US Pharm. 2008;33(1):22-26.

Cerebral palsy is the leading cause of childhood disability.1 Current estimates suggest that 764,000 children and adults in the United States have cerebral palsy.2 The occurrence is 1 to 2.3 cases per 1,000 births.3 The extent of disability in cerebral palsy can vary from a mild motor disorder to major cognitive defects and wheelchair dependence. Cerebral palsy is defined as a primary abnormality of movement and posture secondary to a nonprogressive lesion in the developing brain. The motor disorder is often accompanied by epilepsy and disturbances of sight, hearing, cognition, communication, and behavior.1 This article will review pharmacologic treatments of the most common movement disorder associated with cerebral palsy--spasticity.

Etiology, Classification, and Diagnosis
The precise cause of cerebral palsy is still unknown. It results from the interaction of multiple risk factors before, during, and after birth.4 While prematurity and congenital malformations are considered risk factors, in many cases no specific cause of cerebral palsy is identified.5

Spasticity is the most common movement disorder of cerebral palsy, affecting 75% of patients. Spasticity is defined as increased velocity-dependent resistance to movement. It is characterized by hypertonicity of affected muscles, clonus, and hyperreflexia. Other aspects of spasticity are decreased motor planning, loss of selective motor control, weakness, and poor endurance.6 Other movement disorders of cerebral palsy are less common and may have extrapyramidal features such as athetosis, chorea, dystonia, and ataxia.

Treatment of Spasticity
Spasticity is debilitating. It can impact a patient's mobility and activities of daily living, and may lead to chronic musculoskeletal complications such as contractures, joint dislocation, pain, and decreased growth.5 Treatment of spasticity involves physical and occupational therapy, orthopedic interventions, and medications. Individualized care for a patient may involve a combination of oral, intramuscular, and intrathecal treatments. Oral treatment options for the control of spasticity in children include baclofen, clonidine, diazepam, dantrolene, and tizanidine. Their dosages are summarized in TABLE 1.


Baclofen (Lioresal) is first-line oral therapy for the treatment of spasticity in children with cerebral palsy. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-amino butyric acid (GABA). It acts on the GABA receptors in the central nervous system (CNS), inhibiting the release of excitatory neurotransmitters that cause spasticity. Baclofen is well absorbed orally, but it is 30% protein bound and has low lipid solubility; therefore, it does not readily cross the blood-brain barrier.7 Even though oral baclofen is considered first-line therapy, there are few clinical trials published evaluating its use in children with cerebral palsy.8 The information in pediatrics is from open-label studies or older, controlled clinical trials.8,9 A more recent double-blind, placebo-controlled study from 2006 demonstrated that baclofen improved function in children with cerebral palsy.8

Oral baclofen is approved for adults and children over 12 years of age. The recommended dosage is 5 mg three times a day, titrated every three days to a maximum dose of 80 mg. For children under 12 years, the recommendation is 10 to 15 mg/day, divided three times a day to maximum dose of 40 mg for children between 2 and 7 years, and to a maximum of 60 mg for children older than 8 years.10 A liquid formulation is not commercially available, but there are data on extemporaneous preparations.11,12

The adverse effects of baclofen include sedation, confusion, memory loss, and attention deficits. Other reported adverse effects include weakness, ataxia, and orthostatic hypotension. Baclofen's effect on seizure activity is still unclear. Baclofen has been reported to increase, decrease, or have no effect on the incidence of seizures.13

It is very important for pharmacists to be aware of a potentially serious complication of baclofen therapy. An abrupt discontinuation of baclofen may result in a rebound increase in spasticity, rhabdomyolysis, disorientation, hallucinations, and seizures.10,14,15

The benzodiazepine diazepam (Valium) is one of the oldest treatments for spasticity due to cerebral palsy.14 Benzodiazepines increase the affinity of GABA for its receptor. Studies comparing baclofen and diazepam found both agents to be equally effective in treating spasticity. In the comparison trials, patients receiving diazepam had a higher incidence of sedation than patients receiving baclofen.6 The sedative properties of diazepam limit its clinical use. Other common side effects of diazepam are impaired memory, decreased attention, ataxia, weakness, constipation, and urinary retention.15 The incidence of sedation and impaired memory and attention are particularly concerning in the school-aged child.

If diazepam is discontinued abruptly or tapered too quickly, patients will experience a withdrawal syndrome. Symptoms may include anxiety, agitation, restlessness, irritability, tremor, nausea, hyperpyrexia, and seizures.15

Dantrolene Sodium
Dantrolene (Dantrium) prevents full muscle contraction and therefore spasticity by inhibiting the release of calcium from the sarcoplasmic reticulum of skeletal muscle cells.15 The prevention of full muscle contraction results in generalized muscle weakness. It does not affect smooth muscle or cardiac muscle. Clinical trials determined that dantrolene is superior to placebo in the treatment of children with spasticity due to cerebral palsy.15

Dantrolene is metabolized extensively by the liver. It is involved in the following drug interactions: concomitant use with verapamil can result in hyperkalemia; use of dantrolene and estrogens may increase hepatotoxicity; and use with other CNS depressants may increase sedation. The toxicity of dantrolene may also be increased when used with monoamine oxidase inhibitors.16

Dantrolene's role in the treatment of spasticity is limited because of its association with hepatotoxicity. Fatal and nonfatal hepatitis have been reported. One series reported an incidence of hepatotoxicity of 2% and the incidence of fatal hepatitis at 0.3%.15 Baseline liver function tests should be obtained before initiating therapy and regularly thereafter.

Centrally Acting Alpha2 -Agonists

The centrally acting alpha2 -agonists clonidine (Catapres) and tizanidine (Zanaflex) work in the spinal cord to reduce spasticity by hyperpolarizing motor neurons and reducing excitatory amino acid release.15

Tizanidine does not have published dosing recommendations in children and is only available in tablet form.16 Clonidine has the advantage of many different dosage forms. It is available as a tablet, a patch, and an extemporaneously compounded suspension.10 Clonidine is usually used as adjunctive therapy for the treatment of spasticity.16

Adverse effects of the centrally acting alpha2-agonists include sedation, hypotension, and gastrointestinal upset. Not surprisingly, the adverse effect of hypotension is more common with the use of clonidine. Elevated liver enzymes are associated with tizanidine therapy.15

Intrathecal Baclofen

For many patients, oral medications will not adequately control spasticity. For such patients, baclofen delivered intrathecally could be an option. Baclofen, delivered directly to the spinal cord through an implantable device, provides improved control of spasticity with reduced adverse effects. The intrathecal administration of baclofen results in concentrations in the lumbar cerebrospinal fluid 30 times greater than can be achieved with oral dosing.17

The goals of intrathecal baclofen (ITB) therapy are to slow or prevent contractures, improve comfort and positioning, and ease the burden of care in nonfunctional patients. Contraindications are presence of infections at the time of screening, history of allergy to baclofen, inability to implant the pump 2.5 cm from the skin surface, and concerns about the patient's or family's ability to be compliant with refill appointments.16,18 It is recommended that the child be at least 15 kg in weight or 4 years of age for implantation.16,19 There are numerous studies describing the efficacy of ITB in treating spasticity due to cerebral palsy in adults as well as children.20-23

The battery-powered device contains and delivers drug from the pump reservoir through the catheter to the intrathecal space by peristaltic action (FIGURE 1). The life of the battery is four to seven years. The titanium pump is the size of a hockey puck with a reservoir capacity from 10 to 40 mL.16

If a patient is a candidate for ITB, a test dose is administered by lumbar puncture. An initial dose of 50 mcg is administered and if no response is noted, subsequent doses of 75 mcg and 100 mcg are administered 24 hours apart. If no response is seen at any dose, the patient is not a good candidate for ITB. If a response is evident, the patient may have a pump implanted. The initial daily dose is calculated by doubling the screening dose and delivering it continuously over 24 hours. 16

The pump is programmed from outside the body using a telemetry wand.16 It can be programmed to deliver a constant rate or a variable rate depending on the patient's needs during the day.18 The pump does need to be refilled. A needle is used to enter the device through the skin. Patients must be counseled to recognize the sound of the alarm when the reservoir is low. Usual refill interval is every two to three months depending on the dose of baclofen required by the patient.18

The most common drug-related adverse effects of ITB are chronic constipation, hypotonia, somnolence, headache, vomiting, and paresthesias. ITB does have the potential for some severe complications related to the catheter and the device such as dislodgement, kinking disconnection, cerebrospinal fluid leaks, and infection. 16,18,20 Overdosage can occur after a large dose increase or an error in programming. Overdose symptoms are hypotonia, decreased alertness, decreased respirations, bradycardia, and coma. Another complication is the baclofen withdrawal syndrome.18 Baclofen for intrathecal use was given a black box warning from the FDA to alert clinicians that a very serious withdrawal syndrome can occur with discontinuation of ITB therapy.16 Withdrawal is usually the result of pump or catheter malfunction or neglect in refilling the reservoir. Mild withdrawal is characterized by pruritus, agitation, diaphoresis, and increased tone. In moderate-to-severe withdrawal, fever, tachycardia, and painful muscle spasms can occur. Withdrawal symptoms can progress to seizures, hallucinations, delirium, rhabdomyolysis, and death. All patients receiving ITB therapy must be educated about withdrawal symptoms and should have oral baclofen available for emergency use.16

Local Intramuscular Therapy

Botulinum toxin is used as adjunctive therapy in the treatment of spasticity. Botulinum toxin is produced by the anaerobic bacterium Clostridium botulinum. There are seven toxin subtypes (A, B, C, D, E, F, and G); only A and B are commercially available. The toxin prevents acetylcholine from being released into the synaptic cleft, preventing muscle contraction. Within the nerve cell, vesicles containing acetylcholine fuse with the neuronal cell membrane in order for acetylcholine to be released. The binding of the vesicle is facilitated by a synaptic fusion apparatus called soluble NSF attachment receptor (SNARE) proteins. Botulinum toxin cleaves the fusion proteins and the SNARE complex does not form. This prevents the acetylcholine-filled vesicles from fusing with the cell membrane and releasing acetylcholine (FIGURE 2). Neuromuscular transmission is prevented, resulting in flaccid paralysis and muscle weakness.16

There are two available preparations of botulinum toxin in the U.S.--subtype A (Botox) and subtype B (Myobloc). Botox is approved for the treatment of strabismus and blepharospasm associated with dystonia in patients 12 years and older.24 It is also approved for hyperhidrosis.24 Botox is currently approved in Europe for the treatment of spasticity due to cerebral palsy in children. It does not currently have this indication in the U.S., although spasticity is a common off-label use.25 Myobloc is approved for cervical dystonia. 26 It is used less frequently than Botox for the treatment of spasticity.

Botulinum toxin types A and B have similar onset of action. Declines in muscle action potentials begin one to three days after injection, and the peak effect occurs in one to three weeks. The clinical effects from type AÜ last three to four months. Effects can vary from less than one month to up to six months. The clinical response from type B is similar to that from type A; the maximum paralysis at two weeks is less pronounced, and recovery occurs more quickly.16

The Spasticity Study Group has developed dosing regimens for botulinum toxin based on units/kg of body weight. The maximum dose for a large muscle is 3 to 6 units/kg and for a small muscle, 1 to 2 units/kg. The maximum dose per injection site is 50 units. 27

Botulinum toxin has a mild side-effect profile. Some patients experience pain on injection, muscle soreness, bruising, excessive weakness in injected and nearby muscles, rash, and fever. Falls may be due to greater-than-desired weakness and spread of toxin to adjacent muscles. Diffusion to other muscles is dependent on the dose, volume, dilution, and number of injections given. Patients should be counseled to expect a change in gait to avoid accidental injury and falls. 16

Spasticity is the most common movement disorder of cerebral palsy, exhibiting debilitating effects on the patient. Pharmacologic therapy of spasticity may be composed of oral, intrathecal, and intramuscular therapies. A comprehensive treatment plan for the patient with spasticity involves setting appropriate goals, utilizing physical therapy, orthopedic therapy, surgical therapy, and pharmacologic therapy to achieve the desired response.


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