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The precise mechanisms of action of LIORESAL (baclofen) as an antispastic agent are not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflex transmission at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals. Actions at supraspinal sites may also contribute to its clinical effect. Baclofen is an analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype.
Baclofen has been shown to have general Central Nervous System (CNS) depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia and respiratory and cardiovascular depression.
In neurological diseases associated with spasm of the skeletal muscles, LIORESAL Intrathecal may have beneficial action on reflex muscle contractions, painful spasm, automatism, hyperreflexia, trismus and clonus. Neuromuscular transmission is not affected by baclofen. Baclofen may also reduce pain associated with spasticity.
Pharmacodynamics of LIORESAL Intrathecal
The onset of action is generally half an hour to one hour after administration of an intrathecal bolus dose. Peak antispastic effect is seen at approximately 4 hours after dosing and effects may last 4 to 8 hours. Onset, peak response, and duration of action vary with individual patients depending on the dose and severity of symptoms.
Continuous Intrathecal Infusion
The antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed in 24 to 48 hours.
Pharmacokinetics of LIORESAL Intrathecal
After LIORESAL Intrathecal administration, the concentration of baclofen in the Cerebrospinal Fluid (CSF) is approximately 100 times higher than what is found following oral administration.
Because of slow CSF circulation and a baclofen concentration gradient from the lumbar to the cisternal CSF, the pharmacokinetic parameters as described below should be interpreted considering a high inter- and intra-patient variability.
The clearance of intrathecal baclofen, calculated from intrathecal bolus or continuous infusion studies, approximate its CSF turnover, suggesting elimination via bulk-flow removal of CSF. Direct infusion into the spinal subarachnoid space bypasses absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.
After a bolus lumbar injection of 50 or 100 μg LIORESAL Intrathecal in 7 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. After single intrathecal bolus injection/short-term infusion, the volume of distribution in intrathecal compartment, calculated from CSF levels, ranges from 22 to 157 mL.
A study, conducted in 10 patients, suggests that the mean CSF clearance for continuous intrathecal infusion of LIORESAL is approximately 30 mL/hour.
Continuous intrathecal infusion daily doses of 50 to 1200 μg result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/mL at steady state. According to the half-life measured in the CSF, CSF steady state concentrations will be reached within 1-2 days. During Intrathecal infusion the plasma concentrations do not exceed 5 ng/mL.
Limited pharmacokinetic data suggest that a lumbar-cisternal baclofen concentration gradient of about 4:1 is established during continuous baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap during continuous baclofen infusion at the lumbar level in doses associated with therapeutic efficacy. The interpatient variability was considerable. This gradient suggests that spasticity in the lower extremities may be relieved with little effect on the upper limbs and with fewer cerebral adverse reactions due to diminished effects on the brain.
No pharmacokinetic data is available in elderly patients after administration of LIORESAL Intrathecal. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower rate of absorption and elimination, a slightly prolonged elimination half-life, but a similar systemic exposure to baclofen compared to young adults.
No pharmacokinetic data is available in patients with hepatic impairment after administration of LIORESAL Intrathecal. However, as the liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patient with hepatic impairment.
No pharmacokinetic data is available in patients with renal impairment after administration of LIORESAL Intrathecal. Since baclofen is primarily eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment cannot be excluded. Severe neurological outcomes have been reported in patients with renal impairment after oral administration, thus LIORESAL Intrathecal should be given with special care and caution in these patients (see PRECAUTIONS, Renal Impairment).
Primary Pharmacological Activity
Baclofen depresses monosynaptic and polysynaptic reflex transmission in the spinal cord. The antispastic activity is derived primarily from its action at the spinal level to reduce spasms in voluntary muscles (see also LIORESAL Product Monograph).
Secondary Pharmacological Activity
Intrathecal baclofen exerts an antinociceptive effect in rats and cats. These effects are independent of any debilitation of voluntary motor function. In addition, intrathecal baclofen affects lower urinary tract dynamics of the anesthetized dog. Vesical and urethral pressure was significantly decreased. Within 30 minutes of injection, relaxation of the bladder and a reduction in urethral resistance occurred.
LD50 values following intrathecal dosing are not available.
The oral toxicity of LIORESAL has been thoroughly investigated. LIORESAL Intrathecal requires the use of much smaller doses to achieve a therapeutic effect, with consequential lower systemic exposure.
Repeated dose toxicity
Repeated intrathecal administration of baclofen to rats and dogs was not associated with irritation or inflammation of the spinal cord and surrounding tissues. Inflammation of the spinal cord was observed in one rabbit in a study that administered intrathecal baclofen to 3 rabbits weekly over a period of 3 to 6 months.
Subacute and subchronic studies with continuous intrathecal baclofen infusion in two species (rat, dog) revealed no signs of local irritation or inflammation on histological examination. Preclinical studies in animal models have demonstrated that the formation of inflammatory mass is directly related to high dose and/or high concentration of intrathecal opioids and no inflammatory mass is formed with intrathecal baclofen as a sole agent.
Teratology and Reproduction studies
Oral baclofen showed no significant adverse effects on fertility or postnatal development at non-maternally toxic dose levels in rats (approximately 2.1-times the maximum oral mg/kg dose in adults). At maternally toxic dose levels (8.3-times the maximum oral mg/kg dose in adults), baclofen increased the the incidence of omphalocoeles (ventral hernias) in rats, an effect not seen in mice or rabbits. Delayed fetal growth (ossification of bones) in the fetuses of rats and rabbits was also observed at maternotoxic doses.
Rat: Doses of 4.4-5 and 17.7-21.3 mg/kg/day were administered orally to two groups of female rats during pre-mating, mating, gestation and lactation. The only significant effect was a reduction in litter size and survivability of offspring (possibly due to agalactia) in the high dose group. In another rat study, doses of 5 and 10 mg/kg/day were administered by gavage during the last trimester of pregnancy and throughout the lactation period. Five of 31 dams in the high dose group showed severe weight loss from days 15-21 of gestation as well as agalactia and the entire litter of each of these dams died by day 2 postpartum. In a third study, baclofen doses of 30 mg/kg/day produces symptoms of ataxia and drowsiness in dams and the death of 4 of 24 dams dosed from gestation Days 1 to 12. At this high dose level, there was a slight increase in the resorption rate; however, the number and size of the fetuses remained normal and no malformations were reported.
Rat and Mouse: Doses of 5 and 20 mg/kg/day were administered by gavage to two groups of pregnant rats on days 6-15 of gestation. The only significant finding was the presence of abdominal hernias in 4/160 fetuses in the high dose group. In a second similar study, 1/229 control fetuses and 2/293 fetuses from dams receiving 20 mg/kg/day had abdominal hernias (See also WARNINGS). Comparable lesions did not occur in a similar mouse study.
The average number of stillbirths or viable newborns did not differ significantly between control and medicated groups. The average weight of neonates from the high dose group was significantly reduced.
Rabbit: Doses of 1, 5 and 10 mg/kg/day were administered by gavage to groups of rabbits from the 6th to 18th day of gestation. There was an increased incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in the fetuses from the high dose group. In another study, a slight increase in resorption rates was observed in rabbits receiving 10 and 15 mg/kg/day of oral baclofen.
Baclofen did not cause teratogenic effects in mice, rats, and rabbits at doses up to125-times the maximum intrathecal mg/kg dose. LIORESAL given orally increased the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. LIORESAL dosed orally caused delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits, and when given intraperitoneally, baclofen at high doses caused widening of the vertebral arch in rat fetuses.
A 2-year rat study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or hemorrhagic adrenal glands was observed.
Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters.
DELHAAS EM, and BROUWERS JRBJ. Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Int J Clin Pharmacol Ther Toxicol 1991; 29: 274-280
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McLEAN BN. Intrathecal baclofen in severe spasticity. Br J Hosp Med 1993; 49 (4): 262-267
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MÜLLER H, ZIERSKI J, DRALLE D, HOFFMANN O, and MICHAELIS G. Intrathecal baclofen in spasticity. IN: Müller H, Zierski J, and Penn RD (eds). Local-spinal therapy of spasticity. Springer-Verlag, Berlin, etc.,1988; pp 155-214
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PARKE B, PENN RD, SAVOY SM and CORCOS D. Functional outcome after delivery of intrathecal baclofen. Arch Phys Med Rehabil 1989; 70: 30-32
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Last reviewed on RxList: 1/10/2014
This monograph has been modified to include the generic and brand name in many instances.
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