Pharmacological interventions for ADHD

Pharmacological treatments and ADHD: Key learning points

  • Should only be initiated by child and adolescent psychiatrist or paediatrician with special training
  • Clinicians should measure and record child's height, weight, blood pressure and pulse as a baseline prior to starting any medication

  • First line drugs include:
  • Methylphenidate (Ritalin, Equasym, Equasym XL, Concerta XL)
  • Dexamphetamine (Dexadrine)
  • Atomoxetine (Strattera)

  • Second line drugs include:
  • Antidepressants e.g. TCA's
  • Clonidine

  • N.B. medication is only one element in a multi-modal treatment plan

When behavioural intervention at home and at school alone is insufficient to reduce core ADHD symptoms and improve educational achievement and peer relationships, a trial of medication is usually indicated.

The American Academy of Child and Adolescent Psychiatry have published a practice parameter for the assessment and treatment of children and adolescents with Attention-Deficit/Hyperactivity Disorder (2007) which gives up to date recommendations on the pharmacological management of ADHD. Additional information relevant to UK practitioners will soon be available from the National Institute for Health and Clinical Excellence who are in the process producing guidance for the assessment and management of ADHD (see www.nice.org.uk for drafts out to consultation).

Evidence base for use of medication for ADHD

There is a huge evidence-base to support the use of stimulant medication, at least in the short term, in the management of ADHD with about 75-80% of patients having clinically meaningful benefits (Joughin and Zwi 1999; Greenhill et al. 1999; Lord and Paisley, 2000; Jadad et al. 1999; Swanson et al. 1998).

Stimulant medications available in the UK such as methylphenidate and dexamphetamine act by reducing the core symptoms of hyperactivity, inattention and impulsivity and can also have a beneficial effect on conduct problems, aggression, social skills, academic performance and executive functioning. Beneficial effects in the classroom include a reduction in interrupting, fidgetiness and finger-tapping and an increase in on-task behaviour. In the home setting, stimulants improve parent-child interactions, on task behaviours and compliance. In social settings, stimulants improve peer nomination rankings of social standing and increase attention in sports activities. Despite the efficacy of stimulant medications in improving behaviours, many children who receive them do not demonstrate fully normal behaviour as a consequence. Tricylic antidepressants and atomoxetine offer non stimulant alternatives in the treatment of ADHD. Up to 70% of children show significant improvement when treated with TCA's compared wth 10% with placebo (Biederman et al, 1989).

The multi-modal treatment study of children with ADHD (MTA) has helped to clarify the efficacy of both pharmacological and behavioural interventions and their place in the overall management strategy of children with ADHD (Jensen et al. 1999a; Jensen et al. 1999b). In this study, 597 children with ADHD-combined type were randomly allocated to one of: medication only; an intensive behavioural treatment involving parent, child and school; a combination of the medication and behavioural intervention; and standard community care. Although sizeable reductions were seen in ADHD symptoms over time in all four groups, there were significant differences between the groups in the degree of the change, with the children in the combined medication and behavioural intervention and the medication only groups doing the best of all. Interestingly, the medication only group achieved a greater reduction of core ADHD symptoms than those receiving standard community care, even though most of these latter children were receiving medication. The difference was put down to the careful titration of medication based on close collaboration between parents, teachers and clinicians in the medication only group and this finding is likely to alter clinical practice in this area.

Behavioural interventions thus add little to optimized medication regimes but can be of value in certain individuals. In addition behavioural interventions may reduce the dose of medication required. Children with severe combined type ADHD or hyperkinetic disorder are likely to require a trial of medication, especially if a short trial of behavioural treatments does not lead to any significant improvement. A further analysis of the MTA trial data when broken down into co-morbidity subgroups (Jensen et al, 2001) showed that:

The National Institute of Health consensus statement on ADHD (National Institutes of Health, 2000) notes that (consistent with MTA findings), combined treatments may offer some modest advantages over medication treatments alone, in particular that lower total daily doses of methylphenidate seem to be effective and that parent satisfaction is higher.

Further information on the clinical effectiveness of methylphenidate in children, adolescents and adults can be found via http://www.rcpsych.ac.uk/traindev/cpd/adhd/drug/mpd8.htm

Additional information on the clinical effectiveness of methylphenidate, dexamphetamine and atomoxetine can be found in the National Institute for Health and Clinical Excellence Review of technology Appraisal 13- methylphenidate, atomoxetine and dexamphetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents available via www.nice.org.uk/TA098

See also Remschmidt by the Global ADHD working Group (2005) for consensus statement on current best practice in the treatment of ADHD and treatment algorithms for ADHD and associated co-morbidities.

Indications for the use of psychopharmacological treatment for ADHD

According to the European clinical guidelines for hyperkinetic disorder- first upgrade (Taylor et al, 2004, p15) these are as follows:

The American Academy of Child and Adolescent Psychiatry's summary of the practice parameters for the use of stimulant medications in the treatment of children, adolescents and adults (Greenhill et al, 2001, p.1353) adds that:

The National Institute for Health and Clinical Excellence Review of technology Appraisal 13- methylphenidate, atomoxetine and dexamphetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents available via www.nice.org.uk/TA098 states that

Further information on the clinical indications and usage of methylphenidate can be found via http://www.rcpsych.ac.uk/traindev/cpd/adhd/drug/mpd20.htm

Further information to guide the clinician before starting medication for ADHD can be found in the National Institute for Health and Clinical Excellence Review of technology Appraisal 13- methylphenidate, atomoxetine and dexamphetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents available via www.nice.org.uk/TA098.  This states that

The decision regarding which product to use should be based on the following:

The document goes on to say that “If there is a choice of more than one appropriate drug, the product with the lowest cost (taking into account cost per dose and number of daily doses) should be prescribed”  (pages 4-5).

First line pharmacological options in the treatment of ADHD

(http://www.clinicalevidence.com/ceweb/conditions/chd/0312/0312.jsp). (Ramchandani et al, 2002).

These include the following stimulant medications:

Further up to date information about stimulant medications and other pharmacological treatments for ADHD can be found in the British National Formulary which is updated every 6 months. Clinicians can register to access the contents of the current BNF on line (www.BNF.org).

Single drug options should be considered before combinations of drugs are tried.

Side effects of stimulants such as Methylphenidate, Dexamphetamine and Concerta XL, Equasym XL and Medikinet XL

In addition to this, but to a lesser extent the following side effects may occur:

Many 'side effects' presented, on further questioning, may actually be found to be present pre-treatment. Use of a stimulant drug side effects rating scale both at baseline (before initiating treatment) and thereafter at each follow up appointment will help distinguish new symptoms from those which were pre-existing. Most of the side effects which do occur are dose related and short term. They often reduce within 1-2 weeks of starting treatment and usually disappear if treatment is discontinued or the dose is reduced. Side effects are more likely to occur in pre-school aged children.

For further information on contraindications, drug interactions and unwanted effects of methylphenidate can be obtained via http://www.rcpsych.ac.uk/traindev/cpd/adhd/drug/mpd21.htm

Psychostimulant side effects and suggested management options

(adapted from SIGN guidelines (2001) - Section 5 pharmacological therapy (http://www.sign.ac.uk/guidelines/fulltext/52/index.html)

Side effect

Management options

Anorexia, nausea, weight loss

Monitor carefully, give medication with meals, give calorie supplements or snack late in the evening

Growth concerns

If significant (rare in long term) or causing parental anxiety, attempt weekend or holiday medication breaks

Sleep difficulties

Monitor carefully, reduce or omit late afternoon or evening medication (but note that some patients improve with added evening medication)

Dizziness and headache

Monitor carefully (check blood pressure). Ensure medication is taken with meals and encourage fluid intake

Involuntary movements, tics and Tourette's syndrome

Reduce or if persistent discontinue medication, consider alternative (e.g. TCA) if symptoms are severe *

Loss of spontaneity, dysphoria, agitation

Reduce or discontinue medication (discontinue if thought disorder or psychosis suspected- this is rare)

Sadness

The clinician should first re-evaluate the diagnosis, reduce the dose of stimulant and consider changing to a modified release formulation (e.g. Concerta XL, Equasym XL) because the peak of immediate release formulation may be causing more depressive effects.

Irritability, behavioural rebound

Monitor carefully, reduce or overlap afternoon dose, consider modified release formulation (e.g. Concerta XL, Equasym XL or Medikinet XL ), revaluate for co-morbidity (ODD/CD)
* Also consider converting to atomoxetine

Contraindications to use of psychostimulants:

Caution is required where the following co-exist:

Prescribing guidance for controlled drugs

Clinicians are reminded that all formulations of Methylphenidate and Dexamphetamine are controlled drugs and prescriptions should be written out in accordance to the relevant requirements (see current version of British National Formulary for further up to date guidance on prescribing controlled drugs).

Summary of guidance on writing prescriptions for controlled drugs (BNF: 49, March 2005)

  • Prescriptions should be written in ink, must be signed and dated by the prescriber and specify the prescriber's address.
  • Prescriptions should state in the prescriber's own handwriting:
    • The name and address of the patient;
    • In the case of a preparation, the form and where appropriate, the strength of the preparation;
    • The total quantity of the preparation in both words and figures;
    • The dose.

 

Dose equivalents of the Methylphenidate, Dexamphetamine, Equasym XL and Concerta XL

Immediate Release Methylphenidate dose

Equivalent dose of Concerta XL

Equivalent dose of Equasym XL

Equivalent dose of dexamphetamine

5mg twice or three times daily

18mg once daily at breakfast time

10mg once daily

2.5mg twice or three times daily

10mg twice or three times daily

36mg once daily at breakfast time

20mg once daily at breakfast time

5mg twice or three times daily

15mg twice or three times daily

54mg once daily at breakfast time

30mg once daily at breakfast time

7.5mg twice or three times daily

20mg twice or three times daily

72mg once daily at breakfast time N.B. above BNF recommended limit currently

40mg once daily at breakfast time

10mg twice or three times daily

Non stimulant drugs used as first line treatments for ADHD.

Atomoxetine HCL (Strattera) Atomoxetine has been shown to be comparable to methylphenidate on core symptom efficacy (Heilengenstein et al, 2000). It is the first non stimulant to be licensed for ADHD in the UK and is licensed for the treatment of ADHD in children of 6 years and older and adolescents. It is also licensed in adults who were diagnosed with ADHD as children or adolescents. It should be initiated by a specialist physician experienced in managing ADHD. Atomoxetine is a non-controlled, highly selective noradrenaline re-uptake inhibitor (NRI). It is a once daily preparation. It is available as 10mg, 18mg, 25mg, 40mg and 60mg capsules. The starting and maintenance dose of Atomoxetine is determined by the child's weight (see section on starting Atomoxetine)

Side effects of Atomoxetine

Side-effects are generally mild-moderate and transient. The most common are:

Patients who experience side effects when taking atomoxetine as a single daily dose may benefit from taking it as twice daily evenly divided doses in the morning and late afternoon/ evening.

Calculating the correct dose of Atomoxetine

For children and adolescents less than 70kg body weight

0.5mg/kg/day

1.2mg/kg/day

1.4mg/kg/day or 100mg (which ever is less)

Approximate starting dose (minimum of 7 days)

Daily target dose

Maximum total daily dose evaluated for safety(after an additional 2-4 weeks)

For children and adolescents over 70kg body weight

Approximate starting dose is 40mg (taken for a minimum of 7 days)

Daily target dose is 80mg /day

Maximum total daily dose evaluated for safety
(after an additional 2-4 weeks) is 100mg

Other drug groups as second or third line pharmacological options in the treatment of ADHD:

These are unlicensed and their usage should be restricted to specialist practitioners. They include:

Tricylic antidepressants (TCA's)

In the past TCA's have been widely used as a non stimulant alternative in the treatment of ADHD. Recent concerns about the potential for overdose e.g. accidentally in younger siblings, the necessity for ECG monitoring and the availability of longer acting stimulants and atomoxetine seem to have reduced their popularity in recent years. TCA's have a narrower margin of safety than psychostimulants and a wider range of potential side effects. TCA's used in the treatment of ADHD include: imipramine, desipramine, amitriptyline, nortriptyline and clomipramine. TCA's are usually considered when stimulants have been ineffective or have made tics wore. None of the tricylic antidepressants are licensed for use in ADHD.

Side effects of TCA's

Clonidine

Clonidine is an alpha-2-noradrenergic agonist which acts presynaptically to reduce noradrenaline release. It tends to be used when stimulant medications or tricyclic antidepressants have been ineffective or are contra-indicated. Clonidine is not licensed for use in ADHD. Usage of clonidine tends to be based upon clinical experience and expert opinion as the evidence base for it's use is quite poor (Ramchandani et al, 2002) ( http://www.clinicalevidence.com/ceweb/conditions/chd/0312/0312.jsp)

Side effects of clonidine:

Contraindications to clonidine include:

Caution in:

Adjunctive pharmacological treatments sometimes used in children and young people with ADHD.

Melatonin

Melatonin is prescribed widely by child psychiatrists and paediatricians in the UK. The main indication is for children with sleep-wake cycle disorders including those that co-occur with ADHD. It can also be used to relieve the insomnia side effect of stimulant medication. Prior to prescribing, the clinician should have paid attention to the child's sleep hygiene (e.g. advising measures such as a fixed bedtime routine, a quiet bedroom, a warm bath before going to bed, physical affection and avoiding watching exciting films or playing on computer games before bed) and have considered implementing a behaviour management programme.

Armour and Paton (2004) identified five placebo-controlled studies and several case studies examining the use of melatonin in the treatment of insomnia in children and adolescents. These studies tended to focus on children with learning disabilities including those with Rett's syndrome and autism as well as in children with visual impairment. A few children in the studies were also taking methylphenidate as treatment for ADHD. They concluded that melatonin reduces sleep latency, but does not consistently improve other aspects of sleep disturbance. Safety, particularly in the medium-and long-term, is poorly evaluated; short term concerns include exacerbation of epilepsy and asthma.

Melatonin cannot currently be recommended for routine long term use and it is not licensed in the UK.

Dose

The optimal dose is unknown. Reported studies have used a dose of between 2.5 - 25mg (1-2mg for infants) of the fast release formulation (a slow release formulation is also available). Infants are usually started on 1mg - 2.5 mg and older children on 2.5mg - 5mg. The usual reported dose seems to be between 5-10mg of the fast release formulation given 30 - 60minutes before bedtime. Improvement in sleep can occur within days but may take weeks. Depending on the response during the first few days and weeks, the dose can be adjusted to find the optimal amount. Once improvement in sleep pattern has occurred it may be possible to withdraw melatonin or at least reduce the dose. The lowest effective dose should be sought and treatment should be stopped at least once a year (e.g. in the holidays) to find out if the sleep problem has been cured in the meantime (Smits et al, 2001).

Side effects reported:

Parents should be warned of the uncertain long-term effects on growth and sexual maturation. Height and weight baselines should be established with monitoring every 6 months. This is in line with routine medication monitoring intervals for other medications which may be prescribed for children and young people with ADHD.

“Further information to guide the clinician before starting medication for ADHD can be found in the National Institute for Health and Clinical Excellence’s: Final Appraisal Determination. Methylphenidate, atomoxetine and dexamphetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents via http://www.nice.org.uk/page.aspx?0=260402. This states that

The decision regarding which product to use should be based on the following:

The document goes on to say that “If there is a choice of more than one appropriate drug, the product with the lowest cost (taking into account cost per dose and number of daily doses) should be prescribed”.

Useful web based sources of information on pharmacological treatment of children with ADHD (see also after sections on starting medication and ADHD and co-morbid disorders)