The Influence of Age on Central Effects of Methylnaltrexone in Patients with Opioid-Induced Constipation

Solomon S Liao, Neal E Slatkin, Nancy Stambler, Solomon S Liao, Neal E Slatkin, Nancy Stambler

Abstract

Background: Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across the blood-brain barrier (BBB) and has not been demonstrated to impact opioid-induced central analgesia. Age-related changes in BBB permeability may compromise methylnaltrexone's restricted diffusion and alter opioid-induced central analgesic effects.

Objective: This analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.

Methods: The analysis included adults diagnosed with OIC who received opioids for pain management and who had a terminal illness or chronic nonmalignant pain. Data were pooled from four randomized, double-blind trials and stratified by age (< 65 years and ≥ 65 years). Endpoints included pain intensity scores, symptoms of opioid withdrawal, treatment-related adverse events (TRAEs), and rescue-free laxation (RFL) within 4 h of treatment.

Results: Overall, 1323 patients were < 65 years of age (n = 908, methylnaltrexone; n = 415, placebo) and 304 patients were ≥ 65 years of age (n = 171, methylnaltrexone; n = 133, placebo). Nonsignificant pain intensity score reductions were observed in all groups. In the older cohort, measures of opioid withdrawal did not show statistical differences from baseline in either the methylnaltrexone or placebo groups. The most frequently reported TRAEs were abdominal pain, flatulence, and nausea. Relative to the first dose, gastrointestinal TRAEs potentially related to opioid withdrawal declined with the second dose and were comparable with placebo, regardless of age. RFL response within 4 h of methylnaltrexone treatment increased significantly in both age cohorts relative to placebo.

Conclusions: Methylnaltrexone use did not adversely affect pain control, opioid withdrawal effects, or AEs while providing effective RFL, regardless of age. These results suggest that age does not appear to influence the safety and efficacy of methylnaltrexone for OIC. Further research is needed to assess the impact of other factors that alter BBB permeability, such as dementia, stroke, or drug interactions, on the safety and efficacy of methylnaltrexone.

Clinical trial registration numbers: Study 302, NCT00402038; study 3200K1-4000, NCT00672477; study 3200K1-3356, NCT00529087; study 3201, NCT01186770.

Conflict of interest statement

Solomon S. Liao has no disclosures to report; Neal E. Slatkin is an employee and shareholder of Salix Pharmaceuticals, a division of Bausch Health US, LLC; and Nancy Stambler is a full-time employee of Progenics Pharmaceuticals.

Figures

Fig. 1
Fig. 1
Changes from baseline in a current and b worst pain intensity scores at hour 4 in studies 302 and 4000, and changes from baseline in mean pain intensity scores at c week 2 and d week 4 in studies 3356 and 3201 among those who were < 65 years or ≥ 65 years of age. CI confidence interval, LS least squares
Fig. 2
Fig. 2
Changes from baseline in scores among those who were a OOWS, b SOWS, and c mHOWS at day 1. mHOW modified Himmelsbach Opioid Withdrawal Scale, OOWS Objective Opioid Withdrawal Scale, SOWS Subjective Opioid Withdrawal Scale, CI confidence interval, LS least squares
Fig. 3
Fig. 3
Percentage of responders with rescue-free laxation within 4 h after the first dose. SC subcutaneous

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