When Dr. Jonathan Moss was developing a drug to relieve the severe constipation plaguing end-stage cancer patients taking opioid painkillers, he noticed a few of those patients lived longer than expected.
Although likely to die within a month, some "went on to live for five to six months," Moss said. He began to think the methylnaltrexone (Relistor) might be doing more than simply improving their ability to eat. "I began to wonder in my mind…could it be an effect on the progression of the tumor?" Subsequent laboratory studies confirmed that Relistor inhibited tumor growth and angiogenesis – the sprouting of blood vessels that nourish tumors.
Now, almost a decade later, multiple laboratory and animal studies, are converging with some human research to suggest that opioid drugs and the body's natural opioids may play a role in the growth and spread of cancer, according to two studies and an accompanying commentary published Tuesday in a special issue of the journal Anesthesiology.
Moss, co-author of the commentary and one of the studies, cautioned that it would be premature for cancer patients or their doctors to give up on opioids, which have a 200-year history in relieving cancer pain and post-surgical pain.
"There are no double-blind human studies showing that if you take an opioid, that you are more or less likely to have tumor progression," said the professor of anesthesiology and critical care medicine at the University of Chicago.
Without proof provided by a "large human study," the findings are "very interesting," but "much too early" to change practices, said Dr. Jay Brooks, chairman of hematology/oncology at the Ochsner Clinic Foundation and Hospital in Baton Rouge, La. He expressed concern that cancer patients might become unnecessarily worried that pain meds will make their cancers grow.
However, one result of continued research in this area could be that methylnaltrexone and similar drugs might become additions to the cancer-fighting arsenal with "a side effect of reducing" some of the opioids' downsides, such as constipation and depression of breathing, suggested anesthesiologist Dr. Michael Roizen, chief wellness officer at the Cleveland Clinic in Ohio, a co-developer of methylnaltrexone, which is FDA-approved for palliative care.
Opioids comprise narcotic pain relievers like fentanyl and morphine, as well as chemicals the body generates, such as the feel-good endorphins associated with runner's high. Opioids bind to opioid receptors found on cell membranes in the nervous system as well as in the gut.
In one of the new studies, breast cancer patients survived longer if they had a gene that made them resistant to opioids (meaning they probably needed more medication to control their pain). In the Carolina Breast Cancer Study of more than 2,039 women diagnosed between 1993 and 2001, women with invasive breast cancer who had one copy of the gene variant survived twice as long. Survival quadrupled for those with two copies of the gene variant, according to research led by Dr. Andrey V. Bortsov, an assistant professor of anesthesiology and his colleagues at the University of North Carolina, Chapel Hill.
In the other study, led by Patrick A. Singleton, an assistant professor of medicine at the University of Chicago, researchers found that naturally occurring opioids could fuel the growth of human non-small cell lung cancer in human lung cancer cells transplanted into mice with compromised immune systems. "What we saw was a two-fold increase in tumor growth, and even more strikingly, a 20-fold increase in metastasis," he said in an interview.
"The two papers together are really bookends," Moss said. The finding that lung cancer cells have lots of so-called mu opioid receptors involved in tumor growth and spread provides "a plausible explanation for what people in North Carolina have found. The mu opioid receptor may be very importantly involved in the progression of tumors."
As a result, he said that receptor could become a therapeutic target for new cancer drugs.
In the meantime, anesthesiologists have been re-evaluating how best to provide anesthesia and pain control in advanced cancer while minimizing the negative effects of opioids.
Dr. Eugene Viscusi, director of acute pain management at Thomas Jefferson University in Philadelphia, said the latest findings "are very significant" and fit in with emerging signs that opiates given to cancer patients during and after surgery "may play a role in tumor growth and survival."
Prior studies of breast, prostate and colon cancer, as well as melanoma, have shown fewer recurrences following surgeries that rely more heavily on regional or epidural anesthesia and less on opioids.
"So the data mounts," Viscusi said. Acute pain treatment guidelines published last month in Anesthesiology recommended routine use of epidurals and non-opioid medications such as acetaminophen, non-steroidal anti-inflammatories and ketamine, which he said produce "better pain control, fewer opioid side effects" and may produce better overall outcomes for patients.
For now and until the evidence about opioids and cancer becomes "overwhelmingly clear," Viscusi suggested that patients "seek the best pain management available but not rely primarily or totally on opioids."