Opioid Prescribing and Potential Overdose Errors Among Children 0 to 36 Months Old

Abstract

Introduction

Errors in medication dosing are among the most common medication error types in children.^1–5 However, relatively few studies on dosing errors have been completed in outpatient pediatric, nonemergency department settings, evaluating general pediatric populations.^5–8 Two studies that reviewed large numbers of pediatric prescriptions (not from claims data) found dosing errors in the 8% to 15% range. An evaluation of 1933 child ambulatory visit records where a prescription was given demonstrated dosing errors in 15% of the prescriptions, with approximately 50% of the errors being overdoses.⁷ Similarly, an evaluation of 2259 prescriptions at 6 outpatient sites found dosing errors in 8.9% of prescriptions.⁸ Dosing errors also comprise more than 40% of the medication errors that lead to patient death based on reports to the US Food and Drug Administration (FDA).⁹

Opioid-containing preparations are frequently cited as the drug class most commonly involved in adverse drug events and deaths.^10–13 The American Academy of Pediatrics advocates limiting use of opioids in children based on safety concerns.¹⁴ In addition, recent evidence has shown that opioids offer limited efficacy for treating pain (compared with nonsteroidal anti-inflammatory agents) and cough in children.^15–17 Young children have a narrower margin of safety when using weight-based dosage calculations and may be a particular risk for dosing error. Among 821 reported cardiovascular drug errors in children, approximately 50% were in children younger than 1 year,¹⁸ and children 0 to 4 years old account for 43% of adverse drug event visits.¹⁰

Given the greater risk of adverse drug events posed by opioid medications and the greater risk of adverse drug events in young children, focusing on outpatient opioid prescriptions to children 0 to 36 months old represents a potentially high-yield opportunity to improve patient safety. In this study, we sought to estimate the frequency of potential overdoses among outpatient opioid-containing prescriptions and to determine if the frequency of potential overdose was inversely associated with age.

Method

Results

Of the 442 217 children 0 to 36 months old in the Medicaid data set from the study years, 41 706 (9.4%) received one of the study opioid preparations. There were 59 536 prescriptions for the opioid-containing preparations amounting to ~1.6 opioid prescriptions per patient among those who received an opioid. Mean age of prescription recipients was 20.5 months. Table 1 presents the 10 drug preparations, the number of prescriptions for each preparation, and prescription rank by frequency. The number of prescriptions per preparation varied from 1297 to 30 183.

Overall, 1582 (2.7%) of the 59 536 prescriptions contained a potential overdose quantity dispensed, and the average excess amount dispensed was 48% among the potential overdose prescriptions (average observed/expected = 1.48). In bivariate analyses (χ²), prescriptions dispensed for infants, especially those 0 to 2 months old, were more likely to contain a potential overdose quantity than prescriptions dispensed for children ≥12 months (Table 2). For example, 8.9% of opioid prescriptions dispensed for infants 0 to 2 months old contained a potential overdose quantity, compared with 5.7% of opioid prescriptions dispensed for infants 3 to 5 months old, 3.6% of opioid prescriptions dispensed for infants 6 to 11 months old, and 2.3% of opioid prescriptions dispensed for children older than 12 months (χ², P < .0001).

The adjusted analyses (logistic regression) demonstrated that the overall pattern of potential overdose was similar to that found in bivariate analyses—the association of potential overdose frequency with younger ages remained significant, with each successively younger group less than 12 months old experiencing greater odds of potential overdose relative to older subjects (Table 3). Children classified as “black” in the data set were more likely to experience a potential overdose.

Discussion

These data show that opioid prescriptions dispensed to infants and young children often contain potential overdose quantities, with the excess amount dispensed equaling almost 50% greater than expected using a generous estimate of child weight. Our primary goal for this study was to define the magnitude of the problem of potential overdose in opioids, a high risk drug class, and the frequencies of potential overdose appear concerning. These data suggest that the period of infancy is particularly high risk for improper opioid dosing, with 9% of the opioid prescriptions dispensed for infants containing an excess quantity. These are some of the few data to evaluate age-related risk of dosing errors, but other pediatric studies have also shown that younger children or infants are at higher risk of experiencing a medication error or adverse drug event.^10,18,20 While the nature of these data do not allow us to determine if these potential errors represent errors at the prescribing or dispensing stages, other outpatient studies have demonstrated that ordering errors occur approximately 15 times more commonly than dispensing errors.²¹ Therefore, we believe that most of these potential errors originated at the prescribing stage. While Black race was associated with increased odds of potential overdose, the range of overdose frequency among the races/ethnicities was in the 2.0% to 2.9% range, and there was not a significant difference in percentage overdose. This finding may represent a novel association, but the extent of the demographic data in the data set are limited making further inference about the meaning of the association difficult.

Overall, the frequency of dosing error among the prescriptions in this study, at 2.7%, is qualitatively in the range of dosing errors found in other outpatient pediatric studies. The studies by McPhillips et al⁷ and Kaushal et al⁸ found overdose error frequencies of 7% to 9%, but those studies did not focus specifically on any drug class. It should also be noted that the aforementioned studies reviewed written prescriptions (meaning, after the provider produced the prescription but before dispensing), allowing the investigators to identify prescription errors created by the providers. The data used for this study represent dispensed prescriptions and therefore likely represent an underestimate of the error rate at the point of writing the prescriptions. We have been unable to identify published frequencies of how well pharmacists identify pediatric prescription errors in outpatient settings. However, inpatient data show that pharmacists in pediatric hospital settings identify up to 78% of prescription errors before dispensing.²² Applying the inpatient error correction rate to the potential error frequencies identified in this study suggests that the frequency of potential overdose as written by the providers in these data may be as high as 15%.

More concerning, the frequency of potential overdose error among infants was much higher, especially for those 0 to 2 months old. Our findings suggest that younger infants in particular should have careful review of opioid prescriptions for appropriate dosing. In addition to the frequency of potential overdosing, the degree of potential overdosing is concerning. One might argue that an overall potential error frequency of 2.7% correlates almost exactly with the fact that we assigned each subject the 97th percentile weight. However, we feel that these represent true overdoses because the average excess amount dispensed was 48%. In addition, our assumptions were biased toward underestimation of overdose in that we identified the highest recommended dose at the most frequently recommended intervals to determine the expected doses. If even a portion of the prescriptions were meant to be taken on an as-needed basis, then the excess amount dispensed is even greater than reported, again suggesting that these events represent true errors.

Recently, discussion has intensified as to whether opioid prescribing for children of any age is appropriate based on concerns about both the efficacy and the safety of opioids, particularly codeine.^23–25 Two randomized trials in children with pain demonstrated that ibuprofen performed as well as or better than opioids for pain.^15,16 The American Academy of Pediatrics has long held that opioids are not appropriate for cough in children, and reviews of published studies show that efficacy of opioids for cough is limited.¹⁷ Increasing awareness of genetic variability in metabolism of codeine and potentially fatal outcomes in those with altered codeine metabolism have also heightened safety concerns.²³ In fact, the US FDA has determined to add a “black box warning” to codeine’s FDA label, stating that codeine should not be used posttonsillectomy in children.²⁶ Nevertheless, primary care practitioners appear to be common prescribers of opioid medications, and future research into why office-based practitioners prescribe opioids would be an important aspect of making the use of these medications safer for children.²⁷

Options to reduce dosing error at the provider point of producing the prescription are multiple. To begin, electronic prescribing and other health information technology functions have significant potential to reduce opioid-associated dosing errors.²⁸ If electronic medication ordering, whether inpatient or outpatient, were to complete dose calculations automatically, it would reduce the opportunity for human error.²⁹ At a minimum, electronic prescribing programs could print a patient’s weight on a prescription to allow pharmacy dose checking. Even without electronic prescribing, requiring providers to record a weight on any opioid-containing prescription, especially for infants and younger children, would allow dose checking by pharmacists. Pharmacy work site interventions, including adjusting lighting, limits on pharmacist dispensing volume per hour, and efforts to reduce distractions can play an important role in reducing pharmacist dispensing errors.^30–33 These error-reduction strategies have not been tested specifically regarding pediatric opioid prescribing or dispensing.

The need to reduce dosing error at both the provider and pharmacy dispensing points of the drug delivery process is heightened by documented difficulties that parents have in administering proper medication doses to children. Parents have difficulty properly measuring liquid preparations.³⁴ In an older but very illuminating study of reports to poison control centers, the investigators identified that measuring cups appeared to raise the risk of 2- and 3-fold dosing errors, in part arising from parents’ assumption that the whole cupful was the intended dose.³⁵ Parents have difficulty with or knowledge deficits of measurement concepts, such as “teaspoon,” and marked syringes allow parents to provide more accurate dosing compared with cups, both marked and un-marked, and un-marked syringes.³⁶ Concrete, visually reinforced instructions for dosing and frequency of administration have been effective in reducing parental administration error.^2,34,37

There are several limitations of this study. The most significant limitation is that we did not know the actual weights of the subjects, so we are reporting estimations of overdose frequency. We did, however, use a very generous weight estimate (97th percentile for gender and age in months), so we believe that our estimates of overdose are biased toward underestimation. The frequency of potential overdose would have been higher had we used any lower percentile weight as the estimate for each patient. Although we do not know how many of the subjects experienced a true overdose, the percentage overdose also suggests real errors. With an average overdose amount of 48%, we would have had to underestimate weight by an average of 33% for the “error” dispensed amounts to be appropriate for the subjects. We do not know if the drugs were administered as scheduled or “prn” (pro re nata meaning as needed). Given that many of these drugs are likely prescribed “prn,” the majority of the subjects who received an excess quantity likely did not experience adverse events. However, intending these drugs to be used “prn” but dispensing amounts that would be excessive even if taken on a standing schedule raises even greater potential problems given concerns of opioid diversion, ingestions by children, and inadvertent administration of opioid drugs.^11,38,39 We also do not know the origin of the error—the excess amounts dispensed could have occurred at the prescribing stage or at the dispensing stage. Other studies have demonstrated that many more errors are made in the prescribing (in ambulatory settings) or ordering steps (in inpatient settings) than are made in the dispensing step, suggesting that providers are major contributors to dosing error.⁸ Another limitation is that we evaluated only 1 drug class, so it is unclear if similar error frequencies would be found with a sampling of other drug classes. We note, however, that the frequency of potential overdose error found in these data is similar to that in other pediatric ambulatory studies. These data are from lower income children (Medicaid), and it is unclear whether either privately insured or uninsured children would experience different error frequencies. The data are now 4 years old, but recent national pediatric data suggest that the frequency of opioid prescribing has not appreciably changed despite multiple publications since 2010 in the medical press addressing the potential adverse effects of opioids in children.⁴⁰ Finally, the data are from only 1 state, and data suggest state-by-state variation in opioid prescribing for adults.⁴¹

Conclusions

Prescriptions dispensed for infants and young children often contained potential overdose quantities, with infants receiving potential overdose quantities the most often. When viewed in the light of other studies, these data suggest that greater safeguards are needed to improve the safety of opioid prescribing to children younger than 3 years.

Acknowledgments

Footnotes

References