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.
LIORESAL INTRATHECAL 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 LIORESAL INTRATHECAL:
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.
LIORESAL INTRATHECAL’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.
Continuous Infusion: No additional information is
available for pediatric patients.
Pharmacokinetics of LIORESAL INTRATHECAL:
The pharmacokinetics of CSF clearance of LIORESAL INTRATHECAL
calculated from intrathecal bolus or continuous infusion studies approximates
CSF turnover, suggesting elimination is by bulk-flow removal of CSF.
Intrathecal Bolus: After a bolus lumbar injection of
50 or 100 mcg LIORESAL INTRATHECAL 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.
Continuous Infusion: The mean CSF clearance for
LIORESAL INTRATHECAL (baclofen injection) 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 lumbar-cisternal 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.