Outpatient Opioid Prescriptions

for Children and Opioid-

Related Adverse Events
Cecilia P. Chung, MD, MPH,​a S. Todd Callahan, MD, MPH,​b William O. Cooper, MD, MPH,​b,​c William D. Dupont, PhD,​d Katherine T.
Murray, MD,​a Andrew D. Franklin, MD, MBA,​e Kathi Hall, BS,​c Judith A. Dudley, BS,​c C. Michael Stein, MD,​a Wayne A. Ray, PhDc

BACKGROUND AND OBJECTIVES: Little is known about opioid prescribing for children without severe abstract
conditions. We studied the prevalence of and indications for outpatient opioid prescriptions
and the incidence of opioid-related adverse events in this population.
METHODS: This retrospective cohort study between 1999 and 2014 included Tennessee
Medicaid children and adolescents aged 2 to 17 without major chronic diseases, prolonged
hospitalization, institutional residence, or evidence of a substance use disorder. We
estimated the annual prevalence of outpatient opioid prescriptions and incidence of opioid-
related adverse events, defined as an emergency department visit, hospitalization, or death
related to an opioid adverse effect.
RESULTS: There were 1 362 503 outpatient opioid prescriptions; the annual mean prevalence
of opioid prescriptions was 15.0%. The most common opioid indications were dental
procedures (31.1% prescriptions), outpatient procedure and/or surgery (25.1%), trauma
(18.1%), and infections (16.5%). There were 437 cases of opioid-related adverse events
confirmed by medical record review; 88.6% were related to the child’s prescription and
71.2% had no recorded evidence of deviation from the prescribed regimen. The cumulative
incidence of opioid-related adverse events was 38.3 of 100 000 prescriptions. Adverse
events increased with age (incidence rate ratio = 2.22; 95% confidence interval, 1.67–2.96;
12–17 vs 2–5 years of age) and higher opioid doses (incidence rate ratio = 1.86 [1.45–2.39];
upper versus lower dose tertiles).
CONCLUSIONS: Children without severe conditions enrolled in Tennessee Medicaid frequently
filled outpatient opioid prescriptions for acute, self-limited conditions. One of every 2611
study opioid prescriptions was followed by an opioid-related adverse event (71.2% of which
were related to therapeutic use of the prescribed opioid).
NIH

Departments of aMedicine, bPediatrics, cHealth Policy, dBiostatistics, and eAnesthesia, School of Medicine,
Vanderbilt University, Nashville, Tennessee
Dr Chung conceptualized and designed the study, reviewed and adjudicated all cases, conducted
the analyses, and drafted the initial manuscript; Dr Ray conceptualized and designed the study,
reviewed cases in which there was discrepancy in the adjudication, conducted the analyses, and
drafted the initial manuscript; Dr Callahan conceptualized and designed the study and reviewed
and adjudicated all cases; Drs Cooper, Murray, and Stein conceptualized and designed the study
and reviewed cases in which there was discrepancy in the adjudication; Dr Dupont conceptualized
and designed the study, conducted the analyses, and drafted the initial manuscript; Dr Franklin
conceptualized and drafted critical sections of a revised manuscript; Ms Hall and Ms Dudley
collected data and prepared the analyses files; and all authors reviewed and critically revised the
manuscript, approved the final manuscript as submitted, and agreed to be accountable for all
aspects of the work.
WHAT’S KNOWN ON THIS SUBJECT: The discussion of
pediatric opioid prescribing has been focused on pain related
to major chronic diseases, surgical procedures, or other
severe conditions. Little is known about the prevalence
and consequences of outpatient opioid prescribing for less
serious, often self-limited conditions in children.
WHAT THIS STUDY ADDS: Outpatient opioid prescribing for
children in the study was frequent; an estimated 15% received
a prescription annually. One in every 2611 prescriptions was
followed by an emergency department visit, hospitalization,
or death related to an opioid-related adverse effect, most
commonly related to therapeutic use of the prescribed opioid.
To cite: Chung CP, Callahan ST, Cooper WO, et al. Outpatient
Opioid Prescriptions for Children and Opioid-Related
Adverse Events. Pediatrics. 2018;142(2):e20172156

Downloaded from www.aappublications.org/news by guest on August 30, 2018

PEDIATRICS Volume 142, number 2, August 2018:e20172156 ARTICLE
Although children and adolescents
˂18 years of age constitute one-
quarter of the US population, the
controversy regarding opioid
analgesics‍1–‍ 3‍ has been largely
restricted to adults. However,
there is limited data on the extent
to which the well-documented
secular trend of increased opioid
prescribing and toxicity has affected
children. Some studies suggest that
the marked increase in prescribing
for adults has also occurred among
children. In the United States, the
number of office visits with an opioid
prescription for patients 15 to 19
years of age nearly doubled between
1994 and 2007,​‍4 the treatment of
adolescents for opioid overdose
has increased,​5,​6‍ and the number of
pediatric hospitalizations attributed
to opioid poisoning doubled from
1997 to 2012.‍7 Authors of other
studies report that the prevalence of
opioid use in children has remained
constant‍8 or decreased slightly‍9,​10
since 2010. Further information on
the prevalence of opioid analgesic use
in children and the reasons for which
these medications are prescribed in
this population is needed.
The discussion of opioid analgesics
in pediatric practice has primarily
been focused on pain related to
serious chronic diseases, major
surgical procedures, or other
severe conditions.‍3,​11,​
‍ 12‍ A recent
statement from the Food and
Drug Administration on refining
guidelines for opioid use suggested
that children prescribed these
drugs had “severe conditions that
include cancer, multisystem trauma
and serious chronic diseases such
as sickle cell anemia.”‍3 However,
pediatric pain management reviews
have considered opioids for less
serious conditions,​13,​14
‍ such as
pain occurring after outpatient
surgical or dental procedures‍15,​16
‍ METHODS
and abdominal pain.‍17 If children
frequently take opioids for relatively
minor conditions for which there
often are other therapeutic options,
Downloaded from www.aappublications.org/news by guest on August 30, 2018
2 CHUNG et al
practitioners need better information
on the harms of opioid therapy in
children to make informed risk/
benefit prescribing decisions.
However, the available data are
limited to case series of hospitalized
children or to case reports.18–‍ 20
‍ other types of care and are linked to
Furthermore, the pediatric literature
has been focused on opioid toxicity
related to inadvertent overdose,​‍21
unsupervised use,​‍22 or substance
abuse.23 Hence, the incidence of
adverse opioid effects for children
during appropriate medical use
for relatively minor conditions is
unknown. Indeed, a recent Food
and Drug Administration advisory
committee meeting stressed the need
for data on outcomes in pediatric
patients and concurred that there
should be “a balance in providing
pain control for pediatric populations
and making this population safe from
the risks of misuse, abuse, addiction,
overdose, and death.”‍24,​25
‍
Thus, we conducted a retrospective
cohort study of the outpatient
prescribing of opioids in a large
population of children and
adolescents 2 to 17 years of age.
Because our objective was to study
opioid use for children without
severe conditions, the cohort
consisted of children without
major chronic diseases (cancer or
sickle cell disease) or other severe
conditions. Our objectives were to (1)
describe the prevalence of outpatient
prescriptions for opioid analgesics,
(2) characterize the children
prescribed these medications
(including the prescription
indication), and (3) estimate
the incidence of opioid-related
adverse events and to determine
the proportion of these adverse
events associated with appropriate
therapeutic use.
Study Children
Study data came from the
Tennessee state Medicaid program,
which provides both medical
and dental care for qualifying
children.‍26–‍ 28
‍ Medicaid files record
enrollment, medical encounters,
filled prescriptions, inpatient
admissions, outpatient visits, and
computerized death certificates‍29 and
an “all payers” hospital discharge
database.26 These data provided
an efficient way to define a large
population of children and identify
both prescriptions for opioids and
potential adverse effects.
The study population consisted of
children and adolescents 2 to 17
years of age enrolled in Medicaid
between January 1, 1999, and
December 31, 2014. To ensure
adequate information for study
variables, the children selected
had to be enrolled for at least 1
year and have recorded medical
encounters (including prescriptions)
during that year (Supplemental
Table 4). They had no previous
encounters with diagnoses from
the International Classification of
Diseases, Ninth Revision, Clinical
Modification, procedures from the
Current Procedural Terminology,
Fourth Edition or medication
prescriptions indicating severe
underlying conditions (cancer, sickle
cell anemia, congenital anomalies,
hospitalization for a total of ˃30 days
in the preceding year, or history of
an organ transplant), institutional
residence, or evidence of a substance
use disorder (Supplemental Table 4).
Study Prescriptions for Opioid
Analgesics
The study included outpatient
prescriptions filled during the study
period for children who satisfied the
cohort eligibility criteria on the date
of the prescription fill (Supplemental
Table 4). The study opioids
(Supplemental Table 5) excluded
parenteral opioids (infrequently
prescribed for outpatients),
buprenorphine (primarily used as
treatment of opioid addiction), and
preparations specifically formulated
for cough or diarrhea.
We estimated the dose (milligrams
per kilograms per day) for each
opioid prescription. We first
converted the dispensed dose to
morphine equivalents (Supplemental
Table 5)‍30 and calculated the
milligrams per day from the
prescription days of supply. Because
the Medicaid data do not include
weight, we used the age- and sex-
specific growth charts from the
Centers for Disease Control and
Prevention (https://​www.​cdc.​gov/​
growthcharts/​html_​charts/​wtage.​
htm#males) to estimate each child’s
weight as the median weight for
the child’s age (in months) on the
day the prescription was filled. The
primary analysis included weight-
adjusted doses based on tertiles; the
respective cutoff points (expressed in
morphine equivalents per kilogram
per day) were low tertile (≤0.38
mg/kg per day), intermediate tertile
(0.38–0.66 mg/kg per day), and high
tertile (>0.66 mg/kg per day). We
also performed sensitivity analyses
with weight estimates based on the
upper and lower quartiles of the
Centers for Disease Control and
Prevention growth charts.
Each prescription’s indication was
assigned with an algorithm that
gave priority to temporal proximity
to the prescription fill date and the
type of medical care (Supplemental
Section 3; Supplemental Table 6).
When multiple potential indications
were noted, we assigned the primary
indication in the following order:
outpatient procedure and/or surgery,
trauma, dental procedure, back
pain, other musculoskeletal pain,
abdominal pain, headache or other
neurologic condition, and infection.
Opioid-Related Adverse Events
An opioid-related adverse event
was defined as an emergency
department (ED) visit, hospital
admission, or death related to an
opioid adverse effect. Potential cases
Downloaded from www.aappublications.org/news by guest on August 30, 2018
PEDIATRICS Volume 142, number 2, August 2018
during follow-up were identified
from deaths or medical encounters
possibly indicating opioid adverse
effects (Supplemental Section 5;
Supplemental Fig 3).‍31 The medical
encounters had to have either a
coded diagnosis explicitly indicating
an adverse medication effect (opioid
or an unspecified medication) or
symptoms consistent with an opioid
overdose.‍31 Medical records were
sought for all of these encounters
as well as for all deaths (including
autopsies when available) during
follow-up. Deidentified records were
independently adjudicated by 2 study
physicians (S.T.C. and C.P.C.), with
disagreements resolved by all the
investigators.
A confirmed case of an opioid-
related adverse event required
evidence in the medical record
of an adverse effect that could
be reasonably attributed to an
opioid (Supplemental Section 5;
Supplemental Fig 4).‍31 The following
were the 3 categories of confirmed
cases (Supplemental Section 5): (1)
probable with symptoms (opioid
adverse effect signs or symptoms that
could not be reasonably attributed
to another cause); (2) probable with
intervention (signs or symptoms
not recorded in the chart, but there
was direct intervention or escalation
of care appropriate to manage a
potential opioid adverse effect); and
(3) possible (opioid adverse effect
signs or symptoms, but another
potential cause was documented).
Case severity was assessed by
determining if the medical record
documented an opioid-related
intervention or escalation of care
(Supplemental Section 5) or if there
was hospitalization or death. Medical
records were used to identify the
source of the opioid implicated in
the adverse reaction (the patient’s
prescription or other source) and
characterize the circumstances of the
opioid use as (1) therapeutic use (no
documentation indicating deviation
from the prescribed regimen,
overdose, or substance use disorder),
(2) unintentional overdose, or (3)
substance use disorder and/or
self-harm.
The analysis of opioid-related
adverse events was restricted
to prescriptions filled between
1999 and 2011. This cutoff date
of 2011 was due to the long lead
time required to identify medical
care providers, seek permission to
review records (with human subjects
committee submissions), obtain
the records by an on-site visit if
necessary, and perform deidentified
case adjudication.
Analysis: Opioid Prescription
Prevalence
For each study year, we calculated
the annual opioid prescription
prevalence. The numerator was
the number of children with 1
or more qualifying study opioid
prescriptions filled during a given
year. The denominator was the study
population size during that same
year, calculated as the number of
children enrolled in TennCare on
July 1 who on that date met the study
eligibility criteria (Supplemental
Table 4).
Analysis: Opioid-Related Adverse
Events
The prescription exposure period
(follow-up for opioid-related
adverse events) extended from the
prescription fill date through 14 days
after the end of the prescribed days
of supply (Supplemental Section 4).
The exposure period was further
classified as current use (filling of
the prescription through the end
of days of supply) and recent use
(additional 14 days after the end
of days of supply). Although the
greatest risk for adverse effects
should be during current use, the
exposure period included recent
use to account for pro re nata
prescriptions. It was suggested in a
pilot study that more than one-third
of cases of opioid-related adverse
3
FIGURE 1
Annual opioid prescription prevalence for ambulatory children without major chronic diseases enrolled in TennCare from 1999 to 2014. A, All ages. B,
According to age categories. C, Annual number of children. Additional information is included in Supplemental Table 9.

events occurred during the recent
use period.‍31 We also classified the
exposure period according to days
since the prescription fill (1–3, 4–7,
≥8) because some adverse effects are
more likely to occur early in therapy.
We estimated the cumulative
incidence of opioid-related adverse
events during the prescription
exposure period with the product-
limit method.‍32 To test for differences
in incidence according to current
versus recent use and dose, we
modeled the incidence rate ratio
(IRR) with Poisson regression. In
this analysis, both the person-days
of each prescription exposure period
and the study cases were allocated to
the appropriate covariate categories.
The multivariate model included sex,
age category, calendar year, days
since the prescription fill, current
versus recent use, and dose. The
primary analysis included multiple
instances of adverse events for
the same child (0.5% of cases); an
analysis in which we excluded these
had essentially identical results. All
analyses were done by using Stata/
MP 13.1 (Stata Corp, College
Station, TX).
Human Research Protection
The study was approved by the
Bureau of TennCare and the
Institutional Review Boards of
Vanderbilt University School
of Medicine and the Tennessee
Department of Health, which waived
informed consent.
RESULTS
Opioid Prescription Prevalence
During the study period, the
population included an annual
mean of 401 972 children enrolled
in TennCare without severe
conditions or diagnosed substance
abuse disorders. These children
had 1 362 503 filled outpatient
prescriptions for opioid analgesics,
of which 269 602 (19.8%) were for
children 2 to 5 years of age, 377 823
(27.7%) were for children 6 to
11, and 715 078 (52.5%) were for
children and adolescents 12 to 17.
Of these children, a mean of 15.0%
(annual range: 10.2%–17.2%) had 1
or more filled opioid prescriptions
each year (‍Fig 1A). Children and
adolescents 12 to 17 years of
age were the most likely to be
prescribed opioids (‍Fig 1B); for these
children, the mean annual opioid
prescription prevalence was 22.4%
(15.8%–26.0%). The mean annual
opioid prescription prevalence was
lower for younger children (‍Fig

Downloaded from www.aappublications.org/news by guest on August 30, 2018

4 CHUNG et al
TABLE 1 Characteristics of Children at the Time of Filling of Study Opioid Prescriptions
Age, y All
2–5 6–11 12–17
Prescriptions, n 269 602 377 823 715 078 1 362 503
Female patient 45.4% 48.5% 56.4% 52.0%
Disability enrollment 3.5% 6.1% 7.8% 6.5%
Medical care
  Hospitalized in past y 9.9% 7.8% 14.1% 11.5%
  Hospitalized in past 30 d 4.4% 4.1% 6.6% 5.4%
Opioid indication
  Indication found 84.9% 84.7% 85.4% 85.1%
  Dental 24.7% 32.7% 32.6% 31.1%
  Outpatient procedure and/or surgery 41.0% 26.4% 18.4% 25.1%
  Trauma 9.2% 17.1% 21.9% 18.1%
  Infection 23.7% 19.2% 12.3% 16.5%
   Ear, nose, throat, and/or upper respiratory infection 12.8% 11.4% 6.4% 9.0%
   Bronchitis 8.3% 5.6% 2.7% 4.6%
   Other infection 2.7% 2.3% 3.2% 2.9%
   Other paina 1.3% 4.6% 14.8% 9.3%
  Indication not found 15.2% 15.3% 14.6% 14.9%
Opioid exposure duration and dose; median (IQR)
  Current use (d) 4 (2–6) 3 (2–5) 3 (2–5) 3 (2–5)
  Prescription exposure period (d) 18 (15–20) 17 (16–19) 17 (16–19) 17 (16–19)
  Dose (morphine equivalents) mg/kg per d 0.62 (0.41–0.90) 0.52 (0.33–0.82) 0.55 (0.37–0.82) 0.55 (0.38–0.84)
Specific opioid
  Hydrocodone 26.1% 31.5% 53.7% 42.1%
  Codeine 61.9% 56.9% 23.3% 40.2%
  Meperidine 10.8% 8.7% 1.3% 5.2%
  Oxycodone 0.4% 0.7% 8.2% 4.6%
  Tramadol 0.1% 0.4% 5.3% 2.9%
  Other opioid and/or multiple opioidsb 0.9% 1.9% 8.4% 5.1%
Includes prescriptions filled from 1999 to 2014. IQR, interquartile range.
a Other pain includes headaches and other neurologic, back, musculoskeletal, or abdominal pain.
b Includes propoxyphene (4.2% of all prescriptions) and other or multiple opioids prescribed on the same d (0.9% of all prescriptions).

1B). For children 2 to 5 years and
6 to 11 years of age, the respective
mean annual opioid prescription
prevalences were 11.2% (range:
7.6%–13.1%) and 12.1% (range:
7.9%–14.1%).
For each age group, the annual
prescription prevalence declined
after 2009. By 2014, the annual
opioid prescription prevalences were
10.2% for all children and 7.6%,
7.9%, and 15.8%, respectively, for
those 2 to 5, 6 to 11, and 12 to 17
years of age.
Characteristics of Children With
Opioid Prescriptions
Of the study prescriptions, 52.0%
were for female patients (‍Table 1).
There were 6.5% of prescriptions
for children with disability-related
enrollment and 11.5% for children
hospitalized in the previous year.
For study opioid prescriptions with
an identified indication (85.1%; ‍Table
1), the most common indications
were dental procedures (31.1%),
outpatient surgical or medical
procedures (25.1%), trauma (18.1%),
and minor infections (16.5%), most
frequently ear, nose, throat, and/
or upper respiratory infections. For
children 2 to 5 years of age, 23.7%
of prescriptions had an infection
indication.
The median prescription exposure
period included 3 days of current
use and 14 days of recent use, for a
total study exposure of 17 days. The
median opioid dose was between 0.5
and 0.6 mg/kg per day (morphine
equivalents). The most commonly
prescribed individual opioids (‍Table 1)
were hydrocodone (42.1% of
prescriptions), codeine (40.2%),
meperidine (5.2%), oxycodone
(4.6%), and tramadol (2.9%).
Meperidine was prescribed more
frequently for children 2 to 5 years
of age (10.8% of prescriptions),
whereas oxycodone and tramadol
were prescribed more frequently
for children and adolescents 12 to
17 years of age (8.2% and 5.3% of
prescriptions, respectively).
Opioid-Related Adverse Events
We identified 1179 potential opioid-
related ED visits, hospitalizations,
or deaths between 1999 and 2011.
Medical records with sufficient
information for adjudication were
retrieved for 917 (77.8%) potential
cases (Supplemental Fig 3), of which
437 were confirmed cases that met
the criteria for an opioid-related
adverse event (Supplemental Fig 4).
Of these cases, 272 (62.2%) were
adjudicated as probable with

Downloaded from www.aappublications.org/news by guest on August 30, 2018

PEDIATRICS Volume 142, number 2, August 2018 5
TABLE 2 Characteristics of the Confirmed Opioid-Related Adverse Events hospitalization, or death; to involve
Age, y opioids from an unidentified source;
2–5, 6–11, 12–17, All Ages, and to be related to substance use
n = 56 n = 71 n = 310 n = 437 disorder or self-harm.
Category of case, n (%)
  Probable, with symptoms 33 (58.9) 49 (69.0) 190 (61.3) 272 (62.2) Incidence of Opioid-Related Adverse
  Probable, with intervention 6 (10.7) 0 (0.0) 21 (6.8) 27 (6.2) Events
  Possible 17 (30.4) 22 (31.0) 99 (31.9) 138 (31.6)
Severity of outcome, n (%) The cumulative incidence of opioid-
  Death 1 (1.8) 1 (1.4) 1 (0.3) 3 (0.7) related adverse events during the
  Hospitalization or opioid-related 6 (10.7) 5 (7.0) 71 (22.9) 82 (18.8)
median prescription exposure
intervention and/or care
escalation period was 38.3 (95% confidence
  ED visit onlya 49 (87.5) 65 (91.6) 238 (76.7) 352 (80.6) interval [CI], 34.9–42.1) events per
Source of opioid,​b n (%) 100 000 prescriptions (‍Fig 2A). The
  Patient’s prescription 54 (96.4) 69 (97.2) 264 (85.2) 387 (88.6) cumulative incidence for children
  Other source 2 (3.6) 1 (1.4) 10 (3.2) 13 (3.0)
and adolescents 12 to 17 years of
  Source not indicatedc 0 1 (1.4) 36 (11.6) 37 (8.5)
Circumstances of opioid use related to age was greater than that observed
the adverse event,​d n (%) for children ages 2 to 5 and 6 to 11,
  Therapeutic use 45 (80.4) 67 (94.4) 199 (64.2) 311 (71.2) respectively (‍Fig 2B); the adjusted
  Unintentional overdose 9 (16.1) 3 (4.2) 19 (6.1) 31 (7.1) IRR for children and adolescents 12
  Abusee 0 0 36 (11.6) 36 (8.2)
to 17 years of age (‍Table 3; reference
  Self-harm 0 0 35 (11.3) 35 (8.0)
  Circumstances not indicated 2 (3.6) 1 (1.4) 21 (6.8) 24 (5.5) group of children 2–5 years of age)
Primary symptoms and/or signs of was 2.22 (95% CI, 1.67–2.96).
opioid toxicity,​f n (%)
  Gastrointestinal 19 (33.9) 23 (32.4) 92 (29.7) 134 (30.7)
The adjusted incidence of opioid-
  Neuropsychiatric 13 (23.2) 13 (18.3) 94 (30.3) 120 (27.5)
  Dermatologic 15 (26.8) 21 (29.6) 66 (21.3) 102 (23.3) related adverse events during current
  CNS depression 9 (16.1) 7 (9.9) 81 (26.1) 97 (22.2) use was greater than that observed
  Allergic 10 (17.9) 19 (26.8) 48 (15.5) 77 (17.6) during recent use (‍Table 3; IRR = 2.09;
  Respiratory depression 1 (1.8) 0 11 (3.6) 12 (2.8) 95% CI, 1.58–2.76). Adverse events
  Other 0 5 (7.0) 10 (3.2) 15 (3.4)
occurred more frequently shortly after
These are confirmed cases from 1999 to 2011. the prescription fill; the respective
a In 337 patients, symptoms associated with opioid toxicity were determined to be the main reason for the ED visit. In 15

patients, there was another reason for the visit, but opioid toxicity was part of the encounter. adjusted IRRs for days 1 to 3 and 4 to 7
b The categories were mutually exclusive. after the fill (reference ≥8 days) were
c Medical records did not indicate the source; however, all these patients filled prescriptions for opioids.
d The categories were mutually exclusive, on the basis of the following hierarchy: self-harm was greater than abuse, which
3.31 (95% CI, 2.41–4.53) and 1.51
was greater than unintentional overdose, which was greater than therapeutic use. (95% CI, 1.13–2.02), respectively. The
e Records with signs and/or symptoms of abuse and/or opioid withdrawal. incidence of opioid-related adverse
f Symptoms and signs were not mutually exclusive. See Supplemental Section 5 for lists of specific symptoms.
events increased with increasing dose;
the adjusted IRRs for the high and
symptoms (‍Table 2), 27 (6.2%) as (30.7%), neuropsychiatric (27.5%), intermediate dose tertiles were 1.86
probable with intervention, and 138 dermatologic (23.3%), and central (95% CI, 1.45–2.39) and 1.59 (95% CI,
(31.6%) as possible, most commonly nervous system (CNS) depression 1.23–2.04), respectively. Sensitivity
because another drug could have been (22.2%). For 88.6% of cases, the analyses used to restrict the cases to
used to explain the signs or symptoms opioid prescribed for the child was those adjudicated as probable with
that supported opioid involvement implicated in the adverse event. symptoms of opioid adverse effects
(Supplemental Table 8). There were For 71.2% of cases, there was no had essentially identical findings
19.5% of cases with an opioid-related recorded evidence of deviation from (Supplemental Table 10).
intervention or escalation of care, the prescribed regimen.
hospitalization, or death (‍Table 2).
Each of the 3 deaths had an autopsy, DISCUSSION
The characteristics of opioid-related
the underlying cause of death was an
adverse events for children and Outpatient use of prescribed opioids
adverse medication effect, and there
adolescents 12 to 17 years of age (n = in this large cohort of children
was evidence that the death was
310) differed from those for younger without severe conditions was
related to the prescribed opioid.
children (‍Table 2). They were more common. During the study period,
The most frequent opioid-related likely to result in an opioid-related 15% of children in the qualifying
symptoms were gastrointestinal intervention or escalation of care, Medicaid population had a filled

Downloaded from www.aappublications.org/news by guest on August 30, 2018

6 CHUNG et al
FIGURE 2
Cumulative incidence of opioid-related adverse events. A, Cumulative incidence of opioid-related adverse events, all ages. B, Cumulative incidence of
opioid-related adverse events, by age category. a Indicates the median follow-up of 17 days.

TABLE 3 Incidence of Opioid-Related Adverse Events According to Age Category, Timing of Use, Days 2014, which is consistent with
Since Prescription Filled, and Dose Tertile other recent data from pediatric
Prescription Exposure N Incidence per IRRa 95% CI populations‍9 and secular trends
Period, d Cases 100 000 d in adults.‍33 This decrease may be
Age category, y related to several factors, including
  12–17 9 380 221 310 3.3 2.22 1.67–2.96 greater awareness of the potential
  6–11 5 303 297 71 1.3 0.94 0.66–1.33 harms of widespread opioid use
  2–5 3 997 444 56 1.4 Reference —
and a prescription drug monitoring
Timing of use
  Current 5 048 647 263 5.2 2.09 1.58–2.76 program started in Tennessee in
  Recent 13 632 315 174 1.3 Reference — 2012. Nevertheless, the prevalence
Days since of opioid prescriptions for children
prescription in the study remained >10% by
filled, d
2014. The frequent prescribing of
  1–3 3 339 652 229 6.9 3.31 2.41–4.53
  4–7 4 203 526 87 2.1 1.51 1.13–2.02 opioids in this population, including
 ≥8 11 137 784 121 1.1 Reference — codeine, which now is considered
Dose (mg/kg per a suboptimal analgesic choice for
d) tertile children,​‍34 underscores the need
  High 6 075 031 177 2.9 1.86 1.45–2.39
for education regarding multimodal
  Intermediate 6 426 759 160 2.5 1.59 1.23–2.04
  Low 6 179 172 100 1.6 Reference — opioid-sparing regimens.
—, not applicable.
a The Poisson regression model for adjusted IRRs includes age (2–5, 6–11, and 12–17 years), sex, current versus recent
One of every 2611 opioid
use, days since the prescription fill (1–3, 4–7, and ≥8), dose tertile by age, and calendar year (1999–2003, 2004–2007, and prescriptions for the children in the
2008–2011). Current use was defined as the time between the filling of the prescription and the end of the days of supply. study was followed by an opioid-
Recent use was defined as the additional 14 days after the end of the days of supply.
related ED visit, hospitalization,
or death. The incidence of opioid-
outpatient opioid prescription medical procedures, trauma, and related adverse events increased for
annually, including ˃10% of children minor infections). children and adolescents 12 to 17
2 to 5 years of age. The primary years of age, during current opioid
indications for these prescriptions The prevalence of opioid use, and with higher opioid doses.
were acute and, in most cases, prescriptions for children in
self-limited conditions (dental the study peaked in 2009 and Because we sought to minimize false-
procedures, outpatient surgical or subsequently decreased through positive study events, our findings

Downloaded from www.aappublications.org/news by guest on August 30, 2018

PEDIATRICS Volume 142, number 2, August 2018 7
are likely to underestimate the
incidence of opioid-related adverse
events in children. First, unlike
other definitions,​‍35 opioid-related
adverse events managed with a
physician visit or not resulting in
medical care encounters were not
considered. Second, records with
diagnoses of less serious symptoms
(gastrointestinal or dermatologic)
were not sought unless a coded
diagnosis indicated an adverse
drug effect and did not attribute the
effect to a different drug. Finally,
the medical records required for
case confirmation were unavailable
for 22.2% of potential cases. Thus,
our study provides a conservative
estimate of the clinical impact of
adverse opioid effects in children.
In 89% of the opioid-related adverse
events, the implicated opioid came
from the child’s prescription, and,
in two-thirds of the cases, there
was no recorded evidence of
deviation from the prescribed
regimen. In contrast, in many
pediatric case reports, opioid adverse
effects are attributed to errors in
administration,​‍21 unsupervised use,​‍22
use of leftover medications,​‍36 or
ingestion of opioids from another
person’s prescription.‍37 Our finding
that nontherapeutic opioid use
did not account for the majority of
opioid-related adverse events in
patients who received outpatient
opioid prescriptions suggests that
efforts to improve opioid safety
in children must go beyond the
reduction of administration errors or
inappropriate use.
More than 20% of the children and
adolescents 12 to 17 years of age
in the study were prescribed an
opioid annually. Although the opioids
implicated in the adverse events
for these children predominantly
were those prescribed, more than
one-fourth of the adolescent cases
were attributed to substance use
disorder or attempted self-harm.
These findings indicate that extra
precautions may be needed when
Downloaded from www.aappublications.org/news by guest on August 30, 2018
8 CHUNG et al
prescribing opioids to adolescents
for acute, self-limited conditions,
given the increased likelihood of risk-
taking during this developmental
period.‍38–‍‍ 41
‍ defined pediatric population.
The opioid-related adverse events
identified from ED visits included less
serious reactions, such as nausea,
constipation, pruritus, and rash.
Although not life-threatening, these
symptoms did lead to additional
medical care encounters, which entail
both inconvenience and additional
costs. These findings underscore the
need to develop more comprehensive
pediatric guidelines for the
treatment of acute, self-limited
conditions, which should balance
both the unnecessary exposure of
children to increased risk of adverse
opioid effects and the potential for
undertreatment of painful short-term
conditions.
The generalizability of the study
findings may be limited because
of the characteristics of the study
cohort. To better identify indication,
we required that cohort inclusion
be dependent on active use of
medical care in the past year,
which could underrepresent the
healthiest children. The cohort came
from Medicaid enrollees from a
single state in a region with known
elevated prevalence of opioid use for
adults.‍42 Furthermore, ED use differs
according to Medicaid status, with
greater use of services for less severe
conditions.‍43 However, children
enrolled in Medicaid constitute an
important population per se, because
an estimated 38% of US children
have health insurance coverage by
Medicaid.‍44
The study relied upon a large
computerized database used to
identify both the cohort and potential
opioid-related adverse events. Thus,
it lacked important clinical detail. For
example, because the Medicaid files
did not include weight, the analysis
of dose was based on national
growth charts and was subject to
misclassification. However, the large
database did permit characterization
of opioid prescribing and related
adverse events in a large, well-
Our study had several other
limitations. We relied on medical
records that may be incomplete
to adjudicate potential cases and
to identify the circumstances of
the opioid-related adverse effects,
including the source of the implicated
opioid. Because all children in
the study had a recent opioid
prescription, adjudicators could
not be blinded to opioid exposure
status; however, the adjudication
process used a structured protocol‍31
and required agreement by 2
independent reviewers, with
disagreements resolved by all
investigators.
CONCLUSIONS
In this cohort of children enrolled in
Medicaid without severe conditions,
15% of children filled outpatient
opioid analgesic prescriptions
annually for acute, self-limited
conditions. One of every 2611 study
opioid prescriptions was followed
by an opioid-related ED visit,
hospitalization, or death; more than
two-thirds of these were related to
therapeutic use of the prescribed
opioid.
ACKNOWLEDGMENTS
We acknowledge the Bureau of
TennCare and the Tennessee
Department of Health, which
provided study data.
ABBREVIATIONS
CI: confidence interval
CNS: central nervous system
ED: emergency department
IRR: incidence rate ratio
DOI: https://​doi.​org/​10.​1542/​peds.​2017-​2156
Accepted for publication May 2, 2018
Address correspondence to Cecilia P. Chung, MD, MPH, Department of Medicine, School of Medicine, Vanderbilt University, 1611 21st Ave South, T-3113 MCN,
Nashville, TN 37232. E-mail: c.chung@vanderbilt.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2018 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the National Institute for Child Health and Human Development, award HD074584. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Institutes of Health. Dr Chung was funded by the National Institute of Arthritis
and Musculoskeletal and Skin Diseases of the National Institutes of Health under award K23AR064768 and the Rheumatology Research Foundation Career
Development Research K-supplement. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.​pediatrics.​org/​cgi/​doi/​10.​1542/​peds.​2018-​1623.

REFERENCES
1. Centers for Disease Control and
Prevention. Vital signs: overdoses
of prescription opioid pain
relievers—United States, 1999–2008.
MMWR Morb Mortal Wkly Rep.
2011;60(43):1487–1492
2. Okie S. A flood of opioids, a rising
tide of deaths [published correction
appears in Ann Emerg Med.
2011;364(3):290]. N Engl J Med.
2010;363(21):1981–1985
3. Califf RM, Woodcock J, Ostroff S. A
proactive response to prescription
opioid abuse. N Engl J Med.
2016;374(15):1480–1485
4. Fortuna RJ, Robbins BW, Caiola E,
Joynt M, Halterman JS. Prescribing of
controlled medications to adolescents
and young adults in the United States.
Pediatrics. 2010;126(6):1108–1116
5. Hasegawa K, Espinola JA, Brown
DF, Camargo CA Jr. Trends in U.S.
emergency department visits for
opioid overdose, 1993-2010. Pain Med.
2014;15(10):1765–1770
6. Tormoehlen LM, Mowry JB, Bodle JD,
Rusyniak DE. Increased adolescent
opioid use and complications reported
to a poison control center following
the 2000 JCAHO pain initiative. Clin
Toxicol (Phila). 2011;49(6):492–498
7. Gaither JR, Leventhal JM, Ryan SA,
Camenga DR. National trends in
hospitalizations for opioid poisonings
among children and adolescents,
1997 to 2012. JAMA Pediatr.
2016;170(12):1195–1201
8. Groenewald CB, Rabbitts JA, Gebert
JT, Palermo TM. Trends in opioid
prescriptions among children
and adolescents in the United
States: a nationally representative
study from 1996 to 2012. Pain.
2016;157(5):1021–1027
9. Banerjee S, Roland CL, Willke
R, Mardekian J, Garrison LP Jr.
Prevalence of and comorbid health
conditions associated with pediatric
prescription opioid use in the US.
J Pain Palliat Care Pharmacother.
2017;31(3–4):218–227
10. Centers for Disease Control and
Prevention; US Department of
Health and Human Services. Annual
surveillance report of drug-related
risks and outcomes — United States,
2017. Surveillance Special Report 1.
2017. Available at: https://​www.​cdc.​
gov/​drugoverdose/​pdf/​pubs/​2017-​cdc-​
drug-​surveillance-​report.​pdf. Accessed
November 3, 2018
11. Schechter NL, Walco GA. The potential
impact on children of the CDC
guideline for prescribing opioids for
chronic pain: above all, do no harm.
JAMA Pediatr. 2016;170(5):425–426
12. Berde CB, Sethna NF. Analgesics for
the treatment of pain in children
[published correction appears in N
Engl J Med. 2011;364(18):1782]. N Engl
J Med. 2002;347(14):1094–1103
13. Ali S, Drendel AL, Kircher J, Beno S.
Pain management of musculoskeletal
injuries in children: current state and
future directions. Pediatr Emerg Care.
2010;26(7):518–524; quiz 525–528
14. Tobias JD. Weak analgesics and
nonsteroidal anti-inflammatory agents
in the management of children with
acute pain. Pediatr Clin North Am.
2000;47(3):527–543
15. D’Agostino J, Terndrup TE.
Comparative review of the adverse
effects of sedatives used in children
undergoing outpatient procedures.
Drug Saf. 1996;14(3):146–157
16. Haas DA. An update on analgesics
for the management of acute
postoperative dental pain. J Can Dent
Assoc. 2002;68(8):476–482
17. Anderson M, Collins E. Analgesia for
children with acute abdominal pain
and diagnostic accuracy. Arch Dis
Child. 2008;93(11):995–997
18. Takata GS, Mason W, Taketomo C,
Logsdon T, Sharek PJ. Development,
testing, and findings of a pediatric-
focused trigger tool to identify
medication-related harm in US
children’s hospitals. Pediatrics.
2008;121(4). Available at: www.​pediatrics.​
org/​cgi/​content/​full/​121/​4/​e927
19. Madadi P, Hildebrandt D, Gong IY,
et al. Fatal hydrocodone overdose in
a child: pharmacogenetics and drug
interactions. Pediatrics. 2010;126(4).
Available at: www.​pediatrics.​org/​cgi/​
content/​full/​126/​4/​e986
20. Ferreirós N, Dresen S, Hermanns-
Clausen M, et al. Fatal and severe
codeine intoxication in 3-year-old
twins–interpretation of drug and
metabolite concentrations. Int J Legal
Med. 2009;123(5):387–394
21. Gunn VL, Taha SH, Liebelt EL, Serwint
JR. Toxicity of over-the-counter cough

Downloaded from www.aappublications.org/news by guest on August 30, 2018

PEDIATRICS Volume 142, number 2, August 2018 9
 and cold medications. Pediatrics.
2001;108(3). Available at: www.​
pediatrics.​org/​cgi/​content/​full/​108/​3/​
e52
22. Lovegrove MC, Mathew J, Hampp C,
Governale L, Wysowski DK, Budnitz
DS. Emergency hospitalizations for
unsupervised prescription medication
ingestions by young children.
Pediatrics. 2014;134(4). Available at:
www.​pediatrics.​org/​cgi/​content/​full/​
134/​4/​e1009
23. Kuehn BM. Medication helps make
therapy work for teens addicted
to prescription opioids. JAMA.
2010;303(23):2343–2345
24. US Food and Drug Administration.
Pediatric drug development
regulatory considerations.
Available at: https://​www.​fda.​gov/​
downloads/​AdvisoryCommittee​s/​
CommitteesMeeting​Materials/​Drugs/​
AnestheticAndAnal​gesicDrugProducts​
AdvisoryCommittee​/​UCM522744.​pdf.
Accessed January 14, 2018
25. US Food and Drug Administration
Center for Drug Evaluation and
Research. Summary Minutes of
the Anesthetic and Analgesic Drug
Products Advisory Committee, the Drug
Safety and Risk Management Advisory
Committee, and the Pediatric Advisory
Committee Joint Meeting; September
15–16, 2016. 2016
26. Ray WA, Griffin MR. Use of Medicaid
data for pharmacoepidemiology. Am J
Epidemiol. 1989;129(4):837–849
27. Ray WA, Taylor JA, Lichtenstein
MJ, Meador KG. The nursing home
behavior problem scale. J Gerontol.
1992;47(1):M9–M16
28. TennCare Kids Dental Services.
Available at: https://​www.​tn.​
gov/​tenncare/​tenncare-​kids/​
Downloaded from www.aappublications.org/news by guest on August 30, 2018
10
tenncare-​kids-​dental-​services.​html.
Accessed May 24, 2018
29. Piper JM, Ray WA, Griffin MR, Fought R,
Daughtery JR, Mitchel E Jr. Methodological
issues in evaluating expanded Medicaid
coverage for pregnant women. Am J
Epidemiol. 1990;132(3):561–571
30. Von Korff M, Saunders K, Thomas
Ray G, et al. De facto long-term
opioid therapy for noncancer pain
[published correction appears in Clin
J Pain. 2014;30(9):830]. Clin J Pain.
2008;24(6):521–527
31. Chung CP, Callahan ST, Cooper WO,
et al. Development of an algorithm
to identify serious opioid toxicity in
children. BMC Res Notes. 2015;8:293
32. Kaplan EL, Meier P. Nonparametric
estimation from incomplete
observations. J Am Stat Assoc.
1958;53(282):457–481
33. Guy GP Jr, Zhang K, Bohm MK, et al.
Vital signs: changes in opioid
prescribing in the United States, 2006-
2015. MMWR Morb Mortal Wkly Rep.
2017;66(26):697–704
34. Tobias JD, Green TP, Coté CJ;
Section on Anesthesiology and Pain
Medicine; Committee on Drugs.
Codeine: time to say “no”. Pediatrics.
2016;138(4):e20162396
35. US Food and Drug Administration. What
is a serious adverse event? Available
at: https://​www.​fda.​gov/​Safety/​
MedWatch/​HowToReport/​ucm053087.​
htm. Accessed January 14, 2018
36. Voepel-Lewis T, Wagner D, Tait AR.
Leftover prescription opioids after
minor procedures: an unwitting source
for accidental overdose in children.
JAMA Pediatr. 2015;169(5):497–498
37. Martin TC, Rocque MA. Accidental and
non-accidental ingestion of methadone
and buprenorphine in childhood: a
single center experience, 1999-2009.
Curr Drug Saf. 2011;6(1):12–16
38. Kann L, McManus T, Harris WA, et al.
Youth risk behavior surveillance -
United States, 2015. MMWR Surveill
Summ. 2016;65(6):1–174
39. Miech R, Johnston L, O’Malley PM,
Keyes KM, Heard K. Prescription
opioids in adolescence and future
opioid misuse. Pediatrics. 2015;136(5).
Available at: www.​pediatrics.​org/​cgi/​
content/​full/​136/​5/​e1169
40. Lankenau SE, Teti M, Silva K, Jackson
Bloom J, Harocopos A, Treese M.
Initiation into prescription opioid
misuse amongst young injection
drug users. Int J Drug Policy.
2012;23(1):37–44
41. Cicero TJ, Inciardi JA, Muñoz A.
Trends in abuse of Oxycontin and
other opioid analgesics in the
United States: 2002-2004. J Pain.
2005;6(10):662–672
42. Gwira Baumblatt JA, Wiedeman C, Dunn
JR, Schaffner W, Paulozzi LJ, Jones TF.
High-risk use by patients prescribed
opioids for pain and its role in
overdose deaths. JAMA Intern Med.
2014;174(5):796–801
43. Pukurdpol P, Wiler JL, Hsia RY,
Ginde AA. Association of Medicare
and Medicaid insurance with
increasing primary care-treatable
emergency department visits in
the United States. Acad Emerg Med.
2014;21(10):1135–1142
44. Kaiser Family Foundation. Health
insurance coverage of children 0-18.
Available at: https://​www.​kff.​org/​
other/​state-​indicator/​children-​0-​18/?​
currentTimeframe=​0&​sortModel=​
{“colId”:​”Location”,​“sort”​:​"asc"}.
Accessed May 24, 2018
CHUNG et al
 Outpatient Opioid Prescriptions for Children and Opioid-Related Adverse
Events
Cecilia P. Chung, S. Todd Callahan, William O. Cooper, William D. Dupont,
Katherine T. Murray, Andrew D. Franklin, Kathi Hall, Judith A. Dudley, C. Michael
Stein and Wayne A. Ray
Pediatrics 2018;142;
DOI: 10.1542/peds.2017-2156 originally published online July 16, 2018;

Updated Information &
Services
References
Subspecialty Collections
Permissions & Licensing
Reprints
including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/142/2/e20172156
This article cites 38 articles, 7 of which you can access for free at:
http://pediatrics.aappublications.org/content/142/2/e20172156#BIBL
This article, along with others on similar topics, appears in the
following collection(s):
Pharmacology
http://www.aappublications.org/cgi/collection/pharmacology_sub
Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on August 30, 2018

 Outpatient Opioid Prescriptions for Children and Opioid-Related Adverse
Events
Cecilia P. Chung, S. Todd Callahan, William O. Cooper, William D. Dupont,
Katherine T. Murray, Andrew D. Franklin, Kathi Hall, Judith A. Dudley, C. Michael
Stein and Wayne A. Ray
Pediatrics 2018;142;
DOI: 10.1542/peds.2017-2156 originally published online July 16, 2018;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/142/2/e20172156

Data Supplement at:

http://pediatrics.aappublications.org/content/suppl/2018/07/13/peds.2017-2156.DCSupplemental

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
1073-0397.

Downloaded from www.aappublications.org/news by guest on August 30, 2018