Continuing Education Activity

Baclofen is a medication primarily used as a muscle relaxant for spasticity. Baclofen overdose or withdrawal can be life-threatening. It is utilized as an adjunct in treating painful muscle spasticity, clonus, and rigidity caused by spinal cord-related diseases such as multiple sclerosis, cerebral palsy, or spinal cord injury. This activity reviews the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management in the clinical setting related to the essential points needed by members of an interprofessional team managing the care of patients with toxicity from baclofen.

Objectives:

• Evaluate the pathophysiology of baclofen toxicity.

• Identify the common physical exam findings in patients presenting with toxicity from baclofen.

• Identify the epidemiology of baclofen toxicity.

Introduction

Baclofen is FDA-approved and primarily used as an antispasmodic agent and muscle relaxant. It is utilized as an adjunct in treating painful muscle spasticity, clonus, and rigidity caused by spinal cord-related diseases such as multiple sclerosis, cerebral palsy, or spinal cord injury. It is often administered as an oral medication, but in severe or chronic cases, it can also be delivered centrally using an implantable intrathecal pump. Chronic use of baclofen can result in withdrawal when abruptly discontinued. Baclofen overdose or withdrawal can be life-threatening. This review summarizes the clinical toxicity of baclofen, baclofen withdrawal, and acute management principles.

Etiology

Baclofen is a synthetic derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Therapeutic effects occur at a 0.1 to 0.4 mg/L plasma concentration.[1] The recommended starting oral dose for adults is 5 mg 3 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 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 4 deaths.[9]

Pathophysiology

Baclofen is an agonist of the G-protein-mediated GABA B receptor. GABA B receptors are 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, gamma-hydroxybutyrate (GHB), 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, produces similar signs.[13]

Toxicokinetics

Baclofen taken orally is rapidly absorbed, and 80% is eliminated renally. Unknown cytochrome enzymes hepatically metabolize the remainder. Peak serum concentration occurs 2 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 and 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 and 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 to assess for cardiac abnormalities and a computed tomography of the head to evaluate alternative etiologies of altered mental status. An electroencephalogram 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 initially treat 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]

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, and 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 improves. In most cases, patients 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]

Deterrence and Patient Education

For patients who are prescribed baclofen by mouth or via an intrathecal pump, the following information should be conveyed:

• Please take your medication as prescribed by your clinician.
• Do not abruptly stop taking baclofen if you have been on it for a prolonged period, as it can result in life-threatening withdrawal. 
• If you have chronic kidney disease, you are at an increased risk of baclofen toxicity. Please talk with your physician about any questions regarding your prescription. 
• Avoid the use of alcohol and other sedating drugs, such as opioids or benzodiazepines, unless prescribed by your physician.
• Baclofen toxicity can result in confusion, trouble breathing, seizures, and paralysis.
• Please call your physician or 911 if you or a family member is concerned about baclofen overdose or toxicity.
• If you have any thoughts of harming yourself, please contact your local suicide hotline.

Pearls and Other Issues

Key facts to keep in mind about baclofen toxicity are as follows:

• Baclofen is a GABA B agonist that can be life-threatening in overdose or withdrawal. 
• It can be taken orally or via an intrathecal pump.
• Patients with acute or chronic kidney disease are at greater risk for baclofen toxicity.
• Clinical signs and symptoms of baclofen include confusion, delirium, CNS and respiratory depression, hypotonia, flaccid paralysis, and hemodynamic instability.
• In overdose, baclofen can mimic brain death.
• Most serious toxic effects are seen with doses greater than 200 mg.
• Clinicians should promptly contact the managing physician for patients with intrathecal pumps if a pump malfunction is suspected. 
• Treatment is mainly supportive care.
• Baclofen can be eliminated by dialysis.

Enhancing Healthcare Team Outcomes

If baclofen toxicity is suspected, the patient needs medical assessment immediately. This requires an integrated approach with multiple healthcare professionals. This team often involves emergency management services, nurses, emergency medicine physicians, toxicologists, and intensivists. It may also involve a nephrologist or physician specializing in intrathecal pumps in certain circumstances. Once the patient has reached the emergency department, the nurse and the physician are responsible for the following:

• Obtaining vital signs
• Assessing cardiac conduction delays by obtaining an EKG and placing the patient on a cardiac monitor
• Assessing airway, breathing, and circulation and watching for respiratory depression or profound CNS depression
• Provide endotracheal intubation and ventilation if needed
• Obtain laboratory studies and imaging studies
• Provide cardiovascular support with intravenous fluids or vasopressors as needed 
• Give benzodiazepines if the patient is seizing
• Call a poison control center and/or a medical toxicologist for further recommendations
• Consult a nephrologist for possible dialysis if deemed necessary by the toxicology service 
• Consider an electroencephalogram on intubated or seizing patients 
• If the patient gets baclofen administered via an intrathecal pump, a physician who specializes in intrathecal pumps needs to be consulted
• Consult intensivist for admission and monitor in an intensive care setting

After stabilization in the emergency department, the patient most likely requires an intensive care unit. The involvement of interprofessional healthcare teams early on in the patient’s presentation is vital to provide the best overall outcome. Management is generally supportive. Even in patients with profound CNS depression mimicking brain death, patients may begin to have neurologic improvement after 24 to 48 hours.[12] The patient should be observed for baclofen withdrawal if this is a chronic medication. Once the patient is stabilized and returns to their baseline mental status, the reason for the overdose should be obtained; if there is a concern for an intentional overdose, psychiatry should be involved for further management.