From the Department of Internal Medicine, University of Michigan Health System, Ann Arbor (W.D.C.); PRA International, Salt Lake City (L.W.); AstraZeneca Pharmaceuticals, Wilmington, DE (M.S., J.L., P.N.B.); and the Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium (J.T.).
N Engl J Med. 2014 Jun 19;370(25):2387-96. doi: 10.1056/NEJMoa1310246. Epub 2014 Jun 4.
Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation.
In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements.
Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol.
Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).
阿片类药物引起的便秘很常见且使人虚弱。我们研究了纳洛酮治疗阿片类药物引起的便秘的疗效和安全性，纳洛酮是一种口服、外周作用的 μ 型阿片受体拮抗剂。
在两项相同的 3 期、双盲研究（研究 04，652 名参与者；研究 05，700 名参与者）中，患有非癌症疼痛和阿片类药物引起的便秘的门诊患者被随机分配接受每日剂量为 12.5 或 25mg 的纳洛酮或安慰剂治疗。主要终点是治疗意向人群中 12 周的反应率（每周≥3 次自发性排便，且在 12 周中有≥9 周和最后 4 周中有≥3 周的基线增加≥1 次自发性排便）。关键次要终点是在入组前对泻药反应不足的患者亚组中的反应率、首次给药后首次自发性排便的时间以及每周有 1 次或更多自发性排便的平均天数。
与安慰剂相比，25mg 纳洛酮的反应率显著更高（治疗意向人群：研究 04，44.4%比 29.4%，P=0.001；研究 05，39.7%比 29.3%，P=0.02；对泻药反应不足的患者：研究 04，48.7%比 28.8%，P=0.002；研究 05，46.8%比 31.4%，P=0.01）；在研究 04 中，接受 12.5mg 纳洛酮治疗的患者的反应率也更高（治疗意向人群，40.8%比 29.4%，P=0.02；对泻药反应不足的患者，42.6%比 28.8%，P=0.03）。在两项研究中，与安慰剂相比，接受 25mg 纳洛酮治疗的患者首次给药后首次自发性排便的时间更短，每周有 1 次或更多自发性排便的平均天数更多（P<0.001），而在研究 04 中，接受 12.5mg 纳洛酮治疗的患者也有此情况（P<0.001）。两组患者的疼痛评分和每日阿片类药物剂量相似。在接受 25mg 纳洛酮治疗的患者中，最常见的不良事件（主要是胃肠道）。
与安慰剂相比，纳洛酮治疗可显著提高治疗反应率，而不减少阿片类药物介导的镇痛作用。（由阿斯利康公司资助；KODIAC-04 和 KODIAC-05 临床试验.gov 编号，NCT01309841 和 NCT01323790）。
