baclofen overdose

Pediatric Baclofen Overdose

Case

A 16 year-old male presented to the emergency department after intentional overdose of 200 mg of baclofen. The patient was found in his bedroom by family members approximately 10 hours after ingestion with reported twitching, vomiting, unresponsiveness, and possible seizure activity. On arrival to the emergency department, the patient was awake, alert, and oriented; tearful, but otherwise asymptomatic.

 

Physical Exam

Vital signs included blood pressure 150/76, heart rate 112, temperature 99.2 F (37.3 C), respiratory rate 26, SpO2 97%. Physical exam showed frequent bilateral upper greater than lower extremity myoclonic jerks. The patient’s neurologic exam and physical exam were otherwise unremarkable.

 

Labs/Imaging

The patient’s toxicological workup was pertinent for undetectable salicylate, acetaminophen, and ethanol levels. His urine drug screen was negative. EKG showed sinus tachycardia with normal QRS and QTc intervals. A head CT previously completed at an outside hospital was normal. The rest of his laboratory evaluation including CBC, electrolyte levels, and hepatic function tests, was unremarkable.

 

Discussion

Baclofen is a centrally-acting skeletal muscle relaxant which functions as a GABA-B receptor agonist, believed to inhibit synaptic transmission of signals to the muscle from the spinal cord. Baclofen is typically prescribed for symptoms related to severe muscle spasm, such as in spinal cord injury or chronic neurologic disease (e.g. multiple sclerosis.) The medication can be administered either orally, or via an intrathecal pump.

Baclofen is absorbed rapidly from the GI tract in a dose-dependent manner, with peak serum levels occurring after ~1 hour (with a range of 0.5-4 hours). However, this has been found to be highly variable in pediatric patients. Its volume of distribution is also highly variable among pediatric patients, with nearly 50% interindividual variability. The reason for this variability is not clearly understood.

Baclofen is primarily excreted renally, with a serum half-life of 4.5 hours in pediatric patients, and a CSF half-life of 1.5 hours in intrathecal administration.

Baclofen overdose typically manifests with neurologic symptoms and dysautonomia. Symptoms are variable and may include: CNS depression/coma, hypotonia, hyporeflexia, seizure, respiratory depression, tachycardia, bradycardia, hypertension, hypotension, and arrhythmia. In adults, ingestions of >200 mg appear to correlate with an increased risk of respiratory failure, mechanical ventilation requirement, and ICU admission time.

 In an unfortunate case series, a group of teenagers overdosed on 60-600 mg of baclofen for recreational purposes. Patients displayed symptoms of overdose in 1-2 hours. 9 of 14 were intubated. Of 8 that were followed longitudinally: 7 were comatose, 6 were hypothermic, 5 were bradycardic, 4 were hypertensive, 8 were hyporeflexic, 3 had PVCs, and 2 had tonic-clonic seizures. The mean time of intubation was 40 hours. All patients recovered.

 

Treatment

Treatment of baclofen overdose is primarily supportive with IV fluids, hemodynamic and respiratory support, and antiepileptics as needed. Activated charcoal may also be considered. There are case reports of physostigmine being effective in low/moderate overdoses; however, its use is controversial. Finally, hemodialysis does shorten clearance time and resolution of toxicity in patients with normal and impaired renal function.

 

Disposition

Patients should be monitored until symptoms resolve. Depending on the dose ingested, the length of time since ingestion, clinical status, and laboratory analysis, they may be monitored either on the floor with telemetry or in the ICU.

 

Conclusion

The patient was treated with a 1 liter normal saline bolus and 1 mg of lorazepam IV; his hemodynamics normalized, his myoclonic twitching resolved, and he remained stable without seizure or complication throughout emergency department stay. He was admitted to the pediatric ICU for overnight monitoring, where he remained asymptomatic and had normal vital signs. The patient was then transferred to inpatient psychiatry for mental health treatment.

 

Summary

Baclofen overdoses typically present with a combination of altered mental status and or seizure, hypotonia, and dysautonomia. Treatment is primarily supportive and most patients recover with IV fluids, hemodynamic and respiratory support, and antiepileptics as-needed (usually benzodiazepines.) Activated charcoal should be considered. Patients should be admitted either to medical floor with telemetry or ICU depending on clinical status; they should remain admitted until symptoms resolve (typically several days, depending on ingested dose).

Faculty Reviewer: Dr. Jane Preotle 

References

  1. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1742-6723.2006.00805.x

  2. http://ajcc.aacnjournals.org/content/15/6/611.full.pdf%2Bhtml%20

  3. https://emj.bmj.com/content/22/9/673

  4. https://www.mdpoison.com/media/SOP/mdpoisoncom/ToxTidbits/2012/February%202012%20ToxTidbits.pdf

  5. https://pediatrics.aappublications.org/content/101/6/1045

  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841240/

  7. https://www.acep.org/how-we-serve/sections/toxicology/news/september-2015/baclofen/

  8. https://www.uptodate.com/contents/baclofen-drug-information?search=baclofen&source=panel_search_result&selectedTitle=1~82&usage_type=panel&kp_tab=drug_general&display_rank=1

The Obtunded Patient

The Case

52 y/o male with HTN, hyperlipidemia, chronic back pain, and recent depression came back from a walk and per family was ataxic, dysarthric and confused, so his family drove him to the ED. On the way, he began vomiting repeatedly and became increasing obtunded.  As he entered the ED went into apparent cardiovascular and respiratory collapse. Given 2mg of Naloxone without response and intubated by RSI for further evaluation.

Examination

Vitals on arrival in the ED:  Temp: 36, RR:-no spontaneous breaths noted after entering the ED O2: 88% on bag valve mask, HR: 68 BP: 88/64. Glucose 104.  GCS 3 (non verbal, no motor movement, pupils 2mm and fixed). No corneal or occulacephalic reflexes noted, no cough or gag elicited. All extremities were flaccid and areflexic. EKG show sinus rhythm, no obvious conduction abnormalities.

Medication hx: Simvastatin 40 mg daily, amlodipine 10 mg daily, Baclofen 20 mg TID, Vicodin 5-300 1 tablet q6 hrs

Labs: ETOH: 150. CBC, lactic acid, chemistry, venous blood gas (on ventilator), CPK, LFT’s, troponin asa, acetaminophen, UA, UDS all WNL

Imaging: CTA pan scan negative except for mild aspiration in the R lung base.

 

So what happened…..?

Baclofen Toxicity

What is it?

Baclofen is a synthetic derivative of the naturally occurring inhibitory neurotransmitter GABA.

Acts principally on the GABA-B receptor at the spinal level and reduce the post-synaptic potentials along motor neurons, thus relaxing the skeletal muscles.

Baclofen is primarily used for the treatment of spastic movement disorders and now more ubiquitously for the treatment of chronic back pain.

 

How is it given?

Oral: Until the past 10 years, the primary method of administration of Baclofen was oral.

  • Peak concentration in 2 hours and half life of 3.5hours
  • Dosage 40-80mg daily dosed q8 hrs
  • Centrally acting but crosses the blood brain barrier ineffectively, limiting its bioavailability
  • Very low toxic range with severe toxicity from oral baclofen, necessitating ICU level care occurring fairly consistently with baclofen overdoses of over 200mg (a 3 day supply for most people)
Figure 2: Baclofen pump concept

Figure 2: Baclofen pump concept

Intrathecal: Intrathecal baclofen is administered through the implantation of a pump subcutaneously with a catheter from the pump inserted directly into the CSF fluid.

  • Dosage: 90 mcg to 800 mcg daily
  • Intrathecal baclofen allows for 4x the amount of baclofen to be delivered to the spinal cord with just 1% of the oral dose.

Intrathecal Baclofen Pumps: The pump is surgically implanted under the skin in the abdomen and the catheter is tunneled under the skin and inserted into the intrathecal space usually between the 1st and 2nd lumbar vertebrae.

Currently SynchroMed is the only pump currently being used in the US for intrathecal baclofen, hydromorphone and morphine

  • The catheter holds 3-4ml
  • The reservoir holds 20-40ml
  • Pump battery lasts for 5-7 years
Figure 3: Synchromed Baclofen pump

Figure 3: Synchromed Baclofen pump

Toxicities 

Baclofen has the potential for both overdose and withdrawal, which can both present with a wide array of symptoms.

Overdose Symptoms

Most commonly include CNS depression, lethargy, somnolence, hallucinations, agitation, mydriasis/miosis, nausea and vomiting

Severe toxicity is associated with bradycardia, hypotension (more common) or hypertension, respiratory failure, hypothermia, seizures, coma and death.

Rarely, rhabdomyolysis and conduction disturbances may occur

Causes

Oral Baclofen overdoses:

  • Usually intentional overdoses-either for recreational or self harm

Intrathecal baclofen overdoses:

  • Wrong dose is manually programmed into the pump
  • Wrong concentration is placed in the pump
  • Wrong bolus is given when starting the pump
  • Wrong port is accessed or wrong port filled

Treatment

Patients are usually treated by supportive methods only.

In severe overdoses, this often means supporting blood pressure with fluids and pressors and often-mechanical ventilation for respiratory failure until drug toxicity subsides.

Generally overdose symptoms will resolve in approximately 24-48 hours

For Intrathecal baclofen overdoses:

Most are correctable by emptying the pump reservoir:

  • Turn off pump-programmer (need external device programmer to do this)
  • Empty reservoir: Use a 22 gauge needle to stick the middle of the pump and pull out all the drug
Figure 4: Emptying the reservoir

Figure 4: Emptying the reservoir

Remove the CSF- Use a 24-25 gauge needle to stick the side port and aspirate 30-100 ml of CSF

In severe cases performing a lumbar puncture to reduce circulating baclofen in the CSF while performing all normal supportive strategies (small case reports- this involves replacing entire circulating volume of CSF with saline and has been used successfully in a few cases of massive overdose)

Withdrawal Symptoms

Similar to withdrawal from alcohol or benzodiazepines, with the loss of gaba-mediated inhibition: hyper metabolic states, spasticity/rigidity, hallucinations/seizures, tachycardia, hyperthermia, and hypertension are more commonly observed.

Mild: pruritus, agitation, diaphoresis and increased tone

Moderate: fever, tachycardia, spontaneous clonus and painful muscle spasm

Severe: worsening of above along with seizures, delirium, hallucinations, rhabdomyolysis and death.

Remember the mnemonic, "ITCHY, TWITCHY, BITCHY."

Causes of Withdrawal

Oral Baclofen Withdrawal:

  • Oral Baclofen withdrawal can occur when a person is abruptly stops taking baclofen or weans off to fast.
  • Of note oral baclofen diffuses through the blood brain barrier deep into the brain whereas- intrathecal baclofen stays almost exclusively in the CSF with a penetration of only approximately 1-2 inches into the brain. Therefore, a person who is being switched to intrathecal baclofen must still be tapered off their oral baclofen or they will withdraw.

Intrathecal Baclofen Withdrawal:

  • Intrathecal Pump Malfunction
    • Intrinsic pump malfunction is exceedingly rare.
  • Pocket Refill
    • Rather than an overdose this results in acute withdrawal as intrathecal dosing is 1/100th of oral dosing/subcutaneous dosing.
  • Battery failure
    • Expected to die at 84 months.
    • Will alarm 3 months prior. 

Medication Changes or interactions:

  • SSRI’s especially known for decreasing effect

Catheter malfunctions: (kink, micro/macroleaks, scarring, migration)

  • Most common cause of pump failure
  • KUB and AP/lateral spine first step to look for catheter fracture or migration
Figure 6: KUB demonstrating Baclofen pump

Figure 6: KUB demonstrating Baclofen pump

Treatment

Oral Baclofen withdrawal is usually easily treatable by restarting baclofen and introducing a slow tapered wean if discontinuation is desired.

Intrathecal Baclofen Withdrawal presents more of a challenge in both recognition and treatment.  It can be tricky to recognize baclofen withdrawal as it often masquerades as sepsis (ex-tachycardia, hyperthermia, altered mental status). It is important to recognize that many of these patients have severe spasticity and may have limited verbalization skills. Often they come from long term care facilities without much information, along with the fact that many times the baclofen will not be listed on their daily facility medication list, making it extremely important to look for a pump every time.

Recognizing that a patient’s symptoms may be secondary to intrathecal baclofen and interrogating the pump and obtaining pump series imaging to evaluate for catheter related malfunctions is a key first step

Essentially intrathecal baclofen withdrawal requires intrathecal baclofen. The key is finding the reason for the withdrawal and fixing the primary cause. Everything else is a temporizing measure.

To help with symptoms while attempting to fix the primary cause of pump failure treatment can include:

  • High Dose Oral Baclofen
    • Treating intrathecal baclofen withdrawal with oral baclofen is often unsuccessful as the vast difference in bioavailability of oral doses and intrathecal doses.
  • Benzodiazepine treatment
  • Propofol low dose
  • Experimentation with Dexamedetomidine and cyproheptadine
  • CSF infusion of Baclofen

So what happened to our patient?

After approximately 18 hours intubated, our patient began waking up, became agitated and self-extubated himself. He admitted to taking approximately 900 mg of baclofen in a suicide attempt the day of admission. He was discharged to inpatient psychiatry without any further medical sequela on hospital day 3. 

Take Home Points

  • Overdose: variable presentation, CNS depression is often involved, good supportive care is key.
  • Withdrawal: variable presentation, Itchy/twitchy/bitchy. Will have increased muscle tone from baseline.
  • Always remember the pump is there.
  • Overdose: For intrathecal overdose-2 ports from which you can draw drug and CSF back out.
  • Withdrawal: Look for the cause and treat supportively with oral baclofen, benzos, and propofol.

Faculty Reviewer: Dr. Kristina McAteer

References

Image 1: “Spasticity2” by Bill Connelly- Own Work

https://commons.wikimedia.org/wiki/File:Spasticity2.svg

Image 2: http://www.gablofen.com/patients/intrathecal-baclofen-therapy

Image 3: http://www.ajnr.org/content/32/7/1158

Image 4: http://www.rch.org.au/kidsinfo/fact_sheets/Intrathecal_baclofen_3_the_ITB_pump/

Image 5: http://www.cliparthut.com/clip-arts/175/people-clip-art-175256.gif

Image 6: https://emcow.files.wordpress.com/2014/01/baclofen-3.jpg