Abstract
Opioid treatment often leads to opioid-induced constipation (OIC). We compared the efficacy and safety of naldemedine 0.2mg (NLD), a peripherally-acting mu-opioid receptor antagonist, to alternative OIC treatments. A systematic literature review identified phase III/IV randomized controlled trials (RCTs) of EU-licensed OIC-indicated treatments in adults via searches of MEDLINE, Embase and the Cochrane Library from database inception to 14-Jun-2017, and of congresses, reference lists and grey literature. Outcomes at 12 and 52 weeks were assessed using indirect treatment comparisons (ITCs) or network meta-analyses (NMAs). Of 26 identified placebo/usual care-controlled RCTs, six reported 12-week outcomes (three NLD; two naloxegol 12.5mg [NLX12.5]-vs-naloxegol 25mg [NLX25]; one oxycodone/naloxone). NMAs suggest that NLD was generally comparable to other treatments at 12 weeks for response rate, mean change from baseline in spontaneous bowel movements (SBMs), patient assessment of constipation-symptoms (PAC-SYM) questionnaire, all-cause discontinuation (ACD) and discontinuation due to adverse events (AEs), except that there was a lower risk of discontinuation due to AEs for oxycodone/naloxone over NLD (risk ratio [RR]: 0.22; 95% credible interval [95%CrI]: 0.07, 0.60), and NMAs of SBMs and PAC-SYM favored NLD over NLX12.5 (SBMs: difference -0.82; 95%CrI: -1.33, -0.32; PAC-SYM: difference 0.16; 95%CrI: 0.01, 0.30). ITCs of the two studies reporting 52-week outcomes showed NLD had a lower risk of total AEs (RR: 0.84; 95% confidence interval [95%CI]: 0.75, 0.94), discontinuation due to AEs (RR: 0.19; 95%CI: 0.07, 0.52) and flatulence (RR: 0.10; 95%CI: 0.03, 0.41) versus NLX25; no statistically significant differences were observed in abdominal pain, ACD, serious AEs, deaths, diarrhea, nausea, vomiting or major adverse cardiac events. Efficacy of NLD and NLX25 was similar for OIC treatment, with an improved longer-term safety profile for NLD versus NLX25. 12-week comparisons suggest NLD is superior to NLX12.5 for the treatment of OIC in terms of SBMs and PAC-SYM.
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