Webster Lynn R, Camilleri Michael, Finn Andrew
PRA Health Sciences, Salt Lake City, UT, USA.
Mayo Clinic Rochester, MN, USA.
Subst Abuse Rehabil. 2016 Jun 14;7:81-6. doi: 10.2147/SAR.S100998. eCollection 2016.
Buprenorphine and buprenorphine-naloxone fixed combinations are effective for managing patients with opioid dependence, but constipation is one of the most common side effects. Evidence indicates that the rate of constipation is lower when patients are switched from sublingual buprenorphine-naloxone tablets or films to a bilayered bioerodible mucoadhesive buccal film formulation, and while the bilayered buccal film promotes unidirectional drug flow across the buccal mucosa, the mechanism for the reduced constipation is unclear. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered buprenorphine may expose patients to higher concentrations of norbuprenorphine than buprenorphine, while chronic dosing of the buccal formulation results in higher buprenorphine concentrations than norbuprenorphine. Because norbuprenorphine is a potent full agonist at mu-opioid receptors, the differences in norbuprenorphine exposure may explain the observed differences in treatment-emergent constipation between the sublingual formulation and the buccal film formulation of buprenorphine-naloxone. To facilitate the understanding and management of opioid-dependent patients at risk of developing opioid-induced constipation, the clinical profiles of these formulations of buprenorphine and buprenorphine-naloxone are summarized, and the incidence of treatment-emergent constipation in clinical trials is reviewed. These data are used to propose a potential role for exposure to norbuprenorphine, an active metabolite of buprenorphine, in the pathophysiology of opioid-induced constipation.
丁丙诺啡和丁丙诺啡 - 纳洛酮固定复方制剂对治疗阿片类药物依赖患者有效，但便秘是最常见的副作用之一。有证据表明，当患者从舌下含服丁丙诺啡 - 纳洛酮片或贴膜改用双层生物可蚀性粘膜粘附口腔贴膜制剂时，便秘发生率较低。虽然双层口腔贴膜可促进药物单向透过口腔粘膜，但便秘发生率降低的机制尚不清楚。药代动力学模拟表明，长期舌下给药丁丙诺啡可能使患者接触到比丁丙诺啡更高浓度的去甲丁丙诺啡，而长期使用口腔制剂则导致丁丙诺啡浓度高于去甲丁丙诺啡。由于去甲丁丙诺啡是μ - 阿片受体的强效完全激动剂，去甲丁丙诺啡暴露量的差异可能解释了丁丙诺啡 - 纳洛酮舌下制剂和口腔贴膜制剂在治疗中出现便秘的差异。为便于理解和管理有发生阿片类药物引起便秘风险的阿片类药物依赖患者，本文总结了这些丁丙诺啡和丁丙诺啡 - 纳洛酮制剂的临床特征，并回顾了临床试验中治疗中出现便秘的发生率。这些数据用于提出丁丙诺啡的活性代谢产物去甲丁丙诺啡暴露在阿片类药物引起便秘的病理生理学中的潜在作用。
