Safety and Tolerability of Naloxegol in Patients with Opioid Induced Constipation: Systematic Review and Meta-analysis

Abstract

Introduction: Naloxegol is the first oral peripheral mu opioid receptor antagonist approved for opioid induced constipation. In clinical trials, patients reported shorter times to first spontaneous bowel movement. However, studies have also reported numerous gastrointestinal and non-gastrointestinal side effects. Hence, we performed a systematic review and meta-analysis to assess the safety and tolerability of 25 mg Naloxegol compared to placebo. Methods: All randomized controlled trials enrolling adult patients that reported clinical safety and tolerability of Naloxegol were identified from PubMed, MEDLINE, Embase & Cochrane Central Register of Controlled Trials through May 30, 2016. Four randomized controlled trials were identified. Primary outcome of our study was mortality. Secondary outcomes studied were nausea, vomiting, upper abdominal pain, abdominal pain, flatulence, diarrhea, headache, and back pain. Random effects model was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) using Cochrane Collaborative software, RevMan 5.3. Measure of heterogeneity between the studies was assessed using the chi square test and was considered significant if I2 > 50%. Results: We included 4 RCTs with a total of 1,750 participants in our analysis, of which 1,009 received 25 mg Naloxegol and 741 received a placebo. No statistical significant difference in the primary outcome of mortality (OR=0.50, 95% CI 0.03 - 8.10) was observed in our study. There was an increased risk of adverse effects in Naloxegol group as compared to placebo: nausea (8.9% versus 4.8%, OR 1.90, 95% CI 1.26-2.87; Number Needed to Harm 24.6), upper abdominal pain (4.6% versus 1.5%, OR - 3.10, 95% CI 1.56 - 6.15; NNH 31.9), abdominal pain (17.3% versus 4.8%, OR 4.08, 95% CI 2.68- 6.21; NNH 7.9), flatulence (6.4% versus 2.1%, OR - 2.86, 95% CI 1.45 - 5.64; NNH 23.35), diarrhea (11.3% versus 4.8%, OR - 2.35, 95% CI 1.59 - 3.48; NNH=15.53), headache (6.9% versus 3.5%, OR - 1.83, 95% CI 1.14 - 2.96; NNH=29.09) and back pain (6.8% versus 3%, OR - 2.01, 95% CI 1.22 - 3.31; NNH=26.6). No statistical significant difference in vomiting was observed between the two groups (OR - 1.29, 95% CI 0.70 - 2.39). Conclusion: Use of Naloxegol was associated with an increased risk of gastrointestinal side effects, headache, and back pain without increased risk of mortality as compared to placebo. As with all medications, a discussion with patients regarding the risks and benefits of this treatment is advised.Figure 1