PEDIATRICS Vol. 120 No. 5 November 2007, pp. 1100-1106 (doi:10.1542/peds.2007-0542)
SPECIAL ARTICLE |
Treating Attention-Deficit/Hyperactivity Disorder With a Stimulant Transdermal Patch: The Clinical Art
a Department of Psychiatry, Ohio State University, Columbus, Ohio
b Arizona Child Study Center, St Joseph's Hospital and Medical Center, Phoenix, Arizona
c Children's Developmental Center, Maitland, Florida
d Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida
e Pediatric Psychopharmacology Department, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
f Departments of Psychiatry and Pediatrics, Case Western Reserve University, Cleveland, Ohio
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ABSTRACT |
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 TOP ABSTRACT TITRATION AND MANAGEMENT OF...PATCH-SITE SELECTION AND PATCH...SKIN HYGIENEPATIENT AND PARENT EDUCATIONCONCLUSIONSREFERENCES |
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Stimulant medications (amphetamine and methylphenidate) are the best-documented treatments for attention-deficit/hyperactivity disorder, but their short pharmacokinetic and behavioral half-lives have historically produced irksome time-course effects. New drug-delivery systems designed to eliminate the need for frequent dosing include the methylphenidate transdermal system, in which the matrix acts as both the drug reservoir and the skin adhesive. The methylphenidate transdermal system patch, in contrast to long-acting oral preparations, requires a paradigmatic shift in clinical thinking, as well as refinement of clinical management skills. For dosing with the methylphenidate transdermal system patch, clinicians must think in terms of a retrievable form of drug delivery (in milligrams per hour) rather than a fixed nonretrievable dose (in milligrams per dose or milligrams per day). Clinicians and patients can determine the optimal clinical dose by controlling 2 variables: (1) patch size (controlling milligrams per hour) and (2) duration of patch wear. The new paradigm is worth learning, because the patch offers several advantages over oral preparations for some patients, chiefly individualized control over effect duration (determined by when the patch is applied in the morning and removed in the afternoon/evening). Taking full advantage of this treatment option requires educating the patient and parents regarding practical elements of daily use. These elements include patch-site selection, application techniques, management of wear time to optimize the daily time course of clinical benefits, and skin hygiene. This article summarizes clinical principles that physicians may find useful in managing this new addition to the attention-deficit/hyperactivity disorder treatment armamentarium.
Key Words: attention-deficit/hyperactivity disorder • methylphenidate • transdermal system
Abbreviations: MTS—methylphenidate transdermal system • ADHD—attention-deficit/hyperactivity disorder
Sympathomimetic stimulant medications (ie, various forms of methylphenidate and amphetamine) have long been recognized as the most effective and best-documented treatment for attention-deficit/hyperactivity disorder (ADHD). ADHD is a neurodevelopmental syndrome of chronic inattention, distractibility, impulsiveness, and restless overactivity,1–3 which impairs functioning at home, in school, and in the community (and often later in life on the job or in a marriage). Stimulants have been the medication of choice for the ADHD syndrome since 1937, when Bradley4 reported conduct and academic improvement with stimulant use in children with behavioral and emotional disturbances. Expert consensus guidelines continue to support the use of stimulant medications as first-line therapy for ADHD.5,6 The risk/benefit ratio is highly favorable and well documented, as evidenced in a 1996 meta-analysis that evaluated 155 controlled studies of 5768 children, adolescents, and adults; Spencer et al1 found an average efficacy of 70% for stimulant medications. Goldman et al,7 on behalf of the Council on Scientific Affairs for the American Medical Association, concluded that, with appropriate dose titration, up to 90% of children properly diagnosed as having ADHD respond to 
1 stimulant without experiencing a major adverse event.
Unfortunately, stimulants as originally manufactured (ie, immediate-release forms) have a short half-life and limited duration of effect, which make the management of medication time-course effects somewhat challenging. The need to give a noon dose at school made the immediate-release forms of the stimulants both onerous and stigmatizing for pediatric patients, parents, and schools. Furthermore, it has invited public criticism and political fire from some quarters. The need to remember the exact timing of repeated doses is especially problematic and impractical for a disorder for which forgetfulness in daily activities is 1 of the 18 defining symptoms.2
In response to these problems, a number of longer-acting preparations and delivery systems have been developed to level the diurnal curve and to eliminate the need for school-time dosing. These developments include coated or other forms of sustained-release tablets or pills, encapsulated beads with time-release coatings, an oral osmotic delivery system, a new longer-acting molecule (atomoxetine), a conjugated d-amphetamine molecule (lisdexamfetamine), and a transdermal patch (methylphenidate transdermal system [MTS]).
Use of the new, long-acting, oral, stimulant preparations requires only minor shifts in thinking by clinicians (essentially aggregation of short-acting doses administered 2 or 3 times per day into a single, long-acting dose administered in the morning). However, management of ADHD by using the MTS patch involves a paradigmatic shift in thinking, from a fixed, nonretrievable, oral dosage administered in milligrams per day to a flexible, removable, transdermal dosage form prescribed in terms of hourly drug-delivery rate (ie, milligrams per hour) and adjustable patch wear time (total milligrams per day). The benefits of this paradigm shift are increased flexibility and control over the time course of clinical effects and the duration of benefits and adverse effects, possible avoidance of some gastrointestinal problems, and more-uniform systemic drug delivery than with most oral treatments.8 As is characteristic of transdermal drug delivery, compared with oral dosing,8 MTS patches have more consistent absorption and systemic bioavailability over the wear period than do most oral preparations.9 Table 1 lists some of the advantages and disadvantages of the MTS patch relative to long-acting oral preparations.
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One advantage of the MTS patch is its possible lower abuse potential. Some parents fear that use of stimulant medications may encourage their children to abuse other drugs. Clinicians can assure parents that there is no published evidence that stimulant therapy for ADHD in childhood is associated with increased risk of subsequent substance use disorders. Claims that early stimulant treatment might actually be protective against later abuse10,11 have been questioned.12 Most long-acting oral stimulants somewhat discourage crushing and snorting or injecting (the preferred methods of abuse) but, with some effort, the immediate-release beads can be sorted out of the bead preparations or the 22% overcoat can be dissolved off the osmotic delivery tablets. The incorporation of methylphenidate into the MTS adhesive may do a better job of discouraging snorting or injecting. At this point, however, there are no empirical data to support this expectation.
The most obvious candidates for the transdermal patch include patients who have trouble swallowing pills, those with rapid or erratic metabolism or enteral absorption, those who experience gastrointestinal discomfort with oral preparations, those for whom the long-acting oral preparations do not last long enough, and those who need flexibility in duration of effect from day to day. Whereas an estimated 26% of adults have pill-swallowing difficulties, the proportion of children with this problem is thought to be even greater.9,13,14 Chewable and oral-suspension methylphenidate are potential alternatives for children who have difficulties with pill swallowing, but these are immediate-release formulations, without the convenience and consistency of once per day administration. Sprinkling the beads from long-acting capsules into children's food (eg, applesauce, ice cream, or pudding) can be problematic for children who object to the feel of the beads or cannot refrain from chewing them. Atomoxetine capsules can be opened and the powder dissolved in water-based beverages, but the taste is sometimes objectionable.
This article reviews clinical management strategies for deriving optimal benefits from the new methylphenidate delivery system. Three main categories of issues are addressed: (1) those related to initiation, titration, and management of the daily time course of clinical benefits; (2) those related to patch-site selection and application techniques; and (3) those related to skin hygiene. All 3 categories require clinician, patient, and parent/caregiver education.
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TITRATION AND MANAGEMENT OF TIME COURSE |
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TOPABSTRACTTITRATION AND MANAGEMENT OF...PATCH-SITE SELECTION AND PATCH...SKIN HYGIENEPATIENT AND PARENT EDUCATIONCONCLUSIONSREFERENCES |
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Although long-acting oral preparations of methylphenidate offer only dosage manipulation as a method of titration, the MTS patch offers manipulation of both hourly drug-delivery rate and wear time as possible means of titration for optimal clinical exposure. The patch "dose" has 2 independent components, namely, the size of the patch, from 12.5 cm2 (nominally 10 mg) to 37.5 cm2 (nominally 30 mg), and adjustable wear time, which together determine the milligrams of methylphenidate absorbed per day by a given patient. Naturally, interpatient variations in absorption rates also affect the effective dose and must be considered whether skin or gut mucosa is the absorption route. Skin absorption differences are minimized by consistent selection of proximal application sites (hip) for each patient. Distal sites (arm or leg) have more absorption variability both between and within patients.
As with oral preparations of methylphenidate, clinicians should begin treatment of stimulant-naive pediatric patients, especially those with small body mass, with the lowest convenient amount, the 12.5-cm2 MTS patch. A wear time of 9 hours with this size provides a nominal total daily dose of 
10 mg, but this has the same effect as 15 mg (5 mg administered 3 times per day) administered orally because it avoids first-pass liver metabolism. This is approximately equal to an 18-mg osmotic delivery capsule, which is not absorbed completely. Although it is not recommended in the package insert, treatment can be initiated with larger patches for patients changing from oral doses of >20 mg/day. For example, the 18.75-cm2 patch delivers a 15-mg nominal dose in 9 hours of wear, which has the same effect as a 27-mg osmotic capsule or a 20-mg encapsulated bead preparation. Table 2 lists the doses of the MTS patch that have been investigated and their approximate oral immediate-release methylphenidate equivalents.
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A 9-hour wear time should be tried initially (Fig 1), with increases or decreases according to how rapidly the effect wears off after patch removal (usually
3 hours). Generally, patch removal 3 hours before bedtime results in an appropriate wear time (usually 9–11 hours for schoolchildren), although the patch can be worn for up to 16 hours if extended effects are needed.8 It is useful to remove the patch well before bedtime, to allow a good appetite for a bedtime snack. The clinical effects are assessed within 1 week and, if the results are insufficient during the morning and afternoon, then the patch size is increased. If the clinical benefits are satisfactory during the school day but not in the evening, then the evening can be covered merely by increasing the wear time without changing the patch size. It must be remembered that increasing the wear time without changing the patch size increases the daily dose.
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Systematic monitoring of clinical and adverse effects remains an essential component of treatment and facilitates dosage titration. The American Academy of Pediatrics, in conjunction with the National Initiative for Children's Healthcare Quality, developed a toolkit that facilitates diagnosis of ADHD and systematic monitoring of therapy.15
If the clinical benefits are satisfactory but flawed by interference with sleep or other late-day adverse effects, then the wear time can be decreased gradually to whatever time allows for cessation of the adverse effects. It should be noted, however, that the adverse effects of insomnia and anorexia, which are noted with all stimulants at the initiation of treatment, have been reported to resolve with repeated use, even without changes in wear time, in 40% to 60% of cases.16,17 This finding is consistent with the results for oral dosing. Some children may have such slow metabolism that a removal time of 3:00 to 4:00 PM, with subsequent drug washout, may provide adequate duration of effect. At each weekly assessment, decisions should be made regarding both patch size (milligrams per hour) and wear time (total milligrams per day), on the basis of the individual patient's response, until the optimal patch size and duration of wear are determined.
If an optimal size is not found among the commercially available sizes, then the question of whether an "in-between" size could be home-manufactured by snipping a little off a larger size naturally arises. The protocols in the premarketing studies did not allow for such a strategy; consequently, there has been no evidence to support it. However, there is no logical reason why this could not be done, because the methylphenidate is dispersed uniformly throughout the adhesive. If this is done, then the corners should be rounded, to prevent catching on clothes. Once the correct patch size and wear time are determined for the individual, the patient should be assessed (with inspection of the patch site) every other week for 1 month and monthly thereafter.
The beginning and the end of the day deserve special consideration. Like extended-release oral medications, transdermal delivery of methylphenidate (particularly starting doses) may have a somewhat slower onset of clinical effect than do short-acting (immediate-release) oral preparations. To compensate for the slower onset, the patch should be applied a bit earlier in the morning than an immediate-release oral preparation would be administered. It is important to note that the patch tends not to interfere with breakfast appetite if application precedes breakfast by <1 hour. For a child who exhibits significant difficulty in the morning before medication, parents may choose to apply the patch before the child awakens, to allow some effect to be present on arising.
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PATCH-SITE SELECTION AND PATCH APPLICATION |
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The MTS patch is designed to be worn on the lateral hip beneath the underwear, avoiding the waistline. The site and application process are illustrated in the package insert. Placement of the MTS patch on the lateral hip serves the dual purpose of hiding the patch and standardizing the expected absorption rate. It is important to note that absorption occurs at different rates in different body regions and the variability among and within patients is greater in distal areas, compared with proximal areas. Optimal absorption depends on the maintenance of the hygiene and integrity of the skin at the patch-application site and the use of proper placement techniques.
It is important that the patch be placed where tight-fitting clothing, especially belts, will not rub it. Such abrasion may cause the MTS patch to rub off or may roll up the patch edges and interfere with absorption, as well as causing irritation. The patch should be applied to clean, dry, intact skin that is free of powder, oil, lotion, cuts, abrasions, or irritation. Ordinary bathing is adequate to satisfy the "clean" requirement; the patch site should not be scrubbed or cleaned with alcohol or other agents that might compromise skin integrity. A residual adhesive outline of the patch (like a "bathtub ring" or "Band-Aid ring") is not harmful to leave but, if parents wish to remove it for cosmetic reasons, then removal can be performed with gentle swabbing with a cotton ball with vegetable/mineral oil or lotion.
To allow skin recovery between applications, patch-application sites and hips should be alternated daily. Unless the MTS patch is too large or the hip is too small, each hip should be divided into 2 application sites (anterolateral and posterolateral) to yield a total of 4 application sites, which allows 3 days between applications at a given site. The application site rotation might be as follows: right anterior, left anterior, right posterior, left posterior, and then back to right anterior. A good rule is to allow a fingers’ breadth between the old and current application sites. Occasionally, the child is large enough and the optimal MTS patch size is small enough that each hip can be divided into 4 quadrants, which allows each patch-application site to be used only once every 8 days, but this degree of complexity would be needed only in rare cases of very sensitive skin. Any area subject to stretching or wrinkling, such as flexor/extensor surfaces (eg, inguinal area or buttocks), should be avoided, to prevent discomfort and failure of adhesion.
Proper handling of the MTS patch immediately before application can promote good patch adhesion. The patches are supplied in a sealed tray and are individually sealed in pouches. They should be cool before application, to facilitate removal of the rigid protective liner. (Ten to 15 minutes in the refrigerator may help in hot weather, although the patches are intended for storage at room temperature.) The pouch should be cut open carefully, without cutting into the MTS patch, and the patch should be applied immediately after removal from the pouch. Care should be taken to avoid touching the adhesive surface with the fingers. One half of the rigid protective liner, which is presplit diagonally into 2 sections, can be removed without touching the exposed adhesive directly by first flexing the patch 3 or 4 times to loosen the acute corner at the split. If this is not enough to loosen the acute corner, then the patch may be folded and 1 cover section pushed with a sliding motion. Peel off one half of the protective liner while holding the patch by the other half. With the intact half of the protective liner as a handle, the exposed adhesive surface of the MTS patch should be applied to the selected area of the hip, pressed firmly in place, and smoothed down. While the half of the patch already attached to the skin is held in place, the patch should be folded over. This action should separate the acute corner of the other half of the protective liner, which then can be pulled off gently. The rest of the patch should be pressed firmly in place and the entire patch then smoothed down. After application, the patch should be pressed firmly and warmed with the palm of the hand for 30 to 60 seconds, to enhance adhesion. Several studies demonstrated good adherence of properly applied MTS patches in highly active, summer camp settings (eg, swimming and sports).17,18
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SKIN HYGIENE |
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TOPABSTRACTTITRATION AND MANAGEMENT OF...PATCH-SITE SELECTION AND PATCH...SKIN HYGIENEPATIENT AND PARENT EDUCATIONCONCLUSIONSREFERENCES |
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Methylphenidate, which is a sympathomimetic stimulant, is a mild irritant and dilates blood vessels, inducing reddening ("blush") of the skin under the patch, which is "normal" and clinically benign. This normal erythema should not be confused with a rash or allergic reaction. Clues to identifying normal erythema are that the redness is confined to the patch area, it is flat (with no edema or papules), and it usually resolves 24 to 36 hours after patch removal. Parents should be advised that, if erythema persists for >2 days or is associated with papules or edema, it should receive clinical attention. Figure 2 (from a dermatologic skin test, not an actual MTS patch application) illustrates the kind of rare reaction that should result in the termination of patch treatment and a switch to oral medication.
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Although stimulants are not commonly known allergens, it is possible to have an allergic reaction to the adhesive (rare). Furthermore, other topical dermatitides or mechanical irritation may result infrequently from repeated patch application and removal. If the effect is severe enough, treatment with the patch should be discontinued. It is important to note that most rashes (dermatitides) and other reactions are preventable by adhering to the application instructions and paying attention to maintaining skin integrity.
In addition to rotating patch sites by alternating hips and, if possible, specific areas of each hip, several other measures can be taken to preserve skin integrity. Parents and children should be instructed regarding gentle bathing practices with hydrating lotion soaps (such as CeraVe [Coria Laboratories Ltd, Fort Worth, TX] and Cetaphil [Galderma Laboratories, Fort Worth, TX]) and the use of vegetable or mineral oil to wipe away the glue resins gently. Including children in this discussion introduces a ritual for removing the patch, akin to brushing one's teeth. Clinicians should recommend no rubbing of the area after patch removal and resistance of the natural tendency to scrub off any residual adhesive around the patch outline. Frictional abrasion usually irritates the skin more than does residual adhesive. Emollients such as petrolatum can also be used to hydrate the skin and to help it heal.
The recommendation for the patch site to be clean and dry does not imply the use of special cleaning agents that might be harsh on the skin; ordinary bathing with a fragrance-free moisturizing soap is adequate. If irritation of the skin develops, a simple water-soluble moisturizer or 1% hydrocortisone ointment (available without a prescription) may be applied to the most-recent patch site. The emollient/ointment should be applied only when the MTS patch is removed, allowing 4 daily showers or baths between applications and reuse of the formerly irritated site (assuming that the 4-site rotation described above is used). It is important that emollients/ointments not be used on a site just before patch application, because of potential interference with both adhesion and absorption.
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PATIENT AND PARENT EDUCATION |
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TOPABSTRACTTITRATION AND MANAGEMENT OF...PATCH-SITE SELECTION AND PATCH...SKIN HYGIENEPATIENT AND PARENT EDUCATIONCONCLUSIONSREFERENCES |
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Not only the clinician but also the patient (or, in the case of youngsters, the parent) must be aware of most of the principles described above. Table 3 provides a checklist of important information that must be communicated to patients and parents to obtain optimal results and to promote cooperation and compliance. It may be photocopied and given to them to look at while they receive instructions and then to keep as a reminder.
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The child should be trained gradually to take responsibility for skin hygiene and patch application. Self-application would be performed best with the aid of a mirror, to confirm that the application site from 2 days earlier is not overlapped. As with any ADHD medication, initial visits need to be frequent and long enough not only to titrate dosing accurately but also to educate and to promote communication among all who can help the child (parent, teacher, coach, and child). A daily report card3 is a good way to promote communication between home and school. As the "star of the therapeutic team,"19 the child should take gradually more responsibility for communication, as well as monitoring of adverse effects and skin hygiene, starting with removal of the patch at the proper time with parent prompting.
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CONCLUSIONS |
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TOPABSTRACTTITRATION AND MANAGEMENT OF...PATCH-SITE SELECTION AND PATCH...SKIN HYGIENEPATIENT AND PARENT EDUCATIONCONCLUSIONSREFERENCES |
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Optimization of clinical benefits with any ADHD medication requires the ability of clinicians and patients to control precisely both the robustness of the response and the daily time course of that response. Presently, pharmacologic treatment of ADHD does not consist of a single ideal treatment, and additional treatment options are clinically valuable. The availability of the MTS patch expands clinician and patient options in several ways; it bypasses the gut and its vagaries, it eliminates the need to swallow, it allows for consistent clinical effects throughout the day for as long as needed, it produces greater duration of effect than do existing oral methylphenidate regimens, and, perhaps most importantly, it offers complete control over both onset and offset of effects, empowering the parent and the child to take control of the symptoms and promoting cooperative relationships among the child, the parent, and the clinician. The patch may be an obvious choice for patients who have trouble swallowing pills. It also should be useful for patients who require varying durations of effects from day to day, have rapid metabolism (requiring a second dose even with extended-release oral preparations), require flexible management of late-day adverse effects, or routinely require extended symptom control of longer duration than available with the oral preparations. Therefore, the time needed to master the new treatment option by learning the knowledge and skills summarized here would seem to be well invested.
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FOOTNOTES |
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Accepted May 23, 2007.
Address correspondence to L. Eugene Arnold, MD, Department of Psychiatry, Ohio State University, 479 S Galena Rd, Sunbury, OH 43074. E-mail: arnold.6{at}osu.edu
Financial Disclosure: Dr Arnold has received research funding, consulting honoraria, and speaker fees from Shire, Lilly, Novartis, McNeil, Sigma Tau, and Noven; Dr López has received research funding, consulting honoraria, and/or speaker fees from Shire, Novartis, Noven, New River Pharmaceuticals, Celltech-Medeva, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, and Cephalon; Dr Jacob received speaker honoraria from Shire, Connetics, and Astellas; and Dr Findling receives or has received research support from, has acted as a consultant for, and/or has served on a speakers bureau for Abbott, AstraZeneca, Bristol-Myers Squibb, Celltech-Medeva, Forest, GlaxoSmithKline, Johnson & Johnson, Lilly, New River Pharmaceuticals, Novartis, Otsuka, Pfizer, Sanofi-Aventis, Shire, Solvay, and Wyeth. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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