naloxone and Miosis

This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg.. Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured.. The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference.. A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose.. clinicaltrials.gov : NCT02307721.

Topics: Administration, Intranasal; Adult; Analgesics, Opioid; Cross-Over Studies; Female; Healthy Volunteers; Humans; Injections, Intramuscular; Male; Miosis; Models, Biological; Naloxone; Narcotic Antagonists; Pain; Piperidines; Pupil; Remifentanil; Young Adult

Peripheral mechanisms may be involved in opioid actions on the urinary bladder. This double-blind study investigated whether opioid inhibition of bladder function is reversed by methylnaltrexone, a peripheral opioid antagonist. Thirteen healthy male volunteers received an intravenous (i.v.) infusion of remifentanil, 0.15 mcg/kg/min, then a single i.v. dose of study medication (methylnaltrexone 0.3 mg/kg, naloxone 0.01 mg/kg, or saline). Urodynamics were measured with indwelling bladder and rectal catheters, and pupil size was assessed with infrared pupillometry. Remifentanil decreased detrusor pressure in 21/25 sessions and caused complete urinary retention in 18/25. Voiding was possible in 7/7, 5/12, and 0/6 sessions after naloxone, methylnaltrexone, and saline, respectively (P=0.0013). Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (P<0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Humans; Infusions, Intravenous; Male; Middle Aged; Miosis; Muscle Contraction; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Remifentanil; Treatment Outcome; Urinary Bladder; Urinary Retention; Urination

In a placebo-controlled trial, pupillary constriction was measured in healthy non-addicted subjects and in opiate addicts by using static computer-assisted pupillometry. In contrast to earlier reports, a clear-cut pupillary constriction was observed in healthy persons after a single intravenous injection of 0.4 mg naloxone. No significant changes of pupillary size were recorded in the same subjects after the administration of a placebo. In methadone-maintained subjects, the IV administration of 0.4 mg naloxone caused a significant pupillary dilatation. From these data it can be concluded that naloxone seems to have a central pharmacological action not only in opiate addicts, but also in healthy persons. This is demonstrable by studying the miotic response.

Topics: Adult; Female; Humans; Male; Miosis; Naloxone; Opioid-Related Disorders; Pupil

Previous studies in our laboratory have documented the occurrence of naloxone-precipitated opioid abstinence from 45 minutes to 6 hours after acute morphine administration in humans. This study extended the morphine-naloxone interval to 24 hours and examined the effect of repeated naloxone challenges on withdrawal responses. Six male nondependent opiate users participated in eight experimental sessions in which they received single IM injections of morphine (18 mg/70 kg) followed 6 and 24 hours later by challenge sessions with IM placebo or naloxone (10 mg/70 kg). Naloxone challenge at 6 hours postmorphine reversed morphine-induced miosis and subjective reports of opiate symptoms, drug high, good drug effects, and drug liking. At 24 hours postmorphine, naloxone had no effect on these measures, which had returned to premorphine levels. However, at 6 and 24 hours postmorphine, naloxone precipitated subjective symptoms and observer-rated signs of opioid abstinence. When naloxone challenge at 24 hours was preceded by naloxone at 6 hours postmorphine, the magnitude of abstinence symptoms and signs was attenuated. These data suggest that morphine-induced adaptational changes underlying the development of physical dependence persist beyond other measureable agonist effects, and that these changes are disrupted or reversed by repeated antagonist administration.

Topics: Double-Blind Method; Drug Administration Schedule; Emotions; Humans; Male; Miosis; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i.n. naloxone were compared with i.m. naloxone (2 mg) after administration of oral alfentanil (4 mg) to a separate group of six healthy volunteers pretreated with 240 mL of water or grapefruit juice. The i.m. and i.n. naloxone attenuated miosis by similar extents after water (40 ± 15 vs. 41 ± 21 h*%) and grapefruit juice (49 ± 18 vs. 50 ± 22 h*%) pretreatment. Results merit further testing of this new naloxone formulation.

Topics: Administration, Intranasal; Administration, Intravenous; Adult; Alfentanil; Analgesics, Opioid; Area Under Curve; Chemistry, Pharmaceutical; Female; Healthy Volunteers; Humans; Injections, Intramuscular; Male; Miosis; Naloxone; Time Factors; Young Adult

We describe the first ziprasidone overdose with quantitative serum levels of a pediatric patient in coma and with pinpoint pupils. This case is an important contribution to the pediatric ziprasidone literature because it illustrates that ingestion of just 1 pill may result to profound mental status and respiratory depression in a child. H.C., a 30-month-old girl, presented to the emergency department approximately 30 minutes after an accidental ingestion of an adult family member's medication. The child was found on the floor surrounded by numerous pills and was witnessed to have ingested at least 1 tablet by a caregiver. After finding the child with the pills, the family observed the child for a brief period but transported her to the hospital after she became lethargic and unresponsive. The child received 2 doses of 0.4 mg of intravenous naloxone without change in her neurologic status. The child then underwent a rapid sequence intubation for airway protection and subsequently received gastrointestinal decontamination with 15 g of activated charcoal via the orogastric tube. Ziprasidone is an atypical antipsychotic drug that was approved by the Food and Drug Administration in February 2001 for the general treatment of schizophrenia in adults. Previously reported pediatric ziprasidone overdoses describe a syndrome of sedation, tachycardia, hypotonia, and coma consistent with that of the patient described in this paper. In pediatric ziprasidone overdose, QTc prolongation and hypotension have also been illustrated, but seizures have not been reported. An interesting aspect of this case is the development of pinpoint pupils unresponsive to naloxone. This phenomenon has been reported before with overdose of olanzapine, a similar atypical antipsychotic. The mechanism of miosis associated with overdose of atypical antipsychotics is unclear but is likely related to interference with central innervation of the pupil. Pupil size is maintained by a balance between sympathetic and parasympathetic neurohumeral tones. We propose that an overdose of an alpha-1 receptor blocking agent, such as ziprasidone, results in unopposed parasympathetic stimulation resulting in miosis.

Topics: Adrenergic alpha-1 Receptor Antagonists; Antidotes; Antipsychotic Agents; Charcoal; Child, Preschool; Coma; Drug Resistance; Emergencies; Female; Humans; Hypotension, Orthostatic; Intubation, Intratracheal; Miosis; Naloxone; Piperazines; Tachycardia; Thiazoles

The role of mu3 opioid receptors in morphine-induced intraocular pressure (IOP) lowering effect and miosis was evaluated in conscious, dark-adapted New Zealand white (NZW) rabbits using a masked-design study. IOP and pupil diameter (PD) measurements were taken at just before and 0.5, 1, 2, 4, 6 h after monolateral instillation of morphine (10, 50 and 100 microg/30 microl) as compared to vehicle administered in the contralateral eye. Morphine-induced ocular effects were challenged by a pre-treatment with the non-selective opioid receptor antagonist, naloxone (100 microg/30 microl), the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME, 1%, 30 microl), or the non-selective mu3 opioid receptor inhibitor, reduced L-glutathione (GSH, 1%, 30 microl). Morphine induced a dose-dependent decrease in IOP and PD. Pre-treatment with naloxone totally prevented morphine-induced decrease in IOP and miosis. Ocular administration of L-NAME or GSH alone failed to affect IOP or PD of NZW rabbits. However, pre-treatment with either drugs significantly reduced, but not totally prevented ocular effects of morphine. These results suggest that biochemical mechanisms related to nitric oxide release are involved, at least in part, in morphine effects on the eye. Since the mu3 opioid receptor subtype is able to release nitric oxide and is sensitive to inactivation by GSH, it may be possible that mu3 opioid receptors are involved in morphine-induced miosis and reduction in IOP.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Enzyme Inhibitors; Eye; Glutathione; Intraocular Pressure; Miosis; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rabbits; Receptors, Opioid, mu; Time Factors

The present study was performed to evaluate the role of nitric oxide in the intraocular pressure (IOP) lowering effect and in the miotic action of morphine. The IOP was measured in conscious, normal, dark-adapted New Zealand white rabbits using a calibrated pneumatonometer. Experiments were conducted, in which rabbits' eyes were treated with morphine topically and unilaterally, while the fellow eyes received vehicle. IOP and pupil diameter (PD) measurements were taken 0.5 and 0 h before morphine administration and 0.5, 1, 2, 3, 4, and 5 h thereafter. The effects of a nonselective opioid receptor antagonist (naloxone), a nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methyl ester; L-NAME), and a sulfhydryl reagent (reduced L-glutathione; GSH) on morphine-mediated changes in IOP and PD were also determined. Morphine (10, 33, and 100 microg) produced concentration-dependent decreases in IOP and reduced PD in both treated and untreated eyes of New Zealand white rabbits. IOP-lowering effect of morphine (100 microg) and reduction in PD were both significantly inhibited by pretreatment with naloxone (100 microg), L-NAME (0.5%), or GSH (100 microg). The results from this study indicate that morphine-induced ocular hypotension and reduction in PD are opioid-receptor-mediated responses that are associated with the release of nitric oxide. Because the mu3 opioid receptor subtype has a nitric-oxide-releasing activity and is sensitive to inactivation by GSH, it is concluded that morphine-induced ocular hypotension and miosis are mediated, in part, by activation of mu3 opioid receptors.

Topics: Animals; Dark Adaptation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutathione; Intraocular Pressure; Miosis; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ocular Hypotension; Pupil; Rabbits; Receptors, Opioid, mu

Topics: Analgesics, Opioid; Central Nervous System Diseases; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Miosis; Morphine; Naloxone; Oxycodone; Poisoning; Respiratory Insufficiency; Siblings; Treatment Outcome

The degree and duration of miosis, induced by low doses of parenteral morphine (65 mcg/Kg i.m.) before and after ten days of naloxone treatment, were evaluated in eleven volunteers affected by migraine without aura. Morphine induced miosis was significantly more intense and persistent after chronic naloxone treatment than before the drug was administered. In another group of seven volunteers suffering from migraine without aura, no differences between morphine-induced miosis, prior to and after a ten-day treatment with placebo, were observed. In addition, a third group of fifty-four subjects, suffering from migraine without aura, underwent three-month naloxone treatment (150 mcg/Kg/i.m./day). All subjects included in the third group, were partially or totally refractory to conventional therapy. Pupillopharmacological results indicate that the benefit gained from chronic administration of the opiate antagonist may be related to some type of naloxone-induced supersensitivity of the opioid receptor population.

Topics: Adult; Female; Humans; Male; Migraine Disorders; Miosis; Morphine; Naloxone; Pupil

In previous work we have determined that intracameral (IC) administration of neurotensin (NT) produces strong miosis in rabbits. However, the pharmacological mechanism of this response remains undetermined. Blockade of alpha and beta-adrenoceptor subtypes with phenoxybenzamine and propranolol, blockade of M1 muscarinic receptors with atropine or blockade of mu opioid receptors with naloxone did not affect NT-induced miosis. Of interest however was the observation that destruction of ocular dopamine (DA) nerve endings with 6-hydroxydopamine (6-OHDA) + desmethylimipramine (DMI), or blockade of D-2 DA receptors with haloperidol significantly inhibited the miotic response to IC NT. These findings indicate that an intact iridic DA pathway is required for the expression of NT-induced miosis.

Topics: Animals; Atropine; Autonomic Nervous System; Desipramine; Dopamine; Dopamine Antagonists; Eye; Haloperidol; Hydroxydopamines; Iris; Miosis; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Nerve Endings; Neurotensin; Neurotransmitter Agents; Oxidopamine; Rabbits; Receptors, Opioid, mu

Clonidine is an antihypertensive agent with central and peripheral alpha-2 adrenergic effects. One of the postulated mechanisms of action is the release of endogenous opioids and/or the stimulation of opioid receptors in the central nervous system (CNS). Naloxone, a pure opioid antagonist, has demonstrated reversal effects from clonidine intoxication. During the past 10 y, 25 children with a mean age of 2 y were admitted for clonidine intoxication. Dosage varied widely, but as little as 0.1 mg caused significant signs and symptoms. The most common presenting findings were somnolence-lethargy (96%), miosis (56%), and respiratory depression (48%), a paradoxical hypertensive response (44%) was more common than expected. Supportive management was the mainstay of therapy. Ten patients received naloxone, 50% demonstrated clinical improvement in vital signs and CNS depression. There were no complications as a result of naloxone therapy. Children seem to be unusually sensitive to the depressant effects of clonidine. Naloxone may be an important adjunct to therapy. Expect clonidine intoxications to become more common as the market for antihypertensive drugs expands.

Topics: Clonidine; Humans; Infant; Infant, Newborn; Male; Miosis; Naloxone; Respiratory Distress Syndrome, Newborn; Retrospective Studies; Sleep Stages