Case Studies in Toxicology: Double Take—Is Re-exposure Necessary to Explain Delayed Recurrent Opioid Toxicity?

Case

A previously healthy 10-month-old girl was brought to the ED by her mother, who noted that the child had been excessively drowsy throughout the day. She reported that her husband had dropped an unknown amount of his morphine sulfate extended-release 60-mg tablets and oxycodone 10-mg/acetaminophen 325-mg tablets on the floor 5 days earlier. Although unsure of how many tablets he had dropped, the father believed he had located all of them. The mother, however, found some of the tablets around the crib in their daughter’s room.

When the child arrived to the ED, her vital signs were: blood pressure, 95/60 mm Hg; heart rate, 102 beats/minute; respiratory rate (RR), 18 breaths/minute; and temperature, 98.4°F. Oxygen saturation was 98% on room air. On physical examination, the child was lethargic, her pupils were less than 1 mm in diameter, and her bowel sounds were absent. After the administration of intravenous (IV) naloxone 0.4 mg, the patient became less drowsy and her RR normalized. Approximately 1 hour later, though, the child again became lethargic; she was given a repeat dose of IV naloxone 0.4 mg, and a naloxone infusion was initiated at 0.3 mg/h. Over approximately 20 hours, the infusion was tapered and discontinued. Three hours after the infusion was stopped, the child’s vital signs and behavior were both normal. After a social worker and representative from the Administration for Children’s Services reviewed the patient’s case, she was discharged home with her parents.

Less than 1 hour later, however, the mother returned to the ED with the child, who was again unresponsive. Although the girl’s RR was normal, she had pinpoint pupils. After she was given IV naloxone 0.4 mg, the child awoke and remained responsive for 20 minutes before returning to a somnolent state. Another IV dose of naloxone 0.4 mg was administered, which showed partial improvement in responsiveness. A naloxone infusion was then initiated and titrated up to 1 mg/h to maintain wakefulness and ventilation. In the pediatric intensive care unit, the child required titration of the naloxone infusion to 2 mg/h to which she responded well. Over the next 12 hours, the infusion was tapered off and the child was discharged home with her parents.

Blood samples from both the initial visit and the return visit were sent for toxicologic analysis by gas chromatography-mass spectrometry (GC-MS). Serum from the first visit contained morphine at a concentration of 3,000 ng/mL; serum from the second visit contained morphine at 420 ng/mL. Both samples were negative for oxycodone or any of the other substances checked on the extended GC-MS screen.

What is the toxicologic differential?

Although this patient’s extreme somnolence was suspected to be opioid-induced, and was confirmed by an appropriate response to naloxone, children may present to the ED somnolent for a variety of unknown reasons. Even with a fairly clear history, the clinician should also consider metabolic, neurological, infectious, traumatic, and psychiatric causes of altered mental status.¹ The toxicologic causes of altered mental status are expansive and include the effects of many medications used therapeutically or in overdose. Opioids, benzodiazepines, barbiturates, α-2 agonists (eg, clonidine), sleep aids (eg, zolpidem, diphenhydramine), and ethanol are common causes of induced an altered mental status. When taking a toxicologic history, it is important to inquire not only about the patient’s medications but also the medications of other members of the household to which the patient may have access. This includes not only prescription medications but also over-the-counter, complementary, and herbal preparations.

Why did this child have delayed recurrent opioid toxicity?

When used as directed, opioids cause analgesia and euphoria. Analgesia is mediated by agonism at the μ- , κ-, and δ-opioid receptors throughout the brain and spinal cord. The majority of morphine’s analgesic activity comes from activation of the μ-opioid receptors.² In overdose, opioids classically cause a toxidrome characterized by miosis, coma, decreased bowel sounds, and respiratory depression. These signs can give clues to a patient’s exposure.

Supportive care is the cornerstone of treatment for patients with opioid toxicity, and maintaining the airway and monitoring the respiratory status are extremely important. When ventilation decreases due to the actions of opioids (typically denoted by a RR of <12 breaths/minute in adults, but may be marked by a reduction in depth of breathing as well), the use of an opioid antagonist is appropriate.⁴ The most commonly used antagonist is naloxone, an antidote with antagonism at all opioid receptor subtypes.⁵

In patients who are not dependent on opioids, IV naloxone 0.4 mg is an appropriate initial dose—regardless of patient size or specifics of the exposure. Patients with opioid dependency (eg, patients taking opioids for chronic pain or palliative care, or in those with suspected or confirmed opioid abuse), should receive smaller initial doses of naloxone (eg, 0.04 mg); the dose should be titrated up to effect to avoid precipitating acute opioid withdrawal. The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. The duration of action of naloxone is 20 to 90 minutes in adults.

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.

Case

A previously healthy 10-month-old girl was brought to the ED by her mother, who noted that the child had been excessively drowsy throughout the day. She reported that her husband had dropped an unknown amount of his morphine sulfate extended-release 60-mg tablets and oxycodone 10-mg/acetaminophen 325-mg tablets on the floor 5 days earlier. Although unsure of how many tablets he had dropped, the father believed he had located all of them. The mother, however, found some of the tablets around the crib in their daughter’s room.

When the child arrived to the ED, her vital signs were: blood pressure, 95/60 mm Hg; heart rate, 102 beats/minute; respiratory rate (RR), 18 breaths/minute; and temperature, 98.4°F. Oxygen saturation was 98% on room air. On physical examination, the child was lethargic, her pupils were less than 1 mm in diameter, and her bowel sounds were absent. After the administration of intravenous (IV) naloxone 0.4 mg, the patient became less drowsy and her RR normalized. Approximately 1 hour later, though, the child again became lethargic; she was given a repeat dose of IV naloxone 0.4 mg, and a naloxone infusion was initiated at 0.3 mg/h. Over approximately 20 hours, the infusion was tapered and discontinued. Three hours after the infusion was stopped, the child’s vital signs and behavior were both normal. After a social worker and representative from the Administration for Children’s Services reviewed the patient’s case, she was discharged home with her parents.

Less than 1 hour later, however, the mother returned to the ED with the child, who was again unresponsive. Although the girl’s RR was normal, she had pinpoint pupils. After she was given IV naloxone 0.4 mg, the child awoke and remained responsive for 20 minutes before returning to a somnolent state. Another IV dose of naloxone 0.4 mg was administered, which showed partial improvement in responsiveness. A naloxone infusion was then initiated and titrated up to 1 mg/h to maintain wakefulness and ventilation. In the pediatric intensive care unit, the child required titration of the naloxone infusion to 2 mg/h to which she responded well. Over the next 12 hours, the infusion was tapered off and the child was discharged home with her parents.

Blood samples from both the initial visit and the return visit were sent for toxicologic analysis by gas chromatography-mass spectrometry (GC-MS). Serum from the first visit contained morphine at a concentration of 3,000 ng/mL; serum from the second visit contained morphine at 420 ng/mL. Both samples were negative for oxycodone or any of the other substances checked on the extended GC-MS screen.

What is the toxicologic differential?

Although this patient’s extreme somnolence was suspected to be opioid-induced, and was confirmed by an appropriate response to naloxone, children may present to the ED somnolent for a variety of unknown reasons. Even with a fairly clear history, the clinician should also consider metabolic, neurological, infectious, traumatic, and psychiatric causes of altered mental status.¹ The toxicologic causes of altered mental status are expansive and include the effects of many medications used therapeutically or in overdose. Opioids, benzodiazepines, barbiturates, α-2 agonists (eg, clonidine), sleep aids (eg, zolpidem, diphenhydramine), and ethanol are common causes of induced an altered mental status. When taking a toxicologic history, it is important to inquire not only about the patient’s medications but also the medications of other members of the household to which the patient may have access. This includes not only prescription medications but also over-the-counter, complementary, and herbal preparations.

Why did this child have delayed recurrent opioid toxicity?

When used as directed, opioids cause analgesia and euphoria. Analgesia is mediated by agonism at the μ- , κ-, and δ-opioid receptors throughout the brain and spinal cord. The majority of morphine’s analgesic activity comes from activation of the μ-opioid receptors.² In overdose, opioids classically cause a toxidrome characterized by miosis, coma, decreased bowel sounds, and respiratory depression. These signs can give clues to a patient’s exposure.

Supportive care is the cornerstone of treatment for patients with opioid toxicity, and maintaining the airway and monitoring the respiratory status are extremely important. When ventilation decreases due to the actions of opioids (typically denoted by a RR of <12 breaths/minute in adults, but may be marked by a reduction in depth of breathing as well), the use of an opioid antagonist is appropriate.⁴ The most commonly used antagonist is naloxone, an antidote with antagonism at all opioid receptor subtypes.⁵

In patients who are not dependent on opioids, IV naloxone 0.4 mg is an appropriate initial dose—regardless of patient size or specifics of the exposure. Patients with opioid dependency (eg, patients taking opioids for chronic pain or palliative care, or in those with suspected or confirmed opioid abuse), should receive smaller initial doses of naloxone (eg, 0.04 mg); the dose should be titrated up to effect to avoid precipitating acute opioid withdrawal. The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. The duration of action of naloxone is 20 to 90 minutes in adults.

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.

Case

A previously healthy 10-month-old girl was brought to the ED by her mother, who noted that the child had been excessively drowsy throughout the day. She reported that her husband had dropped an unknown amount of his morphine sulfate extended-release 60-mg tablets and oxycodone 10-mg/acetaminophen 325-mg tablets on the floor 5 days earlier. Although unsure of how many tablets he had dropped, the father believed he had located all of them. The mother, however, found some of the tablets around the crib in their daughter’s room.

When the child arrived to the ED, her vital signs were: blood pressure, 95/60 mm Hg; heart rate, 102 beats/minute; respiratory rate (RR), 18 breaths/minute; and temperature, 98.4°F. Oxygen saturation was 98% on room air. On physical examination, the child was lethargic, her pupils were less than 1 mm in diameter, and her bowel sounds were absent. After the administration of intravenous (IV) naloxone 0.4 mg, the patient became less drowsy and her RR normalized. Approximately 1 hour later, though, the child again became lethargic; she was given a repeat dose of IV naloxone 0.4 mg, and a naloxone infusion was initiated at 0.3 mg/h. Over approximately 20 hours, the infusion was tapered and discontinued. Three hours after the infusion was stopped, the child’s vital signs and behavior were both normal. After a social worker and representative from the Administration for Children’s Services reviewed the patient’s case, she was discharged home with her parents.

Less than 1 hour later, however, the mother returned to the ED with the child, who was again unresponsive. Although the girl’s RR was normal, she had pinpoint pupils. After she was given IV naloxone 0.4 mg, the child awoke and remained responsive for 20 minutes before returning to a somnolent state. Another IV dose of naloxone 0.4 mg was administered, which showed partial improvement in responsiveness. A naloxone infusion was then initiated and titrated up to 1 mg/h to maintain wakefulness and ventilation. In the pediatric intensive care unit, the child required titration of the naloxone infusion to 2 mg/h to which she responded well. Over the next 12 hours, the infusion was tapered off and the child was discharged home with her parents.

Blood samples from both the initial visit and the return visit were sent for toxicologic analysis by gas chromatography-mass spectrometry (GC-MS). Serum from the first visit contained morphine at a concentration of 3,000 ng/mL; serum from the second visit contained morphine at 420 ng/mL. Both samples were negative for oxycodone or any of the other substances checked on the extended GC-MS screen.

What is the toxicologic differential?

Although this patient’s extreme somnolence was suspected to be opioid-induced, and was confirmed by an appropriate response to naloxone, children may present to the ED somnolent for a variety of unknown reasons. Even with a fairly clear history, the clinician should also consider metabolic, neurological, infectious, traumatic, and psychiatric causes of altered mental status.¹ The toxicologic causes of altered mental status are expansive and include the effects of many medications used therapeutically or in overdose. Opioids, benzodiazepines, barbiturates, α-2 agonists (eg, clonidine), sleep aids (eg, zolpidem, diphenhydramine), and ethanol are common causes of induced an altered mental status. When taking a toxicologic history, it is important to inquire not only about the patient’s medications but also the medications of other members of the household to which the patient may have access. This includes not only prescription medications but also over-the-counter, complementary, and herbal preparations.

Why did this child have delayed recurrent opioid toxicity?

When used as directed, opioids cause analgesia and euphoria. Analgesia is mediated by agonism at the μ- , κ-, and δ-opioid receptors throughout the brain and spinal cord. The majority of morphine’s analgesic activity comes from activation of the μ-opioid receptors.² In overdose, opioids classically cause a toxidrome characterized by miosis, coma, decreased bowel sounds, and respiratory depression. These signs can give clues to a patient’s exposure.

Supportive care is the cornerstone of treatment for patients with opioid toxicity, and maintaining the airway and monitoring the respiratory status are extremely important. When ventilation decreases due to the actions of opioids (typically denoted by a RR of <12 breaths/minute in adults, but may be marked by a reduction in depth of breathing as well), the use of an opioid antagonist is appropriate.⁴ The most commonly used antagonist is naloxone, an antidote with antagonism at all opioid receptor subtypes.⁵

In patients who are not dependent on opioids, IV naloxone 0.4 mg is an appropriate initial dose—regardless of patient size or specifics of the exposure. Patients with opioid dependency (eg, patients taking opioids for chronic pain or palliative care, or in those with suspected or confirmed opioid abuse), should receive smaller initial doses of naloxone (eg, 0.04 mg); the dose should be titrated up to effect to avoid precipitating acute opioid withdrawal. The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. The duration of action of naloxone is 20 to 90 minutes in adults.

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.