Evaluation of Methylphenidate Safety and Maximum-Dose Titration Rationale in Attention-Deficit/Hyperactivity Disorder: A Meta-analysis

Key Points

Question  What evidence is available on maximum dose, dose titration, and adverse events associated with dose titration of stimulants for attention-deficit/hyperactivity disorder?

Findings  This meta-analysis of 11 randomized clinical trials and 38 cohort studies found a wide variation of dose ranges for stimulant medications for attention-deficit/hyperactivity disorder, although whether the doses were arbitrarily selected or evidence based is unclear. Common adverse effects of methylphenidate treatment included insomnia, anorexia, abdominal pain, and headache.

Meaning  The literature recommends a range of maximum doses for methylphenidate but offers no discernable scientific justification for any particular dose; future studies into the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds without reference to any set maximum dose are needed.

Importance  Evidence on the titration of stimulant medications for attention-deficit/hyperactivity disorder (ADHD) is lacking. However, this lack of evidence has not prevented medication guidelines from specifying apparently arbitrary dose limitations, which could discourage clinicians from titrating methylphenidate to higher and, perhaps for some patients, more efficacious doses.

Objective  To determine the evidence on dose titration and adverse events associated with dose titration of stimulants for ADHD.

Data Sources  MEDLINE from 1946, Embase from 1974, and PsycINFO from 1806 through April 1, 2019, were searched to identify relevant articles.

Study Selection  The inclusion criteria were that (1) the study was conducted on children up to 18 years of age; (2) children had a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, or hyperkinetic disorder according to the International Classification of Diseases codes; and (3) the dose of methylphenidate was determined by titration.

Data Extraction and Synthesis  The PRISMA guidelines for abstracting data and assessing data quality and validity were followed. Quality assessment was undertaken using the Jadad scoring system. Statistical analysis was undertaken using a random-effects model.

Main Outcomes and Measures  The outcomes of interest were (1) the doses used in published clinical trials, (2) the clinical justification given by researchers for their selected dose range, and (3) the adverse effects associated with methylphenidate when the dose is established by titration.

Results  A total of 11 randomized clinical trials and 38 cohort studies were analyzed. The randomized clinical trials involved 1304 participants treated with methylphenidate and 887 controls; the 38 cohort studies included 5524 participants. Maximum doses of methylphenidate ranged from 0.8 to 1.8 mg/kg/d. Some studies detailed their method of titration, including starting dose, titration interval, increment dose, and maximum dose. Not all of these studies reported justification for the chosen dose range. Common adverse effects of methylphenidate included insomnia (odds ratio, 4.66; 95% CI, 1.99-10.92; P < .001), anorexia (5.11 higher than for those who took placebo; 95% CI, 1.99-13.14; P < .001), abdominal pain (1.9 times more likely; 95% CI, 0.77-4.77; P = .16), and headache (14% of participants; 95% CI, 10%-20%; P < .001).

Conclusions and Relevance  A range of maximum doses for methylphenidate was recommended in clinical studies; no discernable scientific justification for any particular dose was given. Reports of life-threatening adverse events were absent; further studies of the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds, without reference to any set maximum dose, are needed.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobiological condition in Germany and Australia, with a prevalence of 5.9% to 9.9% in children and adolescents and 2.5% to 5% in adults.^1-3 The disorder is characterized by inattention, impulsive behavior, and hyperactivity across a variety of settings, resulting in functional and developmental impairment,⁴ and can progress into psychosocial, educational, and neuropsychological dysfunction in adulthood.⁵Quiz Ref ID However, stimulant medication for treatment of ADHD is often highly effective, with an observed effect size of close to 1.0 for methylphenidate hydrochloride.⁶ In the longer term, effective stimulant treatment may lead to improvement in self-esteem, academic performance, and social outcomes.⁷

The dose of stimulant is normally determined clinically according to the individual’s response. The American Academy of Pediatrics recommends titrating the medication dose for maximum benefit but also for minimum adverse effects.⁸ Similarly, in their review of the use of psychostimulants in childhood, Schachar et al⁹ recommend the use of titration to achieve individual optimal doses. Quiz Ref IDHowever, stimulant medication also has recognized adverse effects, including poor appetite and weight loss, insomnia, abdominal discomfort, and headache along with increases in heart rate and blood pressure.^10,11 At higher doses, stimulants can be associated with transient psychotic symptoms and seizures.⁸ Stimulants also have abuse potential. Therefore, in the interests of safety, the prescribing of these medications is generally directed by guidelines that specify an approved dose range. Prescribing guidelines could lead to a clinical dilemma in some patients if the titrated dose for optimal treatment is higher than the approved dose range.

If guidelines are scientifically well grounded, either there should be few cases in which the principles of optimal dose titration conflict with the specified maximum dose or there should be some guidance for managing such cases. However, little consistency in maximum dose exists between guidelines, suggesting that the evidence for maximum dosing could be unclear.

The 2004 European Clinical Guidelines on Hyperkinetic Disorder recommends titration for immediate-release methylphenidate to a maximum of 0.7 mg/kg/d and for osmotic-release oral system (OROS) methylphenidate to a maximum of 54 mg/d.¹² The American Academy of Pediatrics clinical practice guideline for ADHD acknowledged in 2011 that maximum doses had not been adequately studied and made no recommendations in this regard other than referring to the US Food and Drug Administration (FDA) approval guidelines.⁸ The product information on the FDA website recommends a maximum dose of 60 mg/d for immediate-release and extended-release methylphenidate¹³; for OROS methylphenidate, the recommended maximum dose is 54 mg/d in children aged 6 to 12 years and 72 mg/d in adolescents aged 13 to 17 years.¹⁴

The Australian Therapeutic Guidelines includes both age- and weight-based maximum doses, recommending up to 1 mg/kg/d or 60 mg/d in children aged 4 years or older and a dose titration of extended-release or OROS methylphenidate of 0.5 to 2.0 mg/kg/d in children older than 6 years.¹⁵ The Australian Medicines Handbook states that in children aged 2 to 12 years, doses of immediate-release methylphenidate may be titrated up to 1 mg/kg/d to a maximum of 40 mg/d or to 60 mg/d in children older than 12 years. Modified-release methylphenidate may be increased to doses of 72 mg/d (for OROS) or 80 mg/d (for extended release).¹⁶ None of these guidelines acknowledges any potential conflict between optimal dose titration and a maximum dose cutoff.

To investigate this potential clinical dilemma, we wanted first to find out the dose ranges used in studies that purport to optimize the dose of methylphenidate by titration; second, to identify how the chosen dose ranges were determined; and third, to establish whether the dose ranges were safe. We chose methylphenidate because this drug has been studied in a greater number of clinical trials than any other ADHD medication; the European Clinical Guidelines on Hyperkinetic Disorder specifically states that methylphenidate is usually the first choice of stimulant.¹² We also planned to investigate the evidence these studies cited in support of their dose range. In this review and meta-analysis, the outcomes of interest were (1) the doses used in published clinical trials, (2) the clinical justification given by researchers for their selected dose range, and (3) the adverse effects associated with methylphenidate when the dose is established by titration.

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.¹⁷ A systematic search of the databases MEDLINE from 1946, Embase from 1974, and PsycINFO from 1806 through April 1, 2019, was performed to identify relevant articles. We used the search terms attention deficit disorder or ADHD as well as methylphenidate and titrimetry as text words and as exploded medical subject headings when possible. The reference lists of relevant articles were also searched for appropriate studies; we focused particular attention on a Cochrane review article.¹⁸ No language restrictions were used in either the search or study selection. A search for unpublished literature was not performed.

We included studies that used methylphenidate and met the following inclusion criteria: (1) the study was conducted on children up to 18 years of age; (2) children had a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (Third Edition),¹⁹Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised),²⁰Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition),²¹Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision),²² and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition)⁴ or hyperkinetic disorder according to the International Classification of Diseases, Ninth Revision (ICD-9)²³ or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10),²⁴ codes; and (3) the dose was determined by titration. We excluded studies that did not meet the inclusion criteria.

The data extraction was performed with a standardized data extraction form. We collected information on the study publication year, continent, and design; patient comorbidities; number of cases, number of controls, total sample size, and number of withdrawals; and methylphenidate formulation, titration regimen, justification for titration regimen, mean dose, and number of adverse effects in cases and controls. Quality of the studies was not assessed, and authors were not contacted for missing data. Adjusted ratios were extracted in preference to nonadjusted ratios; however, when ratios were not provided, we calculated unadjusted odds ratios (ORs) and CIs. When more than 1 adjusted ratio was reported, we chose the ratio with the highest number of adjusted variables. When multiple risk estimates were available in the same study (eg, owing to the use of different comparator groups), we included them as separate risk estimates. For cohort studies, proportions were used as data. Funnel plot analyses were used to assess publication bias. Sensitivity analyses were performed to investigate risk of bias and heterogeneity for the overall estimate of effect. In addition, risk of bias and the overall quality of all studies were assessed according to the Jadad scoring system.

Patient demographic and clinical characteristics were reported as means and SDs or as 95% CIs for numerical scaled features and percentages for discrete characteristics. Pooled ORs and 95% CIs were calculated for the association of methylphenidate with the risk of adverse effects using a random-effects model.²⁵ We tested heterogeneity with the Cochran Q statistic, with P < .10 indicating heterogeneity, and we quantified the degree of heterogeneity using the I² statistic, which represents the percentage of the total variability across studies owing to heterogeneity. The I² values of 25% corresponded to low, 50% to moderate, and 75% to high degrees of heterogeneity.²⁶ We quantified publication bias using the Egger regression model,²⁷ with the effect of bias assessed through the fail-safe number method. The fail-safe number was the number of studies that we needed to have missed for the observed result to be nullified to statistical nonsignificance at the P < .05 level. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n +10, with n being the number of studies included in the meta-analysis.²⁸ All analyses were performed with Comprehensive Meta-analysis, version 3.0 (Biostat).

The literature search identified 528 articles from the databases and 172 articles from a Cochrane review study.¹⁸ After the exclusion of duplicates, 400 articles remained, and further exclusion based on titles, adult studies, other medications, and other diseases reduced this total to 99 articles. Additional exclusion based on study design yielded 49 articles for inclusion in the data analysis (Figure 1). The remaining studies consisted of 11 randomized clinical trials (RCTs)^6,9,29-37 and 38 cohort studies.^38-75 The study characteristics are summarized in Table 1 and Table 2. Studies varied in their reporting of maximum doses using mg/d, mg/kg/d, or both.

The 11 RCTs included in this study involved 1304 participants treated with methylphenidate and 887 controls. Of the 11 RCTs, 7 (64%) studied efficacy and/or tolerability in children with ADHD^{6,29-32,36,37}; 1 (9%) looked at efficacy, safety, and adverse effects in children with ADHD and intellectual disability³⁵; 1 (9%) explored the efficacy and safety of methylphenidate in ADHD and substance use disorders³⁴; 1 (9%) investigated clinical doses of methylphenidate in a cohort with preexisting tics³³; and 1 (9%) studied behavioral, situational, and temporal effects of methylphenidate.⁹

The 11 RCTs were evaluated with the Jadad scoring system, which assesses the quality of the study on the basis of methods (score range: 1-5). Eight RCTs (73%) selected for this study had Jadad scores of 4 or 5^{6,30-32,34-37}; 1 study (9%) scored 3²⁹; and 2 studies (18%) scored 1.^9,33 The formulation of methylphenidate varied between the RCTs, including immediate release (Ritalin [Novartis Pharmaceutical Corp]; Equasym [Shire PLC]), extended release (Metadate CD [UCB Inc]; Ritalin LA [Novartis Pharmaceutical Corp]), OROS (Concerta [Actavis]), and methylphenidate transdermal system.

The 38 cohort studies included a total of 5524 participants. The most commonly used methylphenidate formulation was OROS, used in 18 (47%) of the studies.^{38,40,43,44,50-52,54,58-61,63,66-69,73}

In the 11 RCTs, the maximum doses of methylphenidate ranged from 20 to 72 mg/d and 1.4 to 1.5 mg/kg/d. Riggs et al³⁴ and Wilens et al³⁶ used OROS methylphenidate in their study and set the maximum dose at 72 mg/d. Simonoff et al,³⁵ using immediate-release methylphenidate, had a maximum of 1.5 mg/kg/d, and both Greenhill et al,³² using modified-release methylphenidate, and Findling et al,³¹ using immediate-release or extended-release methylphenidate, titrated to a maximum dose of 60 mg/d. Three studies (27%) reported mean doses: Greenhill et al³² used modified-release methylphenidate with a mean of 40.7 mg/d and 1.28 mg/kg/d, Schachar et al⁹ did not report the formulation used but reported mean doses of 31.9 mg/d and 0.6 mg/kg/d, and Wolraich et al³⁷ used both OROS with a mean of 34.3 mg/d and immediate-release methylphenidate with a mean of 29.5 mg/kg/d.

In the 38 cohort studies, the maximum doses of immediate-release methylphenidate used varied from 20 to 60 mg/d and 0.8 to 1.8 mg/kg/d. Maximum doses of OROS methylphenidate varied between 54 mg/d, 72 mg/d, and 90 mg/d. Two studies (5%) using OROS methylphenidate (maximum dose, 54 mg/d) reported maximum doses of 1.4 mg/kg/d and 1.8 mg/kg/d.^60,73 The 4 studies (11%) that evaluated methylphenidate transdermal system had a maximum dose of 30 mg/d.

The mean of the mean doses reported for OROS methylphenidate was 41.3 mg/d and 0.99 mg/kg/d. Three (8%) of the studies into OROS methylphenidate had mean doses above 52 mg/d. For immediate-release methylphenidate, only 1 study (3%) reported a mean dose (25.4 mg/d).⁶² Extended-release methylphenidate had mean doses of 26.01 mg/d; however, no means for mg/kg/d were reported. The mean (21.3 mg/d) for methylphenidate transdermal system was reported in only 1 study (3%).

Some studies detailed their method of titration, including starting dose, titration interval, increment dose, and maximum dose. However, not all of these studies reported the justification for the chosen dose range. It is, therefore, unclear whether the doses were arbitrarily selected or evidence based.

Among the RCTs, Law and Schachar³³ referenced Tannock et al,⁷⁶ Horn et al,⁷⁷ and Schachar and Tannock⁷⁸ to justify their target dose of 0.7 mg/kg/d of methylphenidate. Schachar et al⁹ also titrated to a target dose of 0.7 mg/kg/d in their study with reference to Tannock et al⁷⁶ and Horn et al.⁷⁷ However, none of these cited studies stated that 0.7 mg/kg/d should be considered the optimum dose for treating ADHD. The doses tested by Tannock et al⁷⁶ were 0.3 mg/kg/d and 1.0 mg/kg/d. Horn et al⁷⁷ also cited Tannock et al⁷⁶ but used 0.4 mg/kg/d and 0.8 mg/kg/d. In their review of the use of psychostimulants in childhood, Schachar and Tannock⁷⁸ reported several studies in which the doses ranged from 0.3 to 0.8 mg/kg/d. They did not recommend a specific target dose based on weight but instead recommended that titration be used to achieve individual optimal doses.

Among the cohort studies, McGough et al⁵⁸ cited Wilens et al³⁶ to justify doses up to 72 mg/d; however, Wilens et al³⁶ did not provide any justification for this dose as a maximum. Kronenberger et al⁵⁴ and Su et al⁶⁹ titrated OROS methylphenidate to a maximum of 54 mg/d in adolescents aged 12 to 16 years and in children 6 to 16 years of age, citing FDA recommendations. The FDA recommended this dose as a maximum for children aged 6 to 12 years on the basis of 3 RCTs but up to 72 mg/d for adolescents aged 13 to 17 years on the basis of 1 RCT.¹³ Newcorn et al⁶⁰ selected the same maximum of 54 mg/d in their study for both children and adolescents, in accordance with FDA recommendations, but noted that the higher dose licensed for adolescents might mean that some of the 57 adolescents in their study could have been underdosed. Kemner et al⁵¹ studied children aged 6 to 12 years and used a maximum of 72 mg/d but referred to the physician's clinical experience as well as the FDA when titrating medication. Arnold et al³⁹ based their choice of drug doses on the manufacturer’s recommendations on the package insert, which matches with the FDA licensing. The dose of methylphenidate used by Wang et al⁷¹ was based on the usual practice in China. Soutullo et al⁶⁷ mentioned that their maximum dose of 54 mg/d was in accordance with European Clinical Guidelines on Hyperkinetic Disorder.

Quiz Ref IDThe RCTs showed that participants treated with methylphenidate compared with those given placebo were 1.55 times more likely to experience adverse events (95% CI, 1.08-2.22; P = .02). No heterogeneity among studies (I² = 0.00; P = .75) or publication bias (t, 1.77; P = .32) was found. Only a 1.10-times increased risk of headache was found for the treated population (95% CI, 0.63-1.92; P = .74). Studies demonstrated no heterogeneity (I² = 0.00; P = .50) with no evidence of publication bias (t, 2.51; P = .13). The risk of developing anorexia among those who received methylphenidate was 5.11-times higher than for those who took placebo (95% CI, 1.99-13.14; P < .001). No heterogeneity among studies (I² = 0.00; P = .75) and no publication bias (t, 0.82; P = .56) were noted (Figure 2). Participants who received methylphenidate treatment were shown to be at a statistically significantly increased risk of experiencing insomnia (OR, 4.66; 95% CI, 1.99-10.92; P < .001) (Figure 3). No heterogeneity among studies (I² = 0.00; P = .73) and no evidence of publication bias (t, 1.11; P = .38) were found. Compared with patients given placebo, those treated with methylphenidate were 1.91 times more likely to report abdominal pain (95% CI, 0.77-4.77; P = .16). Minimal heterogeneity (I² = 6.54; P = .34) and no publication bias (t, 0.01; P = .99) were found.

In the cohort studies, the overall adverse events rate was 66% (95% CI, 57%-74%; P = .001). Heterogeneity among studies (I² = 94.05; P < .001) was noted. Anorexia was the most common adverse event experienced in 33% of participants (95% CI, 16%-56%; P < .001), with heterogeneity among studies (I² = 96.84; P < .001). Insomnia occurred at a rate of 15% of participants (95% CI, 10%-22%; P < .001), with heterogeneity among studies (I² = 94.07; P < .001). Headaches occurred in 14% of participants (95% CI, 10%-20%; P < .001), with heterogeneity among studies (I² = 94.05; P < .001).

To our knowledge, this meta-analysis is the first involving methylphenidate treatment that included only RCTs and cohort studies in which the dose was titrated to the clinical response. Dose titration allows the treating physician to balance clinical efficacy with adverse effects. Such studies would, therefore, be expected to show greater clinical efficacy and less loss to attrition than studies that randomize patients to a fixed dosing schedule. In addition, this study is the first to date to examine the rationale for a predetermined maximum dose of methylphenidate in the pediatric population.

Medication guidelines for methylphenidate vary in their maximum dose recommendations. This difference is reflected in the variation in the maximum doses reported among the studies included in this meta-analysis. In 3 of the cohort studies, the mean dose of OROS methylphenidate approached the maximum of 54 mg/d recommended by some guidelines. Similarly, the mean dose of 1 of the cohort studies that used immediate-release methylphenidate approached a maximum recommended dose of 1 mg/kg/d.⁶²

Quiz Ref IDOf the 11 RCTs, only 2 cited any source to justify their study dose, and in neither case did the chosen dose match up with the cited source. Therefore, their choice of dosing remains unsubstantiated.

Eight cohort studies justified their dosing ranges. Arnold et al³⁹ used the dose dictated by the pharmaceutical company but for which the scientific basis was unclear. Kronenberger et al,⁵⁴ Su et al,⁶⁹ and Newcorn et al⁶⁰ referred to the FDA but used the recommended dose for children, although their study population included adolescents. As such, they used a lower maximum dose than was recommended by the FDA for these participants. Kemner et al⁵¹ also used the FDA recommendations as a guide but used the adolescent maximum for this population of children. McGough et al⁵⁸ and Soutullo et al⁶⁷ had the most reasonable justification, with maximum doses consistent with the sources that they referenced. Wang et al⁷¹ were somewhat vague with their reference to the usual practice in China. Their maximum recommended dose matched their citation to the European Clinical Guidelines on Hyperkinetic Disorder.

Thus, although studies into the safety and efficacy of methylphenidate have been published, evidence that supports any set maximum dose appears limited. However, this lack of evidence has not prevented guidelines from being written that specify apparently arbitrary dose limitations, which could discourage clinicians from titrating methylphenidate to higher and, perhaps for some patients, more efficacious doses.

In a 2015 Cochrane review article¹⁸ on the safety of methylphenidate, the parallel group trials and crossover trials (first period data only) show that participants who received treatment had a relative risk of 1.29 of experiencing adverse events. Insomnia was 1.6 times more likely to be reported by participants who underwent methylphenidate treatment. The treatment group was also at a 3.66 increased risk of anorexia. Analysis of data from crossover trials (end point data) showed that the overall risk of adverse events increased 1.33 times. The treatment group was 1.21 times more likely to report a headache, 1.57 times more likely to report insomnia, 3.04 times more likely to experience anorexia, and 1.61 times more likely to describe abdominal pain. However, this review also included trials in which the participants were randomized to a fixed dose of medication.¹⁸

Compared with the data from the Cochrane review article,¹⁸ the risk of any adverse events in the current study was higher overall, as was the risk for insomnia, anorexia, and abdominal pain, but the risk for headache was lower. The current study included only RCTs that had titrated the methylphenidate dosage, suggesting that this method of dosing is associated with an increased risk of adverse events. This method may be associated with the option of increasing the dose of methylphenidate to achieve satisfactory clinical improvement, with the higher dose resulting in increased adverse events.⁷⁹

This study analyzed only the most common adverse events reported in each study for the treatment group. Therefore, treatment with methylphenidate may be associated with substantial increased risk of other adverse events that were less common and not examined in this study. With regard to the adverse events associated with methylphenidate toxic effects, transient psychotic symptoms have been described in several case reports, and concerns about elevated blood pressure and lowered seizure threshold have also been suggested.¹¹ No studies included in this meta-analysis reported any of these adverse events other than 5 cases of transient psychosis and 7 of hypertension.^29,47-51,73 No deaths were reported. The analysis of the cohort studies shows that risk of adverse events for methylphenidate treatment was substantial, with anorexia being the most prevalent, followed by insomnia and headache. These findings are consistent with those from the Cochrane review article.¹⁸

Limitations of this study included the sparsity of RCTs and the small sample sizes. Not all of the studies reported maximum or mean doses of medication or investigated adverse events, further restricting the number of studies available for data analysis. The variation in formulation of methylphenidate across studies limits the scope for comparison. Heterogeneity of RCTs was limited; however, a high degree of heterogeneity was found among the cohort studies. This high degree of heterogeneity may be associated with the population variation (eg, age group, comorbidities) between the studies and the differing methods and outcome measurements.

This meta-analysis found a range of recommended maximum doses for methylphenidate but no discernable scientific justification for any of the recommendations. We also noted an absence of any reported life-threatening adverse events. If the individual’s optimal dose can be established by finding the best balance of therapeutic advantages and tolerability, having a maximum dose may be unnecessary. More carefully monitored studies are needed to investigate the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds without reference to any set maximum dose.

Accepted for Publication: February 5, 2019.

Corresponding Author: Alison S. Poulton, MD, MB, BChir, Charles Perkins Centre Nepean, The University of Sydney, Department of Paediatrics, Nepean Hospital, PO Box 63, Penrith, New South Wales 2751, Australia (alison.poulton@sydney.edu.au).

Published Online: May 28, 2019. doi:10.1001/jamapediatrics.2019.0905

Author Contributions: Dr Eslick had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Eslick, Poulton.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ching.

Critical revision of the manuscript for important intellectual content: Eslick, Poulton.

Statistical analysis: Eslick.

Administrative, technical, or material support: Ching, Eslick.

Supervision: Eslick, Poulton.

Conflict of Interest Disclosures: Dr Poulton reported personal fees and nonfinancial support from Shire outside of the submitted work. No other disclosures were reported.