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Practice Parameter for the Use of Stimulant Medications in the Treatment of Children, Adolescents, and Adults

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ABSTRACT

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed-salts amphetamine, and pemoline. It carries FDA indications for treatment of attention-deficit/hyperactivity disorder and narcolepsy.

Section snippets

EXECUTIVE SUMMARY

The treatment of patients with stimulant medications requires the consideration of many factors that cannot be fully conveyed in the brief executive summary. The reader is encouraged to review the entire practice parameter. Each recommendation in the Executive Summary is identified as falling into one of the following categories of endorsement, indicated by an abbreviation in brackets following the statement. These categories indicate the degree of importance or certainty of each recommendation.

BRIEF HISTORY

Stimulants are among the most effective psychotropic medications in clinical use today. Their effects on disruptive behavior were discovered in 1937, when these drugs proved to increase compliance, improve academic performance, and reduce motor activity in hyperkinetic children. Studies of the short-term benefits of stimulants on the symptoms of ADHD constitute the largest body of treatment literature on any childhood-onset psychiatric disorder. By 1996, 161 randomized controlled trials had

PSYCHOPHARMACOLOGICAL EFFECTS OF STIMULANTS

Short-term trials have reported improvements in the most salient and impairing behavioral symptoms of ADHD. Except for PEM, the immediate release preparations of the major stimulants have a brief duration of action, providing clinical benefits for 3 to 5 hours after oral dosing. This requires multiple doses during the day to maintain improvement. In the classroom, stimulants decrease interrupting, fidgeting, and finger tapping and increase on-task behavior. At home, stimulants improve

INDICATIONS

A clinician determines that a patient (child, adolescent, or adult) has a condition indicated for the use of stimulant medications [MS].

Psychiatric evaluation should include a detailed history (psychiatric and medical) of the patient, collateral information from parents or significant others, documentation of target symptoms, and a mental status examination. It is helpful to gather information from at least two adult sources—preferably from different settings in a child'slife (e.g., home or

CONTRAINDICATIONS

Contraindications to the use of stimulants in clinical practice include previous sensitivity to stimulant medications, glaucoma, symptomatic cardiovascular disease, hyperthyroidism, and hypertension. These medications must be used with great care if there is a history of drug abuse. They are contraindicated in patients with a history of illicit use or abuse of stimulants, unless the patient is being treated in a controlled setting or can be supervised closely [NE]. If a member of the household

USE OF STIMULANTS

Using stimulant medication in treating patients with ADHD or ADHD plus conduct disorder requires careful documentation of prior treatments, selection of the order of stimulants to be used, using the recommended starting dose of each stimulant, deciding on both a minimum and maximum dose, using a consistent titration schedule, deciding on a method of assessing drug response, managing treatment-related side effects, and providing a schedule for the monitoring of long-term medication maintenance

COMPLICATIONS AND SIDE EFFECTS

Almost all stimulant-related side effects reported for children and adolescents with ADHD are rare and short-lived and are responsive to dose or timing adjustments. Mild side effects are common, and serious side effects are rare and short-lived if the medication is reduced in dose or discontinued. Severe movement disorders, obsessive-compulsive ruminations, or psychotic symptoms are very rare and disappear when the medication is stopped. It was recently determined that patients on PEM

LITERATURE REVIEW

The literature on stimulant treatment of children with attention-deficit/hyperactivity disorder (ADHD) is voluminous. Books and journals published from 1980 through the end of 2000 were reviewed in detail; older references were included when pertinent. A National Library of Medicine search using the keywords dextroamphetamine, methylphenidate, pemoline, and Adderall® ensured completeness of coverage. Using Freedom of Information Letters, the Food and Drug Administration supplied data on

BRIEF HISTORY

The behavioral effects of stimulants were discovered more than 60 years ago (Bradley, 1937). dl-Amphetamine, the racemic form of amphetamine (AMP), produced a dramatic calming effect while simultaneously increasing compliance and academic performance. Over the next two decades, Bradley published case reports of children improving during AMP treatment (Bradley and Bowen, 1941). Subsequent studies showed that psychostimulants (AMP only) increased the seizure threshold (Laufer et al., 1957),

STIMULANT PRESCRIBING IN THE UNITED STATES

Data from diverse sources suggest a steeply rising rate of stimulant prescribing in the United States during the past decade. ADHD-related outpatient visits to primary practitioners increased from 1.6 to 4.2 million per year during the years 1990 to 1993 (Swanson et al., 1995). During those visits, 90% of the children were given prescriptions, 71% of which were for the stimulant methylphenidate (MPH). During the same period, MPH production in the United States increased from 1,784 kg/yr to

PSYCHOPHARMACOLOGY

Although the psychostimulants are the medications of choice for the treatment of children with ADHD, their central mechanisms of action are unknown. Studies using positron emission tomography (PET) scanning have demonstrated that untreated adults with a past and current history of ADHD showed 8.1% lower levels of cerebral glucose metabolism than controls (Zametkin et al., 1991), with the greatest differences in the superior prefrontal cortex and premotor areas. MPH and dextroamphetamine (DEX)

LONG-ACTING STIMULANTS

The need for long-duration drugs emanates from a variety of concerns. The time-response characteristics of standard stimulants are such that the plasma level troughs occur at the most unstructured times of the day, such as lunchtime, recess, or during the bus ride home from school (Pelham et al., 2000). Compliance is also a problem with standard, short-duration stimulants. Schools may not reliably administer the medication or may have policies that prohibit its administration. Some

NEW LONG-ACTING STIMULANTS

Pediatric psychopharmacological drug development by the pharmaceutical industry has increased greatly in the past 3 years. Most new drugs are targeted for children with ADHD. A number of the “new” treatments for ADHD address the need for a more effective single-dose-per-day, long-duration stimulant. Children with ADHD now on immediate-release stimulants or the older variety long-duration preparations, such as MPH-SR20 or Dexedrine Spansules, can be switched to these newer preparations. The new

PLASMA LEVELS OF STIMULANTS

MPH plasma levels do not correlate with clinical response (Gualtieri et al., 1982) and provide no more predictive power than teacher and parent global rating forms (Sebrechts et al., 1986).

TOXICOLOGY

Animal toxicity studies using high doses of stimulants have reported abnormal findings not found in humans. This may be a result of differences of species, dose, route of administration, and end point selected. Sprague-Dawley rats given high-dose (25 mg/kg subcutaneous versus 0.3 mg/kg orally in children) injections of DEX, MPH, methamphetamine, and 3,4-methylene-dioxymethamphetamine have shown loss of serotonin reuptake sites (Battaglia et al., 1987). Hepatic tumors increased only in mice (a

THERAPEUTIC EFFECTS OF STIMULANTS

Short-term trials of stimulants, most often 3 months or less in duration, have reported robust efficacy of MPH, DEX, and PEM, with equal efficacy among stimulants (McMaster University Evidence-Based Practice Center, 1998). More than 160 controlled studies involving more than 5,000 school-age children—only 22 lasting more than 3 months (Schachar and Tannock, 1993)—demonstrated a 70% response rate when a single stimulant is tried (Spencer et al., 1996b). Short-term trials have reported

INDICATIONS

The following conditions are indications for treatment with stimulant medication:

  • •

    ADHD without comorbid conditions. This includes all three subtypes of ADHD and ADHD, not otherwise specified (NOS).

  • •

    ADHD with specific comorbidities (oppositional defiant disorder, conduct disorder, anxiety disorder, and learning disorders). ADHD with certain Axis I anxiety disorders (separation anxiety disorder, generalized anxiety disorder, and social phobia) may be treated with stimulants.

  • •

    Narcolepsy. Patients

CONTRAINDICATIONS

The package insert for each stimulant medication is reproduced in full in the PDR (2000). Included are contraindications, warnings, and precautions. Some contraindications are stronger than others. For the psychostimulants, most of their listed contraindications have been found to present only minimal problems. Conversely, the package inserts fail to mention psychosis, which is probably a true contraindication. As a result, the FDA-approved package inserts do not serve as accurate guidelines

USE OF STIMULANTS

Once the clinician and family have agreed to stimulant treatment, several steps must be planned. The parent first should be educated about the natural course of the disorder and the benefit-to-risk ratio of the medication treatment. Then comes the choice of medication. The literature does not help the clinician choose the best stimulant drug for an individual patient. Group studies of psychostimulants—MPH, DEX, and AMP—generally fail to show significant differences between DEX or AMP and MPH (

PHASE I: STARTING A STIMULANT MEDICATION

Treatment should be started with low doses of either MPH, DEX, or AMP (NIH Consensus Statement, 1998). Table 1 shows the titration schedules of the three stimulants. Patients are started on 5 mg of MPH or 2.5 mg of AMP/DEX; ideally, MPH is given after breakfast and lunch, with a third dose after school to help with homework and social activities. AMP/DEX may be started once daily in the early morning, with a noon dose added if it does not last through the school day. Evidence exists that

PHASE 2: ALTERNATIVE STIMULANT

It has been shown that approximately 70% of children with ADHD respond to either DEX or MPH alone. Nearly 90% will respond if both stimulants are tried (although some may have unacceptable side effects) (Elia et al., 1991). If a child fails to respond to the first stimulant tried or has moderate to prohibitive side effects (Table 2), the child can be switched to an alternative stimulant.

SUSTAINED-RELEASE STIMULANTS

For many years, the only long-acting preparations of DEX and MPH have been the DEX Spansule and MPH-SR. Patients have typically been started on the immediate-release preparation, with a later option of converting to the long-acting form. The morning and noon doses are added together; this gives the required dose of MPH-SR20. For example, if a patient were on MPH 10 mg in the morning and at noon, he/she would take 20 mg of MPH-SR20 in the morning. For the DEX Spansules, the morning and noon

USE OF PEMOLINE

Postmarketing surveillance revealed altered liver function tests in 44 children treated with PEM either short- or long-term (Berkovitch et al., 1995). More important, since the drug was introduced, 13 children experienced total liver failure, 11 resulting in death or transplantation within 4 weeks of failure. This rate is 4 to 17 times that expected in the normal population. As a result, PEM has now been listed as an alternative treatment one would select only after three or more stimulants

DRUG–DRUG INTERACTIONS

Patients on MAO inhibitors are likely to develop hypertensive crises if given a stimulant. Drug-drug interactions do not occur, however, between stimulants and other antidepressants. Warning statements included in stimulant package inserts have been based on in vitro studies and anecdotal reports of increased tricyclic antidepressant (TCA) serum levels during combined treatment. More recent work includes a naturalistic study that showed no change in desipramine pharmacokinetics when stimulants

RATING FORMS

There are many rating scales for assessing the symptoms of ADHD. The clinician should select one of these scales—preferably one with age- and gender-specific norms—and use it to gather information on the patient before initiating stimulant treatment and after each major dose adjustment. Lack of teacher or parent cooperation may make the use of these scales difficult, but the clinician should make the effort and document the reason the scale could not be obtained. Table 3 shows the common scales

Preschool Children

Eight published randomized controlled trials in preschool-age children attest to the robust efficacy of MPH. No controlled information is available, however, on dosing, long-term effects on development, or the patient characteristics associated with response.

Validity of the ADHD Diagnosis in the Preschool Age Range. Disruptive behaviors suggestive of ADHD have been identified in children ages 3 to 5 years (the preschool period) (Campbell and Ewing, 1990). The lack of controlled prospective

TREATMENT OF ADHD WITH COMORBID DISORDERS

ADHD may be comorbid with a variety of psychiatric disorders (Biederman et al., 1991;Pliszka, 1992), including but not limited to depression or anxiety, tic disorders, oppositional defiant disorder (ODD), conduct disorder, and/or severe aggressive outbursts.

CAN THE RESPONSE TO STIMULANTS BE AUGMENTED BY OTHER PSYCHOTROPICS?

The above recommendations involve adding a second medication to treat symptoms that are comorbid with the ADHD symptoms. There has been speculation among experienced clinicians for many years that adding an antidepressant such as a tricyclic or bupropion can further enhance the effect of the stimulant on the ADHD symptoms themselves. One case report of leukopenia was reported in a child treated with a combination of imipramine and MPH for 4 months, but the doses were not specified (Burke et

MONITORING TREATMENT: DRUG DISCONTINUATION, FREQUENCY OF VISITS

Once the child with ADHD is stabilized on stimulant medication, visits may be scheduled once a month. In the MTA study (MTA Cooperative Group, 1999a), once-monthly, 30-minute medication visits with the parent and child were found to result in significantly lower ratings of teacher and parent core ADHD symptoms compared with treatment as usual in the community. Compared with children assigned to the MTA'scommunity comparison group, children in the MTA'smedication management treatment arm were

COMPLICATIONS AND SIDE EFFECTS

Stimulant-related side effects reported for children with ADHD appear to be mild, short-lived, and responsive to dose or timing adjustments. Adverse drug reactions usually occur early in treatment and often decrease with dose adjustment. Double-blind, placebo-controlled studies report moderate side effects in 4% to 10% of children treated. Delay of sleep onset, reduced appetite, stomachache, headache, and jitteriness are the most frequently cited (Barkley et al., 1990). No additional delay in

TACTICS FOR DEALING WITH STIMULANTASSOCIATED SIDE EFFECTS

Clinicians have used a variety of tactics to deal with side effects such as insomnia and appetite loss. These include:

  • •

    For appetite loss, the child can be given the stimulants with meals and a high-calorie drink or snack late in the evening, when the stimulant effects have worn off.

  • •

    For difficulty falling asleep, one must distinguish whether the delay in sleep onset is due to a side effect of the stimulant or from oppositionality related to the ADHD or to separation anxiety. First, lower the last

ABUSE POTENTIAL OF STIMULANT MEDICATIONS

Stimulant medications are classified as drugs of abuse by the Drug Enforcement Administration. In animal laboratory experiments, DEX, MPH, and AMP all show characteristics of abuse (e.g., self-administration, chosen in preference over food). Concerns are increasing about the abuse potential, because production and use of MPH increased 5-fold between 1986 and 1996. The increasing production and use have led to the following set of concerns (Goldman et al., 1998): ADHD children are at increased

CONFLICT OF INTEREST

As a matter of policy, some of the authors of this practice parameter are in active clinical practice and may have received income related to treatments discussed in these parameters. Some authors may be involved primarily in research or other academic endeavors and also may have received income related to treatments discussed in this parameter. To minimize the potential for this parameter to contain biased recommendations because of conflict of interest, the parameter was reviewed extensively

SCIENTIFIC DATA AND CLINICAL CONSENSUS

Practice parameters are strategies for patient management, developed to assist clinicians in psychiatric decision-making. This parameter, based on evaluation of the scientific literature and relevant clinical consensus, describes generally accepted approaches to assess and treat specific disorders or to perform specific medical procedures. The validity of scientific findings was judged by design, sample selection and size, inclusion of comparison groups, generalizability, and agreement with

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    • Cited by (0)

    This parameter was developed by Laurence L. Greenhill, M.D., principal author, Steven Pliszka, M.D., Mina K. Dulcan, M.D., and the Work Group on Quality Issues: William Bernet, M.D., Chair, Valerie Arnold, M.D., Joseph Beitchman, M.D., R. Scott Benson, M.D., Oscar Bukstein, M.D., Joan Kinlan, M.D., Jon McClellan, M.D., David Rue, M.D., Jon A. Shaw, M.D., and Saundra Stock, M.D. AACAP staff: Kristin Kroeger. Comments were solicited from expert consultants, including L. Eugene Arnold, M.D., Joseph Biederman, M.D., Louise G. Cohen, Pharm.D., Greg Fritz, M.D., and F. Xavier Castellanos, M.D. In addition, the authors acknowledge the many Academy members for their written and verbal feedback. This parameter was made available to the entire AACAP membership for review in September 2000 and was approved by the AACAP Council on June 4, 2001. It is available to AACAP members on the World Wide Web (http://www.aacap.org).

    Reprint requests to AACAP Communications Department, 3615 Wisconsin Avenue, N.W., Washington, DC 20016.

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