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Mechanism of Action
The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype.
Baclofen when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved with resultant plasma concentrations 100 times less than those occurring with oral administration. In people, as well as in animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.
Pharmacodynamics of Intrathecal Baclofen
Adult Patients: The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms.
Pediatric Patients: The onset, peak response and duration of action is similar to those seen in adult patients.
Adult Patients: Intrathecal baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours.
Pediatric Patients: No additional information on continuous infusions is available for pediatric patients.
The pharmacokinetics of cerebrospinal fluid (CSF) clearance of intrathecal baclofen calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF.
After a bolus lumbar injection of 50 or 100 mcg intrathecal baclofen in seven patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 mL/hour.
The mean CSF clearance for intrathecal baclofen was approximately 30 mL/hour in a study involving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration are expected to be low (0 – 5 ng/mL). Limited pharmacokinetic data suggest that a lumbarcisternal concentration gradient of about 4:1 is established along the neuroaxis during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered by position. Six pediatric patients (age 8 – 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 – 400 mcg/day had plasma baclofen levels near or below 10 ng/mL.
Spasticity of Spinal Cord Origin
Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms.
Spasticity of Cerebral Origin
The efficacy of intrathecal baclofen was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomized controlled cross-over trial of
51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal baclofen was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed.
Last reviewed on RxList: 1/29/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Gablofen Information
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