Intrathecal Baclofen In the Treatment of Adult Spasticity

Joseph C. Hsieh, M.D., M.B.A., M.P.H.; Richard D. Penn, M.D.

Disclosures

Neurosurg Focus. 2006;21(2) 

In This Article

Baclofen

Baclofen, whose chemical name is 4-amino-3-(4-chlorophenyl)-butanoic acid (Lioresal), was approved in 1977 by the Food and Drug Administration for treatment of spasticity (Fig. 1). Historically, baclofen had been designed as an antiepileptic drug in the 1920s. Although its effect on epilepsy was disappointing, investigators found that in certain patients spasticity decreased. Indeed, baclofen is currently the most effective and widely used drug for treatment of spinal cord or cerebral spasticity.

Baclofen is an analog to GABA that is specific to the GABAB (G protein–coupled) receptor.[3] Oral GABA, a hydrophilic agent, is an ineffective antispasmodic drug because it lacks penetration through the BBB and is rapidly degraded by neural tissue. Baclofen (molecular weight 213.67) is slightly more lipid-soluble and stable due to its chlorophenyl moiety, and thus it crosses the BBB in signi ficantly high concentrations without being taken up by cells.

Baclofen has been found to bind to presynaptic GABAB receptors within the brainstem, dorsal horn of the spinal cord, and other CNS sites.[5,13,20,22,25] There is evidence to suggest that baclofen may work at a spinal level. Spec ifically, baclofen administered to isolated spinal cord pre parations inhibits both monosynaptic and polysynaptic reflexes.[40] Presynaptic effects are believed to be secondary to decreases in calcium influx during an action potential, leading to reduced neurotransmitter release. The challenge with baclofen has been to develop a method of delivery that will minimize supraspinal side effects while maintaining efficacy.

Baclofen is most frequently delivered through an oral route. Oral baclofen has been shown to be an effective an ti spasmodic agent by Duncan, et al.[7] Baclofen appears to work best on spasticity caused by multiple sclerosis and spinal cord injury, although some efficacy is also seen in patients with head trauma or CP. The usual dosages for spasticity range from 60 to 100 mg/day. Gradual increases in doses may be necessary as the disease process evol ves, but can also result in tolerance.

Severe spasticity is rarely controlled by oral baclofen, although some relief of symptoms is possible.[32] As might be suspected from its central GABAB inhibitory action, the risks associated with oral baclofen include central side effects of drowsiness and mental confusion. Other risks include dependence and withdrawal symptoms, seizures, psychic symptoms, and hyperthermia. Luckily, withdrawal symptoms are usually mitigated by the reintroduction of baclofen.

In open-label studies of oral baclofen, the drug im proved spasticity in 70 to 87% of patients, with additional improvement in spasms in 75 to 96% of patients.[6] Double-blind, cross-over, placebo-controlled trials demonstrate statistically significant improvements in spasticity with ad ministration of oral baclofen. The a2- adre nergic agonist tizanidine has been the medication most often compared with oral baclofen and has been found to be similar ly efficacious but with a reduced frequency of weakness.

The supratentorial CNS side effect profile of baclofen provides an upper limit to oral baclofen dosing. The suppression of abnormal spinal segment reflex activity in severe spasticity can require oral dosing, which results in clinically hazardous levels of sedation caused by cerebral effects. The most successful solution to this dilemma has been direct delivery of baclofen into the lumbar subarachnoid space with an intrathecal pump.

Intrathecal baclofen represents a significant advancement in drug delivery that bypasses several limitations of oral baclofen. The technology has its roots in successful CNS delivery of intrathecal opiods, resulting in prolonged analgesia with minimal systemic side effects.[38] In trathecal delivery of baclofen overcomes the obstacles of the BBB and theoretically results in greater therapeutic efficacy concentrated at a spinal site of action. Because baclofen is only slightly lipid soluble, it remains within the CSF, with a relatively long half-life of 90 minutes.[26] Fur thermore, slow rostral perfusion of baclofen along the subarachnoid space creates a relatively high concentration of the drug in the spine compared with the brain. Proof of this principle was demonstrated during initial trials in which a single 50-mg bolus of baclofen introduced into the lumbar region reduced severe rigidity in patients with spinal cord injury to normal tone for more than 8 hours, without cerebral side effects.[33]

An implanted drug pump provides continuous infusion within the lumbar subarachnoid space and thus makes it possible to sustain an antispasmodic baseline. Further more, dosing can easily be titrated to attain the desired tone simply by adjusting the rate of infusion. In one double-blind cross-over study, patients with severe spinal spasticity refractory to oral therapy were evaluated in an "on-baclofen" and "off-baclofen" state, and they demonstrated significant reduction in both Ashworth and spasm frequency scale scores.[34] Efficacy was maintained over the course of 2 years.

The only approved pump and catheter system available for ITB therapy is produced by Medtronic, Inc., Minne apolis, Minnesota. The infusion system currently in use con sists of an intrathecal catheter, pump, and external com puter programmer. The pump is based on systems that are also used for intrathecal/epidural delivery of morphine for chronic pain, intravascular delivery of chemotherapeutic drugs such as methotrexate, doxorubicin, or cisplatin in patients with cancer, and intravenous infusion of clindamycin for osteomyelitis. The largest pump available, the SynchroMed II (Medtronic, Inc.), is 87.5 mm in di ame ter, 26 mm thick, has a capacity of 40 ml, and weighs 215 g when full. The pump is powered by a permanent lithium battery that cannot be recharged in situ; consequently, the pump must be surgically explanted and a new one inserted every 4 to 6 years with normal use. Normal refill intervals are usually between 2 and 3 months.

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