COMMENTARY

New-Generation Long-Acting Stimulants for the Treatment of Attention-Deficit/Hyperactivity Disorder

Joseph Biederman, MD

November 21, 2003

Abstract and Introduction

Abstract

A new generation of rapid-acting, long-duration formulations has further advanced the standard of care in attention-deficit/hyperactivity disorder (ADHD). Short-acting stimulants have a duration of action of 2-6 hours and are administered 2-3 times daily. This dosing requirement places the patient with ADHD at risk for breakthrough symptoms between doses and increases the potential for medication noncompliance and abuse. Recent advances in the formulation of stimulant medications resulted in the development of agents with a rapid onset of action and a long duration of effect. Currently, 4 rapid-acting, long-duration stimulant compounds are available: 3 of these contain methylphenidate (Concerta, Metadate CD, and Ritalin-LA), and 1 (Adderall XR) is composed of mixed salts of a single-entity amphetamine. All of these preparations can be used as initial treatment. Two of these agents, Metadate CD and Ritalin-LA, are formulated to control ADHD symptoms for 6-8 hours. In contrast, Adderall XR and Concerta were designed to be effective over 10-12 hours. Thus, the overall duration of therapeutic effect represents an important distinction among these agents. These agents can be used to initiate treatment and are formulated so that the potential for diversion and abuse is minimized. As with all therapeutic agents, the efficacy and safety of stimulant medications should always guide prescribing behavior: careful dosage titration of the selected stimulant product should help to ensure that each patient with ADHD receives an adequate dose, so that the clinical benefits of therapy can be fully attained.

Introduction

ADHD is the most common neurobehavioral disorder in children, estimated to affect between 4% and 12% of all school-aged children and 2% to 4% of adults. The chief features of ADHD are inattention, hyperactivity, and impulsiveness,[1] and this disorder is often associated with substantial impairments, including low self esteem, poor family and peer relationships, school and work difficulties, and academic underachievement.[2] Current guidelines from the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics recommend that a diagnosis of ADHD in children be established based on the criteria defined by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV).[1,2] These include 6 out of 9 symptoms of either inattention or hyperactivity/impulsivity that had been present before age 7, persisted for at least 6 months, are more frequent and severe than is typical for children at comparable age, manifest in multiple settings, and adversely affect functioning.[1]

Establishing the diagnosis of ADHD in children requires a synthesis of information from parents, caregivers, and classroom teachers, as well as a comprehensive assessment of the child. The diagnosis of ADHD in adults relies largely on self-reports and a comprehensive assessment of the adult patient. It is well recognized that the ADHD patient frequently presents with comorbid conditions such as conduct disorder and oppositional defiant disorder, mood disorders (unipolar and bipolar), anxiety disorders, and learning disabilities. Therefore, clinical assessment of these potential coexisting conditions must be considered in the overall evaluation of the child.[2]

Education of the affected patient and his/her family must be considered an essential component of any treatment plan, which may encompass special education programs, psychological intervention, and medical management. Stimulant medications are the predominant pharmacologic treatment of ADHD at all ages. Short-term studies ranging from several weeks up to 3 months indicate that approximately 70% of patients respond to the first stimulant agent administered, with resulting improvement in their ADHD symptoms. Moreover, extended trials over 12 months or longer suggest that symptomatic improvement persists as long as the stimulant medication is taken.[3]

Stimulant medications employed in the treatment of ADHD include methylphenidate, dextro-(D)-amphetamine, D,L-amphetamine, and pemoline. Among these agents, methylphenidate has been the most widely studied and used. Because of its association with rare but potentially fatal hepatotoxicity, pemoline should be used only in the event that other stimulants have failed or cannot be tolerated.[3,4]

While studies have shown that stimulant medications are generally comparable in efficacy, there may be differences in the degree of response to varying compounds. In a 1996 meta-analysis involving 141 subjects, approximately 40% of the patients responded equally well to either methylphenidate or D-amphetamine, but 26% responded better to methylphenidate and 35% had a superior response to D-amphetamine.[5] Thus, the availability of multiple stimulant products increases the likelihood that a patient will achieve effective control of ADHD symptoms.

The varying formulations of methylphenidate, D-amphetamine and D,L-amphetamine currently available have different durations of action, as shown in .

Table 1.  Table 1. Stimulant Medications Available for the Treatment of ADHD*[6-9]

  Onset of Action Peak Clinical Effect Duration of Action Required Number of Daily Doses
Immediate-release preparations
Methylphenidate (Ritalin, Methylin, Metadate, others) 20-60 minutes ~ 2 hours; range, 0.3-4 hours 2-4 hours 2-3
D-amphetamine (Dexedrine, Dextrostat) 20-60 minutes 1-2 hours 3-6 hours 2-3
D,L-amphetamine (Adderall) 30-60 minutes 1-2 hours 3-6 hours 2
First-generation, sustained-release preparations (older delivery systems)
Methylphenidate (Ritalin-SR, Metadate ER, Methylin ER) 60-90 minutes ~ 5 hours; range 1.3-8.2 hours 4-6 hours 2
D-amphetamine (Dexedrine, Spansule) 60-90 minutes NA 4-6 hours 2
Second-generation, extended-release preparations
Methylphenidate (Metadate CD, Ritalin-LA) 30 minutes-2 hours Bimodal pattern 6-8 hours 1-2
Methylphenidate (Concerta) 30 minutes-2 hours Ascending pattern 12 hours 1
D,L-amphetamine 1-2 hours Bimodal pattern 10-12 hours 1

 

*Use of pemoline has been associated with rare but life-threatening hepatic failure. It is not considered first-line therapy for ADHD and is not included in this table.
These products display bimodal patterns representing early and late release of medication.
NA = not available.

 

Short-acting compounds, which have a duration of action ranging from 2-6 hours and must be administered 2-3 times per day, were the first such agents to be used. However, the requirement for multiple daily dosing places the ADHD patient at risk for breakthrough symptoms due to the declining plasma drug concentrations between doses, and it increases the potential for medication noncompliance or abuse. Accordingly, first-generation sustained-release stimulant preparations were formulated with intermediate-range durations of actions ranging from 4 to 8 hours, in order to limit the dosing requirement to twice daily. Unfortunately, the intermediate-acting methylphenidate preparations proved to be less effective than immediate-release formulations, limiting their use.[10]

Second-Generation, Rapid-Acting, Long-Duration Stimulant Preparations

Recent advances in the formulation of stimulant medications have now resulted in the development of agents with a rapid onset of action and a long duration of effect. Currently, 4 rapid-acting, long-duration stimulant compounds are available: 3 of these contain methylphenidate (Concerta, Metadate CD, and Ritalin-LA), and 1 (Adderall XR) is composed of mixed salts of a single-entity amphetamine. All of these preparations can be employed as initial treatment, eliminating the need to use an immediate-release stimulant followed by conversion to another formulation. Two of these agents, Metadate CD and Ritalin-LA, are formulated to control ADHD symptoms for 6-8 hours. In contrast, Adderall XR and Concerta were designed to be effective over 10-12 hours. Thus, the overall duration of therapeutic effect represents an important distinction among these agents.

Concerta

The first second-generation stimulant medication to become available for clinical use,

Concerta

has a duration of effect of approximately 12 hours. It was specifically designed to replace immediate-release methylphenidate administered 3 times daily. This agent has an osmotically released, timed drug-delivery system that delivers a proportion of the dose immediately upon ingestion, providing a rapid onset of action followed by continuous drug delivery over 12 hours. The pharmacokinetic profile of

Concerta

termed "ascending dose," was specifically designed to avoid acute tolerance, which is believed to be the cause of the diminished effectiveness of intermediate-acting methylphenidate preparations compared with immediate-release formulations.

[3,11]

The pharmacokinetic profile of Concerta 18 mg once daily was compared with that of immediate-release methylphenidate 5 mg 3 times a day and sustained-release methylphenidate 20 mg once daily in a study of 36 adults.[12] The immediate-release methylphenidate demonstrated fluctuations in peaks and troughs associated with 3-times-daily dosing, while the sustained-release formulation resulted in a rapid increase in methylphenidate concentration with a peak at about 4 hours, followed by a rapid decline. It is thought that the rapid increase in the plasma concentration of methylphenidate may be associated with acute tolerance, while the subsequent rapid decline in plasma levels may account for the reduced therapeutic benefit of the first-generation sustained-release methylphenidate formulation, compared with 3-times-daily dosing.[10] In contrast, following oral doses of Concerta 18 mg, mean methylphenidate plasma concentrations increased rapidly over the first 2 hours, followed by a slower increase for the next 3-4 hours followed by a gradual decline thereafter. Peak concentrations were reached at 6-8 hours and gradually declined to baseline by 24 hours (Figure 1). This pharmacokinetic profile, with lower peak concentrations than either the 3-times-daily immediate-release or sustained-release formulations, eliminates the large fluctuations associated with these older preparations, securing continued clinical control without the well known "peaks and valleys" of the immediate-release formulation. Recent studies have indicated that the presence of food does not affect the absorption of Concerta.[13]

Figure 1.

 

Mean (± SD) plasma methylphenidate concentrations following Concerta 18 mg daily (), immediate-release methylphenidate 5 mg 3 times daily (), and sustained-release methylphenidate 20 mg daily (). Reprinted with permission from J Clin Pharmacol. 2000;40:379-388.

Two randomized, placebo-controlled studies have demonstrated that once-daily Concerta provides safe and effective treatment for children with ADHD -- equivalent to that of immediate-release methylphenidate 3 times daily.[14,15] In the larger of these trials, 282 children were randomized to receive Concerta, immediate-release methylphenidate 3 times daily, or placebo for 28 days. Three dosage levels were evaluated: 18 mg Concerta daily/5 mg immediate-release methylphenidate 3 times daily; 36 mg Concerta daily/10 mg immediate-release methylphenidate 3 times daily; and 54 mg Concerta daily/15 mg immediate-release methylphenidate 3 times daily. Outcomes in multiple domains were assessed, with the primary measure being the teacher IOWA Conners I/O subscale score. Both drug preparations were superior to placebo and equivalent to each other in reducing core ADHD symptoms. Similar percentages of patients receiving the 2 active drug preparations reported adverse events, all of which were mild.[14]

The second study compared the efficacy of Concerta to that of immediate-release methylphenidate in a randomized, blinded, placebo-controlled crossover trial in 68 children. The same dosage levels were tested as in the larger trial, and the study patients received the respective medication for 7 days. Based on changes in ADHD symptoms, social behavior, and academic performance, both study drugs were statistically superior to placebo but equivalent to each other. The beneficial effects of Concerta were sustained over a 12-hour period; side effects for the 2 methylphenidate preparations were similar.[15] The results of these 2 clinical studies demonstrated that Concerta is equivalent to methylphenidate 3 times daily in terms of safety and efficacy, but with the advantage of once-daily dosing.

Metadate CD

 

Metadate

CD was the second extended-release preparation to be approved by the US Food and Drug Administration (FDA). Its 20-mg capsules contain a mixture of immediate-release and extended-release beads of methylphenidate in a 30:70 ratio. The pharmacokinetic profile indicates a rapid, early release after oral dosing with a peak at approximately 1.5 hours, followed by a second peak at approximately 4.5 hours. In contrast to

Concerta

,

Metadate

CD was designed to replace immediate-release methylphenidate twice daily. Pharmacokinetics of this preparation suggest that the clinical benefit would be expected to extend over a period of approximately 6-8 hours, covering the school day.

[6,15]

In comparison

with Concerta

,

Metadate

CD produces greater exposure to methylphenidate and higher plasma concentrations over the first 6 hours, followed by a more rapid decline, consistent with the expected duration of action of up to 8 hours.

[16]

The safety and efficacy of Metadate CD was established in a double-blind, parallel-group, placebo-controlled trial in 321 children with ADHD. Patients received 3 weeks of treatment consisting of 20 mg daily, after which the dosage was increased weekly to a maximum of 60 mg, depending upon patient response. Patients were evaluated in the morning and afternoon on 3 days of each treatment week, using the teacher's version of the Conners' Global Index Scale. Metadate CD-treated patients demonstrated significant improvement in symptom scores in comparison with patients receiving placebo. Scores from evaluations at both time periods were superior in the active drug group to those of patients who received placebo.[6] In this trial, 2 (1%) Metadate CD-treated patients, vs none in the placebo group, discontinued the study medication due to an adverse event. Pooled data from this and 2 other clinical studies indicated that the incidence of adverse events was low. Headache, stomach ache, loss of appetite, and insomnia were found to occur more frequently with Metadate CD than with placebo.[6]

Ritalin-LA

 

Ritalin-LA

, the most recent addition to the group of long-duration stimulant drugs, received FDA approval in early 2002. Like

Metadate

CD, each capsule contains a mixture of beads, 50% of which are designed to immediately release methylphenidate, with the remaining 50% providing a second, delayed release of the active drug. Accordingly,

Ritalin-LA

produces a bimodal plasma concentration time profile -- the first peak occurs after 1-3 hours, and the second peak is reached approximately 6 hours postdose; the plasma concentration gradually declines thereafter. Like

Metadate

CD,

Ritalin-LA

was designed to replace immediate-release methylphenidate twice daily. Therefore, improvement in ADHD symptoms would be expected to be sustained throughout the school or work day, but not into the evening hours.

[7]

The safety and efficacy of Ritalin-LA were established in a double blind, placebo-controlled, parallel-group study in 124 children with ADHD. The patients received a single dose of either Ritalin-LA (10-40 mg/day) or placebo for 2 weeks. Symptom scores, as rated by patients' schoolteachers using the Conners ADHD/DSM-IV Scale for Teachers, were significantly improved from baseline during the last week of treatment in comparison with placebo-treated patients. During dose titration prior to initiation of the trial, 3.7% of the patients receiving Ritalin-LA discontinued because of adverse events, including headache, insomnia, upper abdominal distress, decreased appetite, and anorexia. In the trial itself, adverse events in Ritalin-LA-treated patients consisted of anorexia and insomnia, each of which occurred in 2 patients,[7] and 1 additional Ritalin-LA-treated patient discontinued the study medication due to an adverse event.

Adderall XR

 

Adderall

XR, which was approved by the FDA for use in 2002, contains a mixture of neutral sulfate salts of D-amphetamine and amphetamine, the D-isomer of amphetamine saccharate, and D,L-amphetamine aspartate monohydrate.

Adderall

XR capsules contain a 50:50 ratio of 2 types of drug-containing beads, one an immediate-release bead designed for rapid onset of response (similar to the immediate-release form of this product), and the second providing delayed release 4-6 hours after oral administration.

[8,17]

The once-daily formulation has a pharmacokinetic profile similar to that seen with twice-daily administration of immediate-release

Adderall

.

[8]

A recently published study examined the efficacy and safety of Adderall XR in 584 children with ADHD. Study patients were randomized to receive either placebo or a once-daily dose of Adderall XR 10 mg, 20 mg, or 30 mg for 3 weeks. Significant improvement was found in all active treatment groups by intent-to-treat analysis of ratings by both teachers and parents, compared with placebo treatment. Scores for the Conners Global Index Scale for Teachers and the Conners Global Index Scale for Parents were significantly improved in comparison with placebo when measured in the morning, afternoon, and late afternoon, indicating that benefits were sustained over most of the patients' waking hours.[17] Global measures of efficacy also demonstrated that the active study drug was superior to placebo, and responses were dose-related. The incidence of adverse events was low, and similar for both active treatment groups and placebo.[17]

Considerations in the Selection of a Long-Acting Stimulant Drug

Efficacy

Although direct efficacy comparisons of the 4 long-acting stimulant drug formulations have not been performed, the efficacy of their active constituents has been studied extensively. Methylphenidate and D,L-amphetamine are generally regarded to be equivalent in improving ADHD symptoms, a presumption that also extends to their long-acting counterparts. However, this question has been formally tested only for Concerta; 2 controlled clinical trials of Concerta have established its equivalent efficacy relative to immediate-release methylphenidate 3 times daily.[14,15]

Duration of Action

One obvious distinction between the new generation of long-acting stimulant preparations is their respective variations in duration of action, an important consideration, as treatment is often based on the period of time over which symptom control is required. As noted above, Concerta was designed to replace immediate-release methylphenidate 3 times daily, and Adderall XR was developed to replace its twice-daily product formulation. With improvement in ADHD symptoms extending over 12 hours for Concerta and for Adderall XR, either of these 2 preparations can cover the duration of a child's school day, as well as homework time and during other after-school activities. Similarly, in adults who require treatment for ADHD, therapeutic benefits would extend longer than the average work day. By contrast, Metadate CD and Ritalin-LA are designed to replace immediate-release methylphenidate twice daily. These agents can therefore be used in patients who require symptom control only over the course of the school day, or in those who experience a loss of appetite in the evening, or do need extended clinical coverage.

Potency

Although methylphenidate and D,L-amphetamine are equally effective, they do differ in terms of potency. Potency measures relative pharmacologic activity of one drug in comparison to another. However, potency does not equate with efficacy. There is an approximate 2:1 difference in potency between D,L-amphetamine and methylphenidate; a suggested guide would be to dose methylphenidate at 1-1.5-2 mg/kg/day, and D,L-amphetamine at 0.5-0.75-1 mg/kg/day. These doses would be expected to provide equivalent clinical benefit.

Side Effects and Complications

The clinical evidence regarding adverse effects associated with stimulant medication use has been extensively analyzed. The findings from a 1998 American Medical Association report and those from an evidence report sponsored by the Agency for Healthcare Research and Quality (AHRQ) agree that most side effects are relatively mild, short-lived, and respond to adjustments in dosing and timing of drug administration.[18] The most commonly reported adverse effects are delayed sleep onset, reduced appetite, stomach ache, headache, and jitteriness.[3] Mood disorders, irritability, anxiety, and behavioral rebound also have been reported. It is important to note that studies comparing methylphenidate and D-amphetamine have found no statistically significant differences in their adverse effect profile.[18] Therefore, these agents are regarded as being both safe and equivalent in tolerability and safety.

Growth delay related to stimulant medication use has been reported in some studies. However, these delays, which previously were attributed to the medication, are now believed to be mediated by ADHD itself. In a study involving 124 boys with ADHD, small but significant differences in height were found between children with and without ADHD. However, while these differences were evident in early adolescence, they disappeared by late adolescence and were not associated with the use of stimulant medication.[19] Similar findings have been reported in girls with ADHD.[20] It should also be noted that emerging 12- and 24-month data document minimal effects on height and weight by early adolescence in treated children.[21]

Dosing

The equivalent efficacy and safety of methylphenidate and D,L-amphetamine have been well established. This suggests that the selection of a stimulant medication for long-term use should be based mainly on the required duration of symptom control. For a patient requiring 6-8 hours of clinical control over ADHD symptoms, either Metadate CD or Ritalin-LA would be appropriate. For those who require 10-12 hours of symptom control, Adderall XR or Concerta may be indicated. provides information regarding respective dosage strengths; suggested starting doses for young children, older children, and adolescents; as well as suggested titration strategies.

Table 2.  Table 2. Long-Duration Stimulant Drugs: Dosage Forms

Agents With an 8-Hour Duration
Drug Titration Dosage Forms Starting Doses and Suggested Titration
Metadate CD 20-mg capsule 20 mg daily, increase at intervals ≥ 1 week until a target range of 1-2 mg/kg/day is reached
Ritalin-LA 20-mg, 30-mg, and 40-mg capsules Younger child: 20 mg daily, increase by 10 mg daily at intervals ≥ 1 week until a target range of 1-2 mg/kg/day is reached

Older child or adolescent: 30 mg daily, increase by 10 mg daily at intervals ≥ 1 week until a target range of 1-2 mg/kg/day is reached
Agents With a 10- to 12-Hour Duration
Drug Titration Dosage Forms Starting Doses and Suggested Titration
Adderall XR 5-mg, 10-mg, 15-mg, 20-mg, 25-mg and 30-mg capsules Younger child: 10 mg daily, increase at intervals ≥ 1 week until a target range of 0.5-1 mg/kg/day is reached

Older child or adolescent: 20 mg daily, increase at intervals ≥ 1 week until a target range of 0.5-1 mg/kg/day is reached
Concerta 18-mg, 27-mg, 36-mg, and 54-mg capsules Younger child: 18 mg daily, increase at intervals ≥ 1 week until a target range of 1-2 mg/kg/day is reached

Older child or adolescent: 36 mg daily, increase at intervals ≥ 1 week until a target range of 1-2 mg/kg/day is reached

As noted above, there is approximately a 2:1 difference in potency between methylphenidate and D,L-amphetamine on a weight-to-weight basis. Clinical opinion suggests that the dose of either methylphenidate or D,L-amphetamine should be increased if tolerated until a therapeutic response is achieved, which should be attained within a dosage range of 1-1.5-2 mg/kg/day of methylphenidate, or 0.5-0.75-1 mg/kg/day of D,L-amphetamine. Examples of approximate dosage strengths for Concerta and Adderall XR are shown in .

Table 3.  Table 3. Approximate Dosage Strengths for Concerta and Adderall XR

Concerta Adderall XR
(Factor = 0.55)
27 mg 15 mg
54 mg 30 mg
72 mg 40 mg
108 mg 60 mg
144 mg 80 mg

Since some patients may selectively respond to either methylphenidate or D,L-amphetamine; if an adequate dose of long-duration methylphenidate (2 mg/kg/day) is reached without achieving symptom control, or if intolerable adverse events develop, the patient could be switched to D,L-amphetamine. Similarly, a patient who is taking the long-acting D,L-amphetamine preparation at doses of 1 mg/kg/day without clinical benefit, or who develops intolerable adverse effects, should be switched to an equivalent methylphenidate-based compound at an equipotent dose. The large therapeutic window associated with these agents indicates that there is a wide dosage range for their safe use. As noted below, underdosing in older adolescents and adults is a significant problem that can be avoided if patient weight is used to guide dosage selection.

Additional Considerations

Although most studies of stimulant medications have been performed in children between 6 and 12 years of age, it is increasingly recognized that other patient populations -- preschool children, adolescents, and adults -- also may benefit from this treatment. Additionally, in up to one third of children with ADHD, this condition coexists with other psychiatric or developmental disorders. These disorders also must be assessed and considered within the context of treatment for ADHD.[2]

Treatment of Preschool Children

Preschoolers are a less well-studied population. Although preschoolers may display symptoms that are consistent with ADHD, data regarding the occurrence of these symptoms in this age group are lacking. The diagnosis of ADHD in a preschooler is further complicated by the need to differentiate between adjustment disorders, other Axis I disorders, and normal behaviors of the younger child.

A second issue regards the limited database of clinical evidence for stimulant use in preschool children. To date, the results of 8 randomized, controlled clinical trials have been published, demonstrating that methylphenidate has efficacy in this younger age group. Ongoing studies are likely to elucidate such remaining issues as the pharmacokinetics, pharmacodynamics, pattern of response (peak and duration of behavioral effects), dosages for initiation and titration, and side effects in the short- and long-term use of stimulant medications in this population.[3] Despite the need for additional data and the diagnostic challenges in this younger population, clinical experience suggests that ADHD symptoms can be effectively treated with stimulant medications in younger children as well.

Treatment of Adolescents and Adults

As most treatment guidelines and prescribing information for stimulant medications relate to experience in school-aged children, prescribed doses for older patients are lacking. Emerging evidence for both methylphenidate and Adderall indicate that when weight-corrected daily doses, equipotent with those used in the treatment of younger patients, are used to treat adults with ADHD, these patients show a very robust clinical response consistent with that observed in pediatric studies. These data suggest that older patients may require a more aggressive approach in terms of dosing, based on the same target dosage ranges that have already been established -- for methylphenidate, 1-1.5-2 mg/kg/day, and for D,L-amphetamine, 0.5-0.75-1 mg/kg/day.

Prior to the advent of long-duration preparations, concerns were expressed that stimulant medication use by adolescents could lead to abuse of these controlled substances. Recently published data strongly contradict the concerns regarding the potential for substance abuse and, interestingly, suggest instead that early treatment may in fact provide protection against the development of an abuse problem.[20,22] Furthermore, because these new formulations are taken once daily and additional dosing outside the home environment is not necessary, they are less likely to be diverted. Significantly, the paste-like consistency of Concerta and the microbeads used in the other second-generation formulations make them less likely to be abused, either by injection or inhalation.

Treatment of Patients With Comorbid Disorders

Patients with comorbid conditions require careful evaluation prior to initiating treatment with a stimulant medication. It is important to establish which disorder is causing the greater degree of morbidity -- ADHD, depression, anxiety, bipolar disorder, or conduct disorder. In some cases, stimulant medications can exacerbate a coexisting condition, or the comorbid disorder may inhibit a clinical response to the stimulant. Therefore, the primary disorder should always be the primary focus of treatment.

Contraindications and Precautions

There are relatively few contraindications to the use of stimulant medications. These include patients with marked anxiety, tension, or agitation, or those with known hypersensitivity to methylphenidate or D,L-amphetamine. Use in patients with a diagnosis of Tourette syndrome should also be avoided.[23] Finally, patients on monoamine oxidase inhibitors (MAOIs) should not be given stimulants, as potential drug-drug interactions could lead to hypertensive crises.[3]

Summary and Conclusions

ADHD often confers a substantial burden on patients and their families. Impaired functioning in school and at home can lead to poor family and peer relationships and diminished self-esteem. Fortunately, ADHD symptoms can be controlled effectively with stimulant medications, and a large body of published evidence has established their efficacy and safety in both short- and long-term treatment.

A new generation of rapid-acting, long-duration formulations has further advanced the standard of care. These agents provide efficacy and safety equivalent to short-acting formulations, but with the advantage of once- or twice-daily dosing. They can be used to initiate treatment, and are formulated so that the potential for diversion and abuse is minimized. The new agents are distinguished by their duration of action, which extends over 8 hours to as long as 12 hours. Therefore, treatment can be individualized depending on a particular patient's need for a specific duration of symptom control. An important issue in the use of long-duration agents is dosing. In particular, adolescents and adults are vulnerable to underdosing, and are thus at potential risk of failing to receive adequate dosage levels. As with all therapeutic agents, the efficacy and safety of stimulant medications should always guide prescribing behavior: careful dosage titration of the selected stimulant product should help to ensure that each patient with ADHD receives an adequate dose, so that the clinical benefits of therapy can be fully attained.

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