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

• Published in: Drugs & aging Vol. 38; no. 6; pp. 503 - 511
• Main Authors: Liao, Solomon S., Slatkin, Neal E., Stambler, Nancy
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-06-2021; Springer Nature B.V
• Subjects: Adults; Age; Age Factors; Aged; Analgesics; Analgesics, Opioid - adverse effects; Blood-brain barrier; Constipation; Constipation - chemically induced; Constipation - drug therapy; Drug dosages; Drug withdrawal; Geriatrics/Gerontology; Humans; Internal Medicine; Laxatives; Medicine; Medicine & Public Health; Naltrexone - analogs & derivatives; Naltrexone - therapeutic use; Narcotics; Older people; Opioid-Induced Constipation; Original; Original Research Article; Pain management; Permeability; Pharmacology/Toxicology; Pharmacotherapy; Quaternary Ammonium Compounds - therapeutic use; Treatment Outcome
• ISSN: 1170-229X; 1179-1969
• DOI: 10.1007/s40266-021-00850-w

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.