Opioid Therapy in Infants, Children, and Adolescents

Opioid analgesics are among the most effective medications for pain management but are associated with serious and increasing public health problems, including abuse, addiction, and death from overdose. Currently, there is an opioid epidemic in the United States with the rate of prescription opioid-related overdose deaths quadrupling over the last 15 years. Pediatric patients are particularly vulnerable to the devastating consequences of opioid misuse. Adolescents who are prescribed opioids are at a higher risk for abusing illicit drugs later in life. Clinicians managing pediatric pain must account for such issues while still delivering effective analgesia to young patients who suffer from both acute and chronic pain. 

 

Opioid Therapy in Children and Adolescents is designed to explore the unique aspects of opioid therapy in pediatric patients.  An introductory framework provides historical context and describes the epidemiology of the opioid crisis with focus on pediatric implications. Subsequent chapters focus on pediatric opioid pharmacology, safe opioid prescribing practices, and non-opioid alternatives to managing pediatric pain states, including multimodal analgesic strategies, interdisciplinary approaches, and complementary medicine. Mitigation strategies against pediatric opioid diversion and misuse are addressed to help clinicians develop practice changes that protect pediatric patients from opioid-related morbidity and mortality. Clinical case examples are also utilized throughout the text to provide grounding for each chapter and a context within which to examine pertinent issues. 

 

This first of its kind book provides a comprehensive approach that will guide clinicians to appropriately and safely prescribe opioid analgesics to pediatric patients suffering from pain. It is an invaluable resource for pediatricians, family practitioners, anesthesiologists,pediatric oncologists, and other clinicians who manage pediatric pain.

• Language: English
• Publisher: Springer
• Release date: Feb 21, 2020
• ISBN: 9783030362874

Book preview

Part IAn Opioid Crisis with Pediatric Implications

© Springer Nature Switzerland AG 2020

R. D. Shah, S. Suresh (eds.)Opioid Therapy in Infants, Children, and Adolescentshttps://doi.org/10.1007/978-3-030-36287-4_1

1. Epidemiology and Public Health Implications of the Opioid Crisis

Michael D. Mendoza¹, ²   and Holly Ann Russell²

(1)

Monroe County Health Department, Monroe County, NY, USA

(2)

Department of Family Medicine, University of Rochester Medical Center, Rochester, NY, USA

Michael D. Mendoza

Email: [e-mail]

Keywords

OpioidOpioid use disorderSubstance use disorderOverdoseAddictionPainPain managementMedication-assisted treatment

The opioid overdose crisis is the public health epidemic of our generation. Our country has seen a decline in life expectancy only twice since the mid-twentieth century. In the first instance, at the height of the AIDS epidemic, life expectancy declined in 1993. In the second instance, at present – and for three consecutive years and counting – the United States has seen life expectancy decline from 2015 to 2017 [1]. Not since the period between 1915 and 1917 has the United States seen three consecutive years of decline. While the opioid crisis is accepted as a major contributor to the present decline in life expectancy, most experts believe that opioids tell only part of the story. A larger trend involving opioid overdoses, together with deaths from suicide and alcohol-related causes, has been characterized as its own epidemic of the so-called diseases of despair, an epidemic whose risk factors and solutions are even more elusive than for any of these conditions alone.

According to the Centers for Disease Control and Prevention, more than 130 Americans die every day from an opioid overdose. Dating back to 1999, the total number of overdoses is estimated at over 700,000. Most concerning about these statistics is the uncertainty over whether we have seen the worst of the epidemic. Deaths from drug overdose increased through 2017 among both men and women, all races, and adults of all ages, and two-thirds of these deaths involved an opioid [2].

The rise in opioid overdose deaths can be described according to three waves. In the first, beginning in approximately 1999, deaths were attributable primarily to prescription opioids. In the second surge, beginning in approximately 2010, heroin was responsible, coinciding with a plateau in deaths attributable to prescription opioids. In the current wave, synthetic opioid overdoses have driven the greatest increase in opioid overdoses fatalities (see Fig. 1.1).

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Fig. 1.1

Three waves of the rise in opioid overdose deaths. (Source: National Vital Statistics System Mortality File)

Addiction and the Rise of the Opioid Epidemic

In order to properly understand the context of the contemporary epidemic it is first important to understand the fundamental role of addiction and chemical dependence. Addiction is defined as a brain disease that is manifested by compulsive substance use despite harmful consequences. People with addiction (severe substance use disorder) have an intense focus on using a certain substance to the point that it takes over their lives even while knowing that use will cause problems [3]. It is important to note that addiction is not a personal choice, nor is it a sign of an individual’s character, spirituality, or morality. This bears repeating given the immense stigma attributed to the illness, its treatment, and, importantly, to those who struggle with this disease.

The protective factors and risk factors for addiction are notable because they are distinct from the risk factors for overdose (see Table 1.1). Efforts to prevent addiction are critical, and these efforts alone will not stem the rising tide of opioid overdose.

Table 1.1

Risk and protective factors for drug addiction

The prevalence of addiction over the years has remained largely unchanged in recent years (Fig. 1.2). Alcohol remains the most common, and addiction rates, in general, have remained relatively unchanged over the past 10 years. Rates of addiction to opioids of all types have also remained relatively stable, a surprising finding given the rapid rise in mortality attributable to overdoses from opioids overall.

../images/462377_1_En_1_Chapter/462377_1_En_1_Fig2_HTML.png

Fig. 1.2

Prevalence of addiction. Notes: ∗Difference between this estimate and the 2014 estimate is statistically significant at the .05 level. Illicit drugs include marijuana/hashish, cocaine (including crack), heroin, hallucinogens, inhalants, or prescription psychotherapeutics used non-medically. Nonmedical use of prescription psychotherapeutics includes the nonmedical use of pain relievers, tranquilizers, stimulants, or sedatives. In 2015, changes were made to the NSDUH questionnaire and data collection procedures that do not allow comparisons between 2015 and previous years for a number of outcomes. (Source: Center for Behavioral Health Statistics and Quality, (2015) [13])

Tolerance and withdrawal develop within weeks of chronic opioid use, and many patients with substance use disorders continue to use simply to avoid symptoms of withdrawal. Tolerance and withdrawal are part of a diagnosis of opioid use disorder but are not enough for a diagnosis if the patient is taking prescription opioids exactly as prescribed. Other symptoms such as using larger amounts and/or for longer periods, the inability to cut down on use, increased time spent obtaining, using, or recovering from use as well as continuing to use despite negative social or physical consequences help determine if a patient’s opioid use disorder is mild (two to three symptoms), moderate (four to five symptoms), or severe (greater than or equal to six) [3].

When comparing the prevalence of addiction and overdose mortality over time, the data show that the former alone does not explain the latter. Although addiction has remained relatively constant, the fatality rate from opioid use has risen dramatically. For this reason, one cannot assume that reducing addiction prevalence alone will reduce opioid overdose mortality.

The Origins of the Contemporary Opioid Crisis

Pain as the fifth vital sign

The contemporary epidemic dates back to the mid-1990s when attention to identifying and treating pain gained greater prominence as a means by which health care providers and practices ought to engage patients in health care decision making. Pain was a common concern around which to promote shared decision making, and on the face of it, pain seemed a logical choice. Unfortunately, this movement coincided with broader efforts within health care reform to improve quality through the use of performance incentives to improve service delivery. Pain was promoted as the fifth vital sign and became a ubiquitous part of routine assessment across virtually every health care setting. As the recognition of pain grew, so did the implicit goal of reducing pain. Often pain reduction was put forward as an explicit goal, subject to performance incentives. Although data to substantiate causation between these occurrences are lacking, it is clear that opioid prescribing increased dramatically in the early 2000s. At the same time, patient expectations for pain relief grew, further driving demand for medications to reduce pain.

Role of the pharmaceutical industry

As insurers limited coverage of behavioral pain therapy, pain medications gained popularity. Sensing an opportunity, pharmaceutical manufacturers produced extended-release formulations, transdermal patches, and nasal sprays, among other formulations in an effort to meet this demand. Although the impact of the pharmaceutical industry and opioid prescribing on the opioid epidemic is complex and currently the subject of much scrutiny, there is little doubt that the proliferation of opioid pain medications is associated with the marked increase in consumption and overdose. This increase coincided with the withdrawal of non-opioid analgesics like COX-2 inhibitors out of concern for cardiovascular risk. Pharmaceutical companies marketed opioids and improperly minimized their addictive potential (e.g., OxyContin®), promoted off-label use (e.g., Actiq®), and devised lucrative incentives to prescribers to promote and prescribe opioids. For OxyContin® alone, through aggressive marketing and promotion, sales grew from $48 million in 1996 to almost $1.1 billion in 2000. By 2004, OxyContin became the leading drug of abuse in the United States [4]. By 2010, the number of opioid prescriptions reached a peak such that there were enough prescriptions to medicate every adult in the United States around the clock for a month.

Aggressive response to overprescription

As the connection between increased opioid-related mortality and increased opioid prescribing became apparent, clinicians and policymakers began to question the effectiveness and safety of outpatient opioid pain medications. Attention shifted to promote non-opioid modalities of managing pain. In 2016, the Centers for Disease Control and Prevention issued guidelines for prescribing opioids for chronic pain in which they concluded that evidence on long-term opioid therapy for chronic pain outside of end-of-life care remains limited, with insufficient evidence to determine long-term benefits versus no opioid therapy [5]. Statewide prescription drug monitoring programs, or PDMPs, developed across the country in an effort to identify doctor-shopping and curb the diversion of controlled medications. These efforts were largely successful and prescription rates dropped nationally almost 13% between 2012 and 2015. Paradoxically, however, the national overdose death rate increased 38% during these years [6]. A widely accepted explanation for this is that as opioid prescriptions grew more difficult to obtain and more expensive to purchase, opioid users who were physically dependent on prescription opioids sought alternatives, typically on the street in the form of diverted prescription pills and heroin. As a result, the prevalence of heroin use increased irrespective of gender, age, and socioeconomic status. Deaths due to heroin-related overdose increased by 286% from 2002 to 2013, and approximately 80% of heroin users admitted to misusing prescription opioids before turning to heroin [7].

Emergence of fentanyl and fentanyl analogs

As the cost of heroin grew in the mid-2010s and as interdiction efforts intensified, a market for more potent and less bulky opioids emerged. Illicitly manufactured fentanyl and its analogs have been implicated in a growing proportion of fatal opioid overdoses, largely due to their potency and unpredictability when mixed with other opioids or other drugs of abuse. Between 2013 and 2016, deaths attributed to fentanyl analogs surged 540% nationally even as prescription opioid rates declined modestly. The preponderance of fentanyl and other synthetic analog-related mortality continues to this day and is a major reason for the opioid crisis having been declared a national public health emergency.

Health and Public Health Implications of the Opioid Epidemic

As a chronic illness, addiction should be treated as such within our health care and public health sector. Efforts to prevent addiction should be prioritized, when possible, and the management of addiction is optimized when integrated team-based models are present to manage a patient’s condition over time and across different care settings. Addiction is particularly complicated because it remains highly stigmatized within the general public, as well as among clinicians and our systems of care. When rules governing reimbursement and compliance differ for addiction when compared to other conditions, however, care for patients with opioid use disorder is further stigmatized.

To an even greater extent than for addiction itself, opioid overdose is a public health epidemic like no other. That prescription opioid overdose death rates have not substantially dropped despite declining opioid prescriptions underscore the reality that the solution to this epidemic will not reside solely within the walls of traditional medical care settings. Within health care, mental health care and substance care will need to play a greater role, especially within integrated primary care settings. Community-based organizations, law enforcement, education, criminal justice, government, and advocacy groups are all important stakeholders. Perhaps more so than in other chronic illnesses, peer advocates and the families and patients themselves are also important stakeholders, both as facilitators and as beneficiaries of care.

History of Addiction Treatment

Like other chronic illnesses, treatment approaches for addiction are complex, involve a diverse array of health disciplines and professionals, and are heavily influenced by social determinants in the relevant communities where those who struggle with addiction reside. To the extent that overdose is related to – though epidemiologically distinct from – addiction, approaches to the prevention and treatment of addiction will be necessarily different from those needed to prevent overdose. In the conventional paradigm of acute on chronic illness overdose could be characterized as an acute exacerbation of chronic addiction.

History of addiction treatment

The contemporary challenges in addiction treatment find their origins in the early twentieth century. The Harrison Anti-Narcotic Act of 1914 which was [an] act to provide for the registration of, with collectors of internal revenue, and to impose a special tax on all persons who produce, import, manufacture, compound, deal in, dispense, sell, distribute, or give away opium or coca leaves, their salts, derivatives, or preparations, and for other purposes. This law focused primarily on taxation and marketing of opiates; however, there was a clause related to physician’s offices which allowed distribution in the course of his professional practice only. This was interpreted to mean that it was illegal to use prescription opioids to treat opioid dependency as addiction was not considered a medical illness at that time. This was codified into law in 1919 when the Supreme Court ruled that the Harrison Act was constitutional and in another court case that firmly stated physicians could not prescribe opioids for maintenance of a person with opioid dependence [8, 9].

Introduction of methadone for treatment of opioid addiction

For many years the law persisted that opioids could not be prescribed as a mainstay of treatment for a person with opioid dependence. In 1939, methadone was introduced in Germany as an alternative pain medication. Thought to be less addictive than morphine, methadone was introduced into the United States as a pain reliever after World War II. It was not until the 1960s when many soldiers were coming home from the Vietnam War suffering from heroin addiction that the United States began looking into using methadone as a treatment option [10]. In 1972 the federal government published guidelines for using methadone as a treatment for opioid use disorder and evidence emerged showing that methadone meets most criteria for a pharmacologic agent for chronic treatment of an addiction [11].

Current Approach to Addiction Treatment

The current paradigm for opioid use disorder treatment crosses multiple levels of care. Care is oriented in this way to facilitate person-centered care, but it can be confusing for professionals outside of addiction medicine, not to mention for patients and families seeking to navigate the complicated system.

Detoxification

Patients with severe opioid use disorder generally begin in an inpatient or outpatient detoxification program (commonly referred to as detox). The goal of detox is for patients to discontinue using the substance to which they are dependent in a safe and monitored environment. Often medications are provided to help with the symptoms of withdrawal including nausea, diarrhea, and cramping. However, the goal of detox is to get patients completely off of opioids and patients do not generally begin any form of Medication for Opioid Use Disorder (MOUD) in detox. Detox is short, often only 7–10 days, and so the goal is typically to directly transfer patients to an inpatient treatment facility (referred to as going bed to bed). Inpatient chemical dependency programs typically last from 14–28 days and provide counseling, structured programming, a safe living environment, and, if appropriate, medication-assisted therapy. After completing inpatient treatment, patients are then transferred to an intensive outpatient program (IOP).

Intensive outpatient program

Patients with a mild or moderate opioid use disorder may begin their treatment at the IOP level. IOP typically involves attending group sessions two to three times a week, meeting with a therapist individually at least once/week, and meeting with a physician once/week to once/month depending on their progress in the program and their use of MOUD. At any point in their treatment progress after detox or inpatient stays, patients may elect (or may be mandated by drug courts or probation) to live in a supportive living environment. These range from highly regulated residential treatment programs where patients are mandated to attend programs, have curfews, and get care management to sober living houses that are peer run to for profit housing that provides little to no structure.

Integrated primary care

As the standard of care has evolved toward viewing addiction as a chronic disease, primary care clinicians have been increasingly called upon in their position as experts in the long-term management of chronic diseases. The Drug Addiction Treatment Act of 2000 enabled physicians who receive a special waiver from the DEA to prescribe buprenorphine for treatment of OUD outside of a chemical dependency center. However, there are many barriers for primary care clinicians to get the waiver including the need for additional training, the fear of the DEA, time constraints in primary care, and concerns about attracting drug addicts to their practice [12]. The development of different models for integrating substance use treatment and MOUD into primary care will help expand access for patients [13].

Residential treatment

Because adequate housing and a supportive environment are strong facilitators of remission – and because securing housing can be complicated – it is important to consider housing within the long-term treatment plan. Community residencies (i.e., halfway houses) can be critical components of treatment for many patients. In a typical community residence, a patient may live for 3–6 months with support from staff and care coordinators who are present 24/7. They often access treatment and recovery programs in the community as well as vocational and educational services on site. In supportive living arrangements, patients live independently with minimal staff support. These arrangements can last for 1 or 2 years.

Peer navigators

Peers can also be an important part of a patient’s recovery process. A peer is someone with lived experience with addiction. A recent review found that there is evidence for the efficacy of peer-delivered services; however, most studies were of low methodologic quality and the definition of a peer and role can vary greatly. There are training programs run by the government to become certified peer advocates, which helps to provide some standardization; however, there is not always complete consistency with peer training and with the services they can provide. This is an area that is a priority for ongoing research [14].

Medication for Opioid Use Disorder

Medication for Opioid Use Disorder (MOUD) is the use of pharmacotherapy, usually in combination with counseling or behavioral therapies, for the treatment of substance use disorders. There are three medications that are currently approved as pharmacotherapy for opioid use disorder. The development of new models for integrating substance use treatment and MOUD into primary care will help expand access for patients [13].

Opioid agonists

Opioid agonists act to prevent the withdrawal symptoms, which are what drive many patients to continue to use opioids, and to help decrease cravings for continued illicit use. Maintenance therapy with opioids is well established through decades of clinical practice and scientific evidence to reduce the risk of fatal overdose and all-cause mortality and are considered first-line treatment options for patients with opioid use disorder [15].

Methadone, a full opioid agonist, can only be prescribed within approved chemical dependency treatment programs and usually requires frequent (either daily or weekly) office visits for dosing with no potential to graduate and little room for spacing out the frequency of visits. Additionally, because the use of methadone requires a specialized treatment center, there are often additional barriers including stigma associated with methadone clinics, distance required to attend the program, and limits on numbers of patients able to enroll [16].

Buprenorphine, a partial opioid agonist, can be prescribed by physicians outside an approved chemical dependency program thanks to the Drug Addiction Treatment Act of 2000 which allows physicians who obtain a special waiver from the DEA to prescribe buprenorphine for treatment of OUD outside of a chemical dependency center. Unlike methadone, it is possible for primary care clinicians to obtain a waiver and to prescribe buprenorphine for OUD within a traditional primary care setting. While this presents great opportunity for expanding access to maintenance therapy in primary care, perceptions among physicians have been slow to evolve: compliance concerns and the fear of the DEA, time constraints in primary care, and concerns about attracting drug addicts to their practice; among others are common barriers that warrant ongoing attention [12].

Opioid antagonists

Naltrexone, available in tablet or injectable form, is an opioid antagonist and acts by blocking the opioid receptor and preventing other opioids from binding. A Cochrane review in 2008 showed no benefit to oral naltrexone for use of opioids and retention in treatment at 1 year as compared to placebo. More recent studies comparing the long-acting injectable form of naltrexone have shown comparable efficacy to buprenorphine [17–19]. No special license or training is required for naltrexone and it can be used routinely in a primary care or chemical dependency treatment setting.

Behavioral Health Treatment for Opioid Use Disorder

Many patients also benefit from counseling or other behavioral health support. The DATA 2000 law requires that buprenorphine prescribers have access to refer patients to counseling. Unfortunately, this has been interpreted by many to mean that patients must be engaged in some type of psychosocial counseling in order to continue the medication, leading some insurance companies to deny payment for MOUD if patients are not engaged in counseling [20]. In fact, while some patients find therapy helpful, some do not and others prefer to obtain psychosocial support from religious, peer, or other community agencies. There is not clear evidence for additional benefit of therapy to medication treatment alone [21, 22]. To help address this common myth SAMHSA recently provided the following guidance: Many patients benefit from referral to mental health services or specialized addiction counseling and recovery support services. However, four randomized trials found no extra benefit to adding adjunctive counseling to well-conducted medical management visits delivered by thebuprenorphine prescriber [23].

Special Populations

Pregnancy, Neonatal Abstinence Syndrome, and Breastfeeding

The prevalence of opioid use increased from 1.2 to 5.6 per 1000 births annually from 2000 to 2009. Opioid use during pregnancy can result in newborns experiencing a drug withdrawal syndrome called neonatal abstinence syndrome or neonatal opioid withdrawal syndrome (NAS/NOWS). It is estimated that the proportion of infants born with NAS increased five-fold from 2004 to 2014.

This is of particular consequence during the postnatal period where newborns with NAS are more likely to have low birthweight and respiratory complications than other newborns [24].

NAS occurs in about 50–80% of infants exposed to opioid agonist maintenance therapy in utero. Buprenorphine results in less severe withdrawal in infants than methadone or morphine. There is no correlation with the dose of opioid maintenance therapy and the duration or severity of NAS [25]. Breastfeeding can help decrease the length of stay and the development of NAS [26]. Unfortunately, pregnant women may face additional barriers to treatment including fear of legal ramifications as in some states substance use in pregnancy can be prosecuted as child abuse [27].

Initiating treatment with buprenorphine requires pregnant women to go into mild to moderate withdrawal, which early studies showed can result in fetal distress and still-birth [28, 29]. More recent studies, however, show that withdrawal management can be safe [30]. Given the significant benefits, opioid agonist maintenance remains the standard of care in pregnancy, and both methadone and buprenorphine are recommended by the American College of Obstetricians and Gynecologists (ACOG) as first-line treatments for OUD during pregnancy. Opioid agonist therapy results in a 70% reduction in overdose-related deaths in pregnant women, decreased risk of HIV and hepatitis, and an increased engagement in prenatal care. Additionally, there are benefits to the fetus including decrease in intrauterine fetal demise, decrease in intrauterine growth restriction, and decrease in preterm delivery [31].

Adolescents

Substance use often starts in childhood or adolescence. In patients 15–24, the rate of OUD increased almost six-fold and rates of opioid related deaths increased 345% from 2001 to 2016 [32, 33]. There is evidence for the use of buprenorphine, naloxone, and methadone for adolescents with OUD. The American Academy of Pediatrics recommends the use of pharmacotherapy in adolescents with OUD and advocates increased resources to help with expanding access to treatment. Currently only 1% of providers with the waiver to provide buprenorphine are pediatricians [34]. Although evidence is lacking for the optimal duration of treatment, or for the impact of long-term exposure to opioid agonist/antagonist therapy, any risks associated with treatment must be balanced against the known risk of ongoing continued substance use. In most states, teens that present to treatment without their parents may consent for treatment for substance use, although it is important to explore why teens wish to withhold this information from their parents.

Overdose Prevention and Harm Reduction

Prevention and treatment for addiction are necessary but not sufficient to address the current opioid epidemic. The increasing lethality associated with fentanyl and its synthetic analogs warrants specific attention focused on addressing the risks factors for overdose.

Naloxone

Naloxone (e.g., Narcan®, Evzio®) is an opioid receptor antagonist that can reverse the toxic effects of an opioid overdose. The medication can be given by intranasal spray, or by intramuscular, subcutaneous, or intravenous injection. Naloxone is also added to buprenorphine to decrease the likelihood of diversion and misuse of the combination drug product (Suboxone®). Public health campaigns and community-based efforts to distribute naloxone and to educate the general public have shown promise in beginning to curb the rapid increase in opioid overdose fatalities nationwide.

Supervised injection sites

For those with injection drug use who may not yet be considering treatment, supervised injection sites may be a way to reduce some of the risk associated with active use. Also known as supervised consumption services, these locations are legally sanctioned facilities that allow people to consume pre-obtained drugs under the supervision of trained staff. Facility staff members do not directly assist in consumption or handle any drugs brought in by clients but are present to provide sterile injection supplies, answer questions on safer injection practices, administer first aid if needed, and monitor for overdose. Staff may also offer general medical advice and referrals to drug treatment, medical treatment, and other social support programs.

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© Springer Nature Switzerland AG 2020

R. D. Shah, S. Suresh (eds.)Opioid Therapy in Infants, Children, and Adolescentshttps://doi.org/10.1007/978-3-030-36287-4_2

2. The Impact of the Opioid Crisis on Neonates, Children, and Adolescents

Julie R. Gaither¹  

(1)

Pediatrics, Yale School of Medicine, New Haven, CT, USA

Julie R. Gaither

Email: [e-mail]

Keywords

OpioidsPoisoningsOverdoseHeroinFentanyl

Introduction

For the past several decades, opioids have been among the most frequently prescribed medications in the United States [1]. Today, they can be found in virtually every American home [2]. The widespread availability of these potent and addictive medications has taken an unprecedented toll on all segments of the US population, including millions of children and adolescents who are now growing up in homes and communities where they are routinely exposed to prescription opioids and increasingly illicit forms of the drug [1–8].

The roots of this crisis can be traced back to a fundamental shift in the late 1990s in how clinicians viewed and managed chronic non-cancer pain. Prior to this point, opioids were mainly used to manage end-of-life pain in patients with terminal cancer. It was not until the World Health Organization and the Department of Veterans Affairs began encouraging clinicians to consider opioids as part of a comprehensive approach to the management of non-cancer pain that opioids were widely used in this country. Between 1999 and 2010, retail sales for prescription opioids increased four-fold [9]. During this time, morbidity and mortality rates from accidental and intentional opioid poisonings (i.e., overdose) rose in tandem as did rates of opioid addiction, both of which have now reached unprecedented levels.

The United States has responded to this epidemic by enacting hundreds of measures at the federal and state level to contain the crisis. The vast majority of these measures focus on adults, specifically on curtailing opioid prescribing in this population. To date, these measures have largely failed. While there has been a slight decline in recent years in the number of opioid medications dispensed annually—from 248 million in 2011 to 240 million in 2013, a 3% decrease—the opioid crisis continues unabated. Nearly 10,000 more Americans died from opioid poisonings in 2016 than in 2015. In total, nearly 43,000 individuals died from opioid poisonings in 2016—more than in any previous year [10].

That opioids continue to be implicated in thousands of deaths each year speaks to the evolving nature of this epidemic. As limits have been placed on prescription opioids, Americans have increasingly turned to heroin and, more recently, illicitly manufactured fentanyl—a synthetic opioid that is 50–100 times more potent than heroin. From 2015 to 2016, overdose deaths from prescription opioids (excluding all synthetics but methadone) [11] increased by 10.6%, whereas fatal heroin poisonings increased 19.5%, and those from synthetic opioids (other than methadone) by 100% [12]. Synthetic opioids—primarily from illicitly manufactured fentanyl as opposed to pharmaceutical fentanyl —were implicated in 46% of opioid deaths in 2016.

Similarly, what was once an epidemic primarily affecting white men between the ages of 25 and 44 has now spread to all segments of US society, including the pediatric population. Opioids are now in virtually every American home, and even today, nearly 20 years after the opioid crisis began, the number of opioid prescriptions written in the United States each year outnumbers the entire adult US population, and in a quarter of states, annual prescribing rates exceed the state’s population [13].

In a young child, even a minimal exposure to opioids can be life threatening, and teens are at risk for accidental and intentional overdose as well as addiction. Yet despite the risks that opioids pose to children and adolescents, it remains an under-recognized public health problem. Nearly all of the measures enacted in recent years to reduce opioid poisonings target adults—a reflection of what little is known about pediatric opioid poisonings and the extent to which children have been harmed.

This chapter will summarize the evidence we have to date on the impact of the opioid crisis on the pediatric population. Specifically, it will address rising trends in morbidity and mortality among neonates, children, and adolescents and explore commonsense solutions to what is likely to remain a growing public health problem in the young unless further safeguards are put into place to protect this vulnerable group.

Neonatal Abstinence Syndrome

Epidemiology

The increased use in recent years of prescription and illicit opioids among women of child-bearing age has led to a substantial rise in neonatal abstinence syndrome (NAS) , a condition that occurs primarily among infants exposed in utero to opioids [14]. Exposure is caused by maternal use of illicit opioids (e.g., heroin) or opioids prescribed for either pain management or as part of medication-assisted treatment (MAT) for an opioid use disorder [14, 15].

NAS manifests in the newborn soon after birth when opioid withdrawal begins. It is characterized by central nervous system irritability (e.g., tremors, high-pitched cry) and overactivity of the autonomic nervous system (e.g., yawning and sneezing) as well as dysregulation of the gastrointestinal system (e.g., feeding difficulties, watery stools) [14–16].

The incidence of NAS in the United States increased by 383% between 2000 and 2012 [14]. Patrick et al. in a 2012 report estimated that between 2000 and 2009 opiate use among pregnant mothers increased from 1.19 to 5.63 per 1000 annual hospital births. During this time, rates of NAS among newborns rose from an annual incidence of 1.20 per 1000 hospital births to 3.39. Subsequent studies have shown that in 2012 alone, nearly 22,000 newborns in the United States were diagnosed at birth with NAS [17] and that the incidence increased five-fold for the United States as a whole in a little over a decade [18, 19].

The incidence of NAS, however, varies widely by state, as noted in a 2016 study by the Centers for Disease Control and Prevention of 28 states that used publicly available data collected by the Healthcare Cost and Utilization Project (HCUP). For the United States as a whole, the authors found that the incidence of NAS increased by 300% between 1999 to 2013 [14]. During this time, NAS rates increased in 27 of the 28 states examined, and the annual percent change in rates over time ranged from a low in Hawaii of 0.05 per 1000 hospital births to a high of 3.6 per 1,000 in Vermont [14]. In terms of actual number of NAS cases, Hawaii had 0.7 cases per 1000 hospital births compared to 33.4 in West Virginia [14].

Clinical Implications

It is estimated that between 60% and 80% of newborns exposed in utero to heroin or methadone will experience NAS, a condition marked by irritability, tremors, seizures, hypertonia, fever, respiratory distress, and intolerance to feedings as well as to a number of other adverse outcomes, including increased mortality risk [18]. Patrick et al. found that NAS infants were more likely than other newborns to experience respiratory complications and to be of low birth weight [18] and that the length of stay for NAS newborns was approximately 15–17 days compared to three days for all other hospital births [18, 20, 21].

Challenges of Caring for NAS Infants

The clinical complexity of caring for NAS newborns is often compounded by the environmental and socioeconomic circumstances faced by the mothers of the children, including lack of education and poor nutrition and prenatal care [16]. Moreover, a disproportionate number of infants with NAS are born to women who reside in low-income areas and receive public assistance [19]. Patrick et al. for instance, found that nearly 80% of charges attributed to NAS treatment in 2009 were covered by Medicaid [21]. Prior research has shown that children covered by Medicaid are at increased risk for a variety of adverse outcomes, including abuse and neglect [22, 23].

In addition, opioid-dependent mothers are often single and suffer from other substance use disorders such as alcoholism [24]. Moreover, studies show that infants born to women who are enrolled in methadone treatment programs—the standard of care for opioid-dependent mothers—continue to have worse neonatal outcomes than the general population, even though their mothers have better access to medical care, including obstetric care, and drug treatment [18, 25–27].

To address the challenges of caring for opioid-dependent mothers [27] and their infants, hospitals are increasingly turning to options such as rooming in. In contrast to the neonatal intensive care unit—which is where the majority of NAS infants still receive care—rooming in allows mother and child to stay in the same room. Some hospitals, such as Yale-New Haven Hospital in New Haven, Connecticut, have even redesigned their facilities to promote rooming in. Studies show that these alternative treatment settings show promise in terms of decreasing length of stay, reducing costs, and better overall outcomes for both mother and child—at least in the short term [15, 28].

Long-Term Outcomes

Data on the implications of NAS on the child’s long-term cognitive/neurological and developmental outcomes are limited, given the difficulty for researchers in isolating the effects of NAS from those related to the environment in which these children are often born [14, 15]. Several recent studies, however, suggest that NAS newborns experience a multitude of physical, mental, and behavioral outcomes throughout childhood [15, 16, 29]. These children are also thought to be at increased risk for maltreatment. A study by Uebel et al., for instance, shows that infants born with NAS are more likely to be hospitalized at some point during childhood for trauma, abuse, or neglect [29].

In all, these findings underscore the importance of prevention initiatives targeted at reducing opioid misuse among women of child-bearing age as well as the need for an expansion of MAT programs for opioid-dependent pregnant women. For the child, the potential long-term impact of opioids on children’s later development warrants the need for social services, early-intervention programs, and frequent follow-up medical care to assess for physical problems, including visual problems, motor deficits, cognitive delays, behavioral or school problems, and signs of abuse and neglect [15, 30].

Opioid-Related Morbidity and Mortality in Children and Adolescents

Epidemiology of Hospitalizations for Pediatric Opioid Poisonings

Drug poisonings are currently the leading cause of injury in the United States: between 1999 and 2015, prescription and illicit drugs were implicated in 568,699 deaths in the United States, two-thirds of which were attributed to prescription and illicit opioids [12].

In 2016, nearly 43,000 Americans died from opioid poisonings, and the epidemic has affected every US demographic, including children and adolescents. Of the 67,188 calls made to US poison controls centers in 2016 for opioid ingestions, nearly 20% were for children and adolescents less than 20 years of age [3, 31]. And as with adults, emergency department (ED) visits for adverse events related to opioid ingestions have risen substantially in