Naloxegol to Prevent Constipation in ICU Adults Receiving Opioids: A Randomized Double-Blind Placebo-Controlled Pilot Trial

Abstract

Background. Constipation is frequent in critically ill adults receiving opioids. Naloxegol (N), a peripherally acting mu-receptor antagonist (PAMORA), may reduce constipation. The objective of this trial was to evaluate the efficacy and safety of N to prevent constipation in ICU adults receiving opioids. Methods and Patients. In this single-center, double-blind, randomized trial, adults admitted to a medical ICU receiving IV opioids (≥100 mcg fentanyl/day), and not having any of 17 exclusion criteria, were randomized to N (25 mg) or placebo (P) daily randomized to receive N (25mg) or placebo (P) and docusate 100 mg twice daily until ICU discharge, 10 days, or diarrhea (≥3 spontaneous bowel movement (SBM)/24 hours) or a serious adverse event related to study medication. A 4-step laxative protocol was initiated when there was no SBM ≥3 days. Results. Only 318 (20.6%) of the 1542 screened adults during the 1/17–10/19 enrolment period met all inclusion criteria. Of these, only 19/381 (4.9%) met all eligibility criteria. After 7 consent refusals, 12 patients were randomized. The study was stopped early due to enrolment futility. The N (n = 6) and P (n = 6) groups were similar. The time to first SBM (N 41.4 ± 31.7 vs. P 32.5 ± 25.4 hours, P = 0.56) was similar. The maximal daily abdominal pressure was significantly lower in the N group (N 10 ± 4 vs. P 13 ± 5, P = 0.002). The median (IQR) daily SOFA scores were higher in N (N 7 (4, 8) vs. P 4 (3, 5), P < 0.001). Laxative protocol use was similar (N 83.3% vs. P 66.6%; P = 0.51). Diarrhea prevalence was high but similar (N 66.6% vs. P 66.6%; P = 1.0). No patient experienced opioid withdrawal. Conclusions. Important recruitment challenges exist for ICU trials evaluating the use of PAMORAs for constipation prevention. Despite being underpowered, our results suggest time to first SBM with naloxegol, if different than P, may be small. The effect of naloxegol on abdominal pressure, SOFA, and the interaction between the two requires further research.

Peripherally‐active mu‐opioid receptor antagonists for constipation in critically ill patients receiving opioids: A case‐series and a systematic review and meta‐analysis of the literature

“…The final selection included 9 papers: two randomized controlled trials, 19,20 one prospective case-series, 21 three retrospective case-series [22][23][24] and three case reports. [25][26][27] Tables 3 and 4 report the study characteristics and the main outcomes.…”

“…Among the cohort studies, only Sawh et al found a clear benefit of Methylnaltrexone over conventional laxative therapy in terms of number of patients laxating within 24 h and hours to laxation. 22 The meta-analysis, instead, shows that both treatment with PAMORAs or non-PAMORAs drugs resulted in overlapping 19,20,23 In particular, both time to laxation and number of patients laxating at the shortest follow-up are similar between the two groups (Figure 1). The meta analysis only shows a trend, without statistical significance, toward a lower residual gastric volume in patients treated with PAMORAs (Figure 1, lower panel).…”

“…Of the five studies comparing PAMORAs versus conventional therapy or placebo, only four were considered of good quality and were included in the main meta-analysis. 19,20,22,23 Three of those studies investigated the use of methylnaltrexone, while only the study of Duprey et al 20 investigated Naloxegol. In summary, the results of the effect of PAMORAs in the recovery of GI motility is contradictory, with some positive and some neutral or negative studies.…”

“…On the other side, the RCTs included in the systematic review 19,20 are neutral; indeed, in the studies, baseline patient characteristics, as well as the distribution of confounding factors are well matched between groups, and the studies enrolled a larger number of patients.…”

“…As a matter of fact, our case-series is, to the best of our knowledge, the first study to assess the effect of naldemedine, whereas the other studies have investigated the use of methylnaltrexone 19,[21][22][23][24][25][26] or naloxegol. 20 As shown in the chronic pain literature, it is likely that naldemedine is more effective than other PAMORAs to treat OIC. 39 Another possibility might lie in the case-mix.…”