Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in April 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Clonidine is an alpha2-adrenergic agonist that is licensed in the UK for adults to prevent migraine, prevent hot flushing associated with menopause, and treat hypertension. It does not have a UK licence to treat attention deficit hyperactivity disorder (ADHD) in any age group. It is sometimes used off-label (generally as an add-on to a licensed psychostimulant medicine, such as methylphenidate) to treat ADHD in children and young people under 18 years. This review does not include evidence for the use of extended-release clonidine preparation (Kapvay), which is approved in the USA for treating ADHD.

NICE has issued a clinical guideline on Attention deficit hyperactivity disorder: diagnosis and management of ADHD in children, young people and adults (NICE clinical guideline 72). This recommends that in children and young people whose ADHD is unresponsive to methylphenidate, atomoxetine and dexamfetamine, further treatment may include medication unlicensed for ADHD (such as bupropion, clonidine, modafinil and imipramine), but this should only be considered in the context of tertiary services.

One randomised controlled trial (RCT; CAT study, Palumbo et al. 2008) provided weak evidence that using clonidine as an add-on to methylphenidate for 16 weeks was no better than using methylphenidate alone at treating ADHD symptoms in children and young people.

A second RCT (Hazell et al. 2003) provided weak evidence that clonidine (added to ongoing treatment with psychostimulants) improved conduct disorder symptoms in children and young people with either ADHD and conduct disorder, or ADHD and oppositional defiant disorder over 6 weeks. However, it did not improve hyperactivity symptoms.

These 2 RCTs were relatively small (n=189 total study population) and short term (6 to 16 weeks of treatment), so did not provide evidence for long-term efficacy and safety.

Adding clonidine to existing stimulant therapy was associated with an increase in moderate to severe side effects, most notably sedation and drowsiness. However, 3 RCTs (CAT study, Daviss et al. 2008, Hazell et al. 2003 and Tourette's Syndrome Study Group 2002) suggested that this may be an acute effect that reduces over time.

One RCT (CAT study, Daviss et al. 2008) found a significantly higher incidence of bradycardia in children using clonidine for 16 weeks. One child taking clonidine and methylphenidate was withdrawn from this study because of asymptomatic heart abnormalities detected by electrocardiogram (ECG).

Because of the small and short-term nature of the RCTs identified, additional serious adverse events due to clonidine cannot be ruled out. Children and young people with serious existing cardiac problems were generally excluded from the RCTs and may be more at risk of serious side effects. The NICE clinical guideline on ADHD recommends that a cardiovascular examination and ECG should be carried out before starting treatment with clonidine in children or young people with ADHD.

One further RCT (Tourette's Syndrome Study Group 2002) found that clonidine monotherapy, methylphenidate monotherapy, and combination therapy with clonidine and methylphenidate were all significantly more effective than placebo in treating ADHD symptoms and tic symptoms in children and young people with ADHD and either Tourette's syndrome or other tic disorders.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.