From Pain Relief to Risk: A Case of Suspected Opioid Overdose in a Pediatric Patient

The Case

A previously healthy 2-year-old male underwent uncomplicated urologic surgery for hypospadias repair. For pain control, the patient was initially prescribed a 5-day course of hydrocodone-acetaminophen 7.5-325 mg/15 mL solution. Instructions were to give the patient 2.2 mL (1.1 mg hydrocodone and 48 mg acetaminophen per dose) by mouth 4 times daily as needed for pain. Routine follow up was scheduled for 13 days after surgery.

Two days after surgery, the patient was brought to the Emergency Department (ED) due to inconsolable crying. The ED workup was unremarkable, and the patient was deemed appropriate for discharge. At this time, the patient’s prescription for pain control was changed from hydrocodone-acetaminophen to oxycodone 1 mg/mL. Instructions were to give the patient 2.3 mL (0.2 mg/kg/dose) by mouth every 4 to 6 hours. The total quantity dispensed was 64.4 mL (4.6-day supply). Family education on the use of opioids or their adverse effects was not documented at the time of initial discharge after surgery or upon discharge from the ED. Naloxone was not prescribed on either occasion.

Four days after discharge from the ED, the patient became apneic, cyanotic, and unresponsive at home. Emergency first responders were called to the scene and the patient’s cardiac rhythm was determined to be pulseless electrical activity. First responders began cardiopulmonary resuscitation and administered naloxone and two doses of epinephrine. Upon arrival at the ED, continued resuscitation was unsuccessful, and the child was declared deceased. There was a high suspicion that the patient’s cardiopulmonary arrest was due to opioid overdose.

The Commentary

By Kristine Markham, PharmD, BCPPS, Maki Usui, PharmD, BCPPS, and Cady Smith, BA

Background

Postoperative pain management in pediatric patients often involves a multimodal approach, with pharmacological treatments typically including acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. The optimal regimen aims to effectively manage pain while promoting physical recovery and minimizing adverse effects.¹ Non-opioid analgesics are generally preferred as first-line agents, and combination regimens have been shown to reduce or eliminate the need for opioid therapy.¹ For example, studies have shown that rectal administration of acetaminophen during surgery led to decreased opioid use without adverse events in the perioperative period.¹ Additional studies that evaluated oral non-opioid analgesics demonstrated less opioid use or equivalent use with improved pain scores.² When opioids are deemed necessary for pain management, they should be prescribed at the lowest effective doses and for the shortest necessary duration to mitigate the risk of serious adverse effects. In the hospital setting, typical opioid regimens include morphine, hydromorphone, fentanyl, or oxycodone. Upon discharge, oxycodone is the most frequently prescribed oral opioid.²

Current guidelines recommend that opioid prescriptions be limited to three-to-seven days duration in opioid-naïve patients.^2,3 Studies have identified postoperative prescriptions as the most common source of excess opioids in the home, which is a primary contributor to both new and persistent opioid use in opioid-naïve children.¹ Best practices for opioid prescribing include comprehensive perioperative education addressing potential adverse drug events, the severity of these events, and appropriate responses. A survey of over 500 parents demonstrated that opioids were more appropriately administered when parents were educated on their adverse effects and associated risks.⁴ Education should also emphasize the importance of proper opioid storage to prevent misuse or accidental ingestion. To minimize the risk of accidental ingestion with overdose, clinicians should provide education on naloxone administration.^1,5

In this case, an initial 5-day course of hydrocodone-acetaminophen was prescribed at discharge, consistent with current guidelines. However, upon presentation to the ED with inconsolable crying, the patient’s opioid regimen was modified to oxycodone for an additional 5 days, presumably due to concern about inadequate pain control. The prescribed oxycodone dose was in the upper end of the dose range for an opioid naive patient, at 0.2 mg/kg/dose, and the original opioid prescription may have still been in the home, yielding an available 10-day supply of multiple agents. Caregiver education on opioid safety was not documented and there was no active prescription for naloxone. It is also unclear whether the family received education on the presence and storage of opioids given multiple agents prescribed for pain management. As a result, inadvertent dose stacking and opioid polypharmacy may have contributed to this mortality event.

Approaches to Improving Safety

System Optimization of EHR Opioid Prescribing 

Various safeguards may be implemented in the electronic prescribing process to ensure safe prescribing of opioids and to reduce the risk of unintentional overdose. For example, pain management order sets function as a clinical decision support tool for providers in selecting the appropriate dosing and duration of opioid therapy for postoperative pain. When the number of doses for an opioid prescription was set to a low default value of 12, overall opioid prescribing in the postoperative setting decreased without affecting pain control.^6,7 Selecting a low default dose is especially important in the pediatric setting where weight-based dosing is utilized. Additionally, electronic order sets encourage providers to select a multimodal approach by incorporating nonopioid pharmacologic agents such as acetaminophen and NSAIDs, sparing the use of opioids when appropriate.³ A recent AHRQ evidence report summarized 34 articles describing the mixed impact of opioid stewardship interventions such as standardized order sets.^8,9

The FDA recommends that health care providers consider prescribing naloxone for patients who are at increased risk of overdose, or for patients with household members (including children) who are at risk for accidental ingestion.⁵ The use of an active alert in the electronic health record (EHR) triggered by new opioid prescriptions may promote appropriate prescribing of naloxone for this purpose. An alert may display as a best practice advisory (BPA) when an opioid is prescribed, prompting providers to prescribe naloxone at the same time. A hospital that implemented such an alert for opioid prescriptions with oral morphine equivalent doses (OME) ≥90 mg, concomitant benzodiazepine prescription, or history of opioid use disorder, reported a 28-fold increase in naloxone co-prescribing.¹⁰ Another hospital reported an increase in naloxone prescribing and a decrease in prescribed opioid doses, presumably due to concern triggered by the prompt for naloxone.¹¹ In a survey of pediatric residents, the most frequently reported barriers to prescribing naloxone were knowledge deficits and a lack of understanding of the eligibility criteria.¹² A naloxone prescribing alert can be a tool to help new practitioners to overcome these barriers, especially for pediatric care providers, whose awareness of the risk of opioid overdose may be relatively low. Although many institutions currently utilize naloxone co-prescribing alerts for patients on higher opioid doses,^5,11 a universal alert may further increase access to naloxone. However, patient and caregiver education are also essential to avoid harm from inappropriate use of naloxone.

Prevention of Opioid Dose Stacking Overdose

Patients receiving opioids via multiple sources or routes are at increased risk for overdose due to the administration of doses at inappropriately close intervals. This is known as “dose stacking” and is documented to be associated with increased patient morbidity and mortality, as demonstrated in several prior PSNet cases. The CDC recommends that prescribers check state prescription drug monitoring program (PDMP) data when initially prescribing opioids for acute, subacute, or chronic pain to determine whether the patient is receiving opioids in dosages or combinations that increase the risk of overdose.⁵ Robust patient and caregiver education is critical when prescribing numerous sedating medications at once or when different opioid prescriptions are provided in overlapping or short succession. In postoperative pediatric populations, counseling by a medical professional increases the probability that excess opioid medications will be disposed of properly.¹³ When a home prescription is changed from one opioid formulation to another, patients and caregivers must be educated on the importance of stopping and disposing of the initial prescription and the risks of administering multiple opioid-containing medications simultaneously. Special attention should be paid to ensuring that patients and caregivers understand the active ingredients in combination medications, such as hydrocodone-acetaminophen, and how these ingredients might interact with subsequent prescriptions or other over-the-counter medications.

Widespread Naloxone Dispensing

Naloxone dispensing has increased in recent years for pediatric patients, with more than 50,000 naloxone prescriptions dispensed between 2017 and 2022 for children between 10 and 19 years of age.^14,15 However there continues to be a need for even more naloxone dispensing and education as the incidence of overdose has risen, especially among adolescents.^15,16 Pharmacists can play a role in increasing access to naloxone for pediatric patients, with all states allowing pharmacy dispensing of naloxone.¹⁷ Further, in March 2023, the FDA approved the first over-the-counter preparation of naloxone without any age restrictions for use. While cost may remain a barrier, expanded access is a step in the right direction to combat opioid overdose.¹⁸ Caregivers of patients with access to opioid-containing medications should be educated on the widespread availability of naloxone and where to find it when needed.

Take-Home Points

• Education on opioid safety including adverse effects, appropriate dosing, and storage of medications should be provided to all caregivers of pediatric patients receiving prescriptions for opioids.
• Opioid use in the postoperative period should be minimized to a 3 to 7-day supply with a single agent to decrease the availability of opioids in the home and mitigate adverse effects.
• Clinical decision support tools in EHR can guide safe opioid prescribing and alert providers to consider naloxone prescribing on discharge.
• Appropriate naloxone prescribing and education can increase the availability of the medication in outpatient settings and enhance caregiver understanding of how to administer it in an emergency. 

Kristine Markham, PharmD, BCPPS
Pediatric Pharmacist 
UC Davis Health 
Kmmarkham@ucdavis.edu

Maki Usui, PharmD, BCPPS
Pediatric Pharmacist 
UC Davis Health 
Mkusui@ucdavis.edu

Cady Smith, BA
Medical Student
University of California Davis
cdysmith@ucdavis.edu

References

1. Kelley-Quon LI, Kirkpatrick MG, Ricca RL, et al. Guidelines for Opioid Prescribing in Children and Adolescents After Surgery: An Expert Panel Opinion. JAMA Surg. 2021; 156(1): 76-90. [Free full text]
2. Cravero JP, Agarwal R, Berde C, et al. The Society of Pediatric Anesthesia recommendations for us of opioids in children during the perioperative period. Paediatr Anaesth. 2019; 26(6): 547-571. [Free full text]
3. Dowell D, Ragan KR, Jones CM, et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain – United States, 2022. MMWR Recomm Rep. 2022;71(3):1-95. [Free full text]
4. Voepel-Lewis T, Zikmund-Fisher BJ, Smith EL, et al. Parents’ analgesic trade-off dilemmas: how analgesic knowledge influences their decisions to give opioids. Clin J Pain. 2016; 32(3): 187-195. [Available at]
5. US Food & Drug Administration. FDA Drug Safety Communication. FDA recommends health care professionals discuss naloxone with all patients when prescribing opioid pain relievers or medicines to treat opioid use disorder. Accessed September, 2024. [Free full text]
6. Chiu AS, Jean RA, Hoag JR, et al. Association of lowering default pill counts in electronic medical record systems with postoperative opioid prescribing. JAMA Surg. 2018;153(11):1012-1019. [Free full text]
7. Chua K, Throne MC, Ng S, et al. Association between default number of opioid doses in electronic health record systems and opioid prescribing to adolescents and young adults undergoing tonsillectomy. JAMA Netw Open. 2022;5(6):e2219701. [Free full text]
8. Waldfogel JM, Rosen M, Sharma R, et al. Making Healthcare Safer IV: Opioid Stewardship. Rapid Review. Rockville, MD: Agency for Healthcare Research and Quality. AHRQ Publication No. 24-EHC019-5. December 2023. [Free full text]
9. Phinn K, Liu S, Patanwala AE, Penm J. Effectiveness of organizational interventions on appropriate opioid prescribing for noncancer pain upon hospital discharge: a systematic review. Br J Clin Pharmacol. 2023;89(3):982-1002. [Free full text]
10. Nelson SD, McCoy AB, Rector H, et al. Assessment of a naloxone coprescribing alert for patients at risk of opioid overdose: a quality improvement project. Anesth Analg. 2022;135(1):26-34. [Free full text]
11. Heiman E, Lanh S, Moran T, et al. Electronic advisories increase naloxone prescribing across health care settings. J Gen Intern Med. 2023;38(6):1402-1409. [Free full text]
12. Wilson JD, Berk J, Adger H, et al. Identifying missed clinical opportunities in delivery of overdose prevention and naloxone prescription to adolescents using opioids. J Adolesc Health. 2018;63(2):245-248. [Free full text]
13. Butler C, Kornberg Z, Copp HL. Practitioner counseling associated with improved opioid disposal among families of postoperative pediatric patients. J Pediatr Urol. 2021;17(5):634.e1-634.e7. [Free full text]
14. Terranella A, Guy G Jr, Mikosz C. Naloxone dispensing to youth ages 10-19: 2017-2022. Pediatrics. 2024;154(4):e2023065137. [Free full text]
15. Tanz LJ, Dinwiddie AT, Mattson CL, O’Donnell J, Davis NL. Drug Overdose Deaths Among Persons Aged 10–19 Years — United States, July 2019–December 2021. MMWR Morb Mortal Wkly Rep. 2022;71:1576–1582. [Free full text]
16. Friedman J, Godvin M, Shover CL, et al. Trends in drug overdose deaths among US adolescents, January 2010 to June 2021. JAMA. 2022;327(14):1398-1400. [Free full text]
17. Guy GP, Haegerich TM, Evans ME, et al. Vital Signs: Pharmacy-Based Naloxone Dispensing – United States, 2012-2018. MMWR Morb Mortal Wkly Rep. 2019;68:679-686. [Free full text]
18. US Food & Drug Administration. FDA News Release. FDA Approves First Over-the-Counter Naloxone Nasal Spray. Accessed September, 2024. [Free full text]