TheElliot J. Krane, National MD,​a,b​ Steven J. Weisman, MD,Opioid​c,​d Gary A. Walco, PhDEpidemice,​f and the Risk of Outpatient Opioids in Children

It is impossible to watch broadcast First is that the authors of this “ news or read a newspaper without editorial are not champions of opioid ” encountering a story of the opioid use, per se. We know that opioids epidemic,​ an unfortunate phrase are associated with many untoward used by the Centers for Disease side effects and are potentially lethal. “ ” 1 Control and Prevention (CDC)‍ from But we believe there is a reason why whom epidemic carries an emotive opioids have been used to treat pain connotation. The national interest in since the Sumerians 5000 years ago: aDepartment of Anesthesiology, Perioperative and the opioid epidemic began when– the2 no other analgesics equal in potency New England Journal of Medicine,​ and effect have been discovered or Pain Medicine, and Department of Pediatrics, Stanford 3 7 University, Stanford, California; bPackard Children’s followed by other sources,​ ‍‍ developed to reduce suffering. We Hospital at Stanford, and Stanford Children's Health, documented increasing opioid-related are staunch advocates for the need to Palo Alto, California; cDepartment of Anesthesiology, and deaths in the United States. With provide adequate treatment of pain Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; dChildren’s Hospital of Wisconsin, media attention (Fig 1)‍ the topic and suffering after surgeries, burns, Wauwatosa, Wisconsin; eDepartment of Anesthesiology and became politicized, later followed by physical trauma, and medical illnesses Pain Medicine, and Department of Psychiatry, University of f regulations, statutes, and litigation such as sickle cell crisis, cancer, and Washington, Seattle, Washington; and Seattle Children’s “ ” Hospital and Regional Medical Center, Seattle, Washington against the pharmaceutical industry pancreatitis, to name but a few. Opinions expressed in these commentaries are in an attempt to solve the crisis,​ Second is that data used in our national while punishing pharmaceutical “ ” those of the authors and not necessarily those debate about opioids are not accurate. of the American Academy of Pediatrics or its manufacturers for causing this CDC reports opioid-related deaths,​ Committees. epidemic. which are deaths that occur with DOI: https://​doi.​org/​10.​1542/​peds.​2018-​1623 Media attention produced many opioids in the blood, without any other Accepted for publication May 29, 2018 attribution for the cause of death. experts, pundits, and politicians who Address correspondence to Elliot J. Krane, MD, offer simplistic blameworthy origins Although many of these deaths are Department of Anesthesiology, Perioperative and for the problem (eg, overprescription indeed the result of opioid toxicity, Pain Medicine, Stanford University, 300 Pasteur Dr, of opioids, deceptive marketing of many are the result of suicide, fatal Stanford, CA 94305. E-mail: [email protected] opioids, The Joint Commission, and/ illness in which opioids were used PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, or an inability of Americans to endure to alleviate suffering, and still more, 1098-4275). discomfort)‍, as well as simplistic indeed most, are the result of multiple Copyright © 2018 by the American Academy of solutions (eg, draconian restriction drug ingestion. For example, when Pediatrics of prescribing, mandatory use of a patient dies at home with alcohol, FINANCIAL DISCLOSURE: Dr Krane has provided benzodiazepines, and opioids found consultation for Collegium Pharmaceuticals and prescription drug monitoring programs, “ ” on toxicology examination, death will receives honoraria for lecturing on pain and nonopioid alternatives to opioids, analgesia. Dr Weisman has provided consultation be coded9 as opioid-related by the acupuncture, meditation, and/or yoga)‍. for Grünenthal Pharmaceuticals and Pfizer 8 CDC,​ although the death may have Pharmaceuticals, has conducted clinical trials Against this background, Chung et al been caused by other substances (the “ for Grünenthal Pharmaceuticals, Cadence have contributed a publication in average number of drugs identified10 Pharmaceuticals, and The Medicines Company this journal, Outpatient Opioid in postmortem toxicology is 6‍ )‍. ” Prescriptions for Children and Opioid- And it is for this reason that CDC To cite: Krane EJ, Weisman SJ, Walco GA. The Related Adverse Events. In this officials recently admitted that in the National Opioid Epidemic and the Risk of Out­ editorial, we will comment on their past few years their statistics likely patient Opioids in Children. Pediatrics. 2018; 142(2):e20181623 findings and put them into what we overestimated the prevalence of 11 believe is the proper context. But prescription opioid deaths by 100%. before we do, there are 2 caveats: In other words, the opioid epidemic Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number 2, August 2018:e20181623 COMMENTARY Number of Publications

Month and Year

FIGURE 1 The number of media publications using the word “opioid” from May 2008 to May 2018, as reported by Google Trends.

“ ” is better called the polypharmacy opioids and more about deaths from the United States. To contribute8 overdose epidemic,​ and furthermore illicit use of prescriptions than from to this knowledge, Chung et al the annual number of "opioid medical use of prescription opioids. examined Medicaid records of >1 related" deaths pales in comparison In other words, we have an epidemic million children and adolescents in with other public health hazards and of substance use disorder (SUD)‍ that Tennessee between 2 and 17 years causes of deaths in America such as is embedded in a complicated matrix of age who had no complicating tobacco-related deaths,– alcoholic of despair and hopelessness across severe medical illness and who were hepatic disease, and12 even14 hospital- the United States and correlates prescribed opioids as outpatients. “ acquired infections. ‍ closely with socioeconomic factors They then identified those who ” such as unemployment, poor had an opioid-related adverse Additionally, many in speaking education, availability of illicit street 15,1​ 6‍ event,​ defined as an emergency and writing of the opioid epidemic and diverted prescription opioids,​ ‍ – 17,18​ department visit, hospitalization, or conflate the annual statistics of all genetic predisposition to SUD,​ ‍ – 19 death after an opioid prescription. drug deaths (~6‍0000 70000)‍, all and psychiatric morbidity. Thus, To confirm the relationship of the opioid deaths (~30000 40000, there is scant evidence to support including both illicit opioids opioid prescription to the adverse the existence of an epidemic of ∼ event, medical records were then and prescription opioids)‍, and deaths due to the appropriate use of prescription opioid deaths (~15000)‍, prescribed opioids. obtained on a subset of 875 cases, further exaggerating the magnitude which were reviewed by 2 study of the problem in the public mind. Nevertheless, there is much we need investigators for confirmation of “ The present problem is therefore to learn about the epidemiology opioid etiology. Their conclusion is much more one of deaths from of opioid prescription, use, alarming: One of every 26‍11 study illicit drugs than from prescription misuse, and effects in children in opioid prescriptions was followed Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 KRANE et al by an opioid-related emergency or the result of SUD? Or, were they data from large health maintenance ” department visit, hospitalization, or tragic outcomes of appropriate use organizations prospectively to death. of an analgesic? This is really the highlight the socioeconomic and But, as in many retrospective studies, question here. Clearly, these data are geographic diversity of various there are inherent factors that can vital and, in our view, if they were pediatric populations using opioids lead to false conclusions: investigator available to the investigators, they will allow safer treatment of children bias (given that the investigators should and could have been included. in the future. have previously published drug Nevertheless, we compliment the In conclusion, it is not possible to8 use toxicity papers)‍ and population authors on the magnitude of work the data reported by Chung et al to bias (having used indigent patients required to study such a database support or refute the prevalence or from a rural state, many or most of and note there are facts that we the severity of opioid adverse effects whom would likely use emergency may derive from their work that are or the epidemic as it affects children departments as a primary source important. and adolescents. Similarly, the data of care and thus meet criteria as presented cannot be considered First is that the largest group of for an opioid-adverse event by causal for associating opioid opioid prescribers to this Medicaid merely presenting to an emergency prescribing with severe morbidity, population were dentists, not department despite having only a more hospital emergency department physicians. These findings parallel minor opioid side effect)‍. visits, and even death for reasons data from a study revealing that The data included in this study highlighted in this commentary. in the 15- to 24-year age group, also coded symptoms of opioid dentists are by far the highest If the concern is that opioid toxicity that are vague or typically 20 prescribers of opioids. This finding prescriptions to children lead to not associated with opioid toxicity “ ” suggests the most fruitful avenue SUD, other work reveals that first as opioid adverse events, such as exposure to nonmedical use of for provider education, for example ’ neuropsychiatric symptoms (found opioids in adolescents occurs most that nonsteroidal anti-inflammatory– ’ in 27.5% of opioid toxicity cases)‍. often from access to family members drugs are usually sufficient21 23 for most Twenty-three percent of cases of or friends prescriptions, not their dental procedures. ‍ ‍ 24 “ opioid toxicity were caused by own. In a comprehensive article, 25 … unintentional overdose, opioid abuse, The second is that the list of opioids Miech et al concluded that In or self-harm despite the premise that prescribed to outpatients without “ ” the very lowest risk stratum this was a study of the complications significant complicating medical legitimate use of prescription opioids of appropriate therapeutic use,​ conditions included codeine, which before high school completion does ” suggesting that these cases might is the subject of a black box Food and not predict opioid misuse after high have been better off being excluded Drug Administration warning and school. from the study analysis. recommendation not to prescribe. Pediatric practitioners must use Grouping of "adverse events" The list also included long-acting opioids (methadone, transdermal their best judgment when using also leaves us unable to compare opioids with solid indications and the frequency of common and fentanyl [Duragesic], sustained- release morphine [MS-Contin] should always make good use of self-limited side effects (pruritus, nonopioid alternatives. But providing nausea, vomiting, constipation)‍ with and controlled-release oxycodone [OxyContin])‍, which have no place appropriate opioid prescriptions what are severe or life-threatening ï in the management of acute pain in for moderately to severely painful events (respiratory depression, conditions should not be curtailed hypotension, and/or central nervous opioid na ve pediatric patients. on the basis8 of the data reported by system depression)‍. In addition, we Although it is reassuring that only Chung et al. Too often, consideration are not informed which prescribed 3 deaths were identified among the of the need to prevent and treat pain opioids were associated with which 1.4 million opioid prescriptions in can be lost in the national discussion. symptoms of toxicity or of any detail this 5-year period, the commonality ABBREVIATIONS of the few fatalities they reference. of opioid prescribing in children Which opioids resulted in fatalities? mandates that objective data about Were these intentional overdoses, the use, abuse, and risks of opioids CDC: Centers for Disease Control unintentional overdoses, fatalities in children be collected. Mining large and Prevention associated with mixing opioids with databases, as was done by Chung 8 SUD: substance use disorder other medications and/or alcohol, et al,​ and using comprehensive

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number 2, August 2018 3 and receives honoraria for lecturing on pain and analgesia. Dr Walco has provided consultation for Pfizer Pharmaceuticals, Collegium Pharmaceuticals, Endo Pharmaceuticals, and Inspirion Pharmaceuticals and receives honoraria for lecturing on pain and analgesia. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: Dr Weisman has conducted clinical trials involving opioid medications in children for The Medicines Company (transdermal iontophoretic fentanyl in postoperative children); Drs Krane and Walco 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.​2017-​2156.

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 KRANE et al The National Opioid Epidemic and the Risk of Outpatient Opioids in Children Elliot J. Krane, Steven J. Weisman and Gary A. Walco Pediatrics originally published online July 16, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2018/07/12/peds.2 018-1623 References This article cites 19 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2018/07/12/peds.2 018-1623#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Pharmacology http://www.aappublications.org/cgi/collection/pharmacology_sub Therapeutics http://www.aappublications.org/cgi/collection/therapeutics_sub Substance Use http://www.aappublications.org/cgi/collection/substance_abuse_sub Addiction http://www.aappublications.org/cgi/collection/addiction_sub Permissions & Licensing 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 Reprints 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 September 25, 2021 The National Opioid Epidemic and the Risk of Outpatient Opioids in Children Elliot J. Krane, Steven J. Weisman and Gary A. Walco Pediatrics originally published online July 16, 2018;

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