Intraoperative opioids are associated with decreased recurrence rates in colon adenocarcinoma: a retrospective observational cohort study

Background: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. Methods: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I–III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. Results: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51–70] yr; 49% female) who underwent curative resection for stage I–III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87–0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21–0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. Conclusions: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I–III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.