Drug options available for opioid-induced constipation

Four FDA-approved drugs for opioid-induced constipation form the backbone of treatment, with more options in the research pipeline.

Opioid-induced constipation is extremely common, affecting 40% to 80% of patients taking the drugs for chronic, noncancer pain, but there are treatment options available, said Brian E. Lacy, MD, PhD. He offered a rundown of these to attendees at a Thursday-morning session on common lower gastrointestinal (GI) diseases.

The ideal option, of course, is to stop opioids altogether, said Dr. Lacy, who is a professor of medicine at Mayo Clinic in Jacksonville, Fla. However, he acknowledged that this can be difficult for both patients and physicians. Lifestyle and diet changes and over-the-counter agents usually don't offer much relief; while fiber, laxatives, and stimulant drugs can be used, the evidence is against them, he noted.

“A number of studies, most of them retrospective … have shown that 50% to 60% of patients at minimum would have tried these and they're not effective. And I would argue probably the number's higher, because these patients come to you for help and advice because they've already tried these things on their own and failed,” he said.

There are four FDA-approved drugs for opioid-induced constipation, falling into two classes, secretagogues and peripherally acting mu-opioid receptors antagonists (PAMORAs), Dr. Lacy said.

Lubiprostone, a secretagogue, was FDA-approved in 2006 for chronic idiopathic constipation and has been shown in studies to increase spontaneous bowel movements, improve stool consistency and straining, and reduce constipation severity. “I think most of you in the audience are very comfortable with the use of lubiprostone,” he said. However, he stressed that lubiprostone is not effective in patients who are taking methadone.

“If you have somebody on chronic methadone, don't waste your time with lubiprostone. It's just not going to work,” he said.

Methylnaltrexone, a quaternary derivative of naltrexone, does not cross the blood-brain barrier and has limited absorption from the GI tract, Dr. Lacy said, “so you really don't have to be concerned that your patient will go into withdrawal.” It is available in oral, IV, and subcutaneous forms. In a small randomized, double-blind study published in the New England Journal of Medicine in 2008, methylnaltrexone decreased time to first spontaneous bowel movement over a two-week treatment period compared to placebo, and less rescue medication was also required, Dr. Lacy said.

A subsequent larger trial involving 460 patients treated for four weeks, published in 2011 in the Journal of Pain, showed that those randomly assigned to methylnaltrexone daily or every other day were much more likely to have a bowel movement without needing rescue medication within the first four hours than those assigned to placebo. “This is very encouraging data,” Dr. Lacy said.

Naloxegol, an oral PAMORA, was approved by the FDA in 2014 for treatment of opioid-induced constipation in noncancer patients, Dr. Lacy said. It is a PEGylated derivative of naloxone, which means that it is unlikely to cross the blood-brain barrier. Two large, randomized controlled trials published in the New England Journal of Medicine in 2014 compared 12.5 mg of naloxegol daily, 25 mg daily, and placebo over a 12-week period. The trial had an ambitious primary end point, Dr. Lacy said: more than three spontaneous bowel movements per week and an increase from baseline of at least one spontaneous bowel movement per week for 9 to 12 weeks and for three of the last four weeks of the treatment phase.

“These patients in the study are pretty much the same patients we all see,” Dr. Lacy said. “They have chronic back pain, and they've been on opioids for more than three and a half years.”

In the intention-to-treat analysis, patients randomly assigned to 12.5 mg or 25 mg consistently did better in terms of relieving constipation symptoms versus those assigned to placebo. This was also true in the subset of patients who were resistant to laxatives, Dr. Lacy said.

Naldemedine, a recently approved PAMORA that Dr. Lacy described as “the new kid on the block,” was found to be effective in two trials in Europe and the U.S. (COMPOSE-1 and COMPOSE-2), which were published in Lancet Gastroenterology and Hepatology in 2017. Eleven hundred patients were randomly assigned to receive 0.2 mg of naldemedine or placebo every day for 12 weeks.

“Once again, patients had to meet this very high bar of success to be considered a responder,” Dr. Lacy said. The primary end point was three or more spontaneous bowel movements per week and an increase of one spontaneous bowel movement from baseline for 9 of 12 weeks and three of the last four weeks. The combined response rate was 50.1% in the naldemedine group and 34.1% in the placebo group, he said.

Dr. Lacy also mentioned alvimopan, an oral PAMORA that is not FDA-approved for opioid-induced constipation but is used in the hospital setting for paralytic ileus. “There's some very good data to support its use within the hospital setting and again, I think it's very safe,” he said.

Other drugs currently in development or testing include prucalopride, bevenopran, axelopran, naloxone, dolcanatide, and a combination of oxycodone and naloxone, Dr. Lacy noted. “If patients fail any of these four FDA-approved drugs, which in my experience is not very common, there are other agents coming down the pike,” he said.