Walsh S L, Preston K L, Bigelow G E, Stitzer M L
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1995 Jul;274(1):361-72.
Buprenorphine, a mixed opioid agonist-antagonist, is being investigated as a treatment for opioid dependence. This study compared the acute subjective and physiological effects of sublingual buprenorphine to those of p.o. methadone over a wide range of doses and compared the ability of both drugs to alter the effects of an opioid challenge. Male inpatient volunteers (n = 9) with histories of opioid abuse participated in this double-blind, double-dummy study. Sublingual buprenorphine (0, 0.5, 2, 8, 16 and 32 mg) and p.o. methadone (3.75, 15 and 60 mg) were administered once weekly according to a Latin-square design, and subjects were monitored on a variety of physiological and subjective measures. Twenty-four hours later, subjects were tested with ascending doses of i.m. hydromorphone (0, 1 and 4 mg) given 45 min apart. Buprenorphine and methadone produced typical opioid agonist effects of long duration, including pupillary constriction, respiratory depression and elevations on subject-rated and observer-rated indices of euphoria, sedation and opioid-like symptoms. The buprenorphine dose-effect curves were nonlinear and maximal effects for most physiological and subjective measures were observed between 4 and 8 mg, with no greater effects observed at higher doses. The methadone dose-effect curves were linear across the range of doses tested. High doses of buprenorphine and methadone both attenuated the response to hydromorphone challenge 24 hr later. These data indicate that there is a ceiling on the effects of buprenorphine in humans that may reduce its abuse liability and increase its safety, and indicate that opioid blockade occurs after acute administration of buprenorphine or methadone.
丁丙诺啡是一种混合性阿片类激动-拮抗剂，目前正作为阿片类药物依赖的一种治疗方法进行研究。本研究比较了舌下含服丁丙诺啡和口服美沙酮在广泛剂量范围内的急性主观和生理效应，并比较了两种药物改变阿片类激发效应的能力。有阿片类药物滥用史的男性住院志愿者（n = 9）参与了这项双盲、双模拟研究。根据拉丁方设计，每周一次给予舌下含服丁丙诺啡（0、0.5、2、8、16和32 mg）和口服美沙酮（3.75、15和60 mg），并通过多种生理和主观指标对受试者进行监测。24小时后，每隔45分钟给受试者注射递增剂量的肌内注射氢吗啡酮（0、1和4 mg）进行测试。丁丙诺啡和美沙酮产生了持续时间较长的典型阿片类激动效应，包括瞳孔收缩、呼吸抑制以及受试者自评和观察者评定的欣快感、镇静和类阿片样症状指标升高。丁丙诺啡的剂量-效应曲线呈非线性，大多数生理和主观指标在4至8 mg之间观察到最大效应，更高剂量时未观察到更大效应。美沙酮的剂量-效应曲线在所测试的剂量范围内呈线性。高剂量的丁丙诺啡和美沙酮均减弱了24小时后对氢吗啡酮激发的反应。这些数据表明，丁丙诺啡对人体的作用存在上限，这可能会降低其滥用可能性并提高其安全性，还表明在急性给予丁丙诺啡或美沙酮后会发生阿片类阻滞。
