Enhanced Analgesic Responses After Preferential Delivery of Morphine and Fentanyl to the Olfactory Epithelium in Rats
| Autor: | Rodney J. Y. Ho, John D. Hoekman |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Central Nervous System
Male Pain Threshold Nasal cavity Central nervous system Pain Pharmacology Models Biological Article Fentanyl Rats Sprague-Dawley Olfactory mucosa Drug Delivery Systems Olfactory Mucosa otorhinolaryngologic diseases medicine Animals Olfactory Region Administration Intranasal Pain Measurement Analysis of Variance Dose-Response Relationship Drug Morphine business.industry Rats Analgesics Opioid Disease Models Animal Anesthesiology and Pain Medicine medicine.anatomical_structure Opioid Anesthesia Nasal administration business Olfactory epithelium Injections Intraperitoneal medicine.drug |
| Zdroj: | Anesthesia & Analgesia. 113:641-651 |
| ISSN: | 0003-2999 |
| DOI: | 10.1213/ane.0b013e3182239b8c |
| Popis: | Background 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. Methods 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. Results 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](effect)) 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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