SPECIAL TOPIC SERIES ON OPIOID THERAPEUTICS AND
Opioid Use Disorder in Children and Adolescents
Risk Factors, Detection, and Treatment
Seth Eisdorfer, MD* and Jeffrey Galinkin, MD†
Abstract: Opioid medications are an important tool in the man-
agement of pain and have been used in clinical practice for cen-
turies. However, due to the highly addictive nature of this class of
medications coupled with the life-threatening side effect of respi-
ratory depression, opioid misuse has become a significant public
health crisis worldwide. Children and adolescents are at risk for
opioid misuse, and early detection is imperative to facilitate treat-
ment and improve outcomes. This review will address the current
state of opioid misuse and treatment in children and adolescents in
the United States.
Key Words: opioid use disorder, tolerance, dependence, addiction,
iatrogenic dependence, opioid, withdrawal, medical misuse, non-
medical use, medication assisted therapy
(Clin J Pain 2019;35:521–524)
O pioid misuse and abuse have become a significant public
health concern. As many as 33 million people abuse
opioids worldwide according to the 2016 World Drug Report.
In the United States alone, 97.5 million people 12 years of age
and older use prescription pain relievers. According to the
National Survey on Drug Abuse and Health (NSDUH), of
the 97.5 million Americans who use prescription opioids, an
average of 12.5 million misused opioid prescriptions in the
year 2015. This includes 2.1 million people who misused pain
relievers for the first time.1 Opioid prescriptions have steadily
increased over the last 25 years, peaking in 2010.2 In con-
junction, opioid-related emergency room visits,3 use of opioid
medications in attempted suicides,4,5 and opioid overdose
deaths6 have all increased. Inappropriate use of prescription
opioids (nonmedical use and medical misuse) as well as heroin
use have also increased as prescription opioids have become
increasingly prevalent. Almost 80% of new heroin users have
previous experience with opioid pain medications.7,8
There is a growing body of evidence that opioid exposure
and opioid use in childhood increases the likelihood of devel-
oping an opioid use disorder (OUD),9,10 and earlier onset of
use is associated with increased severity. Early detection and
Received for publication January 10, 2019; accepted January 22, 2019.
From the Departments of *Anesthesiology; and †Anesthesiology and
Pediatrics, University of Colorado, Children’s Hospital Colorado,
Aurora, CO.
The authors declare no conflict of interest.
Reprints: Jeffrey Galinkin, MD, Departments of Anesthesiology and
Pediatrics, University of Colorado, Children’s Hospital Colorado,
10045 E 16th Avenue, B090, Aurora, CO 80045 (e-mail: Jeffrey.
galinkin@childrenshospital.org).
Supplemental Digital Content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML
and PDF versions of this article on the journal’s website, www.
clinicalpain.com.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/AJP.0000000000000708
Clin J Pain  Volume 35, Number 6, June 2019
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
CONCERNS IN PEDIATRICS
treatment of suspected opioid misuse is key because of the high
relapse rate with OUD without professional involvement.
Medication-assisted treatment (MAT) is effective in treating
OUDs, but is rarely used in pediatrics. Adult programs are not
as appropriate for children and adolescents because of the
complex neurobiological and psychological complexities of
younger patients, and there is a paucity of pediatric providers
trained in the management of OUDs. Recently, the American
Academy of Pediatrics released a policy statement calling for
expanded access to MAT.11
TRENDS IN OPIOID PRESCRIPTIONS IN
CHILDREN AND ADOLESCENTS
Although the total number of annual opioid pre-
scriptions given to children and adolescents age 0 to 17 years
old has not increased over the past several years, 2.5 million
Americans 17 years of age or younger received at least one
opioid prescription in 2012, and of these 2.5 million, 1.14%,
received 5 or more opioid prescriptions.12 According to the
2015 NSUDH, 5.7 million youth age 12 to 17 were past year
users of prescription opioids and 12.5 million people 12 years
or older misused prescription pain relievers. Of these 12.5
million, almost one million were under 17 years old.1 Long-
term trends indicate that 25% of high school seniors report
medical or nonmedical prescription opioid use13 and almost
8% of high school seniors reported prescription opioid use in
2016.2 Among seventh to 11th graders prescribed opioids, the
rate of misuse has been reported to be from 17 to over
20%.14,15 With recent trends towards decreased opioid pre-
scriptions and increased availability and purity of heroin,
there is concern that heroin use has increased in prevalence as
prescription opioids have become harder to attain.16
Early onset of substance abuse can lead to significant
changes in the developing brain;17 therefore early detection
and treatment is of the utmost importance. It is paramount
that pediatric and adult primary care providers as well as
anyone who prescribes opioids are aware of the risks of opioid
use and misuse and are able to screen for a potential OUD.
Although the majority of patients use opioids appropriately,
prescribers must be aware of the risk factors and screening
tools at their disposal.
MEDICAL USE, MEDICAL MISUSE, AND
NONMEDICAL USE OF PRESCRIPTION OPIOIDS
There has been significant debate about the terminology
used when discussing appropriate versus inappropriate use of
prescription opioids. Medical use refers to the appropriate use
of one’s own prescription as written by the prescriber. Medical
misuse suggests the use of one’s own prescribed medication in
a manner incongruent with the prescriber’s instructions (using
more than the recommended dose at one time, taking more
frequently, taking to get high, coingesting with alcohol or
www.clinicalpain.com | 521
Eisdorfer and Galinkin
other substances). Nonmedical use refers to the taking of
medication prescribed to someone else. Either medical misuse
or nonmedical use could be defined as medication abuse.
Because of confusion and issues associated with data report-
ing, the 2015 NSDUH combined questions about medical
misuse and nonmedical use into one category simply termed
“misuse.” This revision addressed the following 3 questions:
(1) “use without a prescription of one’s own,” (2) “use in
greater amounts, more often, or longer than the respondent
was told to take them,” and (3) “use in any way a doctor did
not direct the respondent to use them.”1
Perhaps less important than the terminology used is the
reason individuals chose to misuse or abuse opioids.
According to a 2012 survey of 2964 Detroit area 7th to 12th
graders, pain relief is the most common motive for medical
misuse and nonmedical use of prescription opioids, reported
as the most prevalent motive in 84.2% and 87.6% of
respondents respectively.18 These rates were consistent with
previously published data by the same researchers.19–21 Other
less common responses included to experiment, to relax, to
help sleep, and to get high, which was the second most
popular response. Those who misused prescription opioids
for motives other than pain relief only were more likely to use
other substances, engage in opioid diversion, and test positive
on screening tools (these screening tools will be discussed
later). Those individuals who misused opioids solely for pain
relief had similar screening characteristics to those who used
opioids appropriately and nonusers. So although the source
of prescription opioids is important, it may not be as
important as the impetus for misuse in determining which
patients would most benefit from intervention.
TOLERANCE, DEPENDENCE, AND ADDICTION
Opioids can play a valuable role in both acute and chronic
pain management when medically indicated. However, practi-
tioners must recognize appropriate indications and monitor for
appropriate use. Any provider who prescribes opioids should
be cognizant of the potential for development of tolerance,
dependence, and addiction. Tolerance is defined as a decrease
in pharmacologic response following repeated or prolonged
drug administration. Tolerance can be innate or acquired.
Innate tolerance refers to individuals who are pharmacoge-
netically insensitive to a particular drug. The variable genetics
of opioid metabolism have been well categorized, and this
understanding has led to the American Academy of Pediatrics’
recommendation that codeine not be used in individuals under
12 years old.22 Individuals with innate tolerance for a particular
opioid would expectedly have decreased therapeutic effect after
initial dosing. These patients may benefit from opioid rotation,
as they might be less innately tolerant of different opioids.
Acquired tolerance refers to the diminishing ther-
apeutic effect seen with repeat dosing of a drug. Opioid
tolerance is a multifactorial process, and is complicated by
the differential tolerance to opioid effects- that is, patients
may develop tolerance to the analgesic potential before
developing tolerance to the respiratory effects.23 This leads
to the very real concern that opioid misusers will take
increased doses of medication to obtain pain relief and put
themselves at greater risk of adverse respiratory events.
Dependence is a physiologic phenomenon where the body
needs the drug to be exogenously administered to prevent
withdrawal symptoms. Dependence is seen with a number of
substances and pharmaceutical agents, including caffeine, nic-
otine, alcohol, sugar, antiepileptics, antidepressants, as well as
522 | www.clinicalpain.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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Clin J Pain  Volume 35, Number 6, June 2019
opioids. A more appropriate term is physical dependence as
this highlights the biochemical nature of the drug dependence.
Conversely, addiction is a primary, chronic neurobiological
disease state of altered neurotransmission and reward path-
ways. Characteristics of addiction are inability to consistently
abstain from a substance, cravings, lack of self-control, and
persistent remission/relapse cycle. Individuals struggling with
addiction often engage in harmful behavior, including lack of
self-care, compromise of interpersonal relationships, and crim-
inal behavior for the sake of obtaining the rewarding entity.
According to the American Society of Addiction Medicine,24
addiction is characterized by the following:
(1) Inability to consistently abstain;
(2) Impairment in behavioral control;
(3) Cravings;
(4) Diminished recognition of significant problems;
(5) A dysfunctional emotional response.
It is important to recognize that this is not a diagnostic
tool; a diagnosis of addiction requires a comprehensive
assessment by addiction experts. However, opioid prescrib-
ing providers as well as primary care providers should be
aware of these symptoms and should have a low threshold
for referral to an addiction specialist.
In order to diagnose a substance abuse disorder (SUD),
addiction specialists may refer to the latest iteration of the
Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5). In the DSM-5, the terms abuse and depend-
ence have been removed. The DSM-5 now refers to individual
SUDs, depending on the specific substance. SUD are further
classified on the basis of severity-mild, moderate, or severe,
depending on the number of symptoms or criteria present. The
DSM-5 criteria for OUD can be found in Appendix 1 (Sup-
plemental Digital Content 1, http://links.lww.com/CJP/A566)25.
RISK FACTORS FOR OPIOID USE DISORDER IN
CHILDREN AND ADOLESCENTS
There are various socioeconomic, genetic, and environ-
mental risk factors associated with OUDs in children and
adolescents. There are also numerous psychological and psy-
chiatric comorbidities that may predispose individuals to a
SUD. According to Groenwald and colleagues, the following
socioeconomic characteristics are associated with the highest
rates of opioid prescriptions and opioid use: White non-His-
panic, older adolescence, having insurance, and residing in a
region other than Northeastern United States.12 Several studies
have noted a preponderance of White non-Hispanics among
prescription opioid misusers.18,26–29 According to a study by
McCabe and colleagues in 2013 investigating the motives for
medical misuse of prescription opioids, African Americans were
more likely than Whites to report misuse, but 75% of African
American misusers were motivated solely by pain relief whereas
only 30% of White misusers were motivated solely by pain
relief.18 More recently, Vaughn and colleagues have shown a
decrease in the prevalence among White non-Hispanics to a
similar level as that of African American and Hispanic
adolescents.26 Overall lifetime medical use of opioids is slightly
higher in females, but males are more likely to engage in
misuse.27 As for genetic predisposition, population based twin
studies30 suggest a genetic component to SUDs and more
recent genomic studies31,32 have identified specific poly-
morphisms that may be associated with OUDs.
The most important factors in pediatric opioid misuse
appear to be access to prescription drugs and age of exposure.
Clin J Pain  Volume 35, Number 6, June 2019
The majority of opioid misusers started with appropriate
medical use of opioids (McCabe 2017) and exposure prior to
13 years old was associated with increased chance of pre-
scription drug abuse and dependence.27
A significant number of adolescents and young adults
with SUDs also have psychiatric comorbidities. According
to Welsh and colleagues, individuals who met criteria for an
OUD were over twice as likely to have an anxiety related
diagnosis and over three times as likely to have Generalized
Anxiety Disorder.29 There is also increased association
between opioid misuse and depressive disorders and between
opioid misuse and externalizing behavior disorders such as
attention-deficit/hyperactivity disorder, oppositional defiant
disorder, and conduct disorder.
DETECTION AND TREATMENT OF OPIOID USE
DISORDERS
The detection of opioid misuse is of utmost importance in
the fight to gain control of the opioid epidemic. Multiple
screening tools are available to the pediatric provider and
should be used for the ongoing assessment of SUDs in at-risk
patients. The Drug Abuse Screening Test (DAST), first created
in 198233 has undergone multiple iterations and the current
short form, the DAST-1034 is a useful tool to evaluate past-year
substance use, not including alcohol and tobacco. It is a series
of 10 yes/no questions and the higher the score, the more
concerning for a SUD; a score of 3 or higher may warrant
further investigation.
The CRAFFT tool35 was developed as a brief self-report
screening test to detect alcohol and drug use specifically in
adolescents between the ages of 14 and 18. It is a mnemonic for
6 yes/no questions: (1) Have you ever ridden in a car driven by
someone (including yourself) who was high or had been using
alcohol or drugs? (2) Do you ever use alcohol or drugs to relax,
feel better about yourself, or fit in? (3) Do you ever use alcohol
or drugs while you are by yourself (alone)? (4) Do you forget
things you did while using alcohol or drugs? (5) Do your family
or friends ever tell you that you should cut down on your
drinking or drug use? (6) Have you ever gotten into trouble
while you were using alcohol or drugs? The CRAFFT tool is
highly correlated with the Personal Involvement with Chem-
icals Scale (PICS), and a score of 2 or higher on the CRAFFT
has sensitivity and specificity of 0.80 and 0.86, respectively, for
detecting any substance abuse or dependence, and sensitivity
and specificity of 0.92 and 0.80, respectively, for detecting
substance dependence.36 It has been demonstrated that the
prevalence of opioid diversion, getting high as a primary
motive, and intranasal administration of opioids were higher
with a positive screen on the CRAFFT assessment.37 This same
group demonstrated that the odds of positive lifetime
CRAFFT and past-year DAST-10 screens were 8 and 15 times
higher respectively for medical misusers motivated by nonpain
relief motives versus non-users. Of note, there was no difference
between nonusers, appropriate medical users, or medical mis-
users motivated by pain relief only. These 2 tools, either alone
or in combination, can be very helpful in determining which
patients need closer monitoring and/or referral to an addiction
specialist for formal evaluation.
Once a diagnosis of an OUD is made, appropriate
treatment is imperative to ensure success. OUD has one of
the highest relapse rates, and only a small percentage of
younger patients seek treatment. Appropriate treatment
involves behavioral intervention plus or minus medication
therapy. Currently, only 10% of American children and
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Opioid Use Disorder in Children and Adolescents
adolescents with a SUD receive any sort of treatment, and
those who do rarely receive MAT.38 The use of pharma-
cotherapy in addiction treatment has robust evidence;
however it remains underutilized. Knudsen and colleagues
found that in a nationally representative survey of privately
funded addiction treatment facilities, less than half utilized
pharmacotherapy, and within those that did, only 34.4% of
patients with OUD received medication therapy.39 Phar-
macotherapy for OUD relies on one of 3 agents: methadone,
buprenorphine, and naltrexone. Methadone is an opioid
agonist with a very long half-life and NMDA receptor
effects; although methadone is a highly effective treatment
and a mainstay of therapy in adults, federal regulations
prevent most programs from admitting patients under
18 years old. Buprenorphine is a partial opioid agonist and
has become a very attractive option for pediatric OUD
treatment. Buprenorphine has good evidence in adults, and
2 randomized controlled trials have been conducted in
adolescents. Marsch and colleagues compared 2 weeks of
buprenorphine treatment to 2 weeks of clonidine treatment
in 13 to 18 year olds. Both groups received substance use
counseling. Those in the buprenorphine group were more
likely to continue medical care than the clonidine group.40
Woody and colleagues compared a 2-week treatment period
to an 8-week treatment period in patients age 15 to 21 years
old. Those in the 8-week treatment arm had lower rates of
illicit opioid use during the treatment period; the difference
disappeared after termination of therapy, however.41 In a
more recent retrospective review, Matson found that con-
tinued buprenorphine compliance can lead to long-term
sobriety.42 In 2000, Congress passed the Drug Addiction
Treatment Act, which allows physicians to enroll in an
8-hour course and apply for a waiver to prescribe bupre-
norphine for OUD. The AAP are ensuring pediatricians
have access to this treatment modality and there is an AAP-
endorsed buprenorphine waiver course at http://www.aap.
org/mat.11
Naltrexone, a pure opioid antagonist, has potential
utility as well. It has limited research in the pediatric pop-
ulation and there are issues with compliance. A new con-
trolled release injectable form is now available which has the
potential to improve compliance.
CONCLUSIONS
The opioid public health crisis is well recognized and its
effect on children and adolescents is well documented.
Advances in prescriber education, increased public awareness,
use of state monitoring programs, and more robust federal
oversight over the last few years have led to a decrease in
opioid prescriptions; however, opioid overdose deaths are still
on the rise. Opioids play an important role in pain manage-
ment, and in appropriate cases can be very beneficial. How-
ever, opioid prescribers must be vigilant and maintain a low
threshold for considering an OUD. Providers can utilize
validated screening tools and should consider referral to an
addiction expert if there is significant concern. To help
improve access to MAT, providers can obtain specialized
training in the use of buprenorphine for OUD.
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