An overview of drug therapies used in the treatment of dystonia and spasticity in children
- 1Department of Pharmacy, University College London Hospitals, London, UK
- 2Department of Paediatrics, University College London Hospitals, London, UK
- 3Department of Child Health, University College London, London, UK
- Correspondence to Neil Tickner, Department of Pharmacy, St Mary's Hospital, Paddington, London W2 1NY, UK;
- Received 9 October 2011
- Accepted 11 July 2012
- Published Online First 15 August 2012
Spasticity is defined clinically as ‘a motor disorder characterised by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon acts resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome’.1 Spasticity is a common feature of cerebral palsy (CP) as well as spinal cord and traumatic brain injury.
The most common cause of spasticity in childhood is CP which affects between 2 and 3 of every 1000 live births in industrialised countries.2 Other causes of spasticity include traumatic brain injury, spinal cord injury, central nervous system tumour or infarct, metabolic disorders and hydrocephalus.
Dystonia is defined as ‘a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures or both’.3 Dystonia may be either acute (eg, an oculogyric crisis secondary to drug administration) or chronic. Chronic dystonia can occur either locally (eg, writer's cramp, blepharospasm) or systemically as part of CP or other neurological syndromes.
The management of spasticity and chronic dystonia in children requires multidisciplinary management including neurologists, paediatricians, surgeons, GPs, physiotherapists, occupational therapists and pharmacists. Pharmacotherapy forms one aspect of this management and will be the focus of this review article, but other interventions, such as physical therapy, orthopaedic surgery and procedures, such as selective dorsal rhizotomy, play a major role too. Fundamental knowledge of pharmacologic properties and toxicities of these medications is required for safe and appropriate use, and should be part of an integrated therapeutic approach in which patients, carers, therapists, physicians and surgeons have open and clear communication about the overall rehabilitation process of the patient.
Treatment of generalised spasticity: systemic therapies
Oral, or enteral medication, can provide systemic treatment for the relief of generalised spasticity via different pharmacological mechanisms. These agents can be combined in cases difficult to treat, although the accumulation of central side effects, such as sedation, needs to be assessed. The main advantage of these therapies are their ease of use and low cost, though licensing and availability of suitable liquid presentations presents a problem for some of the agents (see table 1).
Diazepam is a benzodiazepine that has been in use since the 1960s and acts postsynaptically by binding to a specific site of the gamma-aminobutyric acid A receptor (GABAA), enhancing the endogenous effects of GABA as an inhibitory neurotransmitter. There is a huge amount of clinical experience for using diazepam in children, though data for the efficacy and pharmacokinetic profile of diazepam in the literature are limited.
When required for the treatment of spasticity, a low dose of diazepam should be introduced initially at night in an attempt to avoid sedative side effects during the day (see table 1), and then titrated to optimal response with the fewest side effects. If the desired clinical response is not achieved, a daytime dose can be added, but sedation should be monitored. The British National Formulary for Children (BNF-C)4 recommends that the total daily dose should not exceed 40 mg in children aged 12–18 years. Recent guidelines from the American Academy of Neurology (AAN) concluded that diazepam should be considered as a short-term antispasticity treatment in children with CP, as there is insufficient evidence to support or refute the use of diazepam to improve motor function in this population.5
Common side effects are drowsiness, sedation (which can be useful to aid sleep), weakness, ataxia and hypersalivation. Respiratory depression should not normally occur at the doses used to treat spasticity if low starting doses are used. Tolerance and dependence limit the long-term use of diazepam, however, when required for significant periods, a healthcare professional experienced in withdrawal should facilitate discontinuation in such patients. Common withdrawal manifestations include agitation, twitching, nausea, seizures, insomnia and hyperpyrexia.6
Diazepam undergoes complex metabolism in the liver by cytochrome P450 systems, including CYP 3A4 and 2C19,7 to many active and inactive metabolites. Drugs that are inhibitors (eg, omeprazole, erythromycin) or inducers (eg, rifampicin) of CYP 3A4 should be used with caution in patients taking diazepam, and dose adjustments made where necessary (see table 2). CYP 2C19 also shows important genetic polymorphic effects across different ethnic groups, therefore, response to therapy may be reduced or exaggerated in some patients who have extensive or poor metaboliser phenotypes. Particularly of note are those of oriental Asian origin (12–23%), Micronesia and Polynesia (38–79%), who demonstrate a higher prevalence of the poor metaboliser phenotype versus Caucasians (3–5%), which leads to unconsciousness being more frequently noted in Asian populations.8 ,9
Baclofen has been used for spasticity since the 1960s. It acts as a GABAB receptor agonist and is widely used for spasticity. The precise mechanism of its action is not well described but may include crossing the blood-brain barrier to bind to GABAB receptors of laminae I−IV of the spinal cord, where primary sensory fibres end, thereby inhibiting the release of excitatory neurotransmitters and causing presynaptic inhibition of mono- and polysynaptic reflexes.10
Baclofen is licensed for the relief of spasticity of voluntary muscle in children over 1 year of age. The dose (see table 1) should be increased slowly to avoid the common side effects of sedation and muscular hypotonia. Other common side effects include gastrointestinal disturbances, confusion, ataxia, agitation, urinary frequency and insomnia.
Clinical evidence of efficacy of baclofen in children is limited and conflicting. The AAN concluded that there is insufficient evidence to support or refute the use of baclofen for spasticity or functional impairment in childhood CP.5 The pharmacokinetics of baclofen are also inadequately described for paediatric populations11 despite widespread use.
Baclofen is well absorbed from the gastrointestinal tract and is partially metabolised by the liver, but mostly excreted unaltered by the kidneys6 It has a half-life of 3–4 h,12 therefore, regular dosing is required, usually four times a day. Caution is advised in renal failure or with medicines that may induce an acute renal impairment, such as non-steroidal anti-inflammatory drugs. The recommended maximum dosage is age-dependent, however, a retrospective review of usage suggests these are often superseded in practice.13
With exposure to baclofen, the expression of GABAB receptors are downregulated, consequently, abrupt cessation of baclofen therapy can result in a withdrawal syndrome. The Committee of the Safety of Medicines emphasised the potentially serious psychiatric side effects of withdrawal, including hallucinations, paranoia, delusions, psychosis, confusion and agitation. They advise that discontinuation of therapy should be through gradual dose reduction over at least 1–2 weeks or longer, should symptoms occur.14
Dantrolene sodium is unique from other antispasticity drugs in that it acts peripherally through inhibiting the release of calcium from the sarcoplasmic reticulum in muscles, uncoupling excitation and contraction.
The pharmacokinetics of dantrolene sodium has not been reported in children. Initial doses should be low and titrated upwards in weekly intervals until a satisfactory response is achieved (see table 1). The maximum dose is 2 mg/kg three or four times a day, and the total dose should not exceed 400 mg/day in children heavier than 50 kg due to increased risk of hepatotoxicity.4 Studies demonstrate conflicting findings on the efficacy of dantrolene sodium, leading to the AAN evidence-based review to conclude there is insufficient evidence to support or refute its use.5
Common side effects include weakness, drowsiness, dizziness, malaise, gastrointestinal disturbance and acute hypersensitivity. A major side effect requiring monitoring is hepatotoxicity. Serious, irreversible liver failure has been reported, usually in doses over 400 mg/day, although not yet reported in children for the treatment of spasticity. Liver function should be measured before initiation of treatment and at regular intervals during treatment (eg, 2–3-monthly). Children and their carers should be informed about the potential for hepatotoxicity and how to recognise the symptoms, such as anorexia, nausea, vomiting, fatigue, dark urine or pruritis.4
Tizanidine acts as a central α-2 receptor agonist at supraspinal and spinal levels to reduce spasticity by inhibition of spinal polysynaptic reflex activity.15 Tizanidine is licensed for adults for the treatment of spasticity associated with multiple sclerosis, or with spinal cord injury or disease. Specialist paediatric centres are now utilising tizanidine, although dosing recommendations are not currently listed in the BNF-C,4 and pharmacokinetic data is not defined. This limits use to older children and young people who are larger in size and where an ‘adult’ dose is seemingly appropriate. One small paediatric study with a mean age of 4.1 (2–15) years used a dose of 50 μg/kg/day.16 One of the main factors limiting tizanidine use in children is the lack of an appropriate liquid formulation. Extemporaneous suspensions may be available from specials manufacturers, however, the bioavailability and quality of the suspension will be unknown and may need dose titration.
The AAN concluded that tizanidine may be considered for the treatment of spasticity in children with CP, however, there is insufficient evidence to support or refute its use in improving motor function in this population.5 Common side effects include drowsiness, dry mouth, fatigue, dizziness and hypotension. Tizanidine is metabolised in the liver by CYP 1A2 and reversible hepatitis and hepatotoxicity has been observed.15 Concomitant use with inhibitors of CYP 1A2 (eg, ciprofloxacin; see table 2) are contraindicated, resulting in greater than 10 times plasma concentrations of tizanidine leading to prolonged hypotension and QTC prolongation.15
As a way of maximising the spinal cord effects of baclofen and minimising the side effects, intrathecal administration of baclofen (ITB) has been developed as a means of achieving this. Initially used in adults, but now increasingly used in specialist paediatric centres, this involves the insertion of a catheter into the intrathecal space of the spinal column, and linked to a subcutaneously implanted, refillable pump that will deliver baclofen at a controlled rate. Administration of baclofen via this route allows reduction in spasticity at doses far lower than doses administered enterally. As an invasive intervention, ITB administration is associated with a number of complications, therefore, careful identification of appropriate patients is important to achieve therapy goals.
The appropriate dosing for ITB is achieved by initial test doses of 25 μg over at least 1 min, increased in steps of 25 μg not more often than every 24 h (up to 100 μg). Once an appropriate starting dose is identified, a dose titration phase is undertaken using a pump to establish a maintenance dose.
It is estimated that approximately 30% of patients will experience serious problems while receiving ITB, and these include infections (10%), cerebrospinal fluid leakage (17%) and catheter malfunctions (10.5%).1 Life-threatening baclofen withdrawal can occur through catheter malfunction or dislodgement, or if refilling of the reservoir is not achieved at an appropriate time. This can manifest as fever, itching, altered mental status, exaggerated rebound spasticity, and muscle rigidity that, in rare cases, progresses to rhabdomyolysis, multiple organ-system failure and death.17 If ITB cannot be restored immediately, withdrawal may be offset by oral baclofen, supported by other antispasticity agents.
The AAN concluded that there is insufficient evidence to support or refute the use of continuous ITB for the treatment of spasticity in children with CP.5
Localised drugs for focal/segmental spasticity
Botulinum neurotoxin (BoNT) is an exotoxin produced by Clostridium botulinum. There are seven neurotoxins that C botulinum produces, A–G, which are all zinc proteases that inhibit cholinergic presynaptic vesicle fusion at the neuromuscular junction, leading to decreased release of acetylcholine, halting nerve signal transmission.
Only two BoNTs are available therapeutically, BoNT-A and BoNT-B. Only BoNT-A is licensed for use in children and is marketed under the trade names Botox and Dysport, and will be discussed in this review. BoNT-B has been used in a small number of studies in children, but evidence is limited. Both brands of BoNT-A have a similar onset and duration of action, with improvements expected after 2 weeks, and doses repeated after at least 12 weeks.18 ,19 BoNT is administered by targeted injection at specific nerve sites in muscle and is, therefore, most appropriate for the management of localised spasticity or dystonia. Administration in children may require topical anaesthesia, sedation or occasionally general anaesthesia. Depending on the site of administration, effects may be apparent at 12–72 h, and peak at 3–4 weeks. A dosing ceiling limits widespread administration, reducing their role in generalised spasticity.
Botox and Dysport are both only licenced for children over 2 years of age with dynamic equinus foot deformity caused by spasticity in ambulant paediatric CP only. Licensing of BoNT clearly does not reflect the clinical need, especially for children with CP. However, there is considerable published evidence for the off-label use in other muscles that cause functional difficulty, including multilevel lower and upper limb, neck and paraspinal muscles. The AAN has stated that BoNT-A should be offered as an effective and generally safe treatment,5 though this should always be under the guidance of a clinician experienced in the use of BoNT.
It is important for all physicians and pharmacists to be aware of the difference in relative unit potencies of each of these products before prescribing, supplying or administering BoNT. There are no international units, and there is no recognised equivalence between products. Potency is expressed as the amount of toxin required to kill 50% of mice in a standardised assay.20 Dosage calculation for each preparation is based on: total units per treatment session, total units per kilogram body weight per session, units per muscle, units per injection site, and units per kilogram body weight per muscle (U/kg/muscle). The total dosage ceiling used by experienced injectors has risen from the initial recommendation of 4 U/kg to greater than 20 U/kg in specific specialist cases (see table 3). The dosing schedule should be repeated approximately every 12 weeks to reduce antibody development. Antibodies may develop to BoNT limiting the efficacy and duration, though these are seen less frequently with modern formulations.21
The safety profile of BoNT-A is generally good although some adverse reactions are well documented. Most frequently, adverse events are associated with inappropriate dose calculations, dilution or localisation procedures undertaken. Localised events include muscle weakness beyond that intended for the therapy goal. Systemic absorption of BoNT can result in the clinical manifestations of botulism and has been reported when used in children. Symptoms include constipation, generalised paralysis resulting in respiratory compromise, swallowing difficulties, double vision and arrhythmias. Other side effects include pain at the injection site, fatigue, cramps, incontinence; and with long-term use, muscle atrophy.21 Procedural adverse events include haematoma formation and complications arising from the use of sedation or anaesthesia.
Phenol and alcohol
Alcohol and phenol have a historic role in the treatment of localised dystonia. Perineural injections of phenol (3–6%) or alcohol (30–50%, diluted from absolute alcohol) cause a reversible demyelination of motor fibres and axonal degeneration. Reinnervation occurs slowly over months to years. Identification of the correct motor nerve using electrical stimulation is important, as targeting of mixed motor and sensory nerves can result in long-term pain and paraesthesia. These procedures are generally very poorly tolerated in children and require sedation or anaesthesia.
Place of drugs in therapy
The drug treatment of spasticity and dystonia should always be considered as part of the patient's ongoing management plan, and non-pharmacological options should always be considered where appropriate. There are currently no national recommendations for the treatment of spasticity and dystonia in the UK, although the National Institute for Health and Clinical Excellence (NICE) are due to publish their final appraisal determination in the latter half of 2012. Based on the limited evidence for each agent, a systematic and pragmatic approach should be adopted in the decision to initiate drug therapy. Briefly summarised, the draft consultation from NICE22 advocates the following approaches:
For the treatment of acute episodes where spasticity is contributing to pain and discomfort, muscle spasms and functional disability, and a rapid onset of effect is needed, oral diazepam should be used first.
If a sustained, long-term effect is desired, then baclofen should be introduced at a low dose and titrated to response.
Continue using oral diazepam or oral baclofen if they have a clinical benefit and are well tolerated, but consider stopping treatment each time the management is reviewed by a specialist, and at least every 6 months.
If adverse effects (such as drowsiness) occur with oral diazepam or oral baclofen, consider reducing the dose or stopping treatment.
If the clinical response to oral diazepam or oral baclofen used alone is unsatisfactory within 4–6 weeks, stop using the drug, or consider a trial of combination treatment with both oral diazepam and oral baclofen.
Consider treatment with intrathecal baclofen if, despite the use of non-invasive treatments, spasticity, with or without dystonia, is causing difficulties with pain or muscle spasms, posture or function self-care (or ease of care in the case of parents or carers).
Consider BoNT-A when:
Focal spasticity of the upper limb is impeding fine motor function, compromising care and hygiene, causing pain, impeding tolerance of other treatments, causing concerns about appearance to the patient.
Focal spasticity of the lower limb is impeding gross motor function, compromising care and hygiene, causing pain, disturbing sleeping patterns, impeding tolerance of other treatments, causing cosmetic concerns to the patient.
Do not offer BoNT-A in children and young people with severe muscle weakness, with a previous adverse reaction or allergy, or who are currently receiving aminoglycosides.
The treatment of spasticity is a complex process, and should always involve well-defined treatment goals before any pharmacological treatment is initiated. Once an agent is started, regular reviews for efficacy and adverse events should occur. For all healthcare professionals involved in the management of patients with dystonia and spasticity, a good knowledge of the properties and side effects of each pharmacological agent is essential for successful outcomes and monitoring for adverse events.
For the treatment of spasticity, BoNT-A used locally is the only intervention recommended with high-grade evidence. There is still very little robust data for the efficacy and pharmacokinetics of other drug interventions in children, despite many years of use of some drugs by experienced clinicians. Further work is needed in this field to identify optimal treatments through large, well-designed, multicentre studies. In addition, there is a need to assess pharmacokinetic and bioavailability of drug formulations for children to ensure that not only can the best care be delivered, but also that the treatments become licensed for these specific indications via the European Medicines Agency regulatory process for paediatric use marketing authorisations. Until this is achieved, clinicians and pharmacists will continue to work with limited evidence and choices.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.