Baclofen

Mechanism of Action

Baclofen (β-[4-chlorophenyl]-γ-aminobutyric acid) is an agonist at the β subunit of gamma-aminobutyric acid on mono- and polysynaptic neurons at the spinal cord level and brain (GABA-B receptor agonist).[4][14] Baclofen is thought to reduce the release of excitatory neurotransmitters in the presynaptic neurons and stimulate inhibitory neuronal signals in the postsynaptic neurons, resulting in spasticity relief.[15] Baclofen also has an affinity for voltage-gated calcium channels. However, clinical efficacy in this regard is still unclear.

Pharmacokinetics

Absorption: 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. Absorption is dose-dependent and increases with higher doses.

Distribution: Baclofen has a volume of distribution of 0.7 L/kg and, due to high water solubility, does not readily cross the blood-brain barrier. Consequently, CSF drug concentrations following oral administration are significantly lower than plasma concentrations. The plasma protein binding of baclofen is 30%.[16]

Metabolism: The S-enantiomer of baclofen is metabolized in the liver and gut to form the metabolite S-M1, which appears at higher plasma and urine levels compared to previous reports. In contrast, the R-enantiomer does not appear to undergo significant metabolic transformation.[17] Research suggests that the R-enantiomer is the more effective component for reducing alcohol intake and cravings.[18]

Elimination: Due to a short half-life of 2 to 6 hours, baclofen should be administered frequently to achieve optimal effect. Seventy percent of baclofen is eliminated in an unchanged form by renal excretion, and the remaining amount is eliminated via feces. Baclofen is a useful medication for patients with impaired hepatic function or a high potential for cytochrome P450-mediated drug-drug interactions. Recent bolus and continuous infusion study results indicate significant inter-individual variability in baclofen’s absorption and elimination processes. The pharmacokinetics of CSF clearance of intrathecal baclofen suggest that elimination occurs via bulk-flow removal.[19] After a lumbar bolus injection of intrathecal baclofen, the average CSF elimination half-life is approximately 1.5 hours. A lumbar-cisternal concentration gradient has been observed, indicating that CSF concentrations of baclofen are higher in the lumbar region than in the cisternal region.

Administration

Available Dosage Forms and Strengths

Baclofen is available in oral tablets and as a solution for oral, transdermal, and intrathecal administration.

Oral: Tablets are available in 5 mg, 10 mg, and 20 mg strengths and solutions in 5 mg/5 mL (473 mL) bottles. 

Intrathecal: Solutions are available in 0.5 mg/mL, 1 mg/mL, and 2 mg/mL (20 mL vials). The preservative-free intrathecal solution is available in formulations of 0.05 mg/mL (1 mL vial), 0.5 mg/mL (20 mL vial), 1 mg/mL (20 mL vial), and 2 mg/mL (in 5 mL and 20 mL vials). Prefilled syringes are available in 50 μg/mL (1 mL syringe) and 0.5 mg/mL, 1 mg/mL, and 2 mg/mL (20 mL syringes).

Adult Dosage

Oral: Initially 5 mg, 3 times daily. The dose is increased every 3 days until an optimal response is achieved; the daily dose should not exceed 80 mg. The typical daily dose is 40 to 80 mg.[20]

Intrathecal: The protocol for optimizing the daily dose differs based on the origin of the patient's spasticity.

The initial screening or "test" dose is typically 50 μg. The patient is then observed for 4 to 8 hours to assess efficacy. The screening dose that provides a positive response during the first 24 hours is doubled and administered via an implantable pump with an intrathecal catheter. The pump's reservoir is filled regularly by percutaneous injections. The pump is programmed to deliver precise, automated dosing via continuous or bolus dosing. The dose may then be increased or decreased minutely for all patients to achieve the optimal, patient-specific daily dose. The lowest dose producing an optimal response should be maintained.

• Spinal cord spasticity: The daily dose may be adjusted by 10% to 30% until a positive response is achieved. Spasticity originating from the spinal cord usually requires 300 to 800 μg of baclofen daily.
• Cerebral spasticity: The dose may be adjusted by 5% to 15% until a positive response is achieved. Patients with spasticity of cerebral origin typically experience adequate pain relief on daily doses that range from 90 to 703 μg.

Alternative therapy for spasticity should be administered simultaneously.[21] For example, oral baclofen is an adjunct to other treatments for patients with tegmental neuralgia. For these patients, the daily baclofen dose is 40 to 80 mg.[22]

The majority of 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.

Specific Patient Populations

Renal impairment: Baclofen should be administered cautiously and at reduced doses to patients with impaired renal function. The literature review suggests avoiding baclofen therapy for patients with an eGFR ≤30 mL/min/1.73 m². For patients with stage 3 chronic kidney disease (eGFR of 30 to 60 mL/min/1.73 m²), baclofen should be administered at very low doses over extended intervals, titrated to effect, to minimize the risk of neurotoxicity.[23] In patients receiving dialysis, baclofen use is associated with an increased risk of encephalopathy; it is advisable to avoid baclofen for these patients.[24]

Hepatic impairment: The manufacturer's labeling does not provide information for any dose adjustment, so baclofen should be administered with caution.

Pregnancy considerations: Baclofen has been shown to increase the incidence of omphalocele and incomplete sternebral ossification in fetuses of rats receiving the drug at significantly higher doses than the recommended maximum for humans. Baclofen is a pregnancy category C drug; it should only be administered to pregnant women if the benefits outweigh the potential risks to the fetus.

Breastfeeding considerations: Limited data indicates that baclofen does not cause any adverse effects in breastfed infants due to the low drug levels in breast milk. However, newborn infants should be monitored for signs of sedation.[25] Sedation is less likely when intrathecal doses are low, baclofen is applied topically, or if the nursing infant is older than 2 months.

Pediatric patients: Researchers have not established the safety and efficacy of baclofen in pediatric populations younger than 12 years old. In addition, the safety and effectiveness of intrathecal baclofen have not been established in pediatric patients younger than 4 years old. However, a retrospective study examined the safety and efficacy of intrathecal baclofen therapy in infants and children younger than 6 years old. The study findings included no new significant complications when using subfascial implantation techniques and indicated that intrathecal baclofen is as safe and effective in this younger age group as it is for older children. Proper titration is essential to avoid bradycardia in infants.[8] For intrathecal administration of baclofen, the standard initial dose for pediatric patients is typically 50 μg, consistent with adult dosing. However, titration may be started at a reduced dose of 25 μg, depending upon the patient's clinical status. Another study demonstrated that baclofen dosage can be guided by body weight (2 mg/kg per day) and suggested that the gradual dose escalation strategy is suitable for children aged 2 years or older with cerebral palsy.[26]

Older patients: One cohort study involving older adults with musculoskeletal pain indicates that baclofen is associated with higher odds of injury and delirium than tizanidine.[27] The dose of baclofen should be reduced for older patients with renal impairment.[28]

Adverse Effects

Potential adverse effects may involve several organ systems, such as the cardiovascular, gastrointestinal, genitourinary, respiratory, neuromuscular, cutaneous, and central nervous systems.[2][29]

Abrupt withdrawal of intrathecal baclofen after more than 2 months of therapy may result in a hypermetabolic state with hyperpyrexia, impaired mental status, muscle rigidity, and severe rebound spasticity. These patients may advance to rhabdomyolysis and multi-organ system failure. These symptoms improve after resuming baclofen at a similar dose. Withdrawal most commonly occurs due to a delivery system problem. The patient and caregiver must understand the importance of monitoring the pump to prevent withdrawal events.

The most common adverse reactions associated with baclofen administration include:[30]

• Transient sedation
• Confusion
• Muscle weakness
• Vertigo
• Nausea

Less common adverse effects include:

• Neuropsychiatric impairment
• Hypotension
• Peripheral edema
• Dyspnea
• Hypoventilation
• Pneumonia
• Seizure
• Insomnia
• Pain
• Speech alterations
• Depression
• Agitation
• Constipation
• Diarrhea
• Urinary frequency changes
• Incontinence
• Acute urinary retention
• Impotence
• Tremor
• Weakness
• Amblyopia
• Urticaria
• Pruritus

Abrupt discontinuation of oral baclofen therapy may cause seizures and hallucinations. Gradual dose reduction is recommended to prevent withdrawal symptoms.[21][31]

Patients with a history of stroke have demonstrated poor tolerability to baclofen, and its use has not significantly benefited this patient population.

Drug-Drug Interactions

• One study indicated that concomitant use of baclofen with opioids is associated with increased toxicity, particularly with longer treatment durations. Baclofen, along with other skeletal muscle relaxants, significantly increases this risk. Clinicians should exercise caution when prescribing these drugs together to optimize patient safety.[32]
• A case of severe dyskinesia was reported in a patient with a history of physiological tremors and neuropathic pain induced by the combination of GABAergic baclofen and anti-dopaminergic clozapine.[33]

Contraindications

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

Baclofen is not recommended for 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.

Box Warnings (Intrathecal Baclofen)

The FDA requires a box warning for intrathecal baclofen. This drug may cause a hypermetabolic state with hyperpyrexia, impaired mental status, muscle rigidity, and severe rebound spasticity, potentially advancing to rhabdomyolysis and multi-organ system failure.[34] To prevent abrupt discontinuation, it is essential to meticulously manage infusion system programming, refill scheduling, and pump alarms. Patients and caregivers should be instructed on the importance of adhering to refill appointments and recognizing early symptoms of baclofen withdrawal. Special caution is advised for patients with spinal cord injuries at the level of T6 or higher or a history of baclofen withdrawal symptoms. The technical manual on implantable infusion systems provides further guidance.

Warning and Precautions [2][3]

• Urinary retention: Caution is advised for patients with urinary retention.

• Autonomic dysreflexia: Abrupt baclofen withdrawal or the presence of nociceptive stimuli can cause an autonomic dysreflexic episode.

• Gastrointestinal disorders: Caution is advised for patients with peptic ulcer disease, decreased GI motility, or GI obstructive disorders.

• Neuropsychiatric adverse effects: Caution is advised for patients with confused mental states, psychosis, or schizophrenia; baclofen may cause worsening of these conditions. Additionally, patients treated with baclofen injections should be monitored because exacerbations of these conditions have been observed after oral baclofen administration.

• Renal impairment: Caution is advised for patients with renal impairment, as baclofen is primarily eliminated via the kidneys.

• Seizure disorder: Loss of seizure control has been reported in patients receiving baclofen; patients with a history of seizure disorder should be monitored periodically via electroencephalogram (EEG).

• Opioids: Co-administration of epidural morphine and baclofen injection is known to cause dyspnea and hypotension.

• Sedation: Because of the risk of sedation, patients should refrain from operating automobiles or other dangerous machinery and activities made hazardous by decreased alertness. Additionally, the central nervous system effects of baclofen may be additive to those of alcohol and other CNS depressants.

• Screening test: According to International Neuromodulation Society guidelines, patients should demonstrate a favorable response to a screening dose before receiving an implanted device for chronic intrathecal baclofen infusion.[35]

• Prolonged coma mimicking brain death: see the Toxicity section.[36]

Monitoring

Patients receiving baclofen and any other central nervous system depressants require close monitoring. Patients with epilepsy should be monitored with regular electroencephalography due to deterioration in seizure control when receiving baclofen.[37] If the dose is reduced or discontinued, patients must be monitored for signs and symptoms of baclofen withdrawal.[38] Intrathecal baclofen use requires careful attention to program the infusion pump and monitor its function, pump alarms, and refill schedules.[39] Close monitoring is advised during the initial phase of pump use and when adjusting the dosing rate or the formulation in the reservoir, as small errors can result in subtherapeutic or toxic levels. Patients must be monitored for signs or symptoms of overdose, which may occur suddenly, especially during the initial screening phase, dose-titration phase, and reintroduction of therapy after temporary cessation of treatment. The treatment response is assessed using validated scores such as the Modified Ashworth Scale and Penn Spasm scores.[40]

Toxicity

Signs and Symptoms of Overdose

Overdose primarily occurs during 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. Vomiting, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures have been reported in patients with oral intoxication.[41]

Management of Overdose

In the case of an overdose, the medical staff should empty the pump reservoir, and the patient should receive symptomatic management.[42] Clinicians may consider withdrawing 30 to 40 mL of CSF to reduce baclofen CSF concentration if lumbar puncture is not contraindicated. EEG should be ordered in any patient with a baclofen overdose.[41]

When the patient is alert, clinicians may consider vacating the stomach immediately by inducing emesis and then performing lavage. Emesis should not be induced in unconscious patients. Before beginning lavage, the airway is secured with an endotracheal tube. Respiratory stimulants should be avoided. Baclofen is effectively dialyzable due to its low molecular weight, small volume of distribution, and low plasma protein binding. Continuous venovenous hemofiltration (CVVHD) allows for extended toxin removal, improving the clearance of drugs with large volumes of distribution, such as baclofen, more effectively than intermittent hemodialysis.[16]

Recommendations

The EXTRIP (Extracorporeal Treatment in Poisoning) workgroup recommends against using extracorporeal treatments (ECTRs) for acute baclofen poisoning due to a lack of clear benefit. However, for baclofen toxicity in patients with impaired kidney function, particularly in cases with coma requiring mechanical ventilation, ECTR should be considered.[43] The American College of Medical Toxicology (ACMT) notes that baclofen overdose can induce coma that may resemble brain death, with coma lasting up to 7 days. ACMT emphasizes the importance of identifying an irreversible cause of brain injury and confirming the presence of drugs through comprehensive history, physical examination, and targeted testing. At least 5 drug half-lives should be observed to ensure adequate clearance before determining brain death in overdose patients. However, relying solely on a drug screen and clearance calculation based on these half-lives may not be sufficient to rule out intoxication in all cases. Additional tests and consultation should be considered for ambiguity cases.[36]

Enhancing Healthcare Team Outcomes

Healthcare providers who prescribe baclofen should provide the patient with information on the safe usage of this medication. Baclofen 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. Adult and pediatric neurologists should be consulted for appropriate diagnosis and management in complicated cases. The healthcare team's open communication and collaborative work are essential for effective baclofen therapy. The pharmacist should verify the appropriateness of the dose and mode of administration and perform medication reconciliation to rule out potential drug interactions. In many cases, nurses will administer the drug and should be aware of the signs of adverse effects or excessive dosing. One study evaluated traditional lectures versus micro-videos for teaching baclofen pump programming and refilling to physicians with limited experience. Both methods proved equally effective in improving skills and knowledge retention. Participants favored micro-videos for their convenience and accessibility despite instructor availability and platform navigation concerns.[44] Any concerning information should be brought to the attending physician's attention immediately. In an overdose, emergency medicine physicians should stabilize the patient and secure the airway. Nephrologists should be consulted for dialysis. An interprofessional team approach and communication among clinicians (MD, DO, NP, PA), pharmacists, and nurses are crucial to decreasing potential adverse effects, improving disease course and quality of life, and improving patient outcomes related to baclofen therapy.