No Effect of Methylnaltrexone on Acute Pancreatitis Severity: A Multicenter Randomized Controlled Trial

Abstract

Introduction: Opioids used to manage severe pain in acute pancreatitis (AP) might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia.

Methods: This double-blind, randomized, placebo-controlled trial included adult patients with AP and systemic inflammatory response syndrome at 4 Danish centers. Patients were randomized to receive 5 days of continuous intravenous methylnaltrexone (0.15 mg/kg/d) or placebo added to the standard of care. The primary end point was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality.

Results: In total, 105 patients (54% men) were randomized to methylnaltrexone (n = 51) or placebo (n = 54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference 3.8, 95% confidence interval [CI] -40.1 to 47.6; P = 0.87). At 48 hours, we found no differences between the groups in pain severity (0.0, 95% CI -0.8 to 0.9; P = 0.94), pain interference (-0.3, 95% CI -1.4 to 0.8; P = 0.55), and morphine equivalent doses (6.5 mg, 95% CI -2.1 to 15.2; P = 0.14). Methylnaltrexone also did not affect the risk of severe disease (8%, 95% CI -11 to 28; P = 0.38) and mortality (6%, 95% CI -1 to 12; P = 0.11). The medication was well tolerated.

Discussion: Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of AP.

Trial registration: ClinicalTrials.gov NCT04743570.

Graphical abstract

Figure 1.

Flowchart for screening, recruitment, randomization, and follow-up in the trial. SIRS, systemic inflammatory response syndrome.

Figure 2.

PASS scores in the intention-to-treat population. Line graphs show means and 95% CIs (whiskers) of daily PASS scores (a) and PASS points within the 5 scoring elements (b). Data are shown for the intention-to-treat population. Missing data were imputed using the multiple imputation approach. The dashed lines separate the end of treatment and follow-up on day 14. CI, confidence interval; MED, morphine equivalent doses; PASS, Pancreatitis Activity Scoring System; SIRS, systemic inflammatory response syndrome.