Department of Pharmaceutics, University of Washington, 1959 NE Pacific St. HSB H272, Seattle, WA 98195, USA.
Anesth Analg. 2011 Sep;113(3):641-51. doi: 10.1213/ANE.0b013e3182239b8c. Epub 2011 Jun 27.
Centrally acting opioid analgesics such as morphine and fentanyl are effective, but their efficacy is often limited by a delayed response or side effects resulting from systemic first pass before reaching the brain and the central nervous system (CNS). It is generally accepted that drugs applied to the nasal cavity can directly access the brain and the CNS, which could provide therapeutic advantages such as rapid onset and lower systemic exposure. The olfactory region of the nasal cavity has been implicated in facilitating this direct nose-to-CNS transfer. If the fraction of opioid administered to the olfactory region could be improved, there could be a larger fraction of drug directly delivered to the CNS, mediating greater therapeutic benefit.
We have developed a pressurized olfactory delivery (POD) device to consistently and noninvasively deposit a majority of drug on the olfactory region of the nasal cavity in Sprague-Dawley rats. Using the tail-flick latency test and analysis of plasma and CNS tissue drug exposure, we compared distribution and efficacy of the opioids morphine and fentanyl administered to the nasal olfactory region with the POD device or the nasal respiratory region with nose drops or systemically via intraperitoneal injection.
Compared with nose drop administration, POD administration of morphine resulted in a significantly higher overall therapeutic effect (area under the curve [over the time course] AUC) without a significant increase in plasma drug exposure (AUC(plasma)). POD of morphine resulted in a nose-to-CNS direct transport percentage of 38% to 55%. POD of fentanyl led to a faster (5 vs 10 minutes) and more intense analgesic effect compared with nasal respiratory administration. Unlike intraperitoneal injection or nose drop administration, both morphine and fentanyl given by the POD device to olfactory nasal epithelium exhibited clockwise (plasma) versus effect hysteresis after nasal POD administration, consistent with a direct nose-to-CNS drug transport mechanism.
Deposition of opioids to the olfactory region within the nasal cavity could have a significant impact on drug distribution and pharmacodynamic effect, and thus should be considered in future nasally administered opioid studies.
吗啡和芬太尼等中枢作用阿片类镇痛药有效，但由于它们在到达大脑和中枢神经系统 (CNS) 之前通过全身首过效应，其疗效往往受到限制，导致起效延迟或产生副作用。人们普遍认为，应用于鼻腔的药物可以直接进入大脑和中枢神经系统，从而提供快速起效和全身暴露减少等治疗优势。鼻腔的嗅觉区域被认为有助于这种直接的鼻腔-中枢转移。如果可以提高给予嗅觉区域的阿片类药物的分数，那么就可以有更大比例的药物直接递送至中枢神经系统，从而发挥更大的治疗益处。
我们开发了一种加压嗅觉传递 (POD) 装置，以在 Sprague-Dawley 大鼠的鼻腔嗅觉区域持续、非侵入性地给予大部分药物。通过尾部闪烁潜伏期测试和分析血浆和中枢神经系统组织中的药物暴露情况，我们比较了通过 POD 装置给予鼻腔嗅觉区域的阿片类药物（吗啡和芬太尼）与通过鼻腔呼吸区域给予滴鼻剂或通过腹腔内注射给予全身途径的药物分布和疗效。
与滴鼻剂给药相比，POD 给予吗啡导致整体治疗效果（时间过程中的曲线下面积[效果]）显著提高，而血浆药物暴露（血浆）没有明显增加。POD 给予吗啡导致 38%至 55%的鼻-脑直接转运。与鼻腔呼吸给药相比，POD 给予芬太尼导致更快（5 分钟与 10 分钟）和更强的镇痛作用。与腹腔内注射或滴鼻剂给药不同，POD 装置给予鼻腔嗅上皮的吗啡和芬太尼在鼻腔 POD 给药后均表现出（血浆）与效果的顺时针滞后，与直接的鼻腔-中枢药物传递机制一致。
将阿片类药物沉积在鼻腔内的嗅觉区域可能会对药物分布和药效产生重大影响，因此在未来的鼻腔给予阿片类药物研究中应考虑这一点。
