction Tramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via µ-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice (LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ).

Methods Six-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer-related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol’s effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro.

Results Tramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone.

Conclusions These findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the µ-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines.

  • Cancer Pain
  • Analgesics, Opioid
  • Pain Management

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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  • Correction notice This article has been corrected since it published Online First. The corresponding details, figure 3 and figure 3 legend have all been updated.

  • Contributors Experimental design: MS, TS. Data acquisition/analysis: MS, TK, IK. Provision of vehicle-treated mice: IK, YO. Cell proliferative assay: YI. Tissue preparation: JK. Provision of human pancreatic stellate cells: AM. Discussion of data: OK, YI. Writing of paper: MS, TK. Review of paper: HI, TS. Study supervision and guarantor: TS.

  • Funding The Japan Society for the Promotion of Science KAKENHI (JP21K09006).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.