Baclofen was originally designed in 1960 to treat epilepsy. However, the result was not satisfactory. Baclofen was then reintroduced in 1971 when it was found to treat muscle spasticity and has been widely used since. Baclofen is FDA-approved for the management of reversible spasticity, particularly for the relief of flexor spasms, clonus, and concomitant pain, common sequelae of spinal cord lesions and multiple sclerosis. However, for patients who experience intolerable adverse effects or who fail to respond to the oral therapy, intrathecal baclofen might be considered. Intrathecal baclofen administration is FDA-approved for the management of spasticity of cerebral origins, such as traumatic brain injury or severe spasticity of spinal cord origin that is unresponsive to treatment with maximum doses of oral baclofen, tizanidine, and/or dantrolene.
Baclofen is also used off-label for management of alcoholic liver disease, maintenance of alcohol abstinence by decreasing alcohol cravings, and alcohol-related anxiety, trigeminal neuralgia, gastroesophageal reflux disease, and hiccups. Baclofen is also considered as a short-term treatment for spasticity associated with cerebral palsy in children and adolescents. Baclofen is not recommended for use in patients with Parkinson disease and stroke due to a lack of reassuring data. Baclofen is not indicated for skeletal muscle spasms associated with rheumatologic disorders.
Baclofen (beta-[4-chlorophenyl]-GABA) is an agonist at the beta subunit of gamma-aminobutyric acid on mono and polysynaptic neurons at the spinal cord level and brain. It is thought that baclofen reduces the release of excitatory neurotransmitters in the pre-synaptic neurons and stimulates inhibitory neuronal signals in the post-synaptic neurons with resultant relief of spasticity. Baclofen is also found to have an affinity for voltage-gated calcium channels. However, its clinical efficacy in this regard is still unclear.
Baclofen has a bioavailability of 70% to 85% and is therefore rapidly absorbed through the gastrointestinal tract following oral administration. Peak plasma concentrations are generally observed 2 to 3 hours after ingestion. The absorption is dose-dependent and is increased by higher doses. Due to the short half-life of 2 to 6 hours, baclofen should be administrated frequently to achieve optimal effect. Seventy percent of baclofen is eliminated in an unchanged form by renal excretion and the remaining via feces. Thereby, baclofen is a useful agent in patients with impaired hepatic function or a high potential for cytochrome P450-mediated drug-drug interactions. Large inter-individual variability has been observed in baclofen’s absorption and elimination processes.
Baclofen is available for oral, transdermal, and intrathecal administration through pump infusion. Oral administration is initially 5 mg three times a day. The dose is increased every 3 days until an optimal response is achieved; however, the dose should not exceed 80 mg per day. The usual dosage is 40 to 80 mg daily.
Intrathecal administration of baclofen is initiated by screening. The patient receives a single dose, typically 50 mcg baclofen and is observed for 4 to 8 hours to assess its efficacy. The screening dose that gives a positive response for the initial 24 hours will then be doubled and administrated via an implantable pump with an intrathecal catheter. Daily dose adjustments will be made gradually on the order of 10% to 30% for spasticity of spinal cord origin and 5% to 15% for spasticity of cerebral origin until a positive response is achieved. The dose may be increased or decreased slightly to obtain an optimum daily dose. Spasticity of cerebral origin is usually adequately managed on 90 to 703 mcg daily. Spasticity related to the spinal cord usually requires 300 to 800 mcg of baclofen daily. However, the lowest dose that produces optimal response should be maintained. The reservoir in the pump is filled by percutaneous injections on a regular basis, and the pump is programmed to deliver a certain dose automatically, via simple continuous or bolus dosing.
The majority of the patients on chronic baclofen therapy require gradual dose increases over time due to a lack of response to the original maintenance dose. Up to 10% of patients become resistant to dose titrations and may need a drug holiday. Drug holidays should only be done in an inpatient setting with gradual withdrawal over 2 to 4 weeks. Alternative therapy for spasticity should be administrated simultaneously.
Safety and efficacy of baclofen in pediatric populations younger than 12 years old have not been established.
Potential adverse effects on several organ systems such as the cardiovascular, gastrointestinal, genitourinary, respiratory, neuromuscular, cutaneous, and central nervous systems have been reported.
The most common adverse effects are transient sedation, confusion, muscle weakness, vertigo, and nausea.
Less common adverse effects are neuropsychiatric impairment, hypotension, peripheral edema, dyspnea, hypoventilation, pneumonia, seizure, insomnia, pain, speech alteration, depression, agitation, constipation, diarrhea, urinary frequency, incontinence, acute urinary retention, impotence, tremor, weakness, amblyopia, urticaria, and pruritus.
The FDA requires a black box warning for baclofen. Abrupt withdrawal of intrathecal baclofen may occur in patients using the drug over 2 months and may result in a hypermetabolic state with hyperpyrexia, impaired mental status, muscle rigidity, and severe rebound spasticity which may advance to rhabdomyolysis and multi-organ system failure. The symptoms improve upon recommencing of baclofen by similar dose as before the interruption. Withdrawal most commonly occurs because of a delivery system problem. It is crucial that the patient and caregiver are informed of the importance of monitoring the pump to prevent the withdrawal events.
Abrupt discontinuation of oral baclofen therapy might cause seizure and hallucination. Gradual dose reduction is recommended to prevent withdrawal symptoms.
Baclofen is contraindicated in patients with hypersensitivity to baclofen or any component of its formulation.
Baclofen must be used with caution in patients with impaired renal function, and it might be necessary to reduce the dose.
There is limited data reporting that baclofen will not cause any adverse effects in breastfed infants due to low levels of the drug in breast milk. However, newborn infants should be monitored for signs of sedation. This is less of a concern during the administration of low intrathecal doses, topical application, or if the nursing infant is older than 2 months.
Baclofen has been shown to increase the incidence of omphalocele and incomplete sternebral ossification in fetuses of rats receiving baclofen in a significantly higher dose than recommended for humans. Baclofen is listed as pregnancy category C; it should only be administrated in pregnant women if the benefits clearly outweigh the potential risks to the fetus.
Administration of baclofen with any other central nervous system depressants should be closely monitored.
Patients with epilepsy should be monitored with regular electroencephalogram due to deterioration in seizure control when receiving baclofen.
Overdose primarily arises from drug screening before pump implantation or human error during refilling and programming of the pump. Baclofen overdose may cause altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. In the presence of overdose symptoms, the pump reservoir should be emptied, and the patient should be managed symptomatically.