Cumulative Laxation Response with Methylnaltrexone: Implications for Hospitalized Patients with Advanced Illness and Opioid-Induced Constipation

IF 1.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Current Therapeutic Research-clinical and Experimental Pub Date : 2023-01-01 DOI:10.1016/j.curtheres.2023.100694

David Farchadi MD, MS , Neal E. Slatkin MD , Nancy Stambler DrPH , Robert J. Israel MD , Michael Matus MD

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Abstract

Background

Opioid-induced constipation (OIC) may increase the risk of fecal impaction and mortality in patients with advanced illness. Methylnaltrexone (MNTX) is efficacious for OIC.

Objective

The purpose of this analysis was to evaluate cumulative rescue-free laxation response with repeat MNTX dosing in patients with advanced illness who were refractory to current laxative regimens and to assess the influence, if any, of poor functional status on response to MNTX treatment.

Methods

This analysis included pooled data from patients with advanced illness and established OIC who were on a stable opioid regimen in a pivotal, randomized, placebo (PBO)-controlled clinical trial (study 302 [NCT00402038]) or a randomized, PBO-controlled Food and Drug Administration-required postmarketing study (study 4000 [NCT00672477]). Patients in study 302 received subcutaneous MNTX 0.15 mg/kg or PBO every other day, whereas those in study 4000 received MNTX 8 mg (body weight ≥38 to <62 kg), MNTX 12 mg (body weight ≥62 kg), or PBO every other day. Outcomes included cumulative rescue-free laxation rates at 4- and 24-hours postdose for the first 3 doses of study drug and time to rescue-free laxation. To assess if functional status influenced treatment outcomes, we performed a secondary analysis on the outcomes stratified by baseline World Health Organization/Eastern Cooperative Oncology Group performance status, pain scores, and safety.

Results

One hundred eighty-five patients received PBO and 179 patients received MNTX. The median age was 66.0 years, 51.5% were women, 56.5% had a baseline World Health Organization/Eastern Cooperative Oncology Group performance status score >2, and 63.4% had a primary diagnosis of cancer. Cumulative rescue-free laxation rates were significantly higher with MNTX than PBO 4- and 24-hours after doses 1, 2, and 3 (P < 0.0001), and between-treatment comparisons remained significant (P < 0.0001) regardless of performance status. The estimated time to first rescue-free laxation was shorter for patients receiving MNTX versus PBO. No new safety signals were identified.

Conclusions

Repeated use of MNTX represents a safe and effective treatment for OIC in patients with advanced illness regardless of baseline performance status. ClinicalTrials.gov identifier: NCT00672477. (Curr Ther Res Clin Exp. 2023; 84:XXX–XXX)

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甲纳曲酮的累积通便反应:对晚期疾病和阿片类药物引起的便秘住院患者的影响

背景阿片类药物引起的便秘（OIC）可能会增加晚期疾病患者的粪便嵌塞风险和死亡率。甲基纳曲酮（MNTX）对OIC有效。目的本分析的目的是评估对目前的泻药方案难治的晚期疾病患者重复给药MNTX的累积无挽救性泻药反应，并评估功能状态差对MNTX治疗反应的影响（如果有的话）。方法该分析包括在一项关键的、随机的、安慰剂（PBO）对照临床试验（研究302[NCT0402038]）或一项随机的、PBO对照的美国食品药品监督管理局要求的上市后研究（研究4000[NCT00672477]）中使用稳定阿片类药物方案的晚期疾病和已确定OIC患者的汇总数据。研究302中的患者每隔一天接受0.15 mg/kg的MNTX皮下注射或PBO，而研究4000中的患者隔一天接受8 mg的MNTX（体重≥38至＜62 kg）、12 mg的MNTX12 mg（体重≥62 kg）或PBO。结果包括前3剂研究药物在给药后4小时和24小时的累积缓解自由松弛率以及缓解自由松弛的时间。为了评估功能状态是否影响治疗结果，我们对根据基线世界卫生组织/东方肿瘤合作组织的表现状态、疼痛评分和安全性分层的结果进行了二次分析。结果185例患者接受PBO治疗，179例患者接受MNTX治疗。中位年龄为66.0岁，51.5%为女性，56.5%的患者具有世界卫生组织/东方肿瘤合作组织的基线表现状态评分>；2和63.4%的患者有癌症的初步诊断。在第1、2和3次给药后4和24小时，MNTX的累积无挽救松弛率显著高于PBO（P<；0.0001），并且无论表现状态如何，治疗之间的比较仍然显著（P<：0.0001）。与PBO相比，接受MNTX的患者第一次抢救自由松弛的估计时间更短。没有发现新的安全信号。结论无论基线表现如何，重复使用MNTX对晚期疾病患者的OIC都是一种安全有效的治疗方法。ClinicalTrials.gov标识符：NCT00672477。（Curr Ther Res Clin Exp.2023；84:XXX–XXX）©2023 Elsevier HS Journals，股份有限公司。

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来源期刊

Current Therapeutic Research-clinical and Experimental 医学-药学

CiteScore

3.50

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0.00%

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审稿时长

3 months

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