Over the last decade, clinical studies have hinted that opioids, used after cancer surgery, may promote the growth or recurrence of tumors, but the data have been mixed. The April issue of Anesthesiology features three research papers that attack the problem from different angles—using epidemiology, human genetics, and animal models—along with a review that explores potential mechanisms by which opioid signaling may impact cancer. Though the work largely supports the idea that μ-opioid receptor (MOR) activity and cancer progression or survival are linked, it is clear that much more information will be needed to settle the longstanding question of what, if any, effects the clinical use of opioids has on cancer outcomes.
There is substantial molecular and animal evidence that opioids affect cancer progression, but “very little clinical evidence,” said Daniel Sessler at the Cleveland Clinic, Ohio, US, who has conducted clinical studies looking at the issue but was not involved in the new work. “It remains an important hypothesis,” he said, but “as of now, there is not anything resembling compelling evidence for clinicians to change their practice.”
There are myriad ways in which opioids might impact cancer progression, as Frances Lennon, Jonathan Moss, and Patrick Singleton, all at the University of Chicago, Illinois, US, explain in a review article accompanying the new studies (Lennon et al., 2012). Opioids impair immune responses, increase angiogenesis, and may even act directly on tumor cells to encourage their growth and spread. But so far, the evidence that opioid use affects outcomes in cancer patients is murky. Previous studies found that patients who received regional anesthesia and post-operative analgesia such as epidural blocks, rather than general anesthesia and high doses of systemic opioids, tended to have better outcomes. But in other studies, no such relationship turned up. Likewise, one of the new studies, a retrospective database investigation by Kenneth Cummings, also at the Cleveland Clinic, and colleagues yielded ambiguous results: Among 42,000 patients who had surgery for colon cancer, those who had epidural anesthesia and analgesia survived longer, but the rate of cancer recurrence was the same in the epidural and non-epidural groups (Cummings et al., 2012).
In another of the newly published studies, Andrey Bortsov and Samuel McLean at the University of North Carolina at Chapel Hill, US, along with coworkers, looked for genetic evidence for a role of the opioid system in cancer progression. The investigators genotyped over 2,000 women with breast cancer, examining single-nucleotide polymorphisms (SNPs) in the MOR gene, OPRM1 (Bortsov et al., 2012). They found that the A118G SNP, which is associated with reduced MOR expression and function, was associated with cancer survival. Women carrying one copy of the lower-activity G allele were half as likely to have died from their cancer within 10
years as those with the typical A/A genotype; for women with two copies of the G allele, the risk was even lower.
If the results are replicated, they suggest that reduced opioid signaling could protect women against cancer progression. But the situation could be just the opposite, since the G allele is commonly associated with higher opioid use. Moreover, the effects of the polymorphism could reflect differences in response to endogenous opioids, rather than drugs. For the moment, all possibilities are open, since data on opioid intake were not available in the study cohort. “To make any conclusions about the effect of exogenous opioids or endorphins on cancer outcomes,” Bortsov cautioned, “we would need to measure opioids themselves.”
Meanwhile, Singleton and colleagues examined a possible mechanistic basis for MOR involvement in cancer progression (Lennon et al., 2012). In previous work, the group found elevated MOR expression in tissue from lung cancer patients (Mathew et al., 2011). Now, first author Frances Lennon and coworkers report that MOR overexpression in human non-small cell lung cancer cells increased cell migration, proliferation, and metastatic behavior. The effects appeared to be mediated by Akt and mTOR, two serine/threonine kinases involved in cancer progression. When cells were injected into immune-deficient mice, the resulting primary tumors grew more quickly from cells in which MOR was overexpressed, and a marker of lung metastasis was 20-fold higher. Importantly, the effects of opioid drugs were not investigated in these experiments.
The results to date raise the possibility that blocking MOR may have therapeutic value in cancer. As Moss and colleagues point out in their review, the opioid receptor antagonist naltrexone is being tested in patients to treat metastatic breast cancer and glioma.
Despite the plausible mechanistic underpinnings, it remains unclear whether anesthesiologists ought to be concerned about effects of opioids on cancer growth—either in the peri-operative period, the focus of most studies thus far, or in the context of chronic pain treatment. Moss and colleagues propose to address the question with peripherally restricted MOR antagonists such as methylnaltrexone, which should block the potential tumor-promoting effects of opioids in the periphery while preserving pain relief in the central nervous system.
While opioids may affect cancer cells, cancer treatments may also bolster opioid actions: Recently, researchers reported that morphine-induced signaling through the platelet-derived growth factor receptor-β (PDGFR-β) drives opioid tolerance (see PRF related news story), which was reversed in rats by the PDGFR kinase inhibitor and cancer drug imatinib (Gleevec). From all this, one thing is clear: Teasing apart the complicated relationships among the opioid system, cancer, and its treatment will require more work, both in the lab and in the clinic.
Image credit: Daniel Schwen, Wikimedia Commons