Opioid-induced constipation medication may improve OS in advanced cancer

Treatment with and response to methylnaltrexone for opioid-induced constipation appeared associated with improved OS in patients with advanced cancers, according to a post-hoc analysis of two randomized trials.

These data suggest that the µ opioid receptor has a role in cancer progression, according to the researchers.

The µ opioid receptor antagonist methylnaltrexone (Relistor, Salix Pharmaceuticals) is used to treat opioid-induced constipation. Preclinical hypotheses have suggested that targeting the µ opioid receptor pathway may serve as a platform for anticancer therapy.

Jonathan Moss, MD, PhD, professor of anesthesia and critical care at The University of Chicago, and colleagues pooled data from two randomized trials of patients with end-stage advanced cancers and opioid-induced constipation.

A total of 229 patients were randomly assigned methylnaltrexone (n = 117) or placebo (n = 112) during the studies’ double blind periods. The studies also included open-label phases, in which patients initially assigned placebo could cross over to the methylnaltrexone arm.

The distribution of patient characteristics or major tumor types did not significantly differ by arm. The most commonly seen cancer subtypes included lung (25%), prostate (13%), breast (10%) and pancreas (7%).

Longer median OS occurred among patients assigned methylnaltrexone (76 days vs. 56 days; HR = 0.63; 95% CI, 0.42-0.95).

A subset analysis of patients assigned methylnaltrexone found that those who responded to treatment (n = 72) — defined as laxation within 4 hours of administration — achieved longer median OS than those who did not (118 days vs. 58 days; HR = 0.37; 95% CI, 0.2-0.67).

Fifty percent of patients (n = 56) originally assigned placebo ultimately crossed over to methylnaltrexone.

A multivariate analysis identified independent prognostic factors for improved OS, including response to treatment (HR = 0.47; 95% CI, 0.29-0.76) and albumin levels of 3.5 g/dL or higher (HR = 0.46; 95% CI, 0.3-0.69).

Additionally, the researchers observed no OS differences between methylnaltrexone and placebo in 134 study patients with advanced illnesses other than cancer.

The researchers acknowledged study limitations, including the retrospective design and the fact that neither of the studies from which data were extracted were designed to assess survival outcomes.

Further limitations included the relatively brief follow-up period, which led to 58% of patients being censored at the date of last follow-up, and exclusive inclusion of individuals treated with opioids.

“While our findings are in patients with advanced malignancies, the hypothesis that µ opioid antagonism may have a potential therapeutic value also extends to earlier tumors and to the perioperative period,” Moss and colleagues wrote. “Our findings should be interpreted as preliminary, hypothesis generating and insufficient to mandate a change in clinical practice, where pain control remains an important issue. Prospective clinical studies to confirm the role of methylnaltrexone in patients with advanced cancers are merited to confirm clinical relevance of our findings.”

Randomized studies are needed to define the appropriate use of the µ opioid receptor pathway as an anticancer target, Per Sjøgren, MD, PhD, professor of acute pain management and palliative care at University of Copenhagen and Copenhagen University Hospital, and Stein Kaasa, MD, professor of oncology and palliative medicine at Oslo University Hospital and University of Oslo and adjunct professor at Norwegian University of Science and Technology, wrote in an accompanying editorial.

“Weak clinical evidence indicates that opioids may play a role in progression of existing tumors,” Sjøgren and Kaasa wrote. “However, these hypothetical findings as concluded by Janku and colleagues are preliminary and need to be confirmed in later studies. Thus, there is a pronounced need for investigating µ opioid receptor mediated opioid effects on tumor biology and disease stages, as well as effects of opioid types, doses and exposures in different settings.” – by Cameron Kelsall

Disclosure: Moss reports a role in the development of methylnaltrexone, and that he is entitled to royalties from The University of Chicago through Progenetics, its initial licensor. He further reports a consultant role with Salix Pharmaceuticals. Other study researchers report employment with Salix Pharmaceuticals and patents related to methylnaltrexone. Sjøgren and Kaasa report no relevant financial disclosures.