Laird Harrison

October 27, 2015

SAN DIEGO — Methylnaltrexone, which is approved for the treatment of opioid-related constipation, appears to extend survival in people receiving opioids for advanced cancer pain, according to new research.

Increasing evidence indicates that treating cancer pain with opioids can actually shorten people's lives, said Jonathan Moss, MD, professor of anesthesia from the University of Chicago.

"Somehow, the opiate receptor seems to be involved in the progression of tumors," he told Medscape Medical News.

Methylnaltrexone blocks that receptor without diminishing the painkilling power of opiates, so the apparent survival benefit makes sense.

In fact, in a retrospective analysis of two clinical trials, patients with advanced cancer who were being treated with opioids lived 20 days longer if they received methylnaltrexone instead of placebo.

Dr Moss presented the findings here at Anesthesiology 2015 from the American Society of Anesthesiologists.

The study is the result of a research project that began in 1979, but took a dramatic turn when the late Leon Goldberg, MD, PhD, a pharmacologist at the University of Chicago, tried to help a friend who was constipated from the morphine being used to treat his cancer pain.

In his search for a molecule that would stop the constipating effect of opioids by blocking their receptors in the gut but would preserve the analgesic effect because it didn't cross the blood–brain barrier, Dr Goldberg began testing derivatives of naltrexone, an established morphine-blocking drug.

Methylnaltrexone appears to provide relief for patients who have not been helped by conventional laxatives, said Dr Moss, who pursued the research after Dr Goldberg died.

The drug is administered as a subcutaneous injection every other day (in doses of 8 mg to 12 mg, depending on body weight), and is very effective as a laxative in about two-thirds of patients, he reported.

The reasons some patients do not respond are unclear, but genes could play a role. "When the drug works, it works very fast," he said. "They had to run to the bathroom in 1 minute, and none of them had been able to move their bowels in a week."

The patients did suffer some adverse reactions, mostly cramping. "But almost all the patients wanted more of the drug because it was so relieving to them," Dr Moss explained.

As Dr Moss was learning about opioid receptors, he became aware of work by other researchers suggesting that low doses of opioids can make cancer cells grow.

He and his colleagues injected Lewis lung cancer tumor cells into normal mice and mice bred without mu-opioid receptors, which are located in the brain and spinal cord. The mice lacking the mu-opioid receptors did not develop cancer, whereas the normal mice did.

Next, the researchers treated mice with methylnaltrexone, and they, too, did not develop cancer after being injected with Lewis cells.

That led Dr Moss to go back and analyze the data from two randomized controlled clinical trials that involved patients receiving palliative care for various types of late-stage cancers and other terminal diseases. None of the patients had responded to conventional laxatives.

Of the 229 patients, 117 received methylnaltrexone for opioid-induced constipation and 112 received placebo.

Relief from constipation was better in the methylnaltrexone group than in the placebo group (57% vs 43%). And, on average, patients in the methylnaltrexone group live significantly longer than those in the placebo group (76 vs 56 days; P = .033).

Patients in the methylnaltrexone group who experienced a laxative response lived significantly longer than those who did not respond (118 vs 58 days; P = 0.001).

In addition, the rate of tumor progression was significantly lower in patients in the methylnaltrexone group who experienced a laxative response than in patients in the placebo group and in patients in the methylnaltrexone group who did not experienced a laxative response (7.6% vs 25.4% vs 22.0%; P = .003).

"What appears to happen is that opioids enhance the blood supply around tumors and enhance their growth," says Eugene Viscusi, MD, a professor of anesthesiology at Thomas Jefferson University Hospital in Philadelphia, who worked with Dr Moss on the experiments.

Before reaching that conclusion, though, the researchers wanted to satisfy themselves on another point. "We weren't sure if the difference was just better eating," said Dr Moss. "You're feeling better, you're moving your bowels, so you're eating better."

So the team analyzed the effect of methylnaltrexone on another 135 patients from the same trials who had advanced illnesses other than cancer, such as congestive heart failure, advanced chronic obstructive pulmonary disease, and neurologic diseases.

The drug did not affect survival in these patients, reinforcing the link between cancer and opioid receptors.

And other studies have reinforced this link. "There is now an accruing body of literature involving cancer surgery that suggests that even short-term exposure to opioids during anesthetic can reduce cancer survival," said Dr Viscusi.

He cited a study presented last week at the Palliative Care in Oncology Symposium that showed that cancer patients treated with high doses of opioids within 90 days of diagnosis did not live as long as patients treated with low doses (J Clin Oncol. 2015;33[suppl 29S]:abstract 188).

Dr Viscusi said he is already trying to avoid the use of opioids, not only in cancer patients, but in all those in his care. He first turns to nonsteroidal anti-inflammatory drugs, cox-2 selective inhibitors, gabapentin, and other analgesics. "Perhaps it's time to re-evaluate the role of opioids in pain management," he said.

Our findings should not change clinical practice at all.

But he acknowledged that some other studies have failed to find a link between opioid use and cancer progression.

Clinicians should wait for further evidence, said one of Dr Moss's coauthors, Filip Janku, MD, PhD, from the Department of Investigational Cancer Therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

"Our findings should not change clinical practice at all," he told Medscape Medical News. "Patients should continue using opioids if they need them."

Dr Janku said that as a next step, he would like to conduct a randomized controlled trial combining methylnaltrexone with standard anticancer therapies to see if it improves survival. One of the most important questions is whether the drug can improve the survival of cancer patients who are not taking opioids, perhaps by acting on the endogenous opioid system.

He said he has already tried giving methylnaltrexone to a handful of cancer patients who are not taking opioids. The effects look promising, but the sample size was too small to determine anything beyond information on dosing and adverse events, he reported.

Meanwhile, for Dr Moss, the new data justify decades of work. "It's very exciting," he said.

The original clinical trials were funded by Salix, now owned by Valeant Pharmaceuticals. Dr Moss is a consultant for Valeant. Dr Viscusi's institution received a research grant for related research. Dr Janku has disclosed no relevant financial relationships.

Anesthesiology 2015 from the American Society of Anesthesiologists (ASA): Abstract A4032. Presented October 27, 2015.


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