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

James Wild, Lynn Webster, Tadaaki Yamada, Martin Hale, James Wild, Lynn Webster, Tadaaki Yamada, Martin Hale

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 naldemedine-treated 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.

Conflict of interest statement

James Wild received a stipend from Shionogi Inc. for review of the clinical study report. Lynn R. Webster has received honoraria for consultation from Daiichi Sankyo, Insys, Mallinckrodt, Merck, Pain Therapeutics, Pfizer, Shionogi, Teva, Trevena, and Vallon; honoraria for work on advisory boards from BDSI, Ensysce Biosciences, Mallinckrodt, Neurana Pharmaceuticals, Pfizer, and Trevena; and travel expenses from BDSI, Daiichi Sankyo, Ensysce, Elysium, Insys, Mallinckrodt, Pain Therapeutics, Pfizer, Shionogi, Teva, and Trevena. Martin Hale was a consultant to Shionogi Inc. and received a stipend for review of the clinical study report. Tadaaki Yamada is an employee of Shionogi Inc. who may or may not own stock options.

Figures

Fig. 1
Fig. 1
Study designs. R randomization
Fig. 2
Fig. 2
Incidence of any TEAE (a), any ADR (b), and TEAEs of GI disorders SOC (c) by age at baseline (safety population). ADR adverse drug reaction, GI gastrointestinal, SOC system organ class, TEAE treatment-emergent adverse event
Fig. 3
Fig. 3
Incidence of abdominal pain (a), diarrhea (b), nausea (c), and vomiting (d) by age at baseline (COMPOSE-1, COMPOSE-2, and COMPOSE-3 safety population). NAL naldemedine
Fig. 4
Fig. 4
TEAEs of opioid withdrawal (a) and possible opioid withdrawal (b) (COMPOSE-1, COMPOSE-2, and COMPOSE-3 safety population). GI gastrointestinal, MedDRA Medical Dictionary for Regulatory Activities, NAL naldemedine; TEAE treatment-emergent adverse event

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