The gold standards of treatment for ADHD are the stimulants amphetamine and methylphenidate. They are old friends, having been used for decades, and there is a wealth of patient experience with them. Although we use them all the time, an occasional review of the tools in our toolbox is always helpful. Stimulants appear to work by enhancing dopamine and norepinephrine in the prefrontal cortex. (See for example, Stahl SM, J Clin Psychiatry 2010;71(1):12–13.) This seems to enhance frontal lobe functions including planning, delaying gratification, controlling behavior, and focusing. Children with ADHD who also display oppositional or explosive behavior may improve behaviorally when treated with stimulants. Common Side Effects of Stimulants Unfortunately, the dopaminergic effects of the stimulants also lead to unwanted side effects. Dopamine regulates satiety, and children on stimulants often lose their appetites. Tics are also mediated by dopamine, but there is variable response to stimulants. Stimulants alone are not thought to induce new onset tics (Roessner V et al, Dev Med Child Neur 2006;48(7):616–621). There are several other common side effects of stimulants. Insomnia is a regular complaint of patients, although it is also a common complaint of kids with ADHD who are not on stimulants. This is partly because the duration of action of the stimulants is not as long as the half-life, so blood levels may still be significant despite the beneficial action having worn off. This is also true of caffeine, and may be the source of many cases of apparent insomnia. The subjective sensation of anxiety, or worsening anxiety, is another common reason for discontinuing stimulants. ADHD is often comorbid with generalized anxiety disorder or OCD, and in these cases each must be treated separately. The disorder that seems to be most impairing should be treated first. Otherwise, reducing the dose or adding guanfacine (Tenex, Intuniv) or clonidine (Catapres) may help the feeling. Irritability can be an issue, either concurrent with the stimulant or when the stimulant is wearing off. When irritability happens all day long, switching from one stimulant to the other sometimes helps, as does adding guanfacine or clonidine. Rebound irritability can often be successfully eliminated with an afternoon dose of a short-acting stimulant or clonidine. Dry mouth is an often experienced but rarely acknowledged side effect, occurring in many children. In addition to contributing to a loss of appetite, chronic dry mouth may cause cavities. Cardiac Effects of Stimulants The cardiac effects of stimulants are well known, and there is a small risk of sudden cardiac death when taking stimulants. However, in a retrospective study of children in the UK taking methylphenidate, there were seven deaths in more than 18,000 person-years. The cause of six of the deaths was known and none were sudden cardiac death. The majority of kids who have died while taking stimulants had underlying cardiomyopathy, and the American Heart Association (Vetter VL, Circulation 2008, 117(18):2407–2423), the American Academy of Pediatrics, and the combined position statement of the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry all agree that a thorough cardiac history should be obtained, including asking about exercise intolerance, being quick to fatigue or become short of breath, and the experience of palpitations, syncope, or chest pain (Warren AE, Can J Cardiol 2009;25(11):625–630). Practitioners should also listen to the child’s heart for abnormalities. Family history of sudden death, especially under age 35, and including motor vehicle accident and drowning is also a risk factor. An EKG is not necessary but may be reasonable in some circumstances. According to the Canadian consensus statement, children without risk factors and not under the care of a cardiologist can be prescribed without further evaluation, while children with risk factors or findings not previously worked up should be sent to a cardiologist for evaluation. Children with current cardiology involvement need not have a separate appointment to evaluate for stimulants—a phone call will do. Methylphenidates Regular methylphenidate has a peak effect one to two hours after dosing, and a duration of action of three to six hours. It comes in a tablet and a liquid, and there are several extended release versions. Concerta is methylphenidate in an osmotic capsule with an outer coating of methylphenidate. It has an onset to peak action of one to two hours (for the immediate release of the outer coating), and a fairly smooth release of methylphenidate thereafter, for a duration of action of nine to 12 hours. Metadate CD and Ritalin LA also have immediate release methylphenidate coating a slow-release capsule, resulting in two peak blood levels: in effect, two doses of the regular release medication without the visit to the nurse’s office. Duration of action is about eight hours. Methylin ER and Metadate ER have slower onsets of action, and peak between four and seven hours, with a duration of eight to 10 hours in one big curve. Daytrana, the transdermal patch, has a two hour onset of action that can be accelerated by applying heat. It lasts for about three hours after removed from the skin, or 12 hours total. Methylin ER and Metadate ER are markedly less expensive than the other long acting agents and so may be covered by insurance at a lower tier than the other preparations. However, the morning rush to get out the door may be helped by a concurrent dose of short acting preparation. Methylphenidate is chiral molecule, meaning there are two possible molecules that are mirror images of one another. Both are active, but one is quite a bit more active than the other. Focalin and Focalin XR are purified enantiomers of methylphenidate—they contain only the right-hand molecule. Whether this makes a difference is open to debate. Typically the active entantiomer of any given chiral molecule is three or more orders of magnitude more active (ie, a thousand times), and so removing the not very active entantiomer and replacing it with inert ingredients like the packing material in a pharmaceutical tablet seems gratuitous. However, it is patentable. Industry material suggests there are subtle differences in side effects, and onset of action is listed at 30 minutes. Because half the molecules have been removed, equivalent dosing is half the dose of regular methylphenidate. Focalin XR has a reported duration of effect of 12 hours. Amphetamines Like methylphenidate, regular acting amphetamine (Adderall) has an onset of action of 30 to 60 minutes and a duration of action of four to six hours. The extended release preparation, Adderall XR, has an onset of action of 30 to 60 minutes and a duration of action of around 12 hours. The half-life of amphetamine is around nine hours in younger children and 13 to 14 hours in adolescents. There is some evidence to suggest that amphetamine has a longer duration of action than methylphenidate. A single dose of regular Adderall may be sufficient for some children for the entire school day (Pelham et al, Pediatrics 1999;104(6):1300–1311). Like methylphenidate, amphetamine is a chiral molecule. However, the racemic mixture is 75% of the dextro-amphetamine and only 25% of the levo-amphetamine. It is available as a purified active entantiomer, dex-amphetamine, Dexedrine. Dexedrine comes in time release form, Dexedrine Spansules. Onset of action is one to 1.5 hours, and duration of action is comparable to regular amphetamine. A new innovation is lisdexamfetamine (Vyvanse), which is the dextro-amphetamine molecule attached to the peptide lysine. When the molecule encounters a peptidase, the lysine is cleaved off, leaving amphetamine. Peptidases are not difficult to find; saliva is full of them, and so are the rest of the digestive tract and the blood stream. Pharmacokinetic studies suggest that the majority of conversion takes place in the blood stream, primarily in the portal blood system. The half life of lisdexamfetamine is 30 minutes, and serum concentrations of lisdexamfetamine have dropped to negligible by two to three hours after ingestion. Peak serum concentration of dextro-amphetamine occurs at 3.5 hours, and the half life is eight to nine hours. Lisdexamfetamine itself is not active. The theoretical advantage of this system to the patient is less variability from dose to dose: time release capsules are affected by gastric pH. The difference in breakfast from day to day can affect the serum level of the medication. However, there is no direct correlation between serum level and therapeutic effect, so whether the prodrug form is a clinical benefit or merely a stockholder benefit is in the eye (or belly) of the beholder. Use our helpful "Guide to Stimulants" table to keep track of the stimulants you prescribe your patients. You can see it here.
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