Continuing Education Activity

Baclofen is used to treat muscle spasticity; it is FDA-approved for managing reversible spasticity, particularly for the relief of flexor spasms, clonus, and concomitant pain, common sequelae of spinal cord lesions, and multiple sclerosis. Baclofen also has several off-label uses. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring of the broad array of physiological possibilities when using baclofen in the clinical setting.

Objectives:

• Identify the approved and off-label indications for baclofen.
• Summarize the mechanism of action of baclofen.
• Review the potential adverse effects of baclofen.
• Explain interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with baclofen leading to optimal patient outcomes.

Indications

Baclofen was originally designed in 1960 to treat epilepsy. However, the result was not satisfactory. Baclofen was reintroduced in 1971 when it was found to treat muscle spasticity and has been widely used since.

FDA-approved Indications[1]

• Baclofen is FDA-approved for managing reversible spasticity, particularly to relieve flexor spasms, clonus, concomitant pain, common sequelae of spinal cord lesions, and multiple sclerosis.
• Intrathecal baclofen administration is FDA-approved for managing 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. However, intrathecal baclofen might be considered for patients who experience intolerable adverse effects or fail to respond to oral therapy.

Off-labeled Uses[2][3][4] 

• Baclofen is used off-label to manage alcoholic liver disease.
• Maintain alcohol abstinence by decreasing alcohol cravings and alcohol-related anxiety.
• Trigeminal neuralgia, gastroesophageal reflux disease, and hiccups.
• Baclofen is also considered for 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. In addition, baclofen is not indicated for skeletal muscle spasms associated with rheumatologic disorders.

Mechanism of Action

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.[3] The thinking is 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.[5] 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 70% to 85% bioavailability and is 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 increases with 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. Research has observed significant inter-individual variability in baclofen’s absorption and elimination processes.

Administration

Baclofen is available for oral, transdermal, and intrathecal administration through pump infusion.

• Baclofen intrathecal solution is available in 10 mg/20 mL , 20 mg/20 mL, and 40 mg/20 mL in 20mL vial.
• Baclofen preservative free intrathecal solution vials are available in 0.05 mg/mL (1 mL), 10 mg/5 mL (5 mL),  10 mg/20 mL (20 mL), 40 mg/20 mL (20 mL),  and 20,000 mcg/20 mL (20 mL).
• Prefilled Syringe of intrathecal solution is available in 50 mcg/mL (1 mL), 10,000 mcg/20 mL (20 mL), 20,000 mcg/20 mL (20 mL),  and 40,000 mcg/20 mL (20 mL).
• Oral solutions are available in 5 mg/5 mL (473 mL) bottles, and oral tablets are available in 5 mg, 10 mg, and 20 mg strength.

Oral administration is initially 5 mg three times a day. The dose is increased every three days until achieving an optimal response; however, the dose should not exceed 80 mg per day. The usual dosage is 40 to 80 mg daily.[6]

Intrathecal administration of baclofen initiates via 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 provides a positive response for the first 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 attaining a positive response. 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 pump's reservoir is filled by percutaneous injections regularly, and the pump is programmed to deliver a precise 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 in an inpatient setting with gradual withdrawal over 2 to 4 weeks. Alternative therapy for spasticity should be administrated simultaneously.[7]

Researchers have not established the safety and efficacy of baclofen in pediatric populations younger than 12 years old.

Specific Population

Renal Impairment: Baclofen use requires caution in patients with impaired renal function, and it might be necessary to reduce the dose.[8]

Hepatic Impairment: The manufacturer’s labeling has not provided information for any doe adjustment.

Pregnancy: 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 pregnancy category C; it should only be administrated in pregnant women if the benefits clearly outweigh the potential risks to the fetus.

Breastfeeding Patients: Limited data reports that baclofen will not cause any adverse effects in breastfed infants due to low drug levels in breast milk. However, newborn infants should be monitored for signs of sedation.[9] Sedation is less of a concern during the administration of low intrathecal doses, topical application, or if the nursing infant is older than two months.

Adverse Effects

Potential adverse effects on several organ systems such as the cardiovascular, gastrointestinal, genitourinary, respiratory, neuromuscular, cutaneous, and central nervous systems have been reported.[1][10]

• The FDA requires a black box warning for baclofen. Abrupt withdrawal of intrathecal baclofen may occur in patients using the drug over two months. It may result in a hypermetabolic state with hyperpyrexia, impaired mental status, muscle rigidity, and severe rebound spasticity, potentially advancing to rhabdomyolysis and multi-organ system failure. The symptoms improve upon recommencing of baclofen by a similar dose as before the interruption. Withdrawal most commonly occurs because of a delivery system problem. The patient and caregiver must understand the importance of monitoring the pump to prevent withdrawal events.
• The most common adverse effects are transient sedation, confusion, muscle weakness, vertigo, and nausea.[11]
• 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.
• Abrupt discontinuation of oral baclofen therapy might cause seizures and hallucinations. Gradual dose reduction is recommended to prevent withdrawal symptoms.[7][12]
• Patients with stroke have shown poor tolerability to baclofen, and its use has not greatly benefited this patient population.

Contraindications

Baclofen is contraindicated in patients with hypersensitivity to baclofen or any component of its formulation. The baclofen injection solution is not recommended for intravenous, subcutaneous, intramuscular, or epidural administration.

Pregnancy

Warning/Precautions[1][2]

• Use with caution when used in patients with urinary retention or respiratory disease.
• History of autonomic dysreflexia: Abrupt baclofen withdrawal or the presence of nociceptive stimuli can cause an autonomic dysreflexic episode.
• Gastrointestinal disorders: Use caution in patients with peptic ulcer disease, decreased GI motility, and/or GI obstructive disorders.
• Use caution in patients with confusional states, psychotic issues, or schizophrenia; it may cause exacerbation of the condition. In addition, patients treated with baclofen injection should be kept under surveillance because exacerbations of these conditions have been observed with oral administration.
• Use caution in patients with renal impairment, as baclofen is primarily eliminated via the kidneys.
• Seizure disorder: Loss of seizure control is reported in patients treated with baclofen; monitor patients with a history of seizure disorder by checking electroencephalogram periodically.
• Co-administration of epidural morphine and baclofen injection is reported to cause dyspnea and hypotension.
• Because of the risk of sedation, patients should refrain from operating automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. In addition, the central nervous system effects of baclofen may be additive to those of alcohol and other CNS depressants.

Monitoring

Administration of baclofen with any other central nervous system depressants requires close monitoring. Patients with epilepsy should be monitored with a regular electroencephalogram due to deterioration in seizure control when receiving baclofen.[13]

Monitor for signs and symptoms of baclofen withdrawal if the dose is reduced or discontinued.[14]

Intrathecal baclofen use requires careful attention to program the infusion pump and monitor its function, pump alarms, and refill schedules.[15]

Closely monitor when the initial phase of pump use and when adjusting the dosing rate and/or the concentration in the reservoir as small errors can result in subtherapeutic level or toxic levels.

Monitor for signs or symptoms of overdose which may occur suddenly, especially in the initial screening phase, dose-titration phase, and reintroduction of therapy after temporary cessation of treatment.

Toxicity

Overdose primarily arises from drug screening before pump implantation or human error during pump refilling and programming. Baclofen overdose may cause altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. In the presence of overdose symptoms, the medical staff should empty the pump reservoir, and the patient should receive symptomatic management.[16] In patients when the lumbar puncture is not contraindicated, consider withdrawing 30-40 mL of CSF to reduce baclofen CSF concentration.

Overdosed on baclofen tablets has reported vomiting, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures. When the patient is alert, consider vacating the stomach immediately by inducing emesis and then performing lavage. In the unconscious patients, do not induce emesis. Before beginning lavage, secure the airway with an endotracheal tube. Avoid the use of respiratory stimulants and adequately maintain respiratory exchange.

Enhancing Healthcare Team Outcomes

Healthcare workers, including MDs, DOs, PAs, and NPs who prescribe baclofen, should educate the patient on the safe use of this drug. It works well as a muscle relaxant, but its use to manage low back pain is limited. The drug should not be combined with narcotics, sedatives, or hypnotics. Also, baclofen should not be prescribed for a prolonged duration.

The healthcare team's open communication and collaborative work are essential for baclofen use. The prescriber will make the clinical decision to use baclofen, but the pharmacist should verify the appropriateness of the dose, mode of administration and perform medication reconciliation to rule out drug interactions. In many cases, nurses will administer the drug, particularly intrathecally, and should be aware of the signs of adverse effects or excessive dosing. When the pharmacist or nurse encounters a reason for concern, they must be empowered to communicate it to the treating clinicians immediately. This interprofessional team approach will optimize baclofen therapy while minimizing adverse events. [Level 5]