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An Analysis of 34,218 Pediatric Outpatient Controlled Substance Prescriptions

George, Jessica A. MD; Park, Paul S. BS; Hunsberger, Joanne MD; Shay, Joanne E. MD; Lehmann, Christoph U. MD; White, Elizabeth D. RN; Lee, Benjamin H. MD, MPH; Yaster, Myron MD

doi: 10.1213/ANE.0000000000001081
Pediatric Anesthesiology: Research Report

BACKGROUND: Prescription errors are among the most common types of iatrogenic errors. Because of a previously reported 82% error rate in handwritten discharge narcotic prescriptions, we developed a computerized, web-based, controlled substance prescription writer that includes weight-based dosing logic and alerts to reduce the error rate to (virtually) zero. Over the past 7 years, >34,000 prescriptions have been created by hospital providers using this platform. We sought to determine the ongoing efficacy of the program in prescription error reduction and the patterns with which providers prescribe controlled substances for children and young adults (ages 0–21 years) at hospital discharge.

METHODS: We examined a database of 34,218 controlled substance discharge prescriptions written by our institutional providers from January 1, 2007 to February 14, 2014, for demographic information, including age and weight, type of medication prescribed based on patient age, formulation of dispensed medication, and amount of drug to be dispensed at hospital discharge. In addition, we randomly regenerated 2% (700) of prescriptions based on stored data and analyzed them for errors using previously established error criteria. Weights that were manually entered into the prescription writer by the prescriber were compared with the patient’s weight in the hospital’s electronic medical record.

RESULTS: Patients in the database averaged 9 ± 6.1 (range, 0–21) years of age and 36.7 ± 24.9 (1–195) kg. Regardless of age, the most commonly prescribed opioid was oxycodone (73%), which was prescribed as a single agent uncombined with acetaminophen. Codeine was prescribed to 7% of patients and always in a formulation containing acetaminophen. Liquid formulations were prescribed to 98% of children <6 years of age and to 16% of children >12 years of age (the remaining 84% received tablet formulations). Regardless of opioid prescribed, the amount of liquid dispensed averaged 106 ± 125 (range, 2–3240) mL, and the number of tablets dispensed averaged 51 ± 51 (range, 1–1080). Of the subset of 700 regenerated prescriptions, all were legible (drug, amount dispensed, dose, patient demographics, and provider name) and used best prescribing practice (e.g., no trailing zero after a decimal point, leading zero for doses <1). Twenty-five of the 700 (3.6%) had incorrectly entered weights compared with the most recent weight in the chart. Of these, 14 varied by 10% or less and only 2 varied by >15%. Of these, 1 resulted in underdosing (true weight 80 kg prescribed for a weight of 50 kg) and the other in overdosing (true weight 10 kg prescribed for a weight of 30 kg).

CONCLUSIONS: A computerized prescription writer eliminated most but not all the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much of the prescribed medication is actually used by patients.

Published ahead of print November 17, 2015

From the *Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Departments of Pediatrics and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee; and §Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Paul S. Park, BS, is currently affiliated with the University of Maryland School of Medicine, Baltimore, Maryland.

Accepted for publication October 1, 2015.

Published ahead of print November 17, 2015

Funding: Richard J. Traystman endowed chair.

Conflict of Interest: See Disclosures at the end of the article.

JA George and PS Park are co-first authors.

Reprints will not be available from the authors.

Address correspondence to Myron Yaster, MD, Departments of Anesthesiology, Critical Care Medicine, and Pediatrics, Johns Hopkins University, School of Medicine, The Johns Hopkins Hospital, Charlotte R. Bloomberg Children’s Center, 1800 Orleans St., Suite 6320, Baltimore, MD 21287. Address e-mail to myaster1@jhmi.edu.

Among the most common types of iatrogenic errors, prescription errors can cause serious and often preventable injury.1–3 Children are especially vulnerable because they have a 3-fold greater risk than adults experiencing a potentially harmful medication error.4 Opioids are of particular concern because they are highly regulated and have a very narrow therapeutic index. Over- or underdosing can have serious or even fatal consequences.

Medication errors can occur during drug ordering, transcribing, dispensing, administering, and monitoring. Some studies estimate that most adverse drug events occur at the stage of prescription writing or drug ordering.4–6 To minimize medication errors in inpatients, most hospitals use some form of computerized provider ordering system.7,8 Increasingly, computerized prescription writing is also becoming more common in outpatient settings. Indeed, >80% of office-based pediatricians now use electronic health record systems, and virtually all have electronic prescribing capabilities.9 However, unlike hospital-based systems, many office-based systems lack pediatric prescription-writing functionality, such as weight-based dosing or decision support.9,10 We previously reported that handwritten, controlled substance (“narcotic”) prescriptions that were given to children on discharge from our university teaching hospital had an 82% error rate.11 Because the error rate was so high, we developed and instituted a mandatory computer-based narcotic prescription writer for all outpatient narcotic prescriptions.12 This program, which was linked to the hospital’s inpatient census, contained weight-based dosing and decision management support to reduce the potential for errors. A short-term follow-up study revealed that this program reduced narcotic prescription-writing error rates to zero.12 Over the past 7 years, >34,000 opioid prescriptions have been written with this program.

The purpose of this study was to determine the continuing efficacy of the program in preventing errors, as well as the patterns with which providers prescribe controlled substances to children and young adults (ages 0–21 years) at hospital discharge.

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METHODS

The study was conducted at the Johns Hopkins Hospital’s Charlotte Bloomberg Children’s Center, which is an urban, academic, tertiary care hospital specializing in the care of infants, children, adolescents, and young adults in Baltimore, Maryland. After obtaining IRB approval, we examined all cases of pediatric discharge prescriptions since 2007.11,12 Written informed consent was waived by the IRB. This electronic, web-based prescription-writing program was created by using Cold Fusion MX 7.0.2® (Macromedia, San Francisco, CA) and Microsoft Access 2000® (Microsoft Corp., Redmond, WA). This program, which is linked to the hospital’s patient demographic census, downloads the patient’s name, date of birth, and hospital identifier and has 5 key components that include limiting medication choices, dosing defaults, computerized calculations, soft and hard warnings, and prescription printing. The patient’s weight in kilograms must be manually entered by the patient’s health care prescriber, and to reduce error, it must be entered twice. We studied all prescribers, including trainees, who wrote narcotic prescriptions for patients between birth and 21 years old.

Table 1

Table 1

All pediatric discharge prescriptions that were written starting January 1, 2007, when the electronic prescription writer was first implemented, and ending in February, 2014, when the analysis was conducted, constitute the study size. This included all 34,218 controlled substance discharge pediatric (age 0–21 years) prescriptions written during the study period for any clinical diagnosis. We examined these prescriptions for demographic information, including patient age, sex, and weight; type of medication prescribed based on patient age; form of dispensed medication (liquid/patch/tablet); and amount of drug being dispensed at the time of hospital discharge. In addition, one of the investigators, who was not involved in the development of the software or ownership of the copyright, randomly regenerated and examined 700 (2%) prescriptions from the database that were written over the 7-year study period. These regenerated prescriptions were analyzed for errors using “best practice” guidelines based on the Institute for Safe Medication Practice’s List of Error-Prone Abbreviations, Symbols, and Dose Designations; literature review; and the Johns Hopkins Medicine, Department of Pharmacy hospital formulary (Table 1).9 Finally, in these regenerated prescriptions, we compared the weight manually entered into the prescription writer by the prescriber against the weight recorded in the electronic medical record (“gold standard”).

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Statistical Methods

Data were analyzed with Microsoft Excel®, SPSS (IBM, Armonk, NY), and Sigma Plot® (Systat, San Jose, CA) and are presented as mean ± SD. The main goal of the study was to provide descriptive data on the nature of prescriptions based on the entire universe of narcotic prescriptions. Therefore, the main results should only apply to these prescriptions, and no statistical inferences were used to estimate any population parameters, given that the data are based on the entire population itself. In addition, an exact binomial 95% confidence interval for the prescription-reported weight error rate was calculated based on a random sample of 700 prescriptions.

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RESULTS

Patients averaged 9 ± 6.1 (range, 0–21) years old and 36.7 ± 24.9 (range, 1–195) kg. Ninety percent of the prescriptions were written by surgical services. Most were written by the pediatric orthopedic service (53%), followed by the pediatric urology service (15%), plastic surgery service (11%), general pediatric surgery service (10%), and pediatric otorhinolaryngology service (2%). Pediatric medical services, including oncology, hematology, and emergency medicine, wrote the remaining 10% of prescriptions.

Regardless of age, the most commonly prescribed opioid was oxycodone (72.8%; Fig. 1). Acetaminophen with codeine was prescribed to 2506 patients (7.3%) and was more commonly prescribed to patients 0 to 2 years old (15.6%) than to children older than 2 years (5.1%; Fig. 1). Regardless of formulation, codeine was always prescribed in combination with acetaminophen, whereas oxycodone was always prescribed as a single agent. The prescribing of codeine peaked in 2010 and decreased dramatically in 2013 (Table 2). Less commonly prescribed opioids included methadone (3.7%), hydromorphone (3.7%), acetaminophen combined with hydrocodone (2%), and morphine (1.1%). Acetaminophen combined with hydrocodone was prescribed only by the otorhinolaryngology service.

Table 2

Table 2

Figure 1

Figure 1

Opioids were prescribed and dispensed in liquid and tablet form (Fig. 2). In most cases, liquid formulations were prescribed for children <6 years old (98%), but they were also prescribed to 70% of children 6 to 12 years old and to 16% of children >12 years (the remaining 84% received tablet formulations). Regardless of the opioid prescribed, the amount of drug dispensed was electronically calculated based on the provider’s decision regarding dose, frequency, and length of time the drug would be needed. Liquid medication volume averaged 106 ± 125 (range, 2–3240) mL and tablet number averaged 51 ± 51 (range, 1–1080). The amount of each opioid dispensed by age group is shown in Figure 3.

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

The 700 randomly regenerated prescriptions from stored historical data were legible and had the patient’s name, age, and weight; the prescription date; the prescriber’s first and last name; and Drug Enforcement Administration number (Fig. 4; Table 1). The prescriptions also contained the drug name, drug dose, dosage strength, and quantity to be dispensed (either volume or tablet number). In addition, none of the computer-generated prescriptions contained unapproved Institute for Safe Medication Practice abbreviations, none contained terminal zeros, and all included leading zeros for doses <1 (Table 2).13 All dispensing numbers were spelled out in word form to prevent forgery or alteration. Approximately 4% (25/700) (95% confidence interval, 2%–5%) of manually entered patient weights were incorrect. Of these incorrectly entered weights, 60% varied from the real weight by <10% (acceptable deviation) and only 2 varied by >15%. Of the latter, 1 prescription resulted in underdosing (the patient’s actual weight of 80 kg was entered as 50 kg) and the other in overdosing (the patient’s actual weight of 10 kg was entered as 30 kg).

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DISCUSSION

To the best of our knowledge, this is the first comprehensive, long-term examination of how controlled substances are prescribed to pediatric outpatients. We found that outpatient prescription errors can be significantly reduced but not completely eliminated when using a computerized prescription-writing program requiring manual data entry. These results are similar to those from previous studies of inpatients and a short-term study in pediatric outpatients.12 Furthermore, we found that the most commonly prescribed, orally administered opioid is now oxycodone, not codeine, and that unlike codeine or hydrocodone, oxycodone is ordered as a single agent rather than combined with acetaminophen. In addition, we found that opioids are dispensed in both liquid and tablet formulations and that the use of liquid formulations is not limited to the very young. Last, we found that opioids were dispensed in large quantities, regardless of which one was prescribed. How much medication was actually used by patients at home and what happened to the leftover medication are unknown and has enormous implications to public health.

Prescribing remains one of the most error-prone steps in the medication process. Moreover, the risk of error-related harm is greater in children than that in adults.4,14,15 Unlike for adults, drug doses for children and dose alerts are individualized and usually calculated on the basis of age, weight, and clinical condition.16,17 Indeed, patient weight, written in kilograms, may be the single most important element of pediatric drug dosing and calculation. Thus, our requirement of double manual entry by the prescriber of patient’s weight rather than a download from the hospital’s electronic medical record revealed a serious vulnerability of the program’s error prevention. Alternative solutions may include extraction of the patient’s weight from the record18 or population-based weight tables and alerts if weights vary by more than a specified percentage above normal.

Whether children perceive pain or can be safely treated is no longer debated, but how they are treated has undergone major changes in the past 30 years.19–22 We found that the most commonly prescribed orally administered opioid has changed from codeine to oxycodone and that unlike codeine, oxycodone is administered as a single agent rather than in combination with acetaminophen. Mounting evidence suggests that codeine’s unpredictable metabolism and efficacy are clinically relevant.23 Codeine is a prodrug that must be converted in the liver to active morphine by the cytochrome P450 2D6 isoenzyme. The majority of the population metabolizes approximately 10% of codeine into morphine. However, because of genetic variation and ontogeny, the 2D6 isoenzyme may be more or less active in some patients, making them either ultrarapid or slow metabolizers. In slow metabolizers (including virtually all newborns), codeine has little to no analgesic effect because morphine is not produced. In rapid metabolizers, excessive amounts of morphine are produced, resulting in potentially catastrophic respiratory depression and death.23 Fatalities and severe respiratory depression related to codeine have been reported in young children after tonsillectomy,24 as well as in drug-related deaths in Canada.25 Indeed, this risk is of such great concern that the U.S. Food and Drug Administration (FDA) issued a “black box” warning to limit and discourage the use of codeine in children undergoing tonsillectomy.26 We believe that concerns about codeine’s safety profile, our education initiatives, and the FDA black box warning led providers to virtually stop prescribing it after 2013 (Table 2).27

Another interesting finding in our study involved acetaminophen. Institutionally, we advocate a multimodal approach to pain management in which smaller doses of opioid and nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs, local anesthetics, N-methyl-D-aspartate antagonists, anticonvulsants, corticosteroids, muscle relaxants, and α2-adrenergic agonists, are combined in an attempt to maximize pain control and minimize opioid-induced adverse side effects.20,28–30 The fundamental building block in the multimodal approach and the most commonly used nonopioid analgesic in pediatric practice is acetaminophen.31 Multiple studies and systematic reviews have shown that acetaminophen and nonsteroidal anti-inflammatory drugs reduce pain, are cost-effective, have an opioid-sparing effect, and may reduce the risk of opioid-related adverse events.28,30,32–34 Acetaminophen is extremely safe and effective and produces few serious side effects, although it can cause hepatotoxicity when patients take >60 to 90 mg/kg/d.35 Therefore, combination drugs that contain both an opioid and acetaminophen appear ideal. Indeed, hydrocodone is only available in combination with acetaminophen, and our data show that codeine is usually dispensed in this format as well. However, in our hospital, the Pediatric Pain Service discourages the use of combination drugs because inadvertent overdosage with acetaminophen can easily occur when combination formulations are used and pain is poorly controlled.36 In that situation, patients will increase the number of combination tablets or amount of liquid they need to control their pain and may accidentally poison themselves with acetaminophen.36 Because of this risk, our preferred method is to prescribe single-agent opioids and acetaminophen separately. We believe that oxycodone’s availability as a single agent is the reason that it was prescribed so much more commonly than hydrocodone in our study.

Not surprisingly, we found that liquid preparations are essential in the pediatric patient population. Although it is intuitively obvious that young children would require liquids, our finding that a large percentage of older children also require liquids has profound implications for the practicing physician and the pharmaceutical industry. Many drugs administered to children are prescribed “off-label,” that is, for an indication not approved by the FDA.37,38 What is less known is that one of the biggest stumbling blocks for industry in testing and designing drugs for use in children is the need for liquid preparations. Developing liquid formulations is expensive and adds to the regulatory burden of the pharmaceutical industry, despite congressional incentives.39 Ultimately, the questions become “Is it worth it? How many patients will actually use it?” Our study reveals both the financial and the regulatory necessity of developing liquid formulations because the need for liquid analgesics (and other medications) is not limited to the very young but extends throughout the entire pediatric population.

Finally, we found that regardless of opioid or formulation prescribed, patients were dispensed large quantities of opioids. How much was actually used is unknown. In a prospective study that used interviews of postoperative, adult, urology patients, Bates et al.40 found that only 58% of the postoperative pain medication was consumed. Furthermore, 90% of the patients, who had a surplus of opioid medication, stored it at home and had not received information on how to dispose it.41 Invariably, some of these leftover opioids are diverted to the general population or to family members and are contributing to the national epidemic of drug addiction, abuse, and prescription opioid deaths. Often referred to as nonmedical use of prescription opioids, these legally prescribed opioids are the primary source and gateway drug for teenage and young adult drug addiction.41–44

Few hospitals or practices have procedure-specific protocols for writing prescriptions. The fact that each physician or provider can decide how much to prescribe has led nationally to the overprescription of potent narcotic analgesics and nonmedical use of prescription opioids.40 This study has forced us to deal with this problem. With the availability of our computerized prescription writer, we are currently using formalized postoperative interviews to study how much medication patients actually use, how families dispose of surplus medications, and how well they are satisfied with pain control.

The current study has limitations that limit its generalizability. This study was conducted in a single academic tertiary care medical center with a dedicated Pediatric Pain Service and pediatric specialists and subspecialists in both pediatric medicine and surgery. Furthermore, the electronic prescription writer used by these providers is a mandatory method of prescription writing and contains weight-based dosing and decision management support to reduce the potential for error features that are infrequently found in commercially available products. Finally, our discovery of weight-based data entry assumes that the medical record is accurate and the gold standard for weight reporting, assumptions that may or may not be correct.

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CONCLUSIONS

We found that a computerized prescription writer program that required manual entry of weight by the prescriber significantly reduced but did not completely eliminate the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much medication is actually used by patients at home.

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DISCLOSURES

Name: Jessica A. George, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Jessica A. George reported no conflicts of interest.

Attestation: Jessica A. George has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Paul S. Park, BS.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Paul S. Park reported no conflicts of interest.

Attestation: Paul S. Park has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Joann Hunsberger, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Joann Hunsberger reported no conflicts of interest.

Attestation: Joann Hunsberger has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Joanne E. Shay, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Joanne E. Shay reported no conflicts of interest.

Attestation: Joanne E. Shay has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Christoph U. Lehmann, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Christoph U. Lehmann developed the Narcotic Prescription writer program and holds its copyright.

Attestation: Christoph U. Lehmann has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Elizabeth D. White, RN.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Elizabeth D. White reported no conflicts of interest.

Attestation: Elizabeth D. White has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Benjamin H. Lee, MD, MPH.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Benjamin H. Lee developed the Narcotic Prescription writer program and holds its copyright.

Attestation: Benjamin H. Lee has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Myron Yaster, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts: Myron Yaster received honoraria from Purdue Pharma, received honoraria from Endo Pharmaceuticals, and received honoraria from Roxanne Laboratories. Dr. Yaster developed the Narcotic Prescription writer program and holds its copyright with Drs. Lehmann and Lee.

Attestation: Myron Yaster has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: James A. DiNardo, MD.

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ACKNOWLEDGMENTS

The authors acknowledge the Richard J. Traystman endowed chair for financial assistance, Dr. Gayane Yenokyan and Dr. Sapna Kudchadkar for their biostatistical help, and Claire Levine for her editorial assistance.

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