Patients presenting with heroin overdose should be monitored for at least 2 hours after naloxone administration (some suggest 3 hours) to determine whether or not additional dosing will be necessary. After oral opioid exposures, particularly with extended-release or long-acting formulations, longer periods of observation are required (this is unrelated to the naloxone pharmacokinetics, but rather to the slow rise in blood levels from some of these formulations). If repeated opioid toxicity occurs in adults, a naloxone infusion may be helpful to reduce the need for repetitive re-dosing. Initially, an hourly infusion equal to two-thirds of the dose of naloxone that reversed the patient’s respiratory depression is suggested6
Naloxone is eliminated by conjugation with glucuronic acid before is it excreted from the body. Due to decreased hepatic conjugation and prolonged metabolization of drugs in pediatric patients, naloxone may have a longer half-life in children—especially neonates and infants7; in children, the half-life of naloxone may extend up to three times that of adults.8 This extended half-life can lead to a false sense of assurance that a child is free of opioid effects 120 minutes after receiving naloxone—the time by which an adult patient would likely be without significant systemic effects of naloxone—when in fact the effect of naloxone has not yet sufficiently waned. This in turn may prompt discharge before sufficient time has passed to exclude recrudescence of opioid toxicity: The presence of persistent opioid agonist concentrations in the blood, even at consequential amounts, remains masked by the persistent presence of naloxone.
The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. In this patient, it is not surprising that the the ingestion of an extended-relief form of morphine should produce a prolonged opioid effect. At therapeutic concentrations in children (~10 ng/mL), the half-life of morphine is slightly longer than in adults (~3 hours vs 2 hours) and is likely even longer with very high serum concentrations. It is metabolized to morphine 6-glucuronide, which is active and longer lasting than the parent compound. This may account for additional clinical effects beyond the time that the serum morphine concentration falls, and is particularly relevant following immediate-release morphine overdose.
In this case it is also important to consider whether or not the patient was re-exposed to an opioid between the first and second ED visit. The dramatically elevated initial serum morphine concentrations and the relatively appropriate fall in magnitude of the second sample suggest that the recurrence of respiratory depression was not the result of re-exposure. The patient’s recurrent effects, even a day out from exposure, can be explained by the immediate-release morphine exposure and the discharge prior to waning of the naloxone. In children with opioid toxicity, another potential option, though not directly studied, is to administer the long-acting opioid antagonist naltrexone to the patient prior to discharge.
Case Conclusion
When used appropriately and under the correct circumstances, naloxone is safe and effective for the reversal of opioid toxicity. As with any antidote, patients must be appropriately monitored for any adverse effects or recurrence of toxicity. Moreover, the clinician should be mindful of the pharmacokinetic differences between adults and young children and the possibility of a later-than-expected recurrence of opioid toxicity in pediatric patients.
This case is a reminder of the importance of safe medication storage. Infants and young children who are crawling and exploring their environment are especially vulnerable to toxicity from medications found on the floor. Regardless of age, quick recognition of opioid-induced respiratory depression and appropriate use of naloxone can help to decrease the morbidity associated with excessive opioid exposures in all patients.
Dr Berman is a senior medical toxicology fellow at North Shore-Long Island Jewish Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Majlesi is the director of medical toxicology at Staten Island University Hospital, New York.