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Morphine and Other Pain Relief Drugs Used in Cancer Surgery May Spur Return of Malignancy

Could the anesthesia and painkillers used to make operations and recovery bearable also influence the risk that cancer will return?
cancer, anesthesia,morphine



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Morphine is often a cancer patient's best and final friend. So it came as a shock when researchers at the University of Minnesota published a study showing that doses of morphine similar to those used to ease pain actually spurred the growth of human breast cancer cells grafted into mice. "These results indicate that clinical use of morphine could potentially be harmful" in some cancer patients, the scientists wrote in 2002 in Cancer Research.

The results were indeed a surprise—at first, says Kalpna Gupta, a co-author of the 2002 paper and an assistant professor in the Hematology, Oncology and Transplantation Division in the Department of Medicine at the University of Minnesota. "Then I read the literature, and it began to make a lot of sense," she adds.

The findings went relatively unnoticed, despite the study's potentially apple cart–toppling conclusion. Nearly a decade later, however, mounting evidence suggests the group was onto something.

A raft of studies in laboratory animals, molecular models and cancer patients suggest that pain drugs given during and after cancer surgery stimulate the growth and spread of certain tumors.

Cancer seems to thrive on exposure to opioids, particularly morphine, the most widely used narcotic for relief of surgical pain. In the presence of these drugs tumors grow faster and develop more extensive networks of the blood vessels they rely on to feed their expansion—a process called angiogenesis, says Jonathan Moss, an anesthesiologist at the University of Chicago (U. of C.) Medical Center.

The key actors here likely are mu-opioid receptors, molecules on cell membranes that allow opioids to bind to them and interact with the cell itself, he says. Moss has shown that animals lacking these receptors do not develop lung cancer when injected with cancer cells. "If they don't have the receptor they don't get the tumor," adds Moss, whose group presented its findings at a cancer meeting last November and is now submitting them for publication. "That implies that the mu-opioid receptor is somehow involved in tumor progression."

And a team led by Moss and U. of C. Medical Center assistant professor of medicine Patrick Singleton as well as other groups, have also given drugs that block opioid receptors to mice with cancer. The result is a sharp reduction in the growth and spread of tumors, according to Moss and Singleton's findings. Still, Moss admits that more data in people are needed. "You can cure a lot of cancers in mice," he says, "and not necessarily have any effect in humans."

Opioids also may make blood vessels leaky, making tissues more receptive to cancer cells looking for places to build a tumor, Moss says.

A similar link to a risk for returning cancer is cropping up in studies of the form of anesthesia provided during cancer surgeries. Patients who undergo general anesthesia typically require more opioid painkillers after surgery than those who receive general anesthetics—which keep patients asleep but do not deaden nerves—plus injections of local anesthetic to block the nerves at or near the site of surgery.

On top of that, the latter approach—called regional anesthesia, or a nerve block—is thought to reduce the stress of surgery on the body's immune system. Scientists think weakened immunity in the aftermath of cancer surgery might promote recurrence later. Here's why: when surgeons remove a tumor, they inevitably leave behind a few straggler cancer cells. Cells that slough into the bloodstream can take hold at distant sites—and a metastasis is born.

Drifting cancer cells are not unlike invading bacteria, says Edward Nemergut, an anesthesiologist at the University of Virginia (U.V.A.) Health System in Charlottesville: "They spread when cancer is resected [removed], and you need a functioning immune system to take care of them. When the immune system is suppressed, it's less effective at doing that."

Results from a 2006 study in Ireland and the U.S. suggest that patients who undergo surgery to remove breast or prostate cancer might be less prone to recurrence if they are administered regional anesthesia during their procedures, rather than general anesthesia alone. And this approach may be more effective at preventing the disease from returning and spreading than treatment with chemotherapy after the operation, says Marcel Durieux, an anesthesiologist at the U.V.A. Health System .

Along the same lines, Daniel Sessler, an anesthesiologist at Cleveland Clinic in Ohio, is leading two randomized trials looking at whether nerve blocks added to general anesthesia reduce metastases in patients undergoing surgery to remove either breast or lung cancer. The studies are expected to include at least 1,000 patients and should start producing answers in about three years. Cancer specialists have been highly skeptical of the notion that drugs given for hours or days surrounding surgery can influence the spread of tumors months or years later. "And I don't blame them for a second," Sessler adds. "I'll remain skeptical, too, unless the theory is confirmed in large randomized trials."

The human data so far are retrospective—scientists cannot isolate the potential effect of anesthesia from the effects of other factors such as blood transfusion, temperature regulation and statin administration during surgery. "The retrospective data are very intriguing and we have a good physiological rationale for why it may be happening," says Durieux, co-author of a review article on the surgery–cancer connection in the June 2010 issue of Anesthesia & Analgesia. "On the other hand, this may go away once we do well-controlled clinical trials."

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