Articles: narcotic-antagonists.
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Anesthesia and analgesia · Apr 1997
Nalbuphine coadministered with morphine prevents tolerance and dependence.
Nalbuphine, an opioid mixed agonist-antagonist, prevents many morphine-related side effects. In this study, we compared the effects of nalbuphine versus naloxone on the prevention of morphine tolerance and dependence in Sprague-Dawley rats. Group 1 received a morphine 5 mg/kg intraperitoneal (I. ⋯ P.). We found that coadministration of nalbuphine or naloxone with morphine dose-dependently blocked the development of morphine tolerance and dependence. However, unlike naloxone, nalbuphine did not attenuate the antinociceptive effect of morphine.
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Clin. Pharmacol. Ther. · Apr 1997
Randomized Controlled Trial Clinical TrialThe safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time.
Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine-induced changes in gastrointestinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). ⋯ We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine-induced delay in oral-cecal transit time (p < 0.005 compared with morphine alone), and a dose-dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long-term opioid use.
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Naltrexone is a narcotic antagonist that has been shown to reduce alcohol craving and alcohol use in patients with alcohol dependence. It should not be used as exclusive treatment but only as an adjunct to a comprehensive program that includes psychologic and social treatment approaches such as those in Alcoholics Anonymous or professional programs. ⋯ Alcohol is known to enhance opioid receptors. Evidently, naltrexone blockade of these receptors results in reduced craving for alcohol, less of a "high" while drinking and less alcohol use.
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The magnitude of tolerance and dependence is defined in part by agonist concentration and duration of receptor exposure. Therefore, in the face of continued exposure to an opioid agonist, periodic reduction in opiate receptor occupancy should reduce tolerance. Alternately, we have shown that reversal of opiate agonist action yields increased glutamate release and NMDA-antagonist studies indicated that this release may lead to an exacerbation of tolerance. ⋯ On day 8, 24 h after termination of morphine infusion, the magnitude of the analgesic response to the probe i.t. morphine was: group D = group C > group B > group A (P < 0.05, 1-way ANOVA). Thus, in contrast to the expectation that tolerance would be reduced by periodic blockade of opiate receptor occupancy, rats that had daily transient receptor antagonism showed a greater tolerance than rats with simple continuous receptor occupancy. These results are, however, consistent with work showing that (i) naloxone will evoke spinal glutamate release in spinal morphine tolerant rats and (ii) spinal NMDA receptor antagonism ameliorates loss of opiate effect in this spinal infusion model.
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The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During this chronic (cocaine) treatment, all rats received a daily SC injection of 0-1.0 mg/kg ondansetron. ⋯ In contrast, daily injections of ondansetron with cocaine significantly blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT3 receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of behavioral tolerance and sensitization.