Comparison of the Analgesic and Intestinal Effects of Fentanyl and Morphine in Rats
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Background The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. Method Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. Results Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. Conclusions Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.
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Summary The induction dose‐response of propofol was compared with the dose‐response of its combination with fentanyl and with that of fentanyl alone in three groups of 60 women undergoing minor gynaecological surgery. Dose‐response curves were determined for each group using bootstrap and isobolographic analyses. Propofol was found to act additively with fentanyl for induction of anaesthesia. Twenty‐three percent of the ED 50 of fentanyl was required in combination with 75% of the ED 50 for propofol to achieve the ED 50 of the combination. This indicates that, for induction of anaesthesia, propofol and fentanyl are not synergistic.
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There has been a dramatic increase of deaths due to illicit fentanyl. We examined the pharmacology of fentanyl and reviewed data on the number of repeat doses of naloxone used to treat fentanyl overdoses. Multiple sequential doses of naloxone have been required in a certain percentage of opioid overdoses due to fentanyl. In addition, fentanyl appears to differ from other opioids as having a very rapid onset with high systemic levels found in overdose victims. A rapid competition is required by naloxone to out-compete large numbers of opioid receptors occupied by fentanyl in the CNS. Taken together, we propose that higher doses of naloxone are needed to combat the new era of overdoses due to the more potent synthetic opioids such as fentanyl.
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To explore the effect of fentanyl on 50% effective dose (ED50) of emulsified isoflurane for hypnosis and to define the type of interaction between fentanyl and emulsified isoflurane during rat hypnosis.125 male adult Sprague-Dawley rats (240-300 g) were divided into 5 groups depending on the drugs administered via the tail vein. The up-and-down sequential allocation technique was used to determine ED50 of fentanyl in the loss of righting reflex. According to above experiment results, the up-and-down sequential allocation technique was also used to determine ED50 of emulsified isoflurane combined with different fentanyl dose of 7.2 microg/kg (1/4 ED50), 14.3 microg/kg (1/2 ED50) or 21.5 microg/kg (3/4 ED50), respectively, and also without the fentanyl in the loss of righting reflex. Fentanyl was administered intravenously for 20 s followed by emulsified isoflurane for 10 s. The interval between the two was 1.5 min in groups administered with both. ED50 was calculated by using Dixon-Mood method. The isobolographic and algebraic analyses were used to define the type of interaction between fentanyl and emulsified isoflurane.The body weight and sex of rats was not significantly different between the 5 groups. ED50 was (28.7 +/- 2.1) microg/kg (26.5-30.8 microg/kg) in the fentanyl group, (0.525 +/- 0.032) mL/kg in the fentanyl 7.2 microg/kg +/- isoflurane group, (0.108 +/- 0.019) mL/kg in the fentanyl 14.3 microg/kg+isoflurane group, (0.075 +/- 0.011) mL/kg in the fentanyl 21.5 microg/kg+isoflurane group and (0.670 +/- 0.054) mL/kg in the isoflurane group. The isobolographic analysis indicated that ED50 of isoflurane decreased progressively in a non-linear fashion in the presence of increasing dose of fentanyl. The isobolographic and algebraic analyses demonstrated that the combination use of fentanyl and emulsified isoflurane could produce a synergistic effect on hypnosis.Fentanyl enhances the hypnotic effect induced by emulsified isoflurane. The administration of associating fentanyl with emulsified isoflurane produces a synergistic effect on rat hypnosis.
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