Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
Curr Pharm Des. 2012;18(37):6010-20. doi: 10.2174/138161212803582388.
The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.
阿片类镇痛药的治疗作用受到外周不良反应的影响，其中阿片类诱导的便秘（OIC）最为严重，其发生率报告在 15%至 90%之间。尽管 OIC 通常采用泻药治疗，但临床证据不足表明泻药对此适应证有效。相比之下，来自双盲、随机和安慰剂对照试验的充分证据表明，外周阿片受体拮抗剂（PORAs）可对抗 OIC。这种特定的治疗方式目前基于皮下美沙酮来中断晚期疾病患者的 OIC，以及口服延长释放纳洛酮与延长释放羟考酮的固定组合，用于预防非癌症和癌症疼痛治疗中的 OIC。这两种药物在不减弱阿片类药物镇痛作用的情况下对抗 OIC。临床研究表明，接受阿片类药物治疗的便秘患者中，超过 50%可能受益于 PORAs 的使用，而 PORA 耐药患者可能患有非阿片类药物引起的便秘，其发生率随年龄增长而增加。虽然纳洛酮加羟考酮的添加似乎通过预防 OIC 起作用，但每隔一天间歇性给予美沙酮似乎通过引起肠道戒断反应来刺激排便。PORAs 的出现为专门控制 OIC 和阿片类镇痛药的其他外周不良反应（例如，尿潴留和瘙痒）提供了新的机会。PORAs 的连续给药具有不良反应少的优点，而 PORA 的间歇性给药可能与腹痛样痉挛有关。
