medwireNews: The peripherally acting μ-opioid receptor antagonist (PAMORA) naldemedine significantly reduces opioid-induced constipation (OIC) in patients with cancer, Japanese researchers report.
Nobuyuki Katakami (Institute of Biomedical Research and Innovation Hospital, Kobe) and co-investigators explain that “PAMORAs aim to reverse OIC by minimizing the action of exogenous opioids at peripheral μ-opioid receptors, including in the [gastrointestinal] tract, without affecting analgesia.”
In the double-blind phase III COMPOSE-4 trial they evaluated the efficacy of naldemedine in 193 patients, aged 20 years and older, with any type of cancer that did not affect gastrointestinal function.
The researchers report in the Journal of Clinical Oncology that there were significantly more spontaneous bowel movement (SBM) responders, defined as patients with three or more SBMs per week who had an increase of one or more SBM per week from baseline, among the 97 patients randomly assigned to receive oral naldemedine 0.2 mg/day for 2 weeks than among the 96 randomly assigned to receive placebo, at 71.1% versus 34.4%.
Patients in the naldemedine group also experienced a significantly greater change from baseline in the mean frequency of SBMs per week (5.16 vs 1.54), SBMs with complete bowel evacuation per week (2.76 vs 0.71), and SBMs without straining per week (3.85 vs 1.17).
Katakami et al say that naldemedine was “well tolerated” in their study population, but they note that there were significantly more treatment-emergent adverse events (TEAEs) with the study drug than with placebo (44.3 vs 26.0%).
They further investigated the safety of naldemedine in COMPOSE-5, a 12-week open-label extension study that included 131 patients who completed COMPOSE-4.
In COMPOSE-5, 80.2% of the 131 patients reported TEAEs. Among patients taking naldemedine, the most common TEAEs were gastrointestinal events and specifically diarrhea (18.3%). This was also the most common TEAE reported in COMPOSE-4, occurring in 19.6% of patients receiving naldemedine and 7.3% of those receiving placebo.
The researchers note that there were more gastrointestinal disorders reported in COMPOSE-5 than in COMPOSE-4 (43.5 vs 23.7%) overall, but say this is likely due to the longer treatment duration in COMPOSE-5.
In addition, naldemedine was not associated with signs or symptoms of opioid withdrawal, which the authors suggest could have been a safety concern due to the “opposing pharmacology of naldemedine and opioids,” and it had no notable impact on opioid-mediated analgesia.
“Together, these findings, as well as observations from other naldemedine studies, confirm that minimal amounts of, if any, naldemedine cross the blood-brain barrier and stimulate opioid receptors in the [central nervous system],” Katakami and team remark.
They conclude that their findings “highlight the utility of once-daily oral naldemedine 0.2 mg taken with or without food as an effective treatment option for patients with OIC and cancer.”
By Laura Cowen
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