Department of Psychological Science, Creighton University, Omaha, Nebraska, USA.
Behav Pharmacol. 2024 Apr 1;35(2-3):122-131. doi: 10.1097/FBP.0000000000000761. Epub 2023 Nov 15.
Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.
尽管阿片类药物有明确的不良反应，但它们仍是治疗中重度疼痛的金标准。在所有处方药物中，阿片类药物滥用最为广泛，致命的过量用药已达到流行水平。提高阿片类药物安全性的策略之一是将它们与非阿片类药物联合使用，以减少缓解疼痛所需的阿片类药物剂量，从而减少大剂量时出现的不良反应。N-甲基-D-天冬氨酸受体拮抗剂氯胺酮已被安全用作镇痛药，但仅限于非常有限的条件下。目前的研究描述了单独使用吗啡和氯胺酮以及混合物的镇痛、行为抑制和胃肠道作用，以确定它们在 24 只成年雄性 Sprague-Dawley 大鼠（每种测定 8 只）中的相互作用。单独使用时，吗啡和氯胺酮都能产生镇痛作用，减少食物反应，并减少胃肠道转运（即产生便秘）。吗啡：氯胺酮混合物的作用通常是相加的，除了 1:1 混合物的镇痛作用外，观察到的和预测的效应之间斜率（即非平行移位）的差异表明在较小剂量下存在协同作用，在较大剂量下存在相加作用。给予具有镇痛作用的吗啡：氯胺酮混合物并不会增强吗啡引起便秘的效力。吗啡和氯胺酮对不良反应（如依赖、戒断、滥用或呼吸抑制）的相互作用的性质尚不清楚，但也可能与混合物中每种药物的比例有关。确定在人类中产生最大潜在治疗窗的条件将非常重要。
