Effects of ondansetron administration on opioid withdrawal syndrome observed in rats
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milano, Lombardy, Italy European Journal of Pharmacology
(Impact Factor: 2.53).
12/1997; 340(2-3):111-9. DOI: 10.1016/S0014-2999(97)01349-6
This study tested whether a 5-HT3 receptor antagonist could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days. After the four days, half of the rats in each group received naloxone and half received saline. Each animal also received one of four doses of ondansetron (0, 1, 2 and 4 mg/kg i.p.). Administration of ondansetron to rats receiving naloxone after chronic morphine decreased the intensity of withdrawal signs such as increased defecation, jumping and wet-dog shakes, elevated the nociceptive threshold values which were decreased by precipitated withdrawal, but produced no change in urination, rectal temperature or salivation. The effects exhibited by ondansetron administration may be explained through interference of its 5-HT3 receptor antagonist activity with serotoninergic mechanisms involved in the regulation of these withdrawal symptoms. The use of this drug is thus suggested as a possible treatment of opioid withdrawal signs in heroin addicts.
Available from: Joanne C Lin
- "Animal evidence provides additional support for the notion that ondansetron can prevent signs of opioid withdrawal . Roychoudhury and Kulkarni (1996) found that 0.1Ymg/kg ondansetron prevented naloxone-induced opioid withdrawal in mice, and similar findings have been observed in rats (Hui et al., 1996; Pinelli et al., 1997). Previous work from our laboratory exploring genetic data on inbred strains of mice revealed that the gene most strongly associated with withdrawal severity was that for the 5-HT 3 receptor that is targeted by ondansetron. "
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ABSTRACT: Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron.
Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed.
Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal.
This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants.
Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Available from: Judith Wakim
- "One study found that it did not reduce the cravings of opiate addicted rodents , while another suggested that it could be useful in lowering the rate of relapse . Data reported by a group from Italy confirmed that naloxone precipitated withdrawal signs in morphine-dependent rats, and, that ondansetron prevented several of those signs . "
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Patients who are discharged following surgery on an oral opioid, and who have taken the drug for 2 or more weeks often experience withdrawal symptoms when they try to discontinue the drug.
Three weeks after discharge, a 44-year-old female patient decided to reduce her oxycodone (OxyContin®) dosage from 20 mg three times a day to 20 mg two times a day. She experienced severe withdrawal symptoms.
To assist her in withdrawing from the remainder of the drug, a protocol using ondansetron was developed.
After 10 days, the patient was opioid and withdrawal-symptom free.
Use of ondansetron along with tapering of the opioid was safe and effective in preventing further withdrawal symptoms. This case should stimulate research with a larger, more diverse population including those with both short-term and chronic opioid dependence.
Available from: Salvatore Campanella
- "Thus, they were observed after the first injection (Time 1), the second injection (Time 2) and the third injection (Time 3). The following signs were observed: urine by weighing the liquid content absorbed in the paper dishes after feces removal, feces excretion, by weighing stools on paper dishes (Pinelli et al., 1997) and global withdrawal score (GWS hereafter). The GWS was calculated by attributing one point when each of the following signs was present: bwet dog shakesQ, salivation, jumping, head lift, mastication, teeth chattering, abnormal posture, cheek tremors, sniffing, jumps, escape attempts, vocalization when touched. "
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ABSTRACT: In opiate-dependent rats previous studies showed that anaesthetic agents, such as chloral hydrate, midazolam and ketamine interfere with naloxone-precipitated opiate withdrawal. Each anaesthetic induces a specific pattern of interference, indicating that the interference is agent-dependent. In order to further investigate these effects and highlight a potential pharmacological basis of opiate withdrawal interference through anaesthetic agents, we hypothesized that anaesthetic-mediated interference of opiate withdrawal is also dose-dependent. Three groups of rats were compared in an experimental procedure of rapid withdrawal induction by an antagonist under anaesthesia using sub-anaesthetic dosage of midazolam, ketamine or saline. We observed that sub-anaesthetic dosage of ketamine, or midazolam, interferes significantly with opiate withdrawal expression. This brings arguments in favour of a pharmacological basis underlying rapid antagonists induction in opiate dependent rats.
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