Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies

Abstract

Background: The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection.

Methods: A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included.

Results: Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study.

Conclusions: Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.

Figure 1

Flow diagram of screened and included articles.

Figure 2

Comparative efficacy of Concerta^®and Equasym XL^®versus placebo over time in a laboratory school study. Data represent all dose levels combined (Equasym XL^® 20, 40, 60 mg; Concerta^® 18, 36, 54 mg). Corresponding effect sizes for each timepoint are shown in the table. Originally published in Swanson JM, et al. Pediatrics 2004, 113:e206-e216. Reproduced with permission from Pediatrics, Vol. 113, Page(s) e206–e216, Copyright ©2004 by the AAP. *Equasym XL^® was significantly better than Concerta^®; ^†Concerta^® was significantly better than Equasym XL^®; ^‡placebo was significantly better than both Equasym XL^® and Concerta^®. MCD, Equasym XL^®; PERMP, permanent product measure of performance; PLA, placebo; SEM, standard error of the mean; SKAMP, Swanson, Kotkin, Atkins, M-Flynn, Pelham rating scale.

Figure 3

Comparative efficacy of Concerta^®(18, 36 mg) and Ritalin LA^®(20 mg) versus placebo in a laboratory school study. Figure shows change from pre-dose baseline in SKAMP-Attention score over time. In the first 4 hours post-dose, Ritalin LA^® (20 mg) resulted in significantly greater improvements from baseline than Concerta^® (18 mg) in SKAMP-Attention (p = 0.015). Originally published by Springer and Adis Data Information BV/Paediatr Drugs, volume 5, 2003, 545–555, Comparative efficacy of two once daily methylphenidate formulations (Ritalin LA and Concerta) and placebo in children with attention deficit hyperactivity disorder across the school day, Lopez F, et al., Figure 3, ©Adis Data Information BV 2003; with kind permission from Springer Science + Business Media B.V. SKAMP, Swanson, Kotkin, Atkins, M-Flynn, Pelham rating scale.

Figure 4

Comparative efficacy of Concerta^®(d,l-MPH-ER; 36, 54 mg) and Focalin XR^®(d-MPH-ER; 20, 30 mg) versus placebo over time in a laboratory school study. SKAMP, Swanson, Kotkin, Atkins, M-Flynn, Pelham rating scale. Error bars: standard deviation. Reprinted/Reproduced from Silva R, et al. Psychopharmacol Bull 2008, 41:19–33, with permission from MedWorks Media Global, LLC.

Figure 5

Comparative efficacy of Ritalin LA^®(20 mg) and Medikinet^®retard (20 mg) versus placebo in a laboratory school study. Figure shows SKAMP-Combined score over the first 4.5 hours post-dose. 'Clinical relevance’ lines outline the predefined non-inferiority margin. SKAMP, Swanson, Kotkin, Atkins, M-Flynn, Pelham rating scale. Originally published in Schulz E et al. J Child Adolesc Psychopharmacol 2010, 20:377–385. Reproduced with permission. The publisher for this copyrighted material is MaryAnn Liebert, Inc. publishers.