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D-amphetamine
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L-amphetamine

Introduction

This article is about stimulants used in treatment of ADHD. See ADHD and DBDs articles for role of stimulants in the overall treatment strategies. A separate article addresses design and outcomes of the MTA study. Intoxication and overdose with stimulants is addressed separately.

Amphetamines

Amphetamine is a racemic compound (equal parts of D- and L-isomers). D-isomer (dextroamphetamine) is 3-4 times more potent than the L-isomer (levoamphetamine) as a CNS stimulant.[1] Stimulants used in ADHD are modified forms of amphetamine:

  • Dexedrine is a dextroamphetamine (d-amphetamine) which is the D-isomer of amphetamine.
  • Adderall is a mixture of salts of d-amphetamine and racemic amphetamine (d,l-amphetamine)
  • Vyvanse is lesdexamphetamine, a prodrug metabolized by an enzyme on RBCs to d-amphetamine

Amphetamines have a short half-life (3-6 hours), necessitating TID dosing or use of extended-release preparations qAM.

Most (80%) is excreted unchanged by the kidneys, especially if urinary pH is low; acidifying urine increases rate of excretion (consider in overdose).

Methylphenidate

Methylphenidate (MPH) is a racemic compound derived from amphetamine:

  • Concerta, Ritalin, Metadate, and Methylin are d,l-methylphenidate (MPH)
  • Focalin is a D-isomer of MPH, or d-methylphenidate
  • Daytrana is a transdermal MPH patch; it is placed on the skin for 9 hrs/day and can be effective for up to 12 hrs

Since D-isomer is beleived to be the active compund in CNS stimulation, 5 mg of Focalin has similar potency as 10mg of Ritalin,[1] while, theoretically, causing fewer side effects.

MPH has a half-life of 2-3 hours. 75% of MPH is metabolized (extensive 1st-pass metabolism) to inactive ritalinic acid.

Other stimulants

  • Desoxyn is a methamphetamine (not MPH), approved for ADHD and exogenous obesity, but rarely prescribed

Mechanism of Action

Amphetamines and MPH increase synaptic concentrations of dopamine (DA), norepinephrine (NE), and serotonin via different mechanisms. Both MPH and amphetamines cause DA vessicles to relesase their contents at the synapse (amphetamines do this more selectively). MPH and amphetamines also block DA reuptake at the synapse. Amphetamines have more potent effect on the NE pathways than MPH does. [3]

Adverse Effects

Growth retardation is likely 2° to stimulant-induced appetite suppression. In the MTA study 2-year follow-up children on MPH were 1cm/year shorter and 1 kg lighter than children not taking stimulants. There is evidence that children "catch-up" once they enter puberty, or during "drug holidays," (e.g. if the medication is discontinued for the summer), however a cumulative deficit of about 1 inch may persist.[4] Significance of poor appetite can be minimized, if stimulants are taken with food (or after finishing breakfast).

Sleep disturbance is another common adverse effect. Management of this AE starts with sleep hygeine and stimulant dose adjustment. For children whose sleep troubles remain significant, adding an α-agonist (clonidine) qPM, switching to a different stimulant, or Intuniv are fair options.

Stimulants will cause an increase in blood pressure (≤5 mmHg) and heart rate (≤10 beats/min) without changes in electrocardiographic parameters. A subset (5-15%) of children will have greater increase in HR and BP; AACAP parameters call for a complete H&P and vitals before starting stimulants, but an EKG is not indicated for general pediatric population.

Other common side effects include headache, GI symptoms, jitteriness, irritability, dry mouth, blurred vision (anticholinergic AE).

Rarer and more concerning AE include depressed mood, emotional blunting/"zombie appearance"/"amphetamine look," hallucinations, tics, arrhythmias, leukopenia, and alopecia.

Clinical guidelines

Stimulants are contraindicated in patients with glaucoma, symptomatic CVD/HTN, hyperthyroidism, advanced atherosclerosis, and those taking MAO-I in the last 2 weeks.

Check BP and HR before starting a stimulant and at every dose increase. Obtain baseline and follow-up measure of symptom severity in two setting. [2][6] Baseline EKG is not part of the standard screening in the US.

Record height and weight and track yearly.

ADHD patients with manic symptoms can be put on a stimulant after the mood symptoms have been controlled with a mood-stabilizer. [2]

Ordering TSH and lead levels is only warranted if there is evidence of thyroid dysfunction or risk of lead exposure. [2]

Stimulants are generally safe in children with comorbid ADHD and tic disorder, however if tics worsen, or new tics appear, the stimulant should be changed or discontinued. [4]

MPH may lower seizure threshold; children with seizure disorders should be on an anticonvulsant.

Which stimulant to start with?
  • Start a long-acting stimulant with the smallest marketed dose, titrate up q1-3 weeks.
  • A stimulant that worked in a family member is a good first choice.
  • MPH preparations are preferred to amphetmine salts in children under age based on current trials (Gleason)

Extended-Release Stimulants

Long-acting Stimulants approved for ADHD (methylphenidate and amphetamine preparations)

Medication

Mode of Delivery

Pill

Doses, mg

Typical Starting Dose

Max Dose per Day

Duration of Action

Ritalin SR (MPH)

Gradually released from wax matrix;

Pulse release; must swallow whole

20

10mg

60mg

7-8 hrs

Metadate ER

10, 20


Lesser than 2mg/kg/day or 60mg

Methylin ER (MPH)

10, 20

Metadate CD (MPH)

30% IR; 70% 3hrs later

Beaded pearls; can open and sprinkle

10, 20, 30, 40, 50, 60

20mg

8-9 hrs

Ritalin LA (MPH)


50% IR; 50% 4 hrs later

10, 20, 30, 40

20mg

60

7-9 hrs

Focalin XR (d-MPH)

Pearls; capsule

5, 10, 15, 20

5mg

Lesser than 1mg/kg/d or 30mg




Up to 12 hrs

Concerta (MPH)

18% IR tab coating; 82% osmotically; mimics tid IR; ok if cap seen in stool

OROS Pump; don’t open

18, 27, 36, 54

18mg

Lesser than 2mg/kg/d or 72mg

Daytana (MPH)

Gradually releasing MPH

Trans-dermal film

10, 15, 20, 30

10mg

Lesser than 1mg/kg/d or 30mg

12 hrs

Adderall XR

50% IR; 50% 4hr later

Beaded pearls; can sprinkle

5, 10, 15, 20, 25, 30

10mg

Lesser than 1mg/kg or 30mg

10 hrs

Dexedrine

Initial dose released immediately; remainder gradually released

Beaded pearls

5, 10, 15

5-10mg q.d.to b.i.d.

Lesser than 1mg/kg or 40mg

10 hrs

Vyvanse (lisdexamphetamine)

Amphetamine w lysine attached; activated by GI cleavage of lysine

Capsule

20, 30, 40, 50, 60, 70

30mg

Lesser than 1mg/kg or 70mg

10 hrs

Abbreviations: OROS = osmotic-release oral system; IR = immediate release.

Notes: Concerta capsule should not be chewed or opened; pill may be seen in stool intact. Children with reduced GI absorption or transit time will benefit less. Patch: higher bioavailability (no first-pass metabolism).

[5]

Clinical Pearls

Stimulants are contraindicated in patients with glaucoma, psychosis, symptomatic CVD/HTN, hyperthyroidism, advanced atherosclerosis, and those taking MAO-I in the last 2 weeks.

Currently only stimulants, atomoxetine, and guanfacine ER (Intuniv) have approved FDA indications for ADHD.

Black-box warning was briefly considered for MPH-based drugs, because of cardiac-related adverse events, including sudden unexplained deaths.

Rebound is marked worsening of ADHD symptoms at the end of the day, as the blood level of a stimulant drop below a certain threshold. If the child is taking an extended-release stimulant, consider adding a small short-acting dose in the afternoon.

There is no increase in risk of future drug or alcohol abuse from appropriate stimulant use; in fact, children with untreated ADHD are at higher risk for substance use, than children taking stimulants for ADHD; however, stimulants are a Category II drugs, have substantial street value (particularly short-acting preparations), and can not be prescribed for more than 30 d (no refills).

Pemoline is not used due to hepatotoxicity.

When swithcing from MPH to d-amphetamine, half the dose for equivlent potency.

While AMP is approved for children under 6 and MPH is not, AACAP guidilenes recommend a trial of MPH first in pre-school children (if psychosocial interventions are inadequate), based on the PATS study. Slower titration, smaller doses, and increased AE monitoring is advised (see PATS results below) (2)

Prognosis
  • parents often see general improvement within the first week, and up to 80% of children with ADHD respond to their first stimulant.
  • About a third of children with ADHD will need to continue taking stimulants into adulthood to control symptoms
  • Roughly another third will not have significant symptoms as adults
  • Hyperactivity is the symptom most likely to be "outgrown"

Major studies

MTA study

The Multimodal Treatment Study of ADHD (MTA) was a longitudinal 4-arm trial of 7-9.9 year-olds (n=579) with ADHD, combined type. The randomized groups were MPH, intensive standardized therapy, combination MPH + therapy, and "community treatment."

  • All 4 groups improved, with MPH and the combination treatment arms improving the most, without significant differences from each other (NNT was 3 and 4 respectively, and 12 for the standardized therapy alone).
  • The combination arm had more "excellent" outcomes. Non-ADHD symptoms and functional outcomes showed modest improvements as well. Study-specific treatment ended at 14 month and at the 3- and 8-year follow-up there were no differences between the 4 arms. Baseline functioning was a better predictor of long-term outcomes.
  • In 6-8 year follow up, compared with non-ADHD peers, the functioning of children in treatment was comparable with non-ADHD peers only if their medication was continued over that time.

PATS Study

Preschool ADHD Treatment Study (2006) was a radndomized placebo-controlled trial (RCT) in which 303 3-5.5 y.o. children with symptoms of moderate to severe ADHD were prescribed MPH TID or placebo. The trial evaluated short-term (5 weeks) efficacy and long-term (40 weeks) safety of the drug in children who had failed psychosicial intervention.

  • Before randomization to MPH or placebo only 10% of children improved with parent training.
  • There was marked decrease in ADHD symptoms in MPH group (only 21% achieved remission).
  • MPH was mostly well tolerated, but overall, 11% discontinued treatment due to AE. No episodes of mania, suicidality or serious cardiac events were observed. However, preschoolers did have higher rates of emotional lability compared with published rates for older children. Children on MPH had experienced slowed yearly growth rates in both height and weight (Swanson JAACAP 2006).
  • Optimal daily doses ranged from 7.5 to 30 mg/day, divided in three daily doses of immediate-release MPH.
  • Compared to MTA study of school-age children, preschoolers had more emotional adverse events, more study withdrawal (11% vs 1%), and smaller effect size for response (0.35-0.43 vs 0.52-0.75 in MTA).

Other CNS stimulants

  • Cocaine
  • Caffeine
  • Nicotine
  • Modafinil
  • MDMA (Ecstasy)
  • Crystal meth 9methamphetamine)

Stimulants and Tics

Based on a carefully done large meta-analysis (22 studies, n=2385), there is no measurable increase in risk of tics, or severity of existing tics, when stimulant treatmnet is initiated. (Cohen SC JACAAP 2015).

  • Clinically however, it is a worrysome side effect.
  • According to expert panel, (AACAP meeting 2016, WKSH4), placebo, clonidine, and stimulants have an equal risk of causing tics. Youth with underlying anxiety may be more susceptible. Starting a stimluant before a stressful event, such as the last week of August.

References

[1] Labbate LA. Handbook of Psychiatric Drug Therapy 2010

[2] AACAP Practice Parameter JAACAP, 2007;46(7):894-921

[3] Martin A. Lewis's Child and Adolescent Psychiatry 4th edition pp.757-759

[4] Manos MJ. Managing ADHD ni a Fast-Paced World JManagCarePharm Nov.2007

[5] Information in the table is adopted from Lewis's Child and Adolescent Psychiatry 4th edition pp.443-446, [1], [6], and the PDR

[6] Bezchlibnyk-Butler KZ. Clinical Handbook of Psychotropic Drugs for Children and Adolescents 2nd ed. 2007

[7] Swanson J Stimulant-related reductions of growth rates in the PATS J Am Acad Child Adolesc Psychiatry - Nov 2006; 45(11): 1304-13
[8] Gleason et. al. Psychopharmacological Treatment for Very Young Children: Contexts and Guidelines. JACAAP 46:12, 12,2007


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