Baclofen - Central Skeletal Muscle Relaxants

Central Skeletal Muscle Relaxants

Baclofen

Uses

·     Baclofen is used to treat muscle spasticity, clonus, flexor spasms, spinal disorders and multiple sclerosis.

Mode of Action

·              Baclofen is a derivative of the inhibitory neurotransmitter GABA (gamma amino butyric acid).

·              It inhibits both monosynaptic and polysynaptic reflexes at spinal level and also has CNS depressant effects.

·              Baclofen appears to act as a presynaptic GABA-B receptor agonist, and reduces the tonic activity of spinal gamma-motor-neurons, probably by acting at a novel receptor site.

Adverse Effects

·     At therapeutic doses (40 to 80 mg/day), baclofen is rela-tively free of adverse effects, and toxicity usually manifests only at daily doses exceeding 150 to 200 mg/day.

Toxicokinetics

·              Baclofen is well absorbed orally and bioavailability is around 70 to 80%.

·              Peak plasma levels (usually 0.3 to 0.6 mg/ml) are achieved in about 2 hours.

·              Plasma protein binding is to the extent of 30%, while the apparent volume of distribution is 0.8 L/kg.

·              About 15% is metabolised by the liver.

·              Approximately 85 to 90% of baclofen is excreted unchanged in the urine, and about 10% in the faeces.

·              Elimination half-life ranges from 2 to 6 hours, though in overdose this may rise to more than 30 hours.

Drug Interactions

■■  Baclofen can potentiate the effects of other CNS depres-sants and alcohol, as well as that of antihypertensives.

■■   Concomitant administration of levodopa (in Parkinsonism) may sometimes cause confusion, agitation, and hallucina-tions.

Clinical (Toxic) Features

·      Overdose is characterised by agitation, involuntary move-ments, twitching, convulsions, delirium, flaccidity, coma, and respiratory depression.

·      Nausea and vomiting are common.

·      There may also be hypo- or hypertension, cardiac arrhyth-mias, and hypothermia.

o     Hypotension and bradycardia are the most common cardiovascular complications.

o     Mild hypertension, tachycardia, first and second degree AV block, QTc prolongation, atrial fibrillation, and PVCs have also been reported.

·      Pupils are often dilated with sluggish or no reaction to light. Less commonly, pupils may be normal or miotic.

·      Symptoms can occur very suddenly in intrathecal injection overdose of baclofen, which may in fact present as coma. Other effects include bradycardia, hypothermia, itching, dysphoria, drowsiness, light-headedness, dizziness, somno-lence, respiratory depression, seizures, and hypotonia.

·      Baclofen has been associated with encephalopathy. EEG changes in baclofen-induced encephalopathy include periodic sharp waves, bursts of triphasic waves, trains of delta activity, intermittent rhythmical delta waves, burst suppression pattern without reactivity to stimulation, and diffuse background slowing.

·      Long-term administration of therapeutic doses of baclofen may cause fatigue, vertigo, nausea, confusion, depression, headache, and muscle weakness. Movement disorders and memory impairment have been described at therapeutic doses. Dystonia, chorea, akinetic mutism, dyskinesia, and flapping tremor have also been reported at therapeutic doses. Depression, confusion, mania, psychosis, amnesia, catatonia and mood disorders can also occur. Abrupt with-drawal results in convulsions, hallucinations, insomnia, confusion, and agitation. Withdrawal after chronic intrathecal infusion may be more severe including severe rebound spasticity, hyperthermia, hypotension, tachycardia, conduction disturbances (including atrial fibrillation), rhabdomyolysis, disseminated intravascular coagulation, hepatic injury, neuropsychiatric changes (i.e. mental status depression) and in some cases multiorgan failure and death.

Usual Fatal Dose

·              Blood baclofen levels of over 1.5 to 2 mcg/ml are indica- tive of toxicity.

·              Ingestion of 300 mg has caused serious intoxication in healthy adults; elderly patients may develop CNS and respiratory depression after 50 mg.

Treatment

·              Admission to an intensive care facility, with gastric lavage and activated charcoal, has been recommended for adults kg of baclofen.

·              Treatment of overdose involves oxygen administration, assisted ventilation, gastric lavage (if patient is conscious and seen within 2 to 3 hours of ingestion), activated charcoal, IV diazepam for convulsions and trendelen- berg position, IV fluids and pressor amines (dopamine or noradrenaline) for hypotension.

·              Atropine has been reported to be useful in treating brady- cardia and hypotension associated with baclofen overdose.

·              Institute continuous cardiac monitoring and assess adequacy of respirations using pulse oximetry and/or arterial blood gases.

·              Physostigmine is said to be effective in reversing respiratory depression, arreflexia, and coma. The usual dose is 1 to 2 mg by slow IV infusion, repeated cautiously if required, all the while watching out for adverse effects. The use of physostigmine is contraindicated in the presence of cardiac depression. Since the vast majority of patients respond well to supportive care, physostigmine is not recommended except for severe toxicity not responsive to supportive measures.

·              Forced diuresis may be helpful in enhancing the elimination of baclofen. The method advocated is NaCl 0.45% in 5% dextrose-in-water, with furosemide 1 mg/kg (maximum 40 mg), to obtain a urine flow of 3 to 6 ml/kg/hour.

·              Haemodialysis has shortened the duration of toxic effects of baclofen in several patients with severely impaired renal function.

·              Withdrawal symptoms respond to reinstitution of baclofen with subsequent gradual tapering of the dose if indicated. Treatment of intrathecal baclofen withdrawal should include the restoration of intrathecal baclofen (ITB) (i.e. refill pump, change battery, etc.); after ITB dosing clinical improvement should be noted within 30 minutes with maximal benefit in 4 to 6 hours. If intrathecal restoration is not immediately possible, begin oral baclofen and/or oral or intravenous benzodiazepines may prevent potential fatal sequelae. Oral baclofen is not anticipated to relieve all the symptoms related to intrathecal baclofen withdrawal.