Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) 4-amino-3-(4-chlorophenyl) butanoic acid
2) CAS 1134-47-0

Available Forms Sources

A)

1) Baclofen is available as 10 mg and 20 mg tablets (Prod Info baclofen oral tablets, 2014). It is also available as 0.05 mg/mL, 1 mg/mL, and 2 mg/mL intrathecal solution and 0.5 mg/mL and 2 mg/mL intrathecal refill kit for use as single bolus intrathecal injections or in implantable pumps for intrathecal infusion (Prod Info GABLOFEN(R) intrathecal injection, 2015).

B)

1) Baclofen is used orally for the treatment of spasticity resulting from multiple sclerosis and spinal cord injuries/diseases (Prod Info baclofen oral tablets, 2014). It is used intrathecally for severe spasticity of spinal or cerebral origin in adults and pediatric patients age 4 years and older, particularly in patients unresponsive to oral baclofen, or in patients with intolerable CNS side effects with effective doses (Prod Info GABLOFEN(R) intrathecal injection, 2015).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Centrally acting muscle relaxant used in the treatment of muscle spasms secondary to conditions such as multiple sclerosis and spinal cord injuries. Occasionally used as a drug of abuse.
B) PHARMACOLOGY: Derivative of gamma aminobutyric acid (GABA); acts at the spinal end of upper motor neurons, inhibits monosynaptic and polysynaptic reflexes at the spinal level.
C) TOXICOLOGY: Presynaptic GABA-B agonist, in overdose causes CNS depression similar to other GABA agonists.
D) EPIDEMIOLOGY: Deliberate overdose is unusual. Inadvertent intrathecal overdose occurs rarely secondary to pump malfunctions or dispensing errors. Episodically used as a drug of abuse.
E) WITH THERAPEUTIC USE

1) COMMON: Somnolence, dizziness, asthenia, poor muscle tone, headache, nausea, vomiting, and constipation are common adverse effects.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Lethargy, somnolence, confusion, agitation, hallucinations, delirium, nausea, and vomiting are fairly common. Mild elevations in liver enzymes, urinary retention, and incontinence are less common effects.
2) SEVERE TOXICITY: Bradycardia, hypotension, coma, respiratory failure, seizures, mydriasis, flaccidity, and mild hypothermia may develop. Rare effects include status epilepticus, rhabdomyolysis, and first-degree AV block.
3) SYMPTOMS MIMICKING BRAIN DEATH: Coma, flaccidity and loss of reflexes can last for several days after severe overdose and should not be mistaken for brain death.
4) WITHDRAWAL: Abrupt discontinuation of baclofen (usually intrathecal), for any reason, can result in withdrawal symptoms, which have included hyperthermia, tachycardia, altered mental status (ie, hallucinations, delirium, agitation), exaggerated rebound spasticity, muscle rigidity, seizures, hypertension, and hypotension, and in rare cases manifestations may progress to rhabdomyolysis, multiple organ-system failure and death.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Mild hypothermia may develop.

0.2.20)

A) Normal delivery of healthy children have been reported following intrathecal baclofen infusion during pregnancy.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most baclofen exposures require only supportive care. Treat agitation or seizures with benzodiazepines.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treat seizures with benzodiazepines. Treat hypotension with fluids and pressors if needed. Manage airway in patients with CNS depression or recurrent seizures. Coma, flaccidity and absent reflexes can persist for more than 5 days after severe overdose and should not be mistaken for brain death.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal is not recommended because of the risk of CNS depression and aspiration.
2) HOSPITAL: Administer activated charcoal, in patients who are alert or in whom the airway is protected following a recent significant exposure. Fatalities are rare, most patients do well with supportive care; gastric lavage is generally not warranted.

D) AIRWAY MANAGEMENT

1) Monitor for CNS and/or respiratory depression and need for endotracheal intubation.

E) ANTIDOTE

1) None

F) SEIZURES

1) Administer benzodiazepines, if unresponsive administer barbiturates or propofol.

G) HYPOTENSION

1) Administer atropine for bradycardia associated with hypotension. If unresponsive to atropine or no associated bradycardia administer intravenous 0.9% saline, dopamine or norepinephrine if unresponsive to fluids.

H) BRADYCARDIA

1) Evaluate for hypoxia, administer oxygen and manage airway as necessary. If associated with hypotension, administer atropine.

I) WITHDRAWAL

1) Withdrawal symptoms respond to reinstituting baclofen with subsequent gradual tapering of the dose if indicated. Benzodiazepines appear to be of some benefit, but experience is limited.

J) ENHANCED ELIMINATION

1) Hemodialysis may be useful after severe overdose, particularly in patients with impaired renal function. Rarely indicated as most patients do well with supportive care.

K) PATIENT DISPOSITION

1) HOME CRITERIA: A patient with an inadvertent ingestion that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
3) ADMISSION CRITERIA: Admit patients with seizures, mental status depression, respiratory depression, delirium, or hypotension to an intensive care unit.
4) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

L) PITFALLS

1) Patients with intrathecal overdose can develop severe toxicity within minutes.
2) Withdrawal may develop as patients recover after overdose, particularly in patients on chronic intrathecal therapy.
3) Coma, flaccidity and absent reflexes can persist for more than 5 days after severe overdose and should not be mistaken for brain death.

M) PHARMACOKINETICS

1) Rapidly absorbed, peak levels in 2 hours; volume of distribution about 1 L/kg, 85% renal elimination, 30% protein binding, half life 2 to 4 hours.

N) TOXICOKINETICS

1) Volume of distribution 2.4 L/kg in one overdose patient, half life may be prolonged (4.5 hours to 34.5 hours in limited case reports). Absorption may be prolonged after large overdose; rising levels 5 days after ingestion were reported in one patient.

O) PREDISPOSING CONDITIONS

1) Patients with renal insufficiency may develop toxicity at therapeutic doses.

P) DIFFERENTIAL DIAGNOSIS

1) Overdose with other muscle relaxants or sedatives (benzodiazepines, barbiturates, etc).
2) Baclofen withdrawal can present similarly to ethanol, benzodiazepine or barbiturate withdrawal, serotonin syndrome, neuroleptic malignant syndrome, and sepsis.

Range Of Toxicity

A)

B)

C)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) COMMON: Somnolence, dizziness, asthenia, poor muscle tone, headache, nausea, vomiting, and constipation are common adverse effects.

F)

1) MILD TO MODERATE TOXICITY: Lethargy, somnolence, confusion, agitation, hallucinations, delirium, nausea, and vomiting are fairly common. Mild elevations in liver enzymes, urinary retention, and incontinence are less common effects.
2) SEVERE TOXICITY: Bradycardia, hypotension, coma, respiratory failure, seizures, mydriasis, flaccidity, and mild hypothermia may develop. Rare effects include status epilepticus, rhabdomyolysis, and first-degree AV block.
3) SYMPTOMS MIMICKING BRAIN DEATH: Coma, flaccidity and loss of reflexes can last for several days after severe overdose and should not be mistaken for brain death.
4) WITHDRAWAL: Abrupt discontinuation of baclofen (usually intrathecal), for any reason, can result in withdrawal symptoms, which have included hyperthermia, tachycardia, altered mental status (ie, hallucinations, delirium, agitation), exaggerated rebound spasticity, muscle rigidity, seizures, hypertension, and hypotension, and in rare cases manifestations may progress to rhabdomyolysis, multiple organ-system failure and death.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Mild hypothermia may develop.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA

a) Mild hypothermia is common in patients with significant CNS depression (Pape et al, 2014; Perry et al, 1998; Lee et al, 1992; Cohen et al, 1986; Ferner, 1981; Lipscomb & Meredith, 1980).
b) INCIDENCE: In a series of 8 adolescents who developed baclofen toxicity after recreational abuse, 6 developed hypothermia (Perry et al, 1998).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) OCULAR DISORDERS, SYMPTOMS

a) Blurred vision occurred in a 66-year-old man following an inadvertent 30 x 10(3) mcg intrathecal dose. Despite immediate treatment the patient developed persistent diplopia which was observed immediately after the overdose (Fakhoury et al, 1998).

2) PUPIL DISORDERS

a) Pupils are often dilated with sluggish or no reaction to light (Chapple et al, 2001; Cooper & Bergman, 2000; Cooke & Glasstone, 1994; Roberge et al, 1994; Delhaas & Brouwers, 1991; Blankenship & Moses, 1983; May, 1983; Ghose, 1980).
b) Less commonly, pupils are normal sized (Lee et al, 1992; Paulson, 1976) or miotic (Gerkin et al, 1986; Haubenstock et al, 1983; Lipscomb & Meredith, 1980), with decreased reactivity to light (Ostermann et al, 2000; Cooke & Glasstone, 1994).

3.4.4)

A) WITH THERAPEUTIC USE

1) TINNITUS

a) CASE REPORTS: Severe tinnitus was reported in 2 patients who were taking high-dose baclofen to treat alcohol dependence.

1) The first patient, a 60-year-old man with a 15-year history of alcohol dependence, reported continuous tinnitus with a baclofen dose of 180 mg/day. His Visual Analog Scale (VAS) score was 6 out of 10. Because of a continued decrease in his alcohol consumption and despite the tinnitus, the dose was increased to 250 mg/day for 3 months. His tinnitus persisted and his VAS was 7/10. After 3 months, the dose was decreased to 120 mg/day at month 9 of treatment with a decrease in the tinnitus level (VAS 3/10). Further reduction of the dose to 90 mg/day resulted in the complete resolution of symptoms (Auffret et al, 2014).
2) The second patient, a 45-year-old woman with a 6-year history of alcohol dependence, reported mild tinnitus following baclofen therapy at a dose of 210 mg/day (VAS 2/10). An increase in the dose to 240 mg/day at month 5 of therapy resulted in permanent tinnitus (VAS 8/10) and insomnia (less than 3 hours of sleep each day). A reduction of the dose to 170 mg/day resulted in a decrease in the tinnitus level (VAS 4/10); however, a return to the 240 mg/day dose resulted in severe tinnitus (VAS 9/10), a headache, and severe nausea. The tinnitus gradually resolved following a reduction of the baclofen dose to 60 mg/day (Auffret et al, 2014).

Cardiovascular

3.5.2)

A) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Sinus bradycardia is the most common dysrhythmia reported in overdose (Mahvash et al, 2011; Peng et al, 1998; Perry et al, 1998; Delhaas & Brouwers, 1991; Cohen et al, 1986; Gerkin et al, 1986; White, 1985; Haubenstock et al, 1983; Ferner, 1981).
b) INCIDENCE: In a series of 8 adolescents who developed baclofen toxicity after recreational abuse, 5 developed bradycardia (Perry et al, 1998).
c) CASE REPORT/ADOLESCENT: A 17-year-old boy, with spastic quadriplegia due to cerebral palsy, became semi-comatose, with global hypotonia and hyporeflexia, and developed hypotension (87/39 mmHg), bradycardia (54 bpm), and severe respiratory depression (6 to 8 breaths/min) following an intrathecal baclofen (ITB) pump change. The patient was initially given two doses of naloxone IV with no response. Suspecting baclofen toxicity, 1 mg physostigmine (approximately 0.02 mg/kg) and atropine 0.2 mg were administered. The patient showed an immediate response with regaining consciousness, increased muscle tone, and increased heart rate and blood pressure. However, approximately 40 minutes later, he again became unresponsive, hypotensive, and bradypneic, and a second physostigmine dose was administered with a transient response. After switching off the ITB pump and with continued observation in the ICU, the patient's condition improved, he was extubated about 8 hours later, and his ITB pump was restarted at a 15% lower dose (Stroud et al, 2014).
d) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Bradycardia (less than 50 beats/min) was reported in 5 (12%) of the 42 patients (Cao & Wax, 2015).

B) SINUS TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Sinus tachycardia is less commonly described, usually occurring during recovery from severe overdose (Lee et al, 1992; Haubenstock et al, 1983; Ghose, 1980).

C) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Dysrhythmias (with high doses) have been reported in isolated cases (Nugent et al, 1986).
b) CASE REPORT: A 21-year-old man developed first-degree AV block (PR interval 0.22 seconds) and QTc prolongation (0.46 seconds) after ingesting 240 mg of baclofen (Roberge et al, 1994). This progressed to a rapid irregular supraventricular tachycardia (rate 150 to 180). Subsequent cardiograms, following administration with verapamil, revealed atrial fibrillation. The patient spontaneously returned to normal sinus rhythm approximately 6.5 hours postingestion.
c) CASE REPORT: A 25-year-old woman developed sinus bradycardia, intermittent first degree heart block (PR interval up to 0.44 seconds), frequent blocked premature atrial contractions and junctional escape beats after ingesting 500 mg of baclofen (Nugent et al, 1986).
d) CASE REPORT: A 38-year-old woman developed bradycardia and frequent ventricular premature beats after ingesting 500 mg of baclofen (Lee et al, 1992).
e) CASE SERIES: Multifocal PVCs, that did not require therapy, developed in 3 adolescents out of a series of 8 patients who ingested baclofen recreationally (Perry et al, 1998).
f) CASE REPORT: A 36-year-old woman receiving 2.4 mg of baclofen a day by intrathecal pump for control of spasticity from multiple sclerosis, developed sinus bradycardia and hypotension responsive to atropine. The patient developed atrial fibrillation with second-degree AV block and a cardiac arrest, with successful resuscitation, following administration of physostigmine, thus suggesting that physostigmine may not be a safe and effective treatment for baclofen toxicity (Delhaas & Brouwers, 1991).

D) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension is common in severe overdose (Pape et al, 2014; Cooper & Bergman, 2000; Ostermann et al, 2000; Fakhoury et al, 1998; Peng et al, 1998; Aisen et al, 1994; Patterson et al, 1994; Delhaas & Brouwers, 1991; Gerkin et al, 1986; Haubenstock et al, 1983; Ferner, 1981; Paulson, 1976).
b) CASE REPORT/ADOLESCENT: A 17-year-old boy, with spastic quadriplegia due to cerebral palsy, became semi-comatose, with global hypotonia and hyporeflexia, and developed hypotension (87/39 mmHg), bradycardia (54 bpm), and severe respiratory depression (6 to 8 breaths/min) following an intrathecal baclofen (ITB) pump change. The patient was initially given two doses of naloxone IV with no response. Suspecting baclofen toxicity, 1 mg physostigmine (approximately 0.02 mg/kg) and atropine 0.2 mg were administered. The patient showed an immediate response with regaining consciousness, increased muscle tone, and increased heart rate and blood pressure. However, approximately 40 minutes later, he again became unresponsive, hypotensive, and bradypneic, and a second physostigmine dose was administered with a transient response. After switching off the ITB pump and with continued observation in the ICU, the patient's condition improved, he was extubated about 8 hours later, and his ITB pump was restarted at a 15% lower dose (Stroud et al, 2014).

E) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Mild hypertension has also been reported (Perry et al, 1998; Lee et al, 1992; Nugent et al, 1986; May, 1983).
b) INCIDENCE: In a series of 8 adolescents who developed baclofen toxicity after recreational abuse, 6 developed hypertension (Perry et al, 1998).
c) In a retrospective analysis of 19 cases of baclofen overdose, hypertension was reported in 9 patients following high-dose ingestion (greater than 200 mg) as compared with 1 report of hypertension following an ingestion of less than 200 mg (Leung et al, 2006).
d) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Hypertension (systolic greater than 200 and/or diastolic greater than 120) was reported in 2 (5%) of the 42 patients (Cao & Wax, 2015).

F) SYNCOPE

1) WITH THERAPEUTIC USE

a) Syncope has been a rare but serious side effect reported in patients being treated with baclofen and tizanidine (Prod Info baclofen oral tablets, 2005; Eyssette et al, 1988).

G) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) ADULT: A 46-year-old man, with a history of alcohol addiction, was found unresponsive by his son. Current medications for alcohol dependence included baclofen 20 mg four times daily, oxazepam, and alimemazine. At presentation, physical exam showed that the patient was comatose (Glasgow Coma Scale score of 3) with cardiac arrest, mild hypothermia, and bilateral mydriasis. Following aggressive cardiopulmonary resuscitation, the patient reverted to normal sinus rhythm and was placed on extracorporeal membrane oxygenation before transfer to the intensive care unit. Laboratory studies revealed acute renal failure, lactic acidosis, and hepatic failure. Toxicologic analysis revealed a baclofen concentration of 3.3 mcg/mL (therapeutic range for antispastic indication: 0.08/0.4 mcg/mL). Despite hemodialysis, the patient died of multiple organ failure (Pape et al, 2014).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression requiring artificial ventilation is common with severe overdose (Berger et al, 2012; Mahvash et al, 2011; Ostermann et al, 2000; VanDierendonk & Dire, 1999; Peng et al, 1998; Perry et al, 1998; Merchant & Hollis, 1997; Cooke & Glasstone, 1994; Patterson et al, 1994; Delhaas & Brouwers, 1991; Burris, 1986; Cohen et al, 1986; Gerkin et al, 1986; Haubenstock et al, 1983; May, 1983; Ferner, 1981; Ghose, 1980; Lipscomb & Meredith, 1980; Paulson, 1976).
b) INCIDENCE: In a series of 8 adolescents who developed baclofen toxicity after recreational abuse, 7 required mechanical ventilation (Perry et al, 1998).
c) Respiratory arrest may develop (Perry et al, 1998; Kofler et al, 1992; Romijn et al, 1986; Blankenship & Moses, 1983).
d) CASE REPORT: A 6-year-old girl presented to an emergency department without spontaneous respirations and with a collapsed right upper lung lobe (Cooke & Glasstone, 1994). Intubation and artificial ventilation were required. The quantity of baclofen ingested was not known.
e) CASE REPORT: A 66-year-old man with multiple sclerosis developed respiratory depression requiring intubation following an inadvertent overdose of baclofen (30 x 10(3) mcg) intrathecally (Fakhoury et al, 1998). 10 mL of cerebrospinal fluid were removed and the patient became fully alert 40 hours after the injection. The authors, however, reported no symptomatic improvement following flumazenil and physostigmine.
f) CASE REPORT: An adult inadvertently received a 1500 mcg bolus of intrathecal baclofen when the patency of the delivery system was tested. The patient lost consciousness abruptly, and developed miosis and respiratory depression. Mechanical ventilation was required for 2 days, but the patient recovered (Teddy et al, 1992).
g) ADOLESCENT: A 17-year-old boy, with spastic quadriplegia due to cerebral palsy, became semi-comatose, with global hypotonia and hyporeflexia, and developed hypotension (87/39 mmHg), bradycardia (54 bpm), and severe respiratory depression (6 to 8 breaths/min) following an intrathecal baclofen (ITB) pump change. The patient was initially given two doses of naloxone IV with no response. Suspecting baclofen toxicity, 1 mg physostigmine (approximately 0.02 mg/kg) and atropine 0.2 mg were administered. The patient showed an immediate response with regaining consciousness, increased muscle tone, and increased heart rate and blood pressure. However, approximately 40 minutes later, he again became unresponsive, hypotensive, and bradypneic, and a second physostigmine dose was administered with a transient response. After switching off the ITB pump and with continued observation in the ICU, the patient's condition improved, he was extubated about 8 hours later, and his ITB pump was restarted at a 15% lower dose (Stroud et al, 2014).
h) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Respiratory depression was reported in 6 (14%) of the 42 patients (Cao & Wax, 2015).
i) CASE SERIES: According to a retrospective review of baclofen poisoning cases from the National Patient Register (NPR) and the Danish Poison Information Centre (DPIC) from 2007 to 2012, 24 cases were identified, with 11 of the cases classified as severe or life-threatening baclofen intoxication (Poison Severity Score (PSS) of 3). These patients developed deep coma, hyporeflexia, hypotonia, and respiratory depression with insufficiency, in addition to other symptoms including seizures (n=6; 55%), hypotension (n=2; 18.2%), hypertension (n=1; 9%), and bradycardia (n=2; 18.2%). In 3 of the 11 patients, the mean baclofen dose, as a mono-drug ingestion, was 2000 +/- 500 mg, and in the other 8 patients, the mean baclofen dose, as part of a poly-drug ingestion, was 900 +/- 641.3 mg (Kiel et al, 2015).

B) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: A 46-year-old with reactive airways disease developed dyspnea and a decrease in his FEV1 one hour after ingesting 40 mg of baclofen (Dicpinigaitis et al, 1993). A 33-year-old woman with seasonal allergies developed bronchial hyperresponsiveness to methacholine challenge after ingesting 40 mg of baclofen (Dicpinigaitis et al, 1993).

C) HICCOUGHS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 19-year-old woman with spastic diplegic cerebral palsy and repaired tetralogy of Fallot, developed rhythmic hiccup-like respirations that typically occurred every 5 seconds and that increased in frequency with exhaustion and disappeared during sleep. Her symptoms would reappear within 1 hour of waking. Her medication history included oral baclofen therapy for spasticity at a dose of 20 mg three times daily. Suspecting baclofen toxicity, her dose was decreased to 10 mg three times daily and, within 12 hours, her symptoms disappeared without recurrence (Srivastava et al, 2014).

Neurologic

3.7.2)

A) COMA

1) WITH POISONING/EXPOSURE

a) CNS depression is common after oral or intrathecal overdose. Effects may range from lethargy to deep coma (Cleophax et al, 2015; Mahvash et al, 2011; Cooper & Bergman, 2000; VanDierendonk & Dire, 1999; Fakhoury et al, 1998; Perry et al, 1998; Merchant & Hollis, 1997; Lee et al, 1992; White, 1985; Jones & Lance, 1976).
b) Brainstem reflexes (corneal, Doll's eye, cold water caloric, oculocephalic) may be abnormal (Ostermann et al, 2000; Cooke & Glasstone, 1994; Gerkin et al, 1986; Paulson, 1976).
c) In a retrospective analysis of 19 cases of baclofen overdose, CNS depression (a Glasgow Coma Scale score of less than 9) was reported in 7 patients following high-dose ingestion (greater than 200 mg) as compared with no reports of CNS depression following ingestions of less than 200 mg (Leung et al, 2006).
d) Coma, flaccidity and absent reflexes can persist for more than 5 days after severe overdose and should not be mistaken for brain death.
e) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Coma/CNS depression was reported in 24 of the 42 patients (57%) and a sedative-hypnotic toxidrome was reported in 12 (29%) of the 42 patients (Cao & Wax, 2015).
f) CASE SERIES: According to a retrospective review of baclofen poisoning cases from the National Patient Register (NPR) and the Danish Poison Information Centre (DPIC) from 2007 to 2012, 24 cases were identified, with 11 of the cases classified as severe or life-threatening baclofen intoxication (Poison Severity Score (PSS) of 3). These patients developed deep coma, hyporeflexia, hypotonia, and respiratory depression with insufficiency, in addition to other symptoms including seizures (n=6; 55%), hypotension (n=2; 18.2%), hypertension (n=1; 9%), and bradycardia (n=2; 18.2%). In 3 of the 11 patients, the mean baclofen dose, as a mono-drug ingestion, was 2000 +/- 500 mg, and in the other 8 patients, the mean baclofen dose, as part of a poly-drug ingestion, was 900 +/- 641.3 mg (Kiel et al, 2015).
g) CASE REPORTS

1) PEDIATRIC: A 6-year-old girl became comatose, with dilated pupils and doll's eye movements, following an overdose ingestion of baclofen (Cooke & Glasstone, 1994).
2) ADOLESCENT: Multiple coma episodes were reported in a 17-year-old girl following ingestions of large doses of baclofen (approximately 625 mg in one instance). The duration of comas ranged from 12 to 18 hours. Other effects that were reported prior to the decreased level of consciousness included vomiting, headache, agitation, confusion, vertigo, and repetitive motor behaviors (Masi et al, 2013).
3) ADOLESCENT: A 17-year-old girl presented to emergency medical personnel as unresponsive, with subsequent development of a generalized tonic-clonic seizure at the hospital. Intubation was required for respiratory failure. A neurologic exam revealed bilaterally nonreactive pupils, no vestibulo-ocular, cough, or gag reflexes, no deep pain response, and flaccid paralysis with areflexia. Lab results were normal and CT scan and MRI of the brain showed no abnormalities. Given the patient's symptoms, examination findings, and diagnostic testing, a gamma-aminobutyric acid agonist was suspected to be the causative agent. High power liquid chromatography of the patient's serum, performed 12 hours post-admission, detected a baclofen level of 0.81 mcg/mL (laboratory therapeutic range 0.08 to 0.4 mcg/mL). Interview of the patient's parents revealed that approximately 28 10-mg baclofen tablets (prescribed to the father for treatment of spinal stenosis) were missing. With supportive care, the patient's condition gradually improved and she was discharged 12 days post-admission without sequelae (Caron et al, 2014).
4) ADOLESCENT: A 17-year-old boy, with spastic quadriplegia due to cerebral palsy, became semi-comatose, with global hypotonia and hyporeflexia, and developed hypotension (87/39 mmHg), bradycardia (54 bpm), and severe respiratory depression (6 to 8 breaths/min) following an intrathecal baclofen (ITB) pump change. The patient was initially given two doses of naloxone IV with no response. Suspecting baclofen toxicity, 1 mg physostigmine (approximately 0.02 mg/kg) and atropine 0.2 mg were administered. The patient showed an immediate response with regaining consciousness, increased muscle tone, and increased heart rate and blood pressure. However, approximately 40 minutes later, he again became unresponsive, hypotensive, and bradypneic, and a second physostigmine dose was administered with a transient response. After switching off the ITB pump and with continued observation in the ICU, the patient's condition improved, he was extubated about 8 hours later, and his ITB pump was restarted at a 15% lower dose (Stroud et al, 2014).
5) ADULT: Coma with flaccid quadriplegia and hypotension were reported in a 66-year-old multiple sclerosis patient who inadvertently received a 30 x 10(3) mcg dose of baclofen intrathecally (Fakhoury et al, 1998).
6) ADULT: A 50-year-old man presented with coma (Glasgow Coma Score 3/15), fixed 3 mm pupils with neither a direct nor consensual response to light, flaccid extremities with no response to pain, depressed deep tendon reflexes, absent plantar responses, absent oculocephalic and corneal reflexes, and no cough or gag with suctioning (Ostermann et al, 2000).
7) ADULT: A 21-year-old man became comatose and developed paresthesias in his lower extremities, pruritus, hypotonia, bradycardia, seizures, and respiratory difficulties after inadvertently receiving 5 mg baclofen intrathecally via the bolus port of the intrathecal pump instead of via the reservoir port. Two hours postinjection, the patient's intrathecal baclofen concentration was 13.1 mg/L. Within 24 hours, following supportive care, a repeat measurement indicated that the baclofen concentration had decreased to 0.45 mg/L. Over the next several days, the patient completely recovered without neurologic sequelae (Mahvash et al, 2011).
8) ADULT: Two patients (a 40-year-old woman and a 51-year-old woman) presented to the emergency department unresponsive and hypotensive, with flaccid extremities, nonreactive pupils, and no response to stimuli after intentionally ingesting unknown amounts of baclofen. Despite supportive care, the first patient remained unresponsive on hospital day 4, and, although EEG and apnea testing results were inconclusive for determination of brain death, it was decided that the patient's prognosis was poor and the decision was made for removal of support. However, on hospital day 5, the patient became responsive with eye opening and extremity movement. She gradually recovered and was discharged to psychiatry on hospital day 15. The second patient also remained in a deep coma, and on hospital day 5, a request was placed for a neurologic examination to determine brain death. The request was delayed, and on hospital day 7, the patient started showing signs of awakening. She gradually recovered and was discharged on hospital day 24. The serum baclofen concentration of the second patient, obtained approximately 15 hours post-ingestion, was 2.7 mcg/mL (therapeutic range, 0.08 to 0.4 mcg/mL) (Sullivan et al, 2012).
9) ADULT: A 47-year-old woman, who was receiving 800 mcg/day of baclofen intrathecally for treatment of spastic paraplegia secondary to multiple sclerosis, became comatose (Glasgow coma scale of 3) followed by generalized tonic-clonic seizures and apnea, necessitating intubation and mechanical ventilation, after inadvertently receiving an intrathecal bolus dose of baclofen 60 mg. With supportive therapy, including CSF drainage via a lumbar catheter, the patient gradually recovered without neurologic sequelae (Berger et al, 2012).
10) ADULT: A 46-year-old man, with a history of alcohol addiction, was found unresponsive by his son. Current medications for alcohol dependence included baclofen 20 mg four times daily, oxazepam, and alimemazine. At presentation, physical exam showed that the patient was comatose (Glasgow Coma Scale score of 3) with cardiac arrest, mild hypothermia, and bilateral mydriasis. Following aggressive cardiopulmonary resuscitation, the patient reverted to normal sinus rhythm and was placed on extracorporeal membrane oxygenation before transfer to the intensive care unit. Laboratory studies revealed acute renal failure, lactic acidosis, and hepatic failure. Toxicologic analysis revealed a baclofen concentration of 3.3 mcg/mL (therapeutic range for antispastic indication: 0.08/0.4 mcg/mL). Despite hemodialysis, the patient died of multiple organ failure (Pape et al, 2014).
11) ADULT: A 42-year-old man was found comatose at home. His medications included baclofen, hydrocodone-acetaminophen, tizanidine, and gabapentin. The patient was unresponsive to administration of naloxone. At presentation to the emergency department, he experienced one tonic-clonic seizure. Vital signs revealed a body temperature of 32.8 degrees C, heart rate of 55 beats/min, and blood pressure of 116/74 mmHg, and a physical exam indicated midpoint pupils. With his neurological status unchanged over the next 24 hours, brain death was suspected and an EEG was performed indicating no brain activity. Because baclofen ingestion was suspected and signs and symptoms were consistent with baclofen overdose mimicking brain death, supportive care was continued. Within that same day, the patient began moving his extremities. Four days later, he completely recovered and was discharged to a psychiatric unit (Leroy et al, 2015).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures and status epilepticus have also been reported at therapeutic doses (Rush & Gibberd, 1990).

2) WITH POISONING/EXPOSURE

a) Seizures have been reported after oral and intrathecal overdose. Generalized tonic clonic seizures (Caron et al, 2014; Berger et al, 2012; Mahvash et al, 2011; Perry et al, 1998; Cooke & Glasstone, 1994; Lee et al, 1992; Burris, 1986; May, 1983; Ghose, 1980), focal motor seizures (Kofler et al, 1994), status epilepticus (Saltuari et al, 1992), nonconvulsive status epilepticus (Zak et al, 1994), and myoclonus (Nugent et al, 1986; Paulson, 1976) may occur.
b) INCIDENCE: In a series of 8 adolescents who developed baclofen toxicity after recreational abuse, 2 developed seizures (Perry et al, 1998).
c) In a retrospective analysis of 19 cases of baclofen overdose, seizures were reported in 4 patients following high-dose ingestion (greater than 200 mg) as compared with no reports of seizures following ingestions of less than 200 mg (Leung et al, 2006).
d) CASE REPORT/ADULT: A 47-year-old woman, who was receiving 800 mcg/day of baclofen intrathecally for treatment of spastic paraplegia secondary to multiple sclerosis, became comatose (Glasgow coma scale of 3) followed by generalized tonic-clonic seizures and apnea, necessitating intubation and mechanical ventilation, after inadvertently receiving an intrathecal bolus dose of baclofen 60 mg. With supportive therapy, including CSF drainage via a lumbar catheter, the patient gradually recovered without neurologic sequelae (Berger et al, 2012).
e) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Seizures were reported in 3 (7%) of the 42 patients (Cao & Wax, 2015).
f) CASE REPORT: A 29-year-old woman became comatose (Glasgow Coma Score of 3) and developed seizure activity, as noted by EEG monitoring, approximately 16 hours after ingesting 3500 mg baclofen, 150 mg desloratadine, and 84 mg esomeprazole. Her initial plasma baclofen concentration was 2,060 ng/mL (therapeutic range, 60 to 400 ng/mL). Four 6-hour hemodialysis sessions were performed, with a significant decrease in plasma baclofen concentrations by a mean of 50 +/- 2%; however, following cessation of each session, her baclofen concentrations re-increased, until doubled 10 hours later. On day 8, her seizures recurred, with her plasma baclofen concentration increased to 306 ng/mL. With supportive care, including administration of polyethylene glycol and activated charcoal, her seizure activity ceased on day 11. She regained consciousness on day 13 (plasma baclofen 50 ng/mL), was extubated on day 15 (plasma baclofen 22 ng/mL) and was subsequently discharged to a psychiatric care unit (Cleophax et al, 2015).

C) HYPOREFLEXIA

1) WITH POISONING/EXPOSURE

a) Muscle flaccidity and absent deep tendon reflexes may develop in severe overdose (Kiel et al, 2015; Stroud et al, 2014; Mahvash et al, 2011; Ostermann et al, 2000; Peng et al, 1998; Perry et al, 1998; Romijn et al, 1986; Haubenstock et al, 1983; Lipscomb & Meredith, 1980). Hypotonia and hyporeflexia have been reported in several children following acute baclofen overdoses (Cooke & Glasstone, 1994).
b) CASE REPORT: Electrophysiologic studies in a 16-year-old boy with intrathecal baclofen overdose revealed no motor evoked potentials in response to transcranial stimulation during the period of intoxication; response returned to baseline with recovery from the intoxication. There was no effect on response to cervical stimulation, somatosensory simulation or brainstem acoustic evoked potential (Kofler et al, 1992).
c) ADOLESCENT: A 17-year-old girl presented to emergency medical personnel as unresponsive, with subsequent development of a generalized tonic-clonic seizure at the hospital. Intubation was required for respiratory failure. A neurologic exam revealed bilaterally nonreactive pupils, no vestibulo-ocular, cough, or gag reflexes, no deep pain response, and flaccid paralysis with areflexia. Lab results were normal and CT scan and MRI of the brain showed no abnormalities. Given the patient's symptoms, examination findings, and diagnostic testing, a gamma-aminobutyric acid agonist was suspected to be the causative agent. High power liquid chromatography of the patient's serum, performed 12 hours post-admission, detected a baclofen level of 0.81 mcg/mL (laboratory therapeutic range 0.08 to 0.40 mcg/mL). Interview of the patient's parents revealed that approximately 28 10-mg baclofen tablets (prescribed to the father for treatment of spinal stenosis) were missing. With supportive care, the patient's condition gradually improved and she was discharged 12 days post-admission without sequelae (Caron et al, 2014).

D) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) Confusion, disorientation, slurred speech, agitation, lethargy, euphoria, depression, and hallucinations have been reported with baclofen use (Prod Info baclofen oral tablets, 2005; Jones & Lance, 1976; Skausig & Korsgaard, 1976).
b) There are several reports of renal patients who developed encephalopathy with therapeutic doses of baclofen (Chou et al, 2006; Choo et al, 2000; Peces et al, 1998).

2) WITH POISONING/EXPOSURE

a) Confusion, disorientation, slurred speech, agitation, lethargy, euphoria, delirium, and hallucinations have been described at therapeutic doses and early in the course of overdose (Chong & Wang, 2005; Cooke & Glasstone, 1994; Haubenstock et al, 1983; Jones & Lance, 1976; Skausig & Korsgaard, 1976).
b) EEG changes associated with baclofen-induced encephalopathy include periodic sharp waves, bursts of triphasic waves, trains of delta activity, intermittent rhythmical delta waves, burst suppression pattern without reactivity to stimulation, and diffuse background slowing (Meurant et al, 2000; Ostermann et al, 2000; Zak et al, 1994; Liu et al, 1991; Hormes et al, 1988; Wainapel et al, 1986; Abarbanel et al, 1985).
c) Baclofen was associated with encephalopathy in 2 patients (69 and 78 years of age) following administration of higher than normal doses. The 69-year-old patient developed encephalopathic symptoms following 2 doses of baclofen 25 mg. The 78-year-old patient with a history of stroke inadvertently took 90 mg daily, developing similar symptoms. In both patients, withdrawal of baclofen resulted in subsidence of symptoms within 2 days (Abarbanel et al, 1985).
d) In a retrospective analysis of 19 cases of baclofen overdose, delirium was reported in 8 patients following high-dose ingestion (greater than 200 mg) as compared with no reports of delirium following ingestions of less than 200 mg (Leung et al, 2006).
e) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Agitation was reported in 7 (17%) of the 42 patients (Cao & Wax, 2015).

E) DYSKINESIA

1) WITH THERAPEUTIC USE

a) Dystonia, chorea, akinetic mutism, dyskinesia, and flapping tremor have been reported at therapeutic doses (Rubin & So, 1999; Ryan & Blumenthal, 1993; Silbert & Stewart-Wynne, 1992; Parmar, 1991; Crystal, 1990; Sandyk, 1986; Abarbanel et al, 1985).

2) WITH POISONING/EXPOSURE

a) Mild, residual ataxia with confusion has been reported in 2 children following acute baclofen overdose (Cooke & Glasstone, 1994).

F) ASTHENIA

1) WITH THERAPEUTIC USE

a) In a study of children with spasticity secondary to cerebral palsy, 2 out of the 5 children treated with intrathecal boluses of baclofen developed profound muscle weakness that resolved within 2 hours (Soliman et al, 1999).

G) AMNESIA

1) WITH THERAPEUTIC USE

a) Short term memory impairment, particularly involving the names of persons and places, has been reported at therapeutic doses (Sandyk & Gillman, 1985).

H) PARESTHESIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 21-year-old man developed paresthesias in his lower extremities and pruritus in his legs and back within seconds after inadvertently receiving 5 mg baclofen intrathecally via the bolus port of the intrathecal pump instead of via the reservoir port. Over the next 45 minutes, the patient became comatose, with subsequent development of hypotonia, bradycardia, seizures, and respiratory insufficiency. Over the next several days, with supportive care, the patient completely recovered without neurologic sequelae (Mahvash et al, 2011).

I) INSOMNIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Insomnia (less than 3 hours of sleep a night) and severe tinnitus were reported in a 45-year-old woman taking high-dose baclofen therapy (240 mg/day) to treat alcohol dependence (Auffret et al, 2014).

J) HYPERREFLEXIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: A retrospective analysis of data collected from the Toxicology Investigators Consortium registry from January of 2010 to April of 2015 identified 42 single substance baclofen overdose ingestions. The mean age was 44 years (ranging from 4 to 86 years) and baclofen doses ranged from 20 to 300 mg. Hyperreflexia/myoclonus/clonus/tremor was reported in 5 (12%) of the 42 patients (Cao & Wax, 2015).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea is a common side effect at therapeutic doses (Smith et al, 1991; Dapas et al, 1985).

2) WITH POISONING/EXPOSURE

a) Vomiting may occur after oral or intrathecal overdose (Roberge et al, 1994; Muller-Schwefe & Penn, 1989; Blankenship & Moses, 1983). Spontaneous vomiting occurred in two 2-year-old children following ingestion of an unknown quantity of baclofen tablets (Cooke & Glasstone, 1994).

B) EXCESSIVE SALIVATION

1) WITH POISONING/EXPOSURE

a) Hypersalivation is rarely reported (Paulson, 1976).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Mild elevations in hepatic enzyme levels without clinical evidence of liver injury have been reported after overdose (Perry et al, 1998; Lee et al, 1992; Paulson, 1976) and at therapeutic doses (Chui & Pelot, 1984).

Genitourinary

3.10.2)

A) URINARY INCONTINENCE

1) WITH POISONING/EXPOSURE

a) Incontinence has been reported as an adverse effect at therapeutic doses and in overdose (Lee et al, 1992; Smith et al, 1991a).

B) RETENTION OF URINE

1) WITH POISONING/EXPOSURE

a) Urinary retention has been reported in overdose (White, 1985).

C) AT RISK - FINDING

1) WITH THERAPEUTIC USE

a) RENAL INSUFFICIENCY: Patients with overt or subclinical renal insufficiency may develop toxicity at therapeutic doses (Bassilios et al, 2000; Choo et al, 2000; Chen et al, 1997; Aisen et al, 1994; Dahlin & George, 1984).

Dermatologic

3.14.2)

A) MACULOPAPULAR ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A blanching morbilliform rash on the trunk and arms developed in a 52-year-old woman taking therapeutic doses of baclofen. The rash resolved despite continued usage of baclofen (Lynde et al, 1983).

B) ITCHING OF SKIN

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Pruritus of the legs and back was reported in a 21-year-old man who inadvertently received an intrathecal injection of baclofen 5 mg via the bolus port of the intrathecal pump instead of via the reservoir port (Mahvash et al, 2011).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis has been reported after overdose (Lee et al, 1992) and should be anticipated in any patient with prolonged seizures or coma.
b) CASE REPORT: Approximately 36 hours after ingesting 30 baclofen (5 mg/tablet; total 150 mg) tablets, a 20-year-old man with a history of amyotrophic lateral sclerosis presented to the emergency department with disorientation (Glasgow coma scale score 13), acute delirium, and rhabdomyolysis (CPK level greater than 10 x 10(3) International Units/L; normal range 24 to 204; positive urine myoglobin). Although the mechanism for rhabdomyolysis in this case is unknown, baclofen may cause rhabdomyolysis by pressure-induced ischemia due to prolonged immobilization and muscle compression, or by prolonged agitation or seizures. This patient experienced pains, swelling, and some pressure sores in his left buttock and thigh. Following 12 days of supportive care, he recovered and was discharged home (Chong & Wang, 2005).

B) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe weakness of the lower extremities followed by flaccid quadriplegia occurred in a 66-year-old man with multiple sclerosis after an inadvertent overdose of baclofen (30 x 10(3) mcg) intrathecally (Fakhoury et al, 1998). Immediate treatment with flumazenil and physostigmine was given without effect; however, the patient became fully alert at 40 hours. Persistent lower extremity weakness occurred.

Reproductive

3.20.1)

A) Normal delivery of healthy children have been reported following intrathecal baclofen infusion during pregnancy.

3.20.2)

A) LACK OF EFFECT

1) CASE REPORT: A woman with spasticity secondary to C5 quadriplegia treated with an intrathecal baclofen infusion delivered two children over the course of 2 years. Neither had major or minor external malformations and ultrasound examinations of head, heart, and abdominal organs were normal. Skeletal surveys were normal and both children had normal neurologic exams and psychomotor development (Munoz et al, 2000).

3.20.3)

A) PREGNANCY CATEGORY

1) Baclofen is classified as FDA pregnancy category C (Prod Info GABLOFEN(R) intrathecal injection, 2015).
2) Baclofen should be used during pregnancy only if the maternal condition justifies the potential risk to the fetus (Prod Info GABLOFEN(R) intrathecal injection, 2015; Prod Info baclofen oral tablets, 2014).

B) ANIMAL STUDIES

1) RATS: Baclofen increased the incidence of ventral hernias in fetuses of rats given approximately 13 times the maximum oral human recommended dose on a mg/kg basis and 3 times on a mg/m(2) basis. Reductions in food intake and weight gain also occurred at this dose (Prod Info GABLOFEN(R) intrathecal injection, 2015; Prod Info baclofen oral tablets, 2014). At approximately 13 times the maximum recommended human dose, baclofen increased the incidence of incomplete sternebral ossification in fetuses of rats (Prod Info baclofen oral tablets, 2014).
2) RABBITS: Baclofen increased the incidence of unossified phalangeal nuclei of limbs in fetuses of rabbits given approximately 7 times the maximum recommended human dose (Prod Info baclofen oral tablets, 2014).

3.20.4)

A) BREAST MILK

1) Baclofen is considered compatible with breastfeeding by the American Academy of Pediatrics (Anon, 2001). However, because baclofen is excreted in human milk and there is potential for adverse reactions in infants, decide whether to continue baclofen based on the importance of the drug to the mother (Prod Info GABLOFEN(R) intrathecal injection, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Follow CPK in patients with prolonged seizures or coma.
B) Monitor renal function and urine output in patients with prolonged seizures or coma or hemodynamic instability.
C) Institute continuous cardiac monitoring and monitor vital signs frequently. Monitor mental status, adequacy of respirations and the ability to protect the airway. Monitor pulse oximetry.
D) Serum baclofen monitoring is not widely available or clinically useful for managing overdose.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Follow CPK levels and renal function in patients with prolonged seizures or coma.

4.1.3)

A) OTHER

1) Monitor urine output in patients with prolonged seizures or coma or hemodynamic instability.

4.1.4)

A) OTHER

1) MONITORING

a) Institute continuous cardiac monitoring, assess adequacy of respirations and the ability to protect the airway. Monitor pulse oximetry.

Methods

A)

1) A method for determination of baclofen in serum or urine using HPLC with an ultraviolet detector has been described (Fraser et al, 1991).
2) A method for detection of baclofen in plasma and urine using gas chromatography mass spectroscopy has been described (Anderson et al, 1984).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Admit patients with seizures, mental status depression, respiratory depression, delirium, or hypotension to an intensive care unit.
B) In a retrospective analysis of 19 cases of baclofen overdose, high-dose ingestions (greater than 200 mg) resulted in a greater occurrence of toxicity, including CNS depression (GCS less than 9), delirium, seizures and hypertension, as compared with low-dose ingestions (less than 200 mg), resulting in more frequent ICU admissions and longer hospital stays (Leung et al, 2006).

6.3.1.2) HOME CRITERIA/ORAL

A) A patient with an inadvertent ingestion that remains asymptomatic can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) Activated charcoal is not recommended because of the risk of CNS depression and aspiration.

6.5.2)

A) SUMMARY

1) Administer activated charcoal, in patients who are alert or in whom the airway is protected following a recent significant exposure. Fatalities are rare, most patients do well with supportive care; gastric lavage is generally not warranted.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) MONITORING OF PATIENT

1) Follow CPK in patients with prolonged seizures or coma.
2) Monitor renal function and urine output in patients with prolonged seizures or coma or hemodynamic instability.
3) Institute continuous cardiac monitoring and monitor vital signs frequently. Monitor mental status, adequacy of respirations and the ability to protect the airway. Monitor pulse oximetry.
4) Serum baclofen monitoring is not widely available or clinically useful for managing overdose.

B) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

D) BRADYCARDIA

1) Evaluate for hypoxia; administer oxygen and manage airway as clinically indicated.
2) Atropine has been reported to be useful in treating bradycardia and hypotension associated with an overdose of baclofen in two single case reports (Cohen et al, 1986; Ferner, 1981).

a) ATROPINE/DOSE

1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

a) There is no minimum dose (de Caen et al, 2015).
b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

E) FLUID/ELECTROLYTE BALANCE REGULATION

1) Fluids and electrolytes should be monitored closely.

F) PHYSOSTIGMINE

1) Intravenous physostigmine has been reported to reverse the effects of intrathecal baclofen overdoses of 80 to 800 micrograms (Muller-Schwefe & Penn, 1989). Despite the lack of symptomatic response following physostigmine in an adult exposed to a massive inadvertent intrathecal overdose, the patient became fully alert 40 hours after exposure (Fakhoury et al, 1998).
2) It has not been successful in larger overdoses (Saltuari et al, 1990) and has been associated with cardiac arrest in the setting of baclofen overdose (Penn & Kroin, 1990; Delhaas & Brouwers, 1991). Since the vast majority of patients respond well to supportive care, physostigmine is not recommended except for severe toxicity not responsive to supportive measures.
3) PHYSOSTIGMINE/INDICATIONS

a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).

4) DOSE

a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

5) CAUTIONS

a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

6) ATROPINE FOR PHYSOSTIGMINE TOXICITY

a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).

7) CASE REPORT/ADOLESCENT: A 17-year-old boy, with spastic quadriplegia due to cerebral palsy, became semi-comatose, with global hypotonia and hyporeflexia, and developed hypotension (87/39 mmHg), bradycardia (54 bpm), and severe respiratory depression (6 to 8 breaths/min) following an intrathecal baclofen (ITB) pump change. The patient was initially given two doses of naloxone IV with no response. Suspecting baclofen toxicity, 1 mg physostigmine (approximately 0.02 mg/kg) and atropine 0.2 mg were administered. The patient showed an immediate response with regaining consciousness, increased muscle tone, and increased heart rate and blood pressure. However, approximately 40 minutes later, he again became unresponsive, hypotensive, and bradypneic, and a second 1-mg physostigmine dose was administered with a transient response. After switching off the ITB pump and with continued observation in the ICU, the patient's condition improved, he was extubated about 8 hours later, and his ITB pump was restarted at a 15% lower dose (Stroud et al, 2014).

G) FLUMAZENIL

1) Two adults being treated for tetanus developed CNS and respiratory depression one hour after receiving intrathecal baclofen injections (1 mg and 400 mcg). Both had immediate improvement in level of consciousness and ventilation after treatment with flumazenil 0.5 mg as an intravenous bolus. Institution of a flumazenil infusion at 0.1 mg/hour resulted in reappearance of tonic spasms 13 hours later with resultant respiratory failure in one of the patients. The second patient had no recurrence of spasms despite an 18 hour infusion of flumazenil at 0.1 mg/hour (Saissy et al, 1992).
2) Flumazenil 0.25 milligrams had no effect in a 21 year old man with coma after ingesting 240 milligrams of baclofen (Roberge et al, 1994).
3) A 30-year-old woman with cerebral palsy on chronic therapy with diazepam and baclofen developed profound CNS depression 6 hours after ingesting 50 tablets of both diazepam (2 mg) and baclofen (10 mg) (Chern & Kwan, 1996). She was treated with 0.5 mg of flumazenil and developed a tonic clonic seizure within 30 seconds, which resolved after intravenous administration of 30 mg of diazepam. The authors speculated that the flumazenil unmasked the proconvulsant effects of baclofen.
4) ANIMAL DATA/LACK OF EFFECT: In a small randomized control study, 10 rats were given flumazenil following baclofen-induced CNS depression, while 10 were given saline (Wallace et al, 1997). No difference in time to recovery of 'righting reflex' were reported. The authors concluded that flumazenil (10 mg/kg) was ineffective in reversing CNS depression.

H) COMA

1) Coma, flaccidity and absent reflexes can persist for more than 5 days after severe overdose and should not be mistaken for brain death.
2) ADULT: Two patients (a 40-year-old woman and a 51-year-old woman) presented to the emergency department unresponsive and hypotensive, with flaccid extremities, non-reactive pupils, and no response to stimuli after intentionally ingesting unknown amounts of baclofen. Despite supportive care, the first patient remained unresponsive on hospital day 4, and, although EEG and apnea testing results were inconclusive for determination of brain death, it was decided that the patient's prognosis was poor and the decision was made for removal of support. However, on hospital day 5, the patient became responsive with eye opening and extremity movement. She gradually recovered and was discharged to psychiatry on hospital day 15. The second patient also remained in a deep coma, and on hospital day 5, a request was placed for a neurologic examination to determine brain death. The request was delayed, and on hospital day 7, the patient started showing signs of awakening. She gradually recovered and was discharged on hospital day 24. The serum baclofen concentration of the second patient, obtained approximately 15 hours post-ingestion, was 2.7 mcg/mL (therapeutic range, 0.08 to 0.4 mcg/mL) (Sullivan et al, 2012).

I) EXPERIMENTAL THERAPY

1) BACLOFEN ANTAGONIST: A specific baclofen antagonist, phaclofen, has been synthesized and reverses the effects of baclofen on spinal cord afferent transmission as well as anticholinergic effects in animal models (Kerr et al, 1987). This drug is not commercially available and has not been tried in humans.

J) DRUG WITHDRAWAL

1) Withdrawal symptoms respond to reinstituting baclofen with subsequent gradual tapering of the dose if indicated (Kirubakaran et al, 1984; Terrence & Fromm, 1981; Siegfried et al, 1992). Benzodiazepines appear to be of some benefit (Harrison & Wood, 1985), but experience has been limited.
2) See OTHER section for intrathecal baclofen withdrawal.

Enhanced Elimination

A)

1) Excretion of the active compounds is not known to be enhanced by fluid diuresis.

B)

1) Baclofen's clearance may be significantly enhanced by hemodialysis due to it's low-to-medium volume of distribution and low protein binding.
2) Hemodialysis appeared to shorten the duration of toxic effects of baclofen in several patients with severely impaired renal function (Chen et al, 1997).
3) CASE REPORT: Confusion, lethargy, and hypertension occurred in a 70-year-old woman, with end-stage renal disease and on regular hemodialysis, following therapeutic administration of baclofen, 5 mg three times daily for 3 days. Initial serum baclofen level was 385 ng/dL. Following 2 sessions of emergent hemodialysis, spaced approximately 30 hours apart, her serum baclofen level decreased to 20 ng/dL. Elimination half life during dialysis was 2.06 hours compared with 15.5 hours off dialysis (Wu et al, 2005).
4) CASE REPORT: A 60-year-old man, with acute renal failure and on chronic baclofen therapy for treatment of spastic tetraplegia, became comatose (Glasgow coma scale [GCS] score of 5) when the baclofen dosage regimen of 25 mg every 12 hours remained unchanged despite his renal insufficiency. His initial serum baclofen concentration was 0.70 mg/L (upper therapeutic level 0.40 mg/L). After a 4-hour hemodialysis session, the patient became oriented with a GCS of 15. At the end of the hemodialysis session, his serum baclofen concentration was 0.28 mg/L. Pharmacokinetic calculations determined that the dialysis removal rate constant for baclofen was 0.152/hour and dialysis clearance was 0.13 L/min. Baclofen's elimination half-life during hemodialysis was 3.7 hours as compared to 11.3 hours approximately 3 hours post-dialysis. The total amount of baclofen that was recovered in the dialysate was 13.5 mg (Brvar et al, 2007).
5) CASE REPORT: A 29-year-old woman, with normal renal function, presented comatose with evidence of seizure activity, as noted by an EEG, approximately 16 hours after ingesting 3500 mg baclofen, 150 mg desloratadine, and 84 mg esomeprazole. Her initial plasma baclofen concentration was 2,060 ng/mL (therapeutic range, 60 to 400 mg); however, assuming first order elimination kinetics and working backwards to the first 4 time points with neglected absorption and distribution phases, it was estimated that the peak plasma baclofen concentration was approximately 8,000 ng/mL 3 hours post-ingestion, and the elimination half life was approximately 7 hours, similar to the values at therapeutic doses (mean: 3.5 hours, range: 2 to 6 hours). Four 6-hour hemodialysis sessions were performed, with a significant decrease in plasma baclofen concentrations by a mean of 50 +/- 2% and a mean elimination half life of 5 +/- 1.8 hours; however, after cessation of each session, baclofen concentrations re-increased, until they had doubled 10 hours later. Because of the similarities in half-lives in this patient before and after hemodialysis, it is suggested that there is no benefit to hemodialysis in increasing baclofen elimination in patients with normal renal function (Cleophax et al, 2015).

C)

1) CASE REPORT: A 57-year-old man became comatose approximately 2 hours after intentionally ingesting 34 baclofen tablets (10 mg each). His Glasgow coma scale score, at presentation to the ED, was 6 (E1M4V1). Suspecting a possible ingestion of an opioid as well, naloxone was administered with no response. Continuous venovenous hemofiltration (CVVH) was then initiated, with a blood flow rate of 200 mL/min. Following CVVH initiation, an EEG was performed which indicated slow frontal lobe activity; however, there was no indication of epileptiform activity and no response to pain stimuli. At 40 hours post-admission, the patient became responsive, and on hospital day 3, was completely conscious, at which time CVVH was discontinued. On hospital day 4, the patient was discharged from the intensive care unit (Meulendijks et al, 2015).

a) Serum and hemofiltrate baclofen concentrations were measured at various times after hospital admission and after CVVH initiation, and ranged from 1.81 and 0.05 mg/L and 0.74 and 0.05 mg/L, respectively. The elimination half-life during hemofiltration was estimated to be 4.75 hours. The estimated total clearance and clearance via hemofiltration were 6.6 and 2.4 L/hour, respectively, indicating that the clearance can be increased by approximately 57% with hemofiltration (Meulendijks et al, 2015).

Abstracts

Case Reports

A)

1) Paulson (1976) reported a 29-year-old woman who ingested between 900 to 970 mg of baclofen and developed flaccidity, areflexia, coma, hypotension (90/50) and required complete respiratory support(Paulson, 1976). Eyes were fixed in midposition and unresponsive to light. She developed myoclonic jerking and opisthotonos.

a) Marked salivation was observed. Laboratory values revealed increased lactic dehydrogenase and SGOT levels. The patient required intensive supportive care for 72 hours and pupils remained unreactive for 48 hours. She eventually recovered without adverse sequelae.

2) Ghose et al (1980) report the case of a 39-year-old woman who had ingested 450 mg baclofen (Ghose, 1980). She was comatose, flaccid, and in respiratory failure on admission. She later developed muscle twitchings and had several seizures.

a) She became conscious after 36 hours with symptomatic treatment. After 65 hours she developed sinus tachycardia which was treated with propranolol.

3) A 17-year-old woman ingested 420 mg of baclofen. Ninety minutes postingestion she was admitted to the hospital and underwent gastric lavage and forced diuresis with furosemide 20 mg IV every 4 hours and IV fluids.

a) Three and one-half hours after ingestion, she developed marked cerebral, cardiac and respiratory depression, hypothermia, and flaccidity.
b) Eight hours postingestion vital signs were as follows: heart rate 40 BPM, blood pressure 90/50 mmHg, respiratory rate 11 breaths/minute, tidal volume 400 mL, and rectal temperature 34.2 degrees C.
c) Atropine sulfate 600 mcg was given IV and within 15 minutes the patient's heart rate returned to 94 BPM and blood pressure to 110/70 mmHg. Over the next 2 hours respiratory rate increased to 15 breaths/minute, tidal volume 550 mL, and rectal temperature 35.4 degrees C.
d) Although these effects only lasted 90 minutes, she did not require further treatment.

4) TREATMENT: Atropine 1 mg was given by slow intravenous push (over 3 min) to an 18-year-old patient with bradycardia (pulse 52 BPM) and hypotension (110/30 mmHg) occurring approximately 8 hours following an ingestion of 300 mg of baclofen.

a) His vital signs stabilized within 4 hours following the atropine injection (blood pressure 180/100 mmHg, heart rate 99 BPM) (Cohen et al, 1986).

Range Of Toxicity

Summary

A)

B)

C)

Therapeutic Dose

7.2.1)

A) ORAL

1) Initial dose: 5 mg 3 times daily, increasing the dose every 3 days in 5-mg increments, up to a maximum dose of 20 mg 4 times daily (Prod Info baclofen oral tablet, 2010).
2) Usual dose range: 40 to 80 mg per day divided in 3 or 4 doses (Prod Info baclofen oral tablet, 2010).

B) INTRATHECAL

1) SCREENING DOSE: 50 mcg/mL administered intrathecally and observed for 4 to 8 hours; if inadequate response, may increase dose to 75 mcg/1.5 mL as a second bolus or 100 mcg/2 mL as the third and final bolus; separate administration of boluses by 24 hours (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013)
2) INITIAL DOSE: If efficacy of screening dose was maintained for less than 8 hours, screening dose with a positive result is doubled and administered intrathecally over 24 hours. If efficacy of screening dose was maintained for at least 8 hours, initial dose is the same as the screening dose with a positive result and administered intrathecally over 24 hours (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013)
3) SPINAL CORD SPASTICITY: After the first 24 hours, the daily dose should be increased by 10% to 30% once every 24 hours, until the desired clinical response is achieved. Maintenance dosages have ranged from 12 to 2003 mcg/day, administered as a long-term continuous infusion, with the majority of patients well-maintained at doses ranging from 300 to 800 mcg/day (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013)
4) CEREBRAL ORIGIN SPASTICITY: After the first 24 hours, the daily dose should be increased by 5% to 15% once every 24 hours, until the desired clinical response is achieved. Maintenance dosages have ranged from 22 to 1400 mcg/day, administered as a long-term continuous infusion, with the majority of patients well-maintained at doses ranging from 90 to 703 mcg/day (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013)

7.2.2)

A) ROUTE OF ADMINISTRATION

1) ORAL

a) According to the manufacturer, safety in patients under 12 years of age has not been established (Prod Info baclofen oral tablet, 2010).
b) 8 years or older: Starting dose 5 to 10 mg/day orally in divided doses. Titrate by 5 mg/day increments weekly, as tolerated, to 60 mg/day in 3 divided doses (Delgado et al, 2010; Tilton et al, 2010; van Doornik et al, 2008; Scheinberg et al, 2006; Milla & Jackson, 1977); Maximum 60 mg/day (Milla & Jackson, 1977)
c) 2 to 8 years: Starting dose 2.5 to 10 mg/day orally in divided doses. Titrate by 5 mg/day increments weekly, as tolerated, to 30 to 40 mg/day in 3 divided doses (Tilton et al, 2010; Scheinberg et al, 2006; Milla & Jackson, 1977); Maximum dose 40 mg/day (Milla & Jackson, 1977).

2) INTRATHECAL

a) 4 Years or Older:

1) Intrathecal test dose: 25 to 50 mcg intrathecally given over at least 1 minute; may increase dosage by 25-mcg increments every 24 hours; maximum 100 mcg. Observe for response 4 to 8 hour after administration. Patients must have a positive clinical response to a single bolus dose of no greater than 100 mcg/2 mL to be acceptable candidates for chronic therapy with the intrathecal infusion pump (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013).
2) Post-implant titration: After the first 24 hours, the intrathecal daily dose should be increased slowly by 5% to 15% only once every 24 hours, until the desired clinical effect is achieved (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013).
3) Post-implant maintenance: Intrathecal daily dose may be increased by 5% to 20%; maximum, 20%. during periodic pump refills. Dose may be reduced by 10% to 20% as needed. Intrathecal formulations are most often administered in a continuous infusion mode immediately following implant. Most patients require gradual increase in dose over time to maintain optimal response. The average maintenance dose for children younger than 12 years is 274 mcg/day (range 24 to 1199 mcg/day). Dosage requirements for children over 12 years of age do not seem to be different than adults, with a reported maintenance dose for most patients of 90 to 703 mcg per day, with a range of 22 to 1400 mcg/day for cerebral origin spasticity and 300 to 800 mcg/day, with a range of 12 mcg/day to 2003 mcg/day for spinal cord spasticity (Prod Info LIORESAL(R) INTRATHECAL intrathecal injection, 2013).

Minimum Lethal Exposure

A)

1) Ingestion of 1250 to 2500 mg was fatal in one adult (Haubenstock et al, 1983).
2) Ingestion of 1000 to 1800 mg was fatal in a 30-year-old quadriplegic (Fraser et al, 1991).

Maximum Tolerated Exposure

A)

1) Serious intoxication (coma, respiratory depression) has been reported in adults after ingestion of 150 mg/day for 2 days in an elderly man (Haubenstock et al, 1983), and an acute ingestion of 300 to 970 mg (Ferner, 1981; Ghose, 1980; Laplatte et al, 1980; Paulson, 1976).
2) ADULT

a) CASE REPORT: Ingestion of 875 to 1125 mg resulted in coma in a 19-year-old woman within 2 hours of ingestion (Anderson et al, 1984).
b) CASE REPORT: A patient ingested 2 grams baclofen and survived. This is the largest reported overdose (Gerkin et al, 1986).
c) CASE REPORT: Elderly patients have developed marked CNS and respiratory depression following 45 to 90 mg/day (White, 1985; Abarbanel et al, 1985).
d) CASE REPORT: A 29-year-old woman became comatose (Glasgow Coma Score of 3) and developed seizure activity, as noted by EEG monitoring, approximately 16 hours after ingesting 3500 mg baclofen, 150 mg desloratadine, and 84 mg esomeprazole. Her initial plasma baclofen concentration was 2,060 ng/mL (therapeutic range, 60 to 400 ng/mL). With supportive care, including administration of polyethylene glycol and activated charcoal, her seizure activity ceased on day 11. She regained consciousness on day 13 (plasma baclofen 50 ng/mL), was extubated on day 15 (plasma baclofen 22 ng/mL) and was subsequently discharged to a psychiatric care unit (Cleophax et al, 2015).
e) CASE REPORT: A 57-year-old man became comatose approximately 2 hours after intentionally ingesting 34 baclofen tablets (10 mg each). His Glasgow coma scale score, at presentation to the ED, was 6 (E1M4V1). Suspecting a possible ingestion of an opioid as well, naloxone was administered with no response. Continuous venovenous hemofiltration (CVVH) was then initiated. Following CVVH initiation, an EEG was performed which indicated slow frontal lobe activity; however, there was no indication of epileptiform activity and no response to pain stimuli. At 40 hours post-admission, the patient became responsive, and on hospital day 3, was completely conscious, at which time CVVH was discontinued. On hospital day 4, the patient was discharged from the intensive care unit (Meulendijks et al, 2015)
f) CASE REPORT/HIGH DOSE: A 66-year-old man, taking high dose baclofen for treatment of alcohol use disorder, presented with confusion, severe agitation, delirium, and auditory hallucinations. The baclofen dose at the time of presentation was 180 mg daily. Laboratory data revealed anemia, hypernatremia, and renal insufficiency with a creatinine clearance of 32 mL/min. An ECG indicated sinus bradycardia and a urinalysis was positive for cannabis. His blood baclofen level was 1510 mcg/L (therapeutic range for treatment of spasticity is 80 to 400 mcg/L). Following treatment, which included IV fluids and sedation managed by the administration of midazolam, propofol, and fentanyl, and a gradual decrease in the baclofen dosage with eventual cessation, the patient recovered without neurologic sequelae (Reichmuth et al, 2015).
g) CASE SERIES: In a retrospective analysis of 19 cases of baclofen overdose, CNS depression (Glasgow Coma Scale score of less than 9), delirium, seizures, and hypertension occurred more frequently following high-dose ingestions (greater than 200 mg) as compared with patients who ingested less than 200 mg of baclofen. ICU admissions also occurred more frequently and hospital length of stays were longer following high-dose ingestions (Leung et al, 2006).
h) CASE SERIES: According to a retrospective review of baclofen poisoning cases from the National Patient Register (NPR) and the Danish Poison Information Centre (DPIC) from 2007 to 2012, 24 cases were identified and classified according to Poison Severity Score (PSS). Mild toxicity was classified as PSS 1 (n=3), with patients developing drowsiness or agitation. The mean baclofen dose, as a mono-drug ingestion, was 220 +/-105.8 mg. Moderate toxicity was classified as PSS 2 (n=4), with patients developing delirium or were comatose with an appropriate response to pain. In 1 patient, the baclofen dose, as a mono-drug ingestion, was 300 mg , and, in 3 patients, the mean baclofen dose, as part of a poly-drug ingestion, was 270 +/- 42.4 mg . Severe or life-threatening toxicity was classified as PSS 3 (n=11), with patients presenting with a deep coma, hyporeflexia, hypotonia, and respiratory depression with insufficiency. In 3 of the 11 patients, the mean baclofen dose, as a mono-drug ingestion, was 2000 +/- 500 mg, and in the other 8 patients, the mean baclofen dose, as part of a poly-drug ingestion, was 900 +/- 641.3 mg (Kiel et al, 2015).

3) ADOLESCENT

a) CASE REPORT: A 17-year-old girl presented to emergency medical personnel as unresponsive, with subsequent development of a generalized tonic-clonic seizure at the hospital. Intubation was required for respiratory failure. A neurologic exam revealed bilaterally nonreactive pupils, no vestibulo-ocular, cough, or gag reflexes, no deep pain response, and flaccid paralysis with areflexia. Lab results were normal and CT scan and MRI of the brain showed no abnormalities. Given the patient's symptoms, examination findings, and diagnostic testing, a gamma-aminobutyric acid agonist was suspected to be the causative agent. High power liquid chromatography of the patient's serum, performed 12 hours post-admission, detected a baclofen level of 0.81 mcg/mL (laboratory therapeutic range 0.08 to 0.4 mcg/mL). Interview of the patient's parents revealed that approximately 28 10-mg baclofen tablets (prescribed to the father for treatment of spinal stenosis) were missing. With supportive care, the patient's condition gradually improved and she was discharged 12 days post-admission without sequelae (Caron et al, 2014).

4) INFANT

a) CASE REPORT: Respiratory arrest was reported in a 22-month-old child who ingested 120 mg (10.9 mg/kg) (Blankenship & Moses, 1983).

5) ROUTE OF EXPOSURE

a) INTRATHECAL

1) Intrathecal continuous infusion of 2000 mcg/day resulted in deep coma in a 25-year-old man with tetanus, while 1200 mcg/day was tolerated (Romijn et al, 1986).
2) Accidental continuous intrathecal infusion of 1.5 to 2 mg over 3 hours in one patient and 4 mg in another resulted in CNS and respiratory depression. Both remained comatose for 24 to 36 hours and were alert by the third day.

a) A distinct withdrawal syndrome then ensued, with concomitant rapid leg movement and hypotonic lower extremity muscles (Penn & Kroin, 1987).

3) Accidental bolus administration of 10 mg through a lumbar subarachnoid catheter resulted in coma and respiratory arrest in a 16-year-old boy, with an onset of 80 minutes and resumption of spontaneous respirations after 48 hours (Saltuari et al, 1990).
4) CASE REPORT: A 66-year-old man with multiple sclerosis inadvertently received 30,000 mcg baclofen intrathecally. A short time later he developed blurred vision, labored breathing, and weakness in his legs. Over the next several hours he became comatose, with flaccid quadriplegia and hypotension. He gradually recovered over the next 2 days with supportive care (Fakhoury et al, 1998).
5) CASE REPORT: A 16-year-old boy with spasticity secondary to traumatic brain injury was treated with intrathecal baclofen 200 to 400 mcg/day. He inadvertently received an overdose of 10 mg and developed somnolence, flaccidity, areflexia, nystagmus, and respiratory depression requiring mechanical ventilation. He developed focal seizures with secondary generalization 6 hours after the overdose, with status epilepticus lasting 90 minutes. He gradually recovered over the next 6 days with supportive care (including multiple anticonvulsants, intravenous physostigmine, drainage of 30 mL cerebrospinal fluid) (Kofler et al, 1992; Saltuari et al, 1992).
6) CASE REPORT: An adult inadvertently received a 1500 mcg bolus of intrathecal baclofen when the patency of the delivery system was tested. The patient lost consciousness abruptly, and developed miosis and respiratory depression. Mechanical ventilation was required for two days, but the patient recovered (Teddy et al, 1992).
7) CASE REPORT: A 47-year-old woman, who was receiving 800 mcg/day of baclofen intrathecally for treatment of spastic paraplegia secondary to multiple sclerosis, became comatose (Glasgow coma scale of 3) followed by generalized tonic-clonic seizures and apnea, necessitating intubation and mechanical ventilation, after inadvertently receiving an intrathecal bolus dose of baclofen 60 mg. With supportive therapy, including CSF drainage via a lumbar catheter, the patient gradually recovered without neurologic sequelae (Berger et al, 2012).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ACUTE

a) Baclofen levels of 17 milligrams/liter (serum) and 760 milligrams/liter (urine) were obtained 12 hours after ingestion in a fatal overdose (Fraser et al, 1991).
b) Postmortem level of baclofen in blood was 106 mcg/ml and in urine was 774 mcg/ml in one case (De Giovanni & d'Aloja, 2001). Dipyrone was a coingestant (blood and urine levels of 4-methyl-aminoantipyrine 669 mcg/ml and 215 mcg/ml respectively).
c) The intrathecal baclofen concentration of a 21-year-old man, 2 hours after inadvertently receiving 5 mg baclofen intrathecally via the bolus port of the intrathecal pump instead of via the reservoir port, was 13.1 mg/L. Within 24 hours, after receiving supportive care including lumbar drainage of CSF, a repeat measurement indicated that the baclofen concentration had decreased to 0.45 mg/L (Mahvash et al, 2011).
d) CASE REPORT: A 51-year-old woman experienced prolonged coma after intentionally ingesting an unknown amount of baclofen. Her serum baclofen concentration, obtained approximately 15 hours post-ingestion, was 2.7 mcg/mL (therapeutic range, 0.08 to 0.4 mcg/mL) (Sullivan et al, 2012).
e) CASE REPORT: A 29-year-old woman presented comatose with evidence of seizure activity, as noted by an EEG, approximately 16 hours after ingesting 3500 mg baclofen, 150 mg desloratadine, and 84 mg esomeprazole. Her initial plasma baclofen concentration was 2,060 ng/mL (therapeutic range, 60 to 400 mg); however, assuming first order elimination kinetics and working backwards to the first 4 time points with neglected absorption and distribution phases, it was estimated that the peak plasma baclofen concentration was approximately 8,000 ng/mL 3 hours post-ingestion. Four 6-hour hemodialysis sessions were performed, with a significant decrease in plasma baclofen concentrations by a mean of 50 +/- 2%; however, after cessation of each session, baclofen concentrations re-increased, until they had doubled 10 hours later. On day 8, her seizures recurred, with her plasma baclofen concentration increased to 306 ng/mL. With supportive care, including administration of polyethylene glycol and activated charcoal, her seizure activity ceased on day 11. She regained consciousness on day 13 (plasma baclofen 50 ng/mL), was extubated on day 15 (plasma baclofen 22 ng/mL) and was subsequently discharged to a psychiatric unit. The late rebound of plasma baclofen concentration is believed to be due to delayed intestinal absorption possibly as a result of reduced GI motility or the presence of a pharmacobezoar (Cleophax et al, 2015).

Toxicity Information

7.7.1)

A) References: Budavari, 1996

1) LD50- (ORAL)MOUSE:

a) 200 mg/kg

2) LD50- (SUBCUTANEOUS)MOUSE:

a) 103 mg/kg

3) LD50- (ORAL)RAT:

a) 145 mg/kg

4) LD50- (SUBCUTANEOUS)RAT:

a) 115 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Physicochemical

Physical Characteristics

A)

Ph

A)

Molecular Weight

A)

Animal Toxicology

References

General Bibliography

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

FeedBack

BACLOFEN

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Dermatologic

Musculoskeletal

Reproductive

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography