Heishman S J, Stitzer M L, Bigelow G E, Liebson I A
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
J Pharmacol Exp Ther. 1989 Aug;250(2):485-91.
Acute opioid physical dependence refers to the withdrawal symptoms precipitated by an opioid antagonist administered after a single dose or short-term infusion of an opioid agonist. This phenomenon is particularly interesting given that the abstinence syndrome has generally been thought to develop only after chronic exposure to opioid agonists. The purpose of this study was to determine the minimum time after agonist administration when antagonist-precipitated withdrawal could be observed. Naloxone (10 mg/70 kg) was administered i.m. either 0, 15, 45 or 90 min after single i.m. injections of morphine (18 mg/70 kg) in five nondependent male opiate users. Physiological and subjective report measures revealed no effect of morphine or naloxone at the 0 and 15 min morphine-naloxone interval conditions; however, before the naloxone challenge 45 and 90 min post-morphine, agonist effects (e.g., miosis, respiratory depression and good drug effect subjective ratings) were clearly evident. Naloxone reversed these effects to premorphine levels and simultaneously precipitated subjective symptoms and observer rated signs of opiate withdrawal. Thus, this study showed that antagonist-precipitated withdrawal in humans was first observed 45 min after agonist administration. Further, the onset of naloxone-precipitated withdrawal effects closely paralleled the onset of morphine agonist effects. The results of this study suggest that adaptational changes underlying the development of physical dependence begin within minutes after acute exposure to an opiate.
急性阿片类物质身体依赖是指在单次给药或短期输注阿片类激动剂后给予阿片类拮抗剂所引发的戒断症状。鉴于人们通常认为戒断综合征仅在长期接触阿片类激动剂后才会出现，所以这一现象格外引人关注。本研究的目的是确定给予激动剂后能观察到拮抗剂诱发戒断反应的最短时间。在五名未成瘾的男性阿片使用者中，单次肌内注射吗啡（18毫克/70千克）后，分别于0、15、45或90分钟经肌内注射纳洛酮（10毫克/70千克）。生理和主观报告测量结果显示，在吗啡 - 纳洛酮间隔为0和15分钟的情况下，吗啡或纳洛酮均无作用；然而，在吗啡注射后45分钟和90分钟进行纳洛酮激发试验前，激动剂效应（如瞳孔缩小、呼吸抑制和良好的药物效应主观评分）明显可见。纳洛酮将这些效应逆转至吗啡给药前水平，同时引发主观症状以及观察者评定的阿片类戒断体征。因此，本研究表明，在人类中，给予激动剂后45分钟首次观察到拮抗剂诱发的戒断反应。此外，纳洛酮诱发的戒断效应的发作与吗啡激动剂效应的发作密切平行。本研究结果表明，身体依赖发展背后的适应性变化在急性接触阿片类物质后几分钟内就开始了。
