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Dextroamphetamine (Dexadrine)

Judith D. Laval, MD

Initial Therapy

Initial therapy in children diagnosed with uncomplicated ADD always consists of one the psychostimulants: methylphenidate, dextroamphetamine, or a combination of dextroamphetamine and levoamphetamine (Adderall). These medications are extremely safe and require no serologic or hematologic monitoring. Patients may respond better to one or the other of these psychostimulants, and patients who do not respond to the initial choice can be treated with either remaining alternative. Interestingly, parent-rating scales favored dextroamphetamine over methylphenidate, probably secondary to the longer half-life of dextroamphetamine so that effects were observed at home and school. Barkley reviewed 15 studies using dextroamphetamine and 14 using methylphenidate and observed a mean improvement of 75% for both drugs. Large clinical trials directly comparing the two classes of drugs are lacking. Patients with ADD-I frequently require only half the standard dose for ADD-H, administered once daily, because the effects seem to last all day.

A reasonable lower dose for each medication is initiated, as suggested by actual weight. For obese patients, calculations should use ideal body weight (same weight percentile as actual height percentile). This lower dose allows the patient an opportunity to adjust to the novel sensation caused by the medication.

Although selecting with which medication to initiate therapy may be somewhat arbitrary, in children 5 to 14 years old, either Dextroamphetamine Spansules or Adderall (mixture of amphetamine salts) may be preferred because of the longer, smoother duration of effects, reduced likelihood of midday school dosing with its subsequent stigmatization and teasing by classmates, ease of titration, and relatively lower costs. According to Pelham, Dextroamphetamine Spansules may be the preferred medication for children with ADD-H. This medication demonstrated equivalent or superior efficacy to standard methylphenidate. Methylphenidate is short-acting (2 to 3 hours) and optimally should be administered three times a day rather than twice a day for most children. In the past, the amphetamine medications have been avoided for fear of abuse potential and the besmirched name of amphetamines as diet products, "speed," and "uppers." But pharmacologically, methylphenidate is actually a derivative from amphetamines and is just as easily sold on the street for up to $5 per pill. On the other hand, practitioners are more familiar with methylphenidate and may prefer its slightly reduced incidence of anorexia, weight loss, and mood disturbance compared with other amphetamines.

Compared with methylphenidate, sustained-release Dextroamphetamine Spansules (and possibly Adderall) is a significantly more reliable and effective long-acting form of amphetamines. Furthermore, sustained-release preparations are preferred by the children themselves and are less likely to be a factor in nonadherence. As shown in, the spansules and Adderall allow for easier titration in 2.5-mg (half-dose) increments. Adderall tablets may be cut in half. Pediatricians should consider demonstrating to the parents that the dextroamphetamine Spansules can be twisted into two halves, and, by using the small "top" half as a measuring device, the beads from the capsule can be carefully poured up to the brim of the smaller half to make a "half-dose" of the spansule, that is, half of a 5.0-mg spansule is 2.5 mg. This first half-capsule is sprinkled onto a spoonful of liquid substance or applesauce. The remaining half is recapped and saved for the next dose. Patients should avoid concomitant administration of amphetamine formulations with vitamin C preparations and food or drinks high in ascorbic acid because of their interference with absorption.

Sustained-release methylphenidate preparations display notoriously erratic pharmacokinetics, are less effective for disruptive behaviors than are amphetamines, and should be expected to act for 5 to 6 hours in less than half of patients. A brief trial with this sustained-release formulation may occasionally be undertaken in patients, particularly adolescents, who are stable on the short-acting formulation. Brand-name methylphenidate may be preferred because of the occasional erratic responses obtained with the generic preparations.

Children 3 to 4 Years of Age.

Stimulant therapy is often avoided in children aged 3 to 4 years because of lower efficacy; the increased rate of problematic AEs, especially moodiness, irritability, and appetite suppression; and because of the lack of availability of a liquid formulation. Only highly aggressive and pervasively, behaviorally disruptive or defiant children in this group warrant therapy. Because of its reduced rate of AEs, usually short-acting methylphenidate, which can be crushed, is administered twice a day or three times a day to these children. Although amphetamine formulations are the only psychostimulants approved for this younger age group, they should be considered second-line therapy because of their somewhat more frequent, severe AEs in this age group. An important consideration in this age group, Dextroamphetamine Spansules can be administered in half-doses by sprinkling the beads into food or beverages. Maximal behavior modification and discipline techniques are the mainstay of therapy for this age group.

Adolescents.

Prescribing psychostimulants for the adolescent population creates a significant dilemma for pediatricians, who must now choose between the standard stimulants, which demonstrate no evidence of lethality when used appropriately and singly but that are associated with the potential for being abused in this population versus pemoline, which has been associated with an exceptionally rare potential for liver failure in about 1 case per 2 years in the United States since 1975 (M. Yousefi, personal communication, 1997) but which has virtually no abuse potential. Practitioners must consider also that some cases of liver failure have been reported in children with prior liver dysfunction or who were never monitored for liver dysfunction. Asymptomatic chemical hepatitis may occur in 1% to 2% of patients receiving this medication. So it is critical that liver function monitoring be performed at baseline and quarterly at minimum. Families and patients should be warned of potential signs and symptoms of liver dysfunction: persistent vomiting, anorexia, malaise for more than 48 hours, upper abdominal pain for more than several days, jaundiced appearance, or dark colored urine. Medications that potentially interact with liver function (e.g., erythromycin, clarithromycin, antiepileptics, and antifungals) should be avoided.

In adolescents who may abuse or sell the medicine, the number of pills dispensed and purportedly taken when using either amphetamines or methylphenidate should be monitored carefully. Consequently, pediatricians may want to consider pemoline therapy for male adolescents initially, unless the family and adolescent are deemed trustworthy and reliable (which is possible with established patients). Patients previously managed with the other psychostimulants who are approaching age 13 or 14 years, particularly male adolescents who are impulsive, defiant, or have conduct problems, are urged to switch to pemoline. Female adolescents are rarely treated with pemoline because those with ADD-H usually have outgrown their overactivity, conduct disorders are rare, and pregnancy or hepatic interaction with oral contraceptives is possible. Commonly, females are affected by ADD-I, in which psychostimulants often respond adequately to a single morning dose of stimulants. In clinical practice, pemoline seems not as effective (approximately 60%) as do the other first- plus second-line stimulants (85%-90%). In children, pemoline may not be as effective as a third-line agent.

Adolescents and their parents may prefer pemoline for any of five reasons: (1) it usually requires only a single daily dose, removing in-school dosing, a significant source of embarrassment for self-conscious teens; (2) it sustains positive effects into the evening, improving homework productivity; (3) it reduces pharmacologic peaks and troughs; (4) it reduces the potential for personal abuse, street selling of medications, and suspicions on the part of parents or physicians concerning any medication discrepancies or hoarding of pills; and (5) it may have less euphoric interaction with alcohol, marijuana, and other drugs commonly experimented with during adolescence. The family is informed of the extremely rare risk of liver failure relative to their risk of motor vehicle or other accidents, suicide, and drug abuse and the need for a baseline and quarterly liver function testing. This medication should never be initiated in those with any history of alcoholism, quiescent or ongoing liver disease or abnormalities of liver function tests. Contrary to conventional wisdom, the onset of action of this stimulant is usually apparent within 2 or 3 hours in most patients but, in a subset of patients, may take as long as 3 weeks. Also, the pharmacologic duration may be only as long as 9 hours.

Over the long term, these impulsive and risk-taking adolescents, when treated with stimulants, seem to sustain improvement in self-esteem and academic performance, which in turn potentially reduces their already high risk for motor vehicle accidents, depression, suicide, and substance abuse, particularly when they are affected by a comorbid conduct disorder. The limitations, risks, and AEs of the other psychostimulants versus pemoline are carefully explained. Either choice has risks, but pediatricians may grow weary and wary of policing many patients, and of calling police, the Drug Enforcement Agency, and parents about abuses of the medication and discrepant pill counts. Enlightening parents and warning adolescents early on regarding stimulants are prudent. Pemoline nearly eliminates this morass of abuse potential for psychostimulants.

Pemoline may be indicated for other problem groups of patients with ADD, including those living in households with a high risk for or history of substance abuse; history of parental incarceration; or exceptionally thin, diet-conscious, possibly anorexic mothers. This last group may notoriously doctor-shop for two to four prescriptions from pediatricians and other physicians in different areas.

All psychostimulants produce very similar AEs (see Table 4 (Table Not Available) ). The most common AE is appetite suppression and subsequent weight loss, which varies from 0.5 kg to 2.25 kg. This anorexigenic response abates after 1 to 6 months. It may be somewhat more pronounced in children treated with amphetamines (versus methylphenidate) and in those who are overweight pretherapy. Mild headaches and stomachaches occur in about one fourth of children and resolve over 1 or 2 weeks. Weekend "drug holidays" may precipitate recurrence of these symptoms every Monday. Although insomnia is frequently reported, when stimulants are used in low to standard doses, this AE may be less frequent and actually may not vary from baseline. During the first few days of therapy a rare, profound, dysphoric mood disorder or anorexia may be experienced that is more commonly seen with amphetamines than with methylphenidate and in preschoolers than in older patients. This disorder requires immediate discontinuation of medication and switching to a different medication after a few days (Adderall and dextroamphetamines should not be considered interchangeable for patients in whom dysphoria develops). Hepatotoxicity of pemoline is discussed later.

Rebound Effect.

Several days or sometimes even months into therapy, a rebound effect in the afternoon may be experienced by many patients treated with psychostimulants. Rebound effect is defined as irritability, crankiness, increased aggression, overactivity, or crying that occurs as the pharmacologic effects subside. This requires an additional lunch time or afternoon dose of medication to counteract, usually prescribed as a half-dose of long-acting stimulant, or adding a third standard dose to twice-a-day, short-acting methylphenidate; however, children may display increased crying and sensitivity to reprimands at home or school while the medication is working, which may be perceived as an AE. More likely, these patients are beginning to respond socially in a fashion similar to their non-ADD peers, with a heightened awareness of and social receptivity to others that previously were ignored.

Tolerance.

Although tolerance is rarely reported in clinical trials, particularly with short-acting methylphenidate, in clinical practice it is commonly observed in patients who have received their medication for months to years or who are receiving long-acting methylphenidate. Tolerance may be ameliorated by a brief drug holiday or by switching to an alternative, long-acting stimulant. A temporary tolerance may appear before school holidays and vacation breaks, with acute stressors, or transiently during a "bad" week.

Drug Holidays.

In patients who seem to have school-related, situational ADD or children or adolescents with ADD-I or milder ADD-H, drug-free holidays on weekends, holidays, and summer vacations can be considered, but only if no significant behavioral, social, or family difficulties are noted. Medication-free days tend to eliminate some of the weight loss and medication tolerance problems. Drug holidays should be strongly discouraged for most children with ADD-H, especially those with significant behavioral or social problems, more aggressive or pervasive ADD-H, or comorbid oppositional defiant disorder or conduct disorder. Nonetheless, an occasional drug holiday may be necessary in some children who develop marked weight loss on or refractory tolerance to several stimulants.

Tics.

Less than 1% of children with ADD develop tics. Previously, stimulants were believed to be contraindicated in children with Tourette's syndrome; however, current literature suggests that tics are not caused by stimulants but rather that stimulants exacerbate the underlying propensity for a tic disorder. Among children with Tourette's syndrome, approximately 40% to 50% have comorbid ADD. Clonidine, which has minimal effect on inattentiveness, is the preferred drug of choice for the treatment of tics in these patients; stimulants may safely be used concomitantly to treat the inattentiveness.

Follow-up Visits for Titration

After the medication is prescribed, families are instructed to telephone right away if they become concerned or if the child experiences any marked negative adverse effects. Not uncommonly, the child may develop an intercurrent viral illness, such as gastroenteritis with concomitant vomiting, or upper respiratory infection (URI) with rhinorrhea and cough, which they may promptly and inaccurately attribute to the medication. The first follow-up titration visit is scheduled for 15 minutes after 2 or 3 weeks to quickly address any concerns or problems with the medication. Checklists from teachers and parents, which are requested at every visit, are returned and scored. Medication dose may be adjusted upward if minimal efficacy is noted and AEs are nonproblematic. The need for a second afternoon dose is discerned within the first several months. Additional 15-minute follow-up visits are scheduled monthly for the following 2 to 4 months.

Depending on the stability of the child's response to the medication, long-term follow-up visits are then scheduled every 4 months for school-aged children, every 6 months for adolescents prescribed amphetamine-like medications, and every 3 months for those on pemoline to serologically monitor for liver dysfunction. At each visit, weight, height, blood pressure, cursory examination as needed, and beneficial effects and adverse events are monitored. ADD checklists from the teacher(s) and parents are obtained at each follow-up visit. Phone calls for between-visit problems are readily accepted. Families often become concerned about these medications after being provoked by well-intentioned friends or sensationalistic, "journalistic" television talk shows. A promptly scheduled office visit to rationally allay these trepidations is prudent.

Unfortunately, one of the most tedious and unrewarding aspects of managing ADD is the monthly prescription for stimulant medications. This must be handwritten by a licensed physician, dated, without error, and specifically spelled out for brand name, if so desired, and the reason for medication. Most insurance plans allow only a month's supply of these Schedule II medications to be prescribed. Thus, families are instructed to call several days before each prescription renewal. For those with transportation problems, monthly maintenance prescriptions can be mailed directly to the pharmacist. Occasional families may be at sufficiently high risk for drug abuse or sufficiently dysfunctional or impoverished intellectually or socially that no caregiver is sufficiently reliable to handle the prescription; yet these youngsters may desperately need the medication to function. In these cases, the author has worked closely with school nurses for clinical evaluations and visits. The medication is dispensed strictly at school and only by the nurse. Rarely, drug-seeking family members may furtively attempt to circumvent this procedure by demanding the prescription. Treatment with either pemoline or nonstimulant, or social-worker intervention is required.

If minimal or no response is obtained initially or after a trial of two or three medications, the physician should carefully evaluate for compliance problems (e.g., not swallowing the pills, inadequate doses, generic substitution, concomitant vitamin C, or pilfering of pills) or other problems. For patients with ADD-H who are nonresponders to psychostimulants, the dose may be increased to the maximum reasonable level (about 1.5- to 2-fold above the standard dose) of medication or until bothersome AEs are observed. Generally, for nonresponders, the dose of medication can be pushed until weight loss or dysphoria is observed. If this fails, at least three different psychostimulant medications may be tried. Interestingly, although Adderall and dextroamphetamines are chemically similar, patients may still respond to the other one if tolerance develops or no initial response is observed.

Nonresponders with associated comorbidities of significant aggression, oppositional defiance, or conduct disorder frequently improve when clonidine is introduced concomitantly with stimulant medication. In older children or adolescents in whom depression and anger are major components of symptomatology, selective serotonin reuptake inhibitors (SSRIs) may be introduced early, together with psychostimulants. If no response is seen after 1 to 2 months, then the patient should be referred for psychotherapy. Physicians must also assess for new-onset home difficulties or stressors, including recent deaths, divorce, or family discord; school difficulties including teacher-child personality conflicts, severe learning disabilities, or mild mental retardation; medication noncompliance; reduced half-life; and rebound effects.