背景:与癌症相关的疼痛通常需要阿片类药物治疗,阿片类药物引起的便秘(OIC)是其最常见的胃肠道副作用。对于OIC的预防和治疗,广泛使用渗透性(例如聚乙二醇)和刺激性(例如比沙可啶)泻药。较新的药物,例如与羟考酮固定组合的外周作用μ阿片受体拮抗剂(PAMORAs)和纳洛酮,已可用于OIC的管理。本系统综述和荟萃分析旨在概述预防和治疗癌症患者OIC的药理学策略的科学证据。
方法:在PubMed中进行系统搜索,Embase,WebofScience和Cochrane图书馆从成立到2022年10月22日完成。系统选择随机和非随机研究。评估肠功能和药物不良事件。
结果:20项试验(预防:5项随机对照试验和3项队列研究;治疗:10项随机对照试验和2项比较队列研究)纳入综述。关于防止伊斯兰会议组织,三个随机对照试验将泻药与其他泻药进行了比较,发现所用泻药的有效性没有明显差异。一项队列研究表明,与没有泻药相比,氧化镁具有显着的益处。与氧化镁相比,一项RCT发现PAMORA纳地米定具有显着的益处。与羟考酮或芬太尼相比,预防性使用羟考酮/纳洛酮在其他三项研究中没有显着差异。无法进行荟萃分析。关于OIC的治疗,两个随机对照试验比较了泻药,其中一项RCT发现聚乙二醇明显比人参皂苷更有效。七项研究比较了阿片类药物拮抗剂(纳洛酮,甲基纳曲酮或纳迪米定)与安慰剂和三项研究比较了不同剂量的阿片类药物拮抗剂。这些使用阿片样物质拮抗剂的研究用于荟萃分析。与使用泻药的羟考酮相比,羟考酮/纳洛酮在肠功能指数方面显着改善(MD-13.68;95%CI-18.38至-8.98;I2=58%)。两组药物不良事件发生率相似,除了恶心有利于羟考酮/纳洛酮(RR0.51;95%CI0.31-0.83;I2=0%)。与安慰剂相比,纳地米定(NAL)和甲基纳曲酮(MNTX)表现出明显更高的反应率(NAL:RR2.07,95%CI1.64-2.61,I2=0%;MNTX:RR3.83,95%CI2.81-5.22,I2=0%)。关于不良事件,用甲基纳曲酮治疗时腹痛更明显,而用纳地米定治疗时腹泻更明显.不同剂量的甲基纳曲酮在疗效和不良药物事件发生率方面没有显著差异。
结论:氧化镁和纳地米定对预防癌症患者OIC最有可能有效。纳洛酮与羟考酮的固定组合,纳地米定和甲基纳曲酮可有效治疗癌症患者的OIC,不良事件可接受。然而,它们的效果尚未与标准(渗透和兴奋剂)泻药相比。在提出临床实践建议之前,有必要进行更多的研究来比较标准泻药之间以及与阿片类药物拮抗剂之间的关系。
BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic
review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients.
METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed.
RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the
review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of
oxycodone/naloxone did not show a significant difference in two out of three other studies compared to
oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis.
Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to
oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates.
CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.