Portland, Ore.— For cancer patients with opioid-induced constipation, with or without active disease, a single dose of subcutaneous methylnaltrexone was found to be very effective in producing a rescue-free bowel movement within four hours, and similar effectiveness was also seen in patients with other severe illnesses, according to a new study. The research was a post hoc analysis of three randomized trials conducted between 2003 and 2012.
“Moreover, the results for cancer patients were highly clinically and statistically significant,” said senior author Michelle Rhiner, DNP, MSN, RN-C, an assistant professor of family medicine and a practitioner of palliative medicine at Loma Linda University Health, in California.
Among 198 cancer patients treated with methylnaltrexone (Relistor, Salix), 61.1% achieved a rescue-free bowel movement within four hours versus 15.3% of 157 placebo-treated patients, for a marginal difference of greater than 45%.
“This outcome is especially striking because over 95% of patients who entered these trials had been laxative-refractory,” Dr. Rhiner said.
This is the first analysis of methylnaltrexone treatment in cancer patients, despite the fact that more than 60% of the patients enrolled in the three advanced illness studies had cancer, said Dr. Rhiner, who presented the poster results (abstract C12) at the 29th annual conference of the American Society for Pain Management Nursing.
“Because cancer patients may have multiple etiologies for constipation related to treatments, apart from opioid use, or to their disease state, it was important to study and compare the results of opioid-induced constipation (OIC) treatment in this patient population to patients who had other severe illnesses,” Dr. Rhiner said.
The analysis found that for both cancer and noncancer patients, the median time to rescue-free laxation was significantly shorter after the first dose of methylnaltrexone compared with placebo: four and 24 hours, respectively.
But the median change in pain scores (scale, 0-10) was similar among the four groups: –0.4 for cancer patients treated with methylnaltrexone; –0.2 for placebo-treated cancer patients; –0.2 for noncancer patients treated with the drug; and –0.4 for placebo-treated noncancer patients.
“The overall outcomes of the analysis validate the clinical observations of the three trials,” Dr. Rhiner said. “The treatment results were often impressive, even when all other therapies like standard laxatives and enemas had failed. I was particularly surprised by how well methylnaltrexone worked in cancer patients compared to those with noncancer illnesses, as cancer patients could have had so many other potential causes of constipation apart from opioids.”
In addition, although trial patients treated with methylnaltrexone had more adverse events, such as abdominal pain and nausea, than those receiving placebo, previous analysis demonstrated that these events primarily occurred with the initial doses of methylnaltrexone and appear to have been related to rapid inducement of bowel movement after severe constipation, according to Dr. Rhiner.
“Once constipation was relieved, these adverse effects abated,” she said. “However, patients with mechanical intestinal obstructions from tumors or other causes should not receive methylnaltrexone—or for that matter any agent that may increase bowel contractions—for fear of producing or exacerbating bowel perforations.”
Dr. Rhiner said several articles indicate that opioids may have harmful effects in certain cancer patients by shortening survival, due to the expression of opioid receptors on tumors. “The literature in this area is controversial. But if our results are validated through additional research, then a drug like methylnaltrexone could potentially allow for cancer pain control while blocking certain harmful peripheral effects of opioids on tumors.”
‘Profound’ Treatment Advantages
“The results of the analysis do not surprise me at all,” said Theresa Mallick-Searle, MS, RN-BC, ANP-BC, an adult nurse practitioner in the Division of Pain Medicine at Stanford Health Care, in Redwood City, Calif. “The initial clinical trials of the peripherally acting mu-opioid receptor antagonists (PAMORAs) demonstrated undeniable clinical efficacy for improving bowel function in patients with chronic noncancer pain” (Clin J Pain 2019;35[2]:174-188).
Ms. Mallick-Searle, who was not involved in the new study, said methylnaltrexone’s unique mechanism of action is effective, regardless of opioid dose and medical comorbidities. “Additionally, for doses evaluated, methylnaltrexone does not cross the blood–brain barrier, thus maintaining an analgesic benefit,” she said.
The utility of a chemical like methylnaltrexone, whose mechanism of action is localized to the site of acute exacerbation (mu-opioid receptor in the gut), without affecting analgesia, “has profound advantages in caring for patients already benefiting from opioid analgesics yet struggling with intolerable constipation,” Ms. Mallick-Searle said.
Furthermore, methylnaltrexone’s ability to provide consistent and dependable relief of constipation within the anticipated time frame of four to 24 hours ensures confidence and compliance among patients treated, Ms. Mallick-Searle said.
“The medication should definitely be considered as first-line therapy,” she said, noting that methylnaltrexone is effective regardless of the total daily opioid intake; consistently efficacious in both cancer and noncancer chronic opioid use; and cost-effective, when considering time to efficacious treatment, possible emergency department visits and trials of over-the-counter laxatives.
However, to date, there have been no head-to-head studies assessing the efficacy and safety of the PAMORAs: methylnaltrexone, naloxegol and naldemedine, Ms. Mallick-Searle said. “Therefore, conclusions from the current analysis may not be similar for all PAMORAs.”
—Bob Kronemyer
Dr. Rhiner reported participation on the Salix speakers bureau for Relistor, and previous consultantships with Pfizer, Salix and Wyeth. Dr. Rhiner also reported funding from Progenics as a subinvestigator for Relistor. Ms. Mallick-Searle reported serving on the speakers bureau for Amgen and Lilly Pharmaceuticals.