Methylnaltrexone: Pharmacological Probe of Morphine Effects

甲基纳曲酮：吗啡作用的药理学探讨

• 批准号: 8328879
• 负责人: JAMES P. ZACNY
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328879
• 关键词: Absence of pain sensation; Address; Adverse effects; Affect; Amines; Analgesics; Attenuated; Blood - brain barrier anatomy; Chronic; Clinical; Constipation; Cross-Over Studies; Dose; Double-Blind Method; Human; Laboratories; Literature; Measures; Mediating; Morphine; Naltrexone; Narcotic Antagonists; Nausea; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Palliative Care; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Placebo Control; Placebos; Pruritus; Psychopharmacology; Randomized; Recording of previous events; Running; Stomach; Testing; Therapeutic; cell motility; healthy volunteer; innovation; lipid solubility; methyl group; mu opioid receptors; opioid abuse

DESCRIPTION (provided by applicant): The purpose of this application is to determine whether a peripherally acting mu-opioid receptor antagonist, methylnaltrexone (MTNX), attenuates certain subjective effects of a mu opioid analgesic, morphine, and to determine if MTNX changes the abuse liability-related profile of morphine to be more positive in healthy volunteers. It is currently used in patients on chronic opioid therapy for the relief of opioid-induced constipation, a peripherally-mediated side effect. Because it does not cross the blood-brain barrier, it does not antagonize the analgesic effect of opioids that is centrally mediated. Results from two small-N studies conducted in healthy volunteers indicate that aversive subjective effects that are induced by opioids, such as nausea, might be attenuated by pretreatment with MTNX. The study results were not definitive for several reasons, and we feel a more systematic laboratory analysis would clearly be of value. We intend to use MTNX as a probe to determine whether, and to what extent, certain subjective effects of opioids are mediated by peripheral opiate receptors. Healthy volunteers with no history of opioid abuse or dependence will participate in a placebo- controlled, double-blind, randomized, crossover trial in which they will be exposed to placebo, morphine alone (0.14 mg/kg, iv), two doses of MTNX (0.225, 0.45 mg/kg, sc) combined with morphine, and the higher dose of MTNX tested alone. The primary dependent measure in this study is subjective effects. Secondary measures include physiological and psychomotor effects. The study is significant from a basic psychopharmacology and pharmacology standpoint in that it will address the extent to which prototypic subjective effects of mu opioids are mediated at peripheral opiate receptors. It is significant from a clinical standpoint in that will address whether MTNX might have potential therapeutic implications beyond its ability to relieve constipation. It is significant and innovative from an abuse liability standpoint. Abuse liability of a drug is putatively influenced not only by positive effects of a drug but also negative effects, so if negative effects of morphine are attenuated by MTNX, the abuse liability-related profile of morphine may shift to where morphine is predominantly liked by the majority of healthy volunteers, a finding which would run counter to a number of studies in the extant literature with healthy volunteers.

描述（由申请人提供）：本申请的目的是确定外围作用的MU-阿片受体拮抗剂甲基曲霉（MTNX）是否会减弱MU阿片类镇痛药的某些主观效应，形态学，并确定MTNX是否会改变滥用责任责任责任对新的良好的阳性较高的阳性，以呈现健康的良好效果。目前，它用于慢性阿片类药物治疗的患者，以缓解阿片类药物诱导的便秘，这是一种外围介导的副作用。由于它没有穿过血脑屏障，因此不会拮抗中心介导的阿片类药物的镇痛作用。在健康志愿者中进行的两项小型N研究的结果表明，阿片类药物诱导的厌恶主观作用（例如恶心）可能会通过MTNX预处理来减弱。由于几个原因，研究结果并不确定，我们认为更系统的实验室分析显然是有价值的。我们打算使用MTNX作为探针，以确定阿片类药物的某些主观作用是否由外围鸦片受体介导。没有阿片类药物或依赖病史的健康志愿者将参加安慰剂控制，双盲，随机，跨界试验，其中将暴露于安慰剂，单独的吗啡（0.14 mg/kg，iv），两剂MTNX（单独的MTNX（0.225，0.45 mg/kg，sc）均与Morphine相结合，并构成Morphine，以平等剂量。这项研究的主要依赖措施是主观效应。次要措施包括生理和精神运动效应。从基本的心理药理学和药理学的角度来看，这项研究很重要，因为它将解决MU阿片类药物的原型主观作用的程度。从临床的角度来看，这将是重要的，它将解决MTNX是否可能具有缓解便秘能力的潜在治疗意义。从虐待责任的角度来看，这是重要的和创新的。药物的滥用责任不仅受到药物的积极影响，而且还受负面影响的影响，因此，如果吗啡的负面影响受到MTNX的衰减，与吗啡相关的滥用责任可能会转移到大多数健康志愿者中吗啡所见的地方，这将与健康的研究中的许多研究相反，这会与许多健康的研究相反。