Our study has assessed the effects of treatments of opioid-induced constipation based on diverse patient response outcomes. This analysis shows that, using the diverse patient response outcomes and the GRADE criteria, the response of opioid-induced constipation to treatment is best achieved with the PAMORAs (methylnaltrexone, naloxegol and naldemidine) and oxycodone/naloxone. After weighing the risk of serious adverse events seen with oxycodone/naloxone, naldemedine, methylnaltrexone and naloxegol had the best efficacy to adverse event ratio, particularly as naloxegol 12.5 mg had similar improvement in bowel function as naloxegol 25 mg without the adverse events.
Overall, naldemedine, naloxegol and methylnaltrexone resulted in a clinically significant increase in spontaneous bowel movements per week, and complete spontaneous bowel movements per week. Unfortunately, only studies with fixed-dose combinations of oxycodone/naloxone analysed change in the Bowel Function Index scores, and therefore it is not possible to assess comparative ORs for the diverse treatments of opioid-induced constipation based on the Bowel Function Index. Combination oxycodone/naloxone resulted in a clinically significant change in the Bowel Function Index (11.6 units [95% CI 9.1–14.1]) based on previously defined minimal clinically significant change of 12. However, there was no clinically significant change in studies that utilised naloxone alone as a treatment of opioid-induced constipation. Combination oxycodone/naloxone did result in increased spontaneous bowel movements per week and complete spontaneous bowel movements per week, but there were limitations in the assessment, including a single trial and significant heterogeneity in the effects on spontaneous bowel movements and complete spontaneous bowel movements. PAMORAs had the highest odds ratio of achieving the FDA endpoints based on spontaneous bowel movements and complete spontaneous bowel movements that is the combination of >3 spontaneous bowel movements or complete spontaneous bowel movements per week plus >1 over baseline. Alvimopan and axelopran did demonstrate improvements in complete spontaneous bowel movements and spontaneous bowel movements, but these assessments were based on small number of studies that require further validation in larger studies.
With regards to safety, all medications analysed (PAMORAs, secretory, promotility agents and oxycodone/naloxone) had similar rates of treatment emergent adverse events, serious adverse events and major cardiac adverse events. Naloxegol and lubiprostone were associated with statistically significant increase in treatment emergent adverse events (Table S5), but are not considered clinically elevated based on the OR and confidence interval. Oxycodone/naloxone was associated with a clinically significant increase in serious adverse events (as in the Results section, eg pneumonia, bile duct obstruction, cholecystitis, grand mal convulsion and fall complicated by skin laceration). Methylnaltrexone and naloxegol were associated with numerically lower rates of serious adverse effects, but this was not statistically significant. The secretory agents (lubiprostone and linaclotide) had the highest rates of abdominal pain and diarrhoea (see Figures 5 and 6), followed by methylnaltrexone, naldemedine and naloxegol. Of note, naloxegol 25 mg had the statistically significant side effects, but naloxegol 12.5 mg did not. Combination oxycodone/naloxone had the lowest rates of abdominal pain. This observation argues against the concern that the ability of naloxone to cross the blood-brain barrier constitutes a risk of opiate withdrawal and recurrence of pain, presumably because of the low bioavailability and total dose of naloxone in the fixed-dose combinations. Based on the rates of adverse events with the PAMORAs compared to the combination oxycodone/naloxone, further analysis would be required to consider the naloxone-to-oxycodone ratio or the dose of PAMORAs relative to the average dose of the narcotic medication using a standard metric such as oral morphine equivalent dose.
Previous meta-analyses found generally similar results as our analysis. However, our analysis provided a more detailed assessment subdivided on the different bowel function outcomes. Nee et al and Ford et al pooled many different outcomes together to determine response to therapy. However, only 10/26 studies and 4/17 studies included the FDA endpoint outcomes of spontaneous bowel movements and complete spontaneous bowel movements. None of the other outcomes pooled from these studies were considered continuous outcomes and were largely based on timing to first bowel movement or other change in bowel frequency. Luthra et al also reported that naldemedine had the highest rates of meeting the FDA endpoint for spontaneous bowel movements, consistent with our analysis. Lastly, Sridharan et al pooled outcome data for the number of patients with rescue medication-free bowel movements, an assessment that is equivalent to spontaneous bowel movement. However, they utilised binary evaluation instead of the continuous measurement as used in our analysis. None of the other systematic review and meta-analysis studies compared adverse events between trial drugs.
Meta-analyses require sufficient homogeneity of baseline characteristics. For opioid-induced constipation, this might be baseline Bowel Function Index score on first-line laxative therapy, and the median dose of opioids expressed as the oral morphine equivalents. For example, patients with opioid-induced constipation included in the larger naloxone trials[61,64,84] were on lower oral morphine equivalents than the patients included in the naldemedine and naloxegol trials. The effect of oral morphine equivalents dose on the relative efficacy of the opioid antagonists requires individual patient data analysis and collaboration among trialists; however, such an analysis would provide additional insights to the choice of drug(s) used for opioid-induced constipation.
Aliment Pharmacol Ther. 2020;52(1):37-53. © 2020 Blackwell Publishing