Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy: A Subgroup Analysis of Patients ≥ 65 Years of Age

Abstract

Background Opioid-induced constipation (OIC), the most common side effect of opioid treatment, is under-recognized and undertreated in older patients. Naldemedine, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), is approved in Japan, the United States, and the European Union for treatment of OIC in adult patients. Objective This integrated analysis of three phase 3 trials (COMPOSE-1, COMPOSE-2, and COMPOSE-3) evaluated the safety and efficacy of naldemedine for up to 12 weeks in a subgroup of patients aged ≥ 65 years. Methods Patients aged 18-80 years with chronic non-cancer pain for ≥ 3 months (treated with opioids for ≥ 3 months in COMPOSE-1 and COMPOSE-2) and OIC received oral naldemedine 0.2 mg or placebo once daily. Safety assessments included overall incidence of treatment-emergent adverse events (TEAEs), TEAEs in the gastrointestinal disorders System Organ Class, and TEAEs of opioid withdrawal or possible opioid withdrawal. Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2, defined as having ≥ 3 spontaneous bowel movements/week and a ≥ 1-spontaneous bowel movement/week increase from baseline for ≥ 9 of 12 weeks and ≥ 3 of the last 4 weeks. Results A total of 14.8% (344/2328) of patients were aged ≥ 65 years in all studies. The incidence of TEAEs in naldemedinetreated patients aged ≥ 65 years (45.9%) was comparable to that in patients aged ≥ 65 years receiving placebo (51.6%) and in the overall naldemedine group (47.1%). The incidence of gastrointestinal disorders System Organ Class TEAEs in naldemedine-treated patients aged ≥ 65 years (20.2%) was also comparable to that in patients aged ≥ 65 years receiving placebo (16.1%) and in the overall naldemedine group (21.8%). The incidence of TEAEs of opioid withdrawal with naldemedine was 1.1% in patients aged ≥ 65 years and 1.0% overall, and the incidence of TEAEs of possible opioid withdrawal was 1.1% in patients aged ≥ 65 years and 1.7% overall. The proportion of responders was higher in naldemedine-treated patients versus placebo, both overall (50.1% vs 34.1%; p < 0.0001) and in those aged ≥ 65 years (51.8% vs 37.6%). Conclusions This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients aged ≥ 65 years with chronic non-cancer pain. Safety and efficacy results were consistent with the overall patient population. ClinicalTrials.gov registration NCT01965158, NCT01993940, NCT01965652. Key PointsIndividuals aged 65 years or older can safely use naldemedine to treat opioid-induced constipation.Naldemedine is effective in improving symptoms of opioid-induced constipation in adults, regardless of age.Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s4026 6-020-00753 -2) contains supplementary material, which is available to authorized users.Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or nationa...

The Involvement of the Endogenous Opioid System in the Gastrointestinal Aging in Mice and Humans

“…Due to the high clinical relevance of ORs agonists in pain management, our study was limited to the assessment of the action of agonists, not antagonists, in the GI tract. In clinics, the only antagonists that are applied in patients are peripherally acting antagonists of MOP receptors, such as methylnaltrexone [ 31 ] or naldemedine [ 32 ]. Noteworthy, it was reported that their activity in the human GI tract was independent of age [ 31 , 32 ].…”

“…In clinics, the only antagonists that are applied in patients are peripherally acting antagonists of MOP receptors, such as methylnaltrexone [ 31 ] or naldemedine [ 32 ]. Noteworthy, it was reported that their activity in the human GI tract was independent of age [ 31 , 32 ].…”

Real-World Patient Characteristics and Treatment Patterns of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Cancer: A Multicenter Retrospective Chart Review Study

“…Although elderly patients may generally be excluded from clinical trials, COMPOSE-4 and -5 included patients over 20 years of age, with no upper age limit [6]. In a subgroup analysis of phase III trials, naldemedine had been reported to be generally well tolerated and effective in patients over 65 years of age suffering from chronic non-cancer pain [13]. This analysis appears to suggest that naldemedine can be effectively and safely used to treat older populations.…”

Efficacy and Safety of Peripherally Acting μ-Opioid Receptor Antagonist (PAMORAs) for the Management of Patients With Opioid-Induced Constipation: A Systematic Review

“…Safety: Naldemedine was generally well tolerated in terms of potential adverse effects. One study evaluated the safety and efficacy of naldemedine for up to 12 weeks in a subgroup of patients aged over 65 years from three trials (COMPOSE-1, COMPOSE-2 and COMPOSE-3) [50]. In these studies, the incidence of TEAEs in the naldemedine group (45.9%) was comparable to that in patients receiving placebo (51.6%).…”