Oral medications are often used as an early treatment strategy for global spasticity. Medications that are most frequently used include baclofen (Lioresal), dantrolene sodium (Dantrium), clonidine, diazepam (Valium), and tizanidine (Zanaflex). All of these medications work through the central nervous system, with the exception of dantrolene sodium and, therefore, have the potential for sedation (Table 14.2). None of these medications have been found to be universally effective in relieving spasticity (168), and evidence related to functional improvement is extremely sparse. The choice of medications is, therefore, often based on the impact of potential side effects on the individual patient. Widely accepted dosing guidelines do not exist for any of these medications for CP and therefore most clinicians utilize a low starting dose followed by a gradual dose escalation to find the best clinical response with tolerable side effects.
Benzodiazepines have an inhibitory effect on both the spinal cord and supraspinal levels mediated through binding near but not at the gamma-aminobutyric acid (GABA) receptors and increasing the affinity of GABA for GABAA receptors (169). Diazepam is the most frequently used benzodiazepine and oldest antispasticity medication that is still in use (170), but like other oral medications in CP, its effectiveness has not been well evaluated. It is rapidly absorbed, reaching peak drug levels an hour after drug administration. The positive effect of diazepam may be related to general relaxation that permits improvements, especially in those individuals with athetosis and spasticity (171,172).
Baclofen is a GABA analogue that acts at the spinal cord level to impede the release of excitatory neurotransmitters implicated in causing spasticity (173). Low lipid solubility impedes passage through the blood-brain barrier with more than 90% of the absorbed drug remaining in the systemic circulation (174). As a result, large doses may be necessary to achieve an effect. A study of pharmacokinetics (PK) in children with CP taking oral baclofen found that the PK was largely proportional to dose/kg, making dose adjustments uncomplicated by PK issues (175). Very few studies have been published regarding the use of oral baclofen in CP. Two small double-blind, placebo-controlled, crossover trials produced differing conclusions regarding the effectiveness of baclofen in reducing spasticity, but neither employed validated outcome measures (176,177). Additional studies assessed the effect of oral baclofen for reduction of spasticity and improved function in small numbers of subjects with moderate to severe spasticity. One study showed possible deleterious effects on motor function (178), while the other demonstrated no difference with placebo except in goal attainment (179).
Dantrolene sodium is unique in that it works primarily through actions on the skeletal muscle and not through central nervous system pathways. It inhibits the release of calcium from the sarcoplasmic reticulum, thereby uncoupling electrical excitation from muscle contraction and reducing contraction intensity. It is well absorbed within 3 to 6 hours after ingestion and is metabolized in the liver to 5-hydroxydantrolene, with peak effect in 4 to 8 hours (180). Doses in children range up to 12 mg/kg/day (172). It is often suggested that dantrolene be considered for the treatment of spasticity of cerebral origin because its mode of action is not central nervous system mediated and it is less likely to be sedating (170,172,181), although an expert panel noted that it is rarely used in clinical practice to reduce spasticity in children with CP (155). Their conclusion is that this is most likely due to the lack of evidence in the literature to support its efficacy along with the potential for frequent and serious side effects. Side effects from treatment can include sedation, nausea, vomiting, and diarrhea. Use of dantrolene is also associated with hepatotoxicity (180,182). Liver function studies should be done prior to instituting treatment and periodically while on maintenance therapy (170). There are a few published trials of Dantrium in CP. One report of long-term use of dantrolene in children with spastic diparesis indicated that young children achieved greater levels of function than predicted prior to dantrolene administration and older children were able to move more easily and maintain their highest levels of function (183).
Additional oral medications used to treat spasticity in children with CP include alpha 2 agonists, such as
TABLE 14.2 MEDICATIONS USED TO TREAT SPASTICITY IN CHILDREN
Source: Reprinted from Ref. (188). Green LB, Hurvitz EA. Cerebral palsy. Phys Med Rehabil Clin N Am. 2007;18(4):866-867, with permission from Elsevier.
clonidine and tizanidine, as well as certain anticonvulsants, including gabapentin (Neurontin). The alpha 2 agonists result in decreased motoneuron excitability by decreasing the release of excitatory amino acids (182). The side effects associated with these agents are frequently the cause of their more limited use and include nausea, vomiting, hypotension, sedation, dry mouth, hallucinations, and hepatotoxicity. In addition, reversible liver enzyme elevations have been noted in 2% to 5% of patients (170). There is little literature to guide the effective use of tizanidine for the management of spasticity in children with CP (155). Gabapentin is structurally similar to GABA, readily crosses the blood-brain barrier, and is not protein-bound.
It does not activate GABA, but results in increased brain levels of it (170). Reports of its use in children with spasticity are not available as of yet.