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.