Chemical formula: C₁₀H₁₂ClNO₂ Molecular mass: 213.661 g/mol PubChem compound: 2284
Baclofen is an antispastic agent acting at the spinal level. A gamma-aminobutyric acid (GABA) derivative, chemically unrelated to other antispastic agents.
Baclofen depresses monosynaptic and polysynaptic reflex transmission, probably by stimulating the GABAB-receptors. This stimulation in turn inhibits the release of the excitatory amino acids glutamate and aspartate. Neuromuscular transmission is unaffected by baclofen.
The major benefits of baclofen stem from its ability to reduce painful flexor spasms and spontaneous clonus thereby facilitating the mobility of the patient, increasing their independence and helping rehabilitation.
Baclofen also exerts an antinociceptive effect. General well being is often improved and sedation is less often a problem than with centrally acting drugs.
Baclofen stimulates gastric acid secretion.
In neurological diseases associated with spasm of the skeletal muscles, the clinical effects of baclofen take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism, and clonus. Baclofen improves the patient’s mobility, makes it easier for him/her to manage without aid, and facilitates physiotherapy.
Consequent important gains include improved ambulation, prevention and healing of decubitus ulcers, and better sleep patterns due to elimination of painful muscle spasms. In addition, patients experience improvement in bladder and sphincter function and catheterisation is made easier, all representing significant improvements in the patient’s quality of life. Baclofen has been shown to have general CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression.
Baclofen when introduced directly into the intrathecal space, permits effective treatment of spasticity with doses at least 100 times smaller than those for oral administration.
The onset of action is generally half an hour to one hour after administration of a single intrathecal dose. Peak spasmolytic effect is seen at approximately 4 hours after dosing, the effect lasting 4 to 8 hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms and the method and speed of drug administration.
Baclofen’s antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed within 24 to 48 hours.
Intrathecal amdinisttration: Because of the slow CSF circulation and the baclofen concentration gradient from the lumbar to the cisternal CSF the pharmacokinetic parameters observed in this fluid and as described below should be interpreted considering a high inter- and intra-patients variability.
Baclofen is rapidly and completely absorbed from the gastrointestinal tract. Following oral administration of single doses (10-30 mg) peak plasma concentrations are recorded after 0.5 to 1.5 hours and areas under the serum concentration curves are proportional to the dose.
Direct infusion into the spinal subarachnoid space by-passes absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.
The volume of distribution of baclofen is 0.7 l/kg. The protein binding rate is approximately 30% and is constant in the concentration range of 10 nanogram/ml to 300 microgram/ml. In cerebrospinal fluid active substance concentrations are approximately 8.5 times lower than in the plasma.
After single intrathecal bolus injection/short-term infusion the volume of distribution, calculated from CSF levels, ranges from 22 to 157 ml.
With continuous intrathecal infusion daily doses of 50 to 1200 micrograms 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, confirming that baclofen passes only slowly across the blood-brain barrier.
The plasma elimination half-life of baclofen averages 3 to 4 hours.
Baclofen is eliminated largely in unchanged form. Within 72 hours, about 75% of the dose is excreted via the kidneys with about 5% of this amount as metabolites.
The elimination half-life in the CSF after single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms baclofen ranges from 1 to 5 hours. Elimination half-life of baclofen after having reached steady-state in the CSF has not been determined.
After both single bolus injection and chronic lumbar subarachnoid infusion using an implantable pump system, the mean CSF clearance was about 30 ml/h.
At steady-state conditions during continuous intrathecal infusion, a baclofen concentration gradient is built up in the range between 1.8:1 and 8.7:1 (mean: 4:1) from lumbar to cisternal CSF. This is of clinical importance insofar as spasticity in the lower extremities can be effectively treated with little effect on the upper limbs and with fewer CNS adverse reactions due to effects on the brain centres.
Baclofen is metabolised to only a minor extent. Deamination yields the main metabolite, β-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive.
Oral administration: The pharmacokinetics of baclofen in elderly patients are virtually the same as in patients below 65 years of age. Following a single oral dose, elderly patients have slower elimination but a similar systemic exposure of baclofen compared to adults below 65 years of age. Extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetic difference between patients below 65 years of age and elderly patients.
Intrathecal administration: 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 elimination but a similar systemic exposure to baclofen compared to young adults. However, the extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetics difference between young adults and elderly patients.
Oral administration: Following oral administration of 2.5 mg Baclofen tablet in children (aged 2 to 12 years), Cmax of 62.8 ± 28.7 nanogram/ml, and Tmax in the range of 0.95-2h have been reported. Mean plasma clearance (Cl) of 315.9 ml/h/kg; volume of distribution (Vd) of 2.58 l/kg; and half-life (T1/2) of 5.10 h have been reported.
Intrathecal administration: In paediatric patients, respective plasma concentrations are at or below 10 ng/mL.
No pharmacokinetic data are available in patients with hepatic impairment after administration of baclofen. However, as the liver does not play a significant role in the disposition of baclofen, it is unlikely that baclofen pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.
Oral administration: No controlled clinical pharmacokinetic study is available in patients with renal impairment after administration of baclofen. Baclofen is predominantly eliminated unchanged in urine. Sparse plasma concentration data collected only in female patients under chronic hemodialysis or compensated renal failure indicate significantly decreased clearance and increased half-life of baclofen in these patients. Dosage adjustment of baclofen based on its systemic levels should be considered in renal impairment patients, and prompt hemodialysis is an effective means of reversing excess baclofen in systemic circulation.
Intrathecal administration: No pharmacokinetic data is available in patients with renal impairment after administration of Lioresal Intrathecal. Since baclofen is majorly eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment can not be excluded.
Baclofen increases the incidence of omphaloceles (ventral hernias) in the foetuses of rats given approximately 13 times the maximum oral dose (on mg/kg basis) recommended for human use. This was not seen in mice or rabbits.
An apparently dose related increase in the incidence of ovarian cysts, and a less marked increase in enlarged and/or haemorrhagic adrenals have been observed in female rats treated for 2 years. The clinical relevance of these findings is not known.
Experimental evidence to date suggests that baclofen does not possess either carcinogenic or mutagenic properties.
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.
Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters. There was no evidence of a mutagenic potential of baclofen.
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 haemorrhagic adrenal glands was observed.
Repeated intrathecal administration of baclofen was not associated with the development of inflammatory masses in studies in rats and dogs. No changes to the spinal cord and adjacent tissue and no signs of irritation or inflammation of the spinal cord and surrounding tissues were noted in either species.
Intrathecal baclofen is unlikely to have adverse effects on fertility or on prenatal or postnatal development based on oral studies in rats and rabbits. Baclofen is not teratogenic in mice, rats, and rabbits at doses at least 125-times the maximum intrathecal mg/kg dose. Lioresal given orally has been shown to increase 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 has been shown to cause delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits. Baclofen caused widening of the vertebral arch in rat fetuses at a high intraperitoneal dose.
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