EditorialProposed mechanisms for association between opioid usage and cancer recurrence after surgery☆,☆☆
Introduction
Cancer remains one of the most prevalent and burdensome diseases on the modern health care landscape. Although significant success has been made toward effective medical and surgical treatment, cancer pain management presents a unique and continuing challenge. Recent epidemiological evidence has suggested that the selected anesthetic and analgesic management modalities for operative, postoperative, and long-term pain control appear to be associated with increased recurrence of certain malignancies [1], [2], [3], [4], [5], [6], [7], [8]. Several hypotheses to explain these clinical observations have been formulated and substantiated by basic science research. However, a lack of well-designed, prospective clinical trials precludes the dominance of one hypothesis over the other. There also exists the possibility of multiple near-simultaneous mechanisms being responsible for the finding.
Amelioration of cancer pain is typically achieved through the use of potent opioid analgesics. A 2007 review of pain management suggested that concerns about opioid abuse have led to the undertreatment of pain with opioid by “opioid-phobic” physicians [9]. Numerous practice guidelines have been established that stress the importance of individualized treatment of pain with both opioid and nonopioid analgesics. Rigorous adherence to these guidelines can yield significant pain relief [10], [11], [12]. With both chronic and cancer-related pain, dose escalation typically occurs in an effort to achieve a favorable balance of effective analgesia and opioid-related adverse effects [13]. Opioid analgesic use in cancer patients during the perioperative period is largely based on their presurgical opioid requirement. However, this common practice may need to be reexamined based on recent publications describing an association between opioid usage and cancer recurrence after excision of the primary tumor. We hypothesize that the immediate use of opioids in the perioperative period could act to suppress activity of natural killer cells (NK cells), whereas the long-term use of opioids in patients who develop persistent pain states may act to directly promote tumor growth.
Section snippets
Preliminary clinical studies examining the effect of opioid analgesia on cancer recurrence rates after surgery
Use of regional anesthesia decreases the requirement for postoperative opioid analgesics [14]. For example, Irish researchers found that surgery for breast cancer performed with paravertebral blockade using only levobupivicaine was associated with a 94% disease-free survival at both 24 and 36 months compared with 82% and 77% at the same time points in a similar surgical patient population not receiving regional anesthesia (P = .012) [2]. The use of paravertebral blocks for breast surgery
Potential mechanisms for association between opioid analgesics and cancer recurrences after surgery
A leading hypothesis for the apparent association between opioids and cancer recurrence rates is that chronic μ-opioid receptor (MOR) agonism results in direct stimulation of neoplastic cells and associated cellular pathways essential to tumor cell growth and metastatic spread. Stimulation of MORs has been found to promote the growth of existing tumors but not the growth of new tumors in rodents [28]. μ-Opioid receptors have been identified on the cellular surface of malignant tissue [29].
Conclusion
Basic science research and retrospective clinical studies have provided growing evidence of an association between postsurgical cancer recurrence and the perioperative use of opioid analgesics. It is likely that multiple pathways are responsible for this observation including the suppression of NK cells with immediate opioid administration and direct stimulation of neoplastic pathways with more prolonged opioid use. Although direct stimulation of neoplastic cellular growth pathways likely
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Disclosures: This study was not associated with any grants, sponsors, or funding (including National Institutes of Health, Wellcome Trust, Howard Hughes Medical Institute, or departmental or institutional funding). However, Dr White receives support for his academic activities from the White Mountain Institute, The Sea Ranch, CA. This study has not been published elsewhere and is not under consideration for publication in another journal.
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This manuscript has been read and approved by the 2 authors.