Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Neurogastroenterology Unit, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Eur J Pharm Sci. 2018 May 30;117:187-192. doi: 10.1016/j.ejps.2018.02.008. Epub 2018 Feb 9.
Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo.
In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale.
During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01).
In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.
阿片类药物治疗会干扰肛门括约肌在排便时的功能及其调节，这可能导致用力、不完全排空，并导致阿片类药物引起的肠功能障碍（OIBD）。我们采用羟考酮诱导的 OIBD 实验模型，假设与安慰剂相比，同时给予外周作用μ-阿片受体拮抗剂纳洛酮可改善肛门括约肌功能。
在一项双盲随机交叉试验中，将 24 名健康男性随机分为两组，分别接受六天的每日两次口服羟考酮 15mg 联合口服纳洛酮 25mg 或安慰剂治疗。在基线和第 6 天，使用测压法和直肠球囊扩张评估肛门静息压和直肠肛门抑制反射（RAIR）。此外，使用功能腔成像探头测量肛门管的可扩张性。使用患者便秘症状评估量表（PAC-SYM）和布里斯托粪便形状量表评估胃肠道症状。
在羟考酮治疗期间，纳洛酮使 RAIR 诱导的括约肌松弛增加了 15%（-45.9 与-38.8mmHg；P<0.01）。两种治疗方法之间的肛门静息压和肛门管可扩张性无差异（均 P>0.5）。纳洛酮改善了 PAC-SYM 症状（每日平均评分；2.6 与 4.5，P<0.001）和粪便一致性评分（每日平均评分；3.3 与 2.9，P<0.01）。
在 OIBD 的实验模型中，纳洛酮改善了 RAIR 并减轻了胃肠道症状。因此，与传统的泻药相比，纳洛酮可能调节阿片类药物引起的肛门括约肌功能障碍并促进排便过程。
