Baclofen Toxicity

Etiology

Baclofen is a synthetic derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Therapeutic effects occur at a plasma concentration of 0.1 to 0.4 mg/L.[1] The recommended starting oral dose for adults is 5 mg three times a day (usual maximum dose 80 mg per day).[2] 

Serious toxicity can occur with doses greater than 200 mg.[3] Impaired kidney function increases the risk for baclofen toxicity since it undergoes renal elimination. While oral overdoses can be severe, intrathecal pump errors have a greater risk of worse clinical outcomes.[4]

Epidemiology

The incidence of adverse effects with therapeutic baclofen dosing varies between 10 to 65%.[5] The most common side effects are drowsiness and dizziness. Complications with intrathecal baclofen pumps are high, with approximately 21% of pump recipients experiencing some type of adverse drug event.[6] In a group of intentional overdoses of oral baclofen, the median age was 35 years old, and 56% were women.[3] 

With increasing off-label use of baclofen, such as alcohol use disorder, intractable hiccups, gastroesophageal reflux disease, and anxiety, there is an increase in the cases of intentional and accidental baclofen toxicity. A French retrospective study looking at intentional baclofen overdoses saw an increase from 8 cases in 2001 to 91 cases in 2015.[7] Data in the United States show similar trends.[8] In 2020 there were 4,786 baclofen exposures reported to US poison centers. Of these, there were 980 serious outcomes and four deaths.[9]

Pathophysiology

Baclofen is an agonist of the G-protein-mediated GABA B receptor. GABA B receptors are located in the brain and spinal cord presynaptically and postsynaptically. At therapeutic levels, baclofen works in the spinal cord. It binds presynaptically, decreasing calcium influx which impairs the release of neurotransmitters.[10] At the postsynaptic neuron, baclofen causes potassium efflux and cell hyperpolarization, which produces an inhibitory effect.[11] 

These effects result in reducing spasticity at the level of the spine. In overdose, baclofen loses specificity for receptors in the spinal cord and exerts greater effects on receptors in the central nervous system (CNS). This can result in CNS depression, respiratory depression, flaccid paralysis, autonomic abnormalities such as hypotension and hypertension, bradycardia and tachycardia, and seizures. Central nervous system depression can be so severe that it can mimic brain death.[12] 

Of note, GHB (gamma-hydroxybutyrate), an illicit drug classically used in nightclubs as well as for drug-facilitated sexual assault, has a similar structure to both GABA and baclofen and, in overdose, produce similar signs.[13]

Toxicokinetics

Baclofen taken orally is rapidly absorbed, and 80% is eliminated renally. The remainder is hepatically metabolized by unknown cytochrome enzymes. Peak serum concentration occurs two hours post-ingestion and has a half-life of approximately 3.5 hours (with a range of 2.5 to 6.8 hours) in healthy subjects. With baclofen overdose, the half-life can be markedly prolonged. One case report documented a 36-hour half-life following a baclofen overdose of 450 mg.[14] 

Baclofen is moderately lipophilic, which can result in the redistribution of baclofen out of tissues, causing a delayed second rise in serum levels as well as prolonged clearance. With plasma protein binding of 30% and a small volume of distribution of 0.7L/kg, hemodialysis can effectively remove baclofen.

History and Physical

Clinicians should initially assess the patient’s airway, breathing, and circulation and provide as-needed supportive care to stabilize the patient. Once the patient has been stabilized, a careful history should be obtained. This includes a history of symptoms, timing of symptom onset, the dose of baclofen, timing of the last dose, how long the patient has been taking it, recent adjustments of dosing, and urine output. If the patient has an intrathecal baclofen pump, identifying the date of pump implantation, last pump battery change, and most recent drug refill should also be obtained.[15] 

Patients with intrathecal baclofen pumps should have their pump insertion site examined for signs of infection or fluid pockets and any pump alarms evaluated. A neurologic physical examination should be performed, including assessing the patient’s mental status, pupillary response, reflexes, muscle tone, and clonus. Physical exam findings suggestive of baclofen toxicity are hypotonia and flaccid paralysis. Hyperreflexia and spasticity are more common with baclofen withdrawal.[4] 

Signs and symptoms of baclofen toxicity can be mixed. Baclofen toxicity can present with CNS depression, ranging from lethargy, somnolence, and confusion to delirium coma. Paradoxically, myoclonus and convulsions may also be seen due to disinhibition. Complete loss of brainstem reflexes may be seen mimicking brain death.[12] 

Common vital sign abnormalities include hypothermia, hypotension, and bradycardia; however, hypertension and tachycardia may also present.[4] Cardiac conduction abnormalities include first-degree heart block, prolonged QTc interval, premature atrial contractions, and supraventricular tachycardia.[16][17] 

Severe baclofen withdrawal shares many similarities to ethanol or sedative-hypnotic withdrawal, including delirium, tachycardia, hypertension, hyperreflexia, and seizures.[18] 

Evaluation

After a careful history and physical exam are completed, laboratory studies should be obtained. If the patient has altered mental status, bedside blood glucose should be obtained. Additional laboratory tests include a complete blood count a basic metabolic panel to assess for electrolyte abnormalities and kidney function. Additionally, a hepatic panel, creatine kinase, and urine analysis may be useful. If intentional ingestion is suspected, a salicylate and acetaminophen concentration should also be obtained. A baclofen level is not typically available in time to be clinically useful. However, a serum baclofen level may be sent to a specialty laboratory if confirmation is required.

Additional diagnostic tests include an electrocardiogram (ECG) to assess for cardiac abnormalities and a computed tomography of the head to evaluate alternative etiologies of altered mental status. An electroencephalogram (EEG) may be helpful in a comatose patient with concerns for non-convulsive status epilepticus. If the patient has an intrathecal baclofen pump, the managing physician should be contacted, and the pump should be interrogated. Plain radiographs of the thoracic and lumbar spine can be obtained to confirm the location and patency of the pump and pump tubing.[15]

Treatment / Management

Treatment for baclofen toxicity is mostly supportive. Stabilization of the airway, breathing, and circulation should be the priority in management. Due to the likely onset of respiratory depression and profound CNS depression, endotracheal intubation and ventilation may be necessary. Activated charcoal can be given early after the ingestion if the patient can safely tolerate it. Intravenous fluids would be the initial treatment for hypotension, with vasopressors reserved for refractory hypotension. Atropine can be used for bradycardia associated with hypotension or mental status change. Seizures should be treated with benzodiazepines.

Symptomatic baclofen ingestions should be admitted. In the case of an overdose, baclofen should be discontinued. However, to prevent withdrawal, baclofen should be resumed at therapeutic doses once the signs and symptoms of toxicity have improved. Patients with hemodynamic instability or significant CNS depression should be admitted to the intensive care unit.

If the patient has an intrathecal pump, they should ideally be managed at a medical facility with physicians experienced in managing intrathecal pumps. If there are concerns for pump malfunction resulting in overdose, the pump should be stopped, the reservoir replaced with saline, and in severe cases, CSF removal via lumbar puncture could be considered.[19] The pump should be restarted within 48 hours of discontinuing to prevent baclofen withdrawal.[20] 

Hemodialysis can be beneficial by shortening the elimination time, especially in patients with underlying kidney disease.[21][22] The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup recommends intermittent hemodialysis in baclofen toxicity with coma requiring mechanical ventilation and concomitant impaired kidney function.[23](B3)

Differential Diagnosis

Clinicians should consider baclofen toxicity in patients with access to baclofen if they present with altered mental status, abnormal vital signs, or an abnormal neuromuscular exam. Baclofen toxicity can be difficult to identify as it can mimic other medical conditions such as other sedative-hypnotic drugs, opioids, or other central nervous system depressants. Other medical etiologies that could be considered include sepsis, stroke, intracranial hemorrhage, hypoglycemia, electrolyte imbalances.

Prognosis

Patients typically have good outcomes if they are stabilized early in their toxicity. As the serum concentration of baclofen decreases, the patient’s mental status will improve. In most cases, patients will exhibit improved mental status within 24 to 48 hours but might be longer in more serious overdoses.[24][25][26] Massive baclofen overdoses, up to 1 to 2 g, may be fatal.[27]

Complications

Complications from baclofen toxicity are often secondary to severe CNS and respiratory depression. Anoxic brain injury, aspiration pneumonia, pressure ulcers, rhabdomyolysis, and hypothermia may be seen in patients with prolonged periods without medical intervention. Rhabdomyolysis may also occur in patients with severe spasticity associated with baclofen withdrawal.[28]