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By Sara Joseph, with Jason Hack
Division of Medical Toxicology, Brown University

Excerpts from the Toxic Matter Newsletter

was synthesized for the first time in 1962 by the Swiss chemist Heinrich Keberle as an anti-epileptic drug. Overall, it was found to be a disappointing anticonvulsant but studies noted that it significantly decreased spasticity in certain patients [1,2]. This remains its primary FDA approved use today and it is widely used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis. It is also being prescribed for many off label uses including trigeminal neuralgia, tardive dyskinesia, chronic hiccups, migraine prophylaxis, and Tourette’s syndrome. Most ubiquitously though, is its prescription as a muscle relaxer, in patients with chronic back pain. Currently there are many active studies exploring further uses for baclofen, especially in the treatment of alcohol withdrawal symptoms and marijuana dependence, however these have yet to become mainstream uses for the drug [4]. As Baclofen seeps further and further into everyday medical care physicians need a greater understanding of the mechanism of action, routes of delivery and complications of this drug across the board.

"Spasticity2" by Bill Connelly - Own work.
 Licensed under CC BY-SA 3.0 via Wikimedia Commons

What is it? Baclofen is a synthetic derivative of the naturally occurring inhibitory neurotransmitter GABA. Although the precise mechanism of action of Baclofen is not fully understood, it is thought to act principally on the GABA-B receptor at the spinal level and reduce the postsynaptic potentials along motor neurons, thus relaxing the skeletal muscles. It rapidly and completely absorbed from the GI tract, and reaches peak serum concentrations in 2 hours with a mean plasma elimination half-life of 3.5 hours when it is excreted unchanged primarily by the kidneys [3]. The rapid time on/time off of baclofen necessitates frequent dosing of the drug in order to maintain its effects.  

Toxicities: Baclofen has the potential for both overdose and withdrawal, which can both present with a wide array of symptoms. The variability of presentation is related to the fact that both overdoses and withdrawal, functionally present as dysautonomia- leading to variable presentations with, hypotension/hypertension, agitation/lethargy, miosis/myadrisis, seizures, bradycardia/tachycardia and less commonly other cardiac conduction disturbances with both.

Overdose: Most common are side effects to the nervous system: largely CNS depression with lethargy and somnolence, although patients with acute overdoses often present with hallucinations and agitation. Acute overdoses are also associated with GI side effects, most commonly with nausea, vomiting and diarrhea. Severe toxicity is associated with coma, respiratory failure, hypothermia, and seizures, and if unsupported death. Hypotension is more common in severe overdoses than hypertension and hypothermia is also more commonly featured in overdoses than in withdrawal.Baclofen3

Withdrawal: 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. 

The autonomic dysreflexia produced in baclofen withdrawal is often remembered by the mneumonic Itchy, Twitchy, Bitchy. Mild withdrawal is characterized by pruritus (itchy), increased tone (twitchy) and agitation (bitchy). As the withdrawal worsens, tachycardia, hyperthermia, and spontaneous clonus are usually noted. If withdrawal continues to go untreated usually there is worsening of all these symptoms, along with seizures, delirium/hallucinations, rhabdomyolosis and if unchecked death. 


How is it given?

Oral: Until the past 10 years, the primary method of administration of Baclofen was oral. In the oral form, dosage usually ranges from 40-80mg daily, dosed every 8 hours given the short drug half-life. Oral Baclofen, is centrally acting, but crosses the blood brain barrier ineffectively, limiting its bioavailability when taken orally. This effectively limits its efficacy before toxic adverse effects outweigh the benefit of the drug. Oral forms of the drug, therefore, have a very low toxic range with severe toxicity from oral baclofen, necessitating ICU level care occurring fairly consistently with baclofen overdoses of over 200mg [5]. This is just a 3-day supply of the drug for most people!

Intrathecal: The small toxic window for oral baclofen, led to the introduction of intrathecal baclofen. Intrathecal baclofen is administered through the implantation of a pump subcutaneously with a catheter from the pump inserted directly into the CSF fluid. These devices usually last about 5 years before they need replacement. Most patients have been adequately maintained on doses of 90 mcg to 800 mcg daily [8]. 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 have radically changed the quality of life for many patients with chronic spasticity- allowing them daily basic functionality and helping to control severe pain from protracted muscle spasms, without many of the CNS side effects that are seen with oral baclofen.


Overdose Treatment/Concerns:  

Oral baclofen overdoses with severe side effects are usually due to intentional overdoses-either for recreational or self harm purposes and are usually treated with good supportive measures until symptoms subside. In severe overdoses, this often means supporting blood pressure with fluids and pressors and often-mechanical ventilation for respiratory failure until drug toxicity subsides.

Baclofen4Intrathecal overdose can happen due to a couple common errors: the wrong dose is manually programmed into the pump, the wrong concentration is placed in the pump, the wrong bolus is given when starting the pump, the wrong port is accessed, or the wrong port is filled. Usually errors are man made- the pump has never had an incident on record of spontaneously releasing medication. Most are correctable by emptying the pump reservoir and in severe cases performing a lumbar puncture to reduce circulating baclofen in the CSF while performing all normal supportive strategies.


Withdrawal Treatment/Concerns:

Oral Baclofen withdrawal can occur when a person is abruptly stops taking baclofen or weans off to fast. It is important to note that oral baclofen diffuses through the blood brain barrier deep into the brain, causing many secondary effects apart from the intended spasticity relief; whereas- intrathecal baclofen stays almost exclusively in the CSF with a penetration of only approximately 1-2 inches into the brain [7]. Therefore, a person who is being switched to intrathecal baclofen must still be tapered off their oral baclofen or they will withdraw! Oral baclofen withdrawal is usually easily treatable by restarting baclofen and introducing a slow tapered wean if discontinuation is desired.

Intrathecal baclofen withdrawal poses more of a challenge in both recognition and treatment. Intrathecal baclofen withdrawal can occur secondary to pump malfunction, premature battery failure, medication interactions (SSRI’s are especially notorious for decreasing effects), wrong dose/wrong bolus/wrong concentration errors, and most commonly catheter malfunctions (kink/micro/macro leak, scarring, migration, and infection). Treating intrathecal baclofen withdrawal with oral baclofen is often unsuccessful as the vast difference in bioavailability of oral doses and intrathecal doses (1/100th) makes equivalent oral doses impossible to achieve without causing cardio-respiratory collapse. Supplementation of treatment with benzodiazepines, propofol and experimentally with dexomedetomidate and cyproheptadine can help with severe withdrawals. Ultimately though the best treatment for intrathecal baclofen withdrawal is intrathecal baclofen, and patients may require a CSF injection of baclofen while pump/catheter malfunction is investigated.

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. It is important to recognize that many of these patients have severe spasticity and may have limited verbalization skills, making them a vulnerable population, especially as the symptoms of baclofen withdrawal often masquerade as sepsis (ex-tachycardia, hyperthermia, altered mental status).

Given its highly variable clinical presentation always remember to consider baclofen withdrawal or overdose as the source of a patient’s symptoms especially as utilization of this drug both in intrathecal form and oral form grows across the country.


  1. Froestl, W( 2010). "GABAReceptor Pharmacology - A Tribute to Norman Bowery". Advances in Pharmacology 58:19–62. doi:10.1016/S1054-3589(10)58002-5.
  2. Yogeeswari, P.; Ragavendran, J. V.; Sriram, D. (2006). "An update on GABA analogs for CNS drug discovery" (PDF). Recent patents on CNS drug discovery 1 (1): 113–118. doi:10.2174/157488906775245291. PMID 18221197.
  3. Anderson P, Noher H, Swahn CG. “Pharmacokinetics in baclofen overdose”. Clin. Toxicol.1984; 22: 11–20
  4. Liu, J; Wang, LN (Feb 28, 2013). "Baclofen for alcohol withdrawal.". The Cochrane database of systematic reviews 2: CD008502. doi:10.1002/14651858.CD008502.pub3. PMID 23450582.
  5. Perry, HE; Wright, RO; Shannon, MW; Woolf, AD (1998). "Baclofen overdose: Drug experimentation in a group of adolescents". Pediatrics 101 (6): 1045–8. doi:10.1542/peds.101.6.1045. PMID 9606233.
  6. Leung NY1, Whyte IM, Isbister GK. (Feb 18,2006) Emerg Med Australas.: “Baclofen overdose: defining the spectrum of toxicity”.77-82
  7. Furr-Stimming, Boyle AM, Schiess MC (Nov 2014). Semin Neuol: Spasticity and intrathecal baclofen. PMID: 25520030
  8. Watve SV, Sivan M, Raza WA (2012) “Management of acute overdose or withdrawal state in intrathecal baclofen therapy”. Spinal Cord 50, 107-111
  9. Haranhalli Neil, Dhanya A (2011). “Intrathecal Baclofen therapy: complication avoidance and management”. Child’s Nervous System 2011: 27: 421-427


  1.  http://www.drugs.com/ppa/baclofen.html
  2.  Uptodate: “Baclofen” https://DanaInfo=www.uptodate.com+baclofen-drug-informationsource=search_result&search=baclofen+overdose&selectedTitle=2~150. Accessed 07/10/15


  1. Turner, Michael (July 31,2013) “Trouble Shooting the Synchromed Infusion Pump”- https://www.youtube.com/watch?v=otkiufGK9bE. Accessed 07/13/15


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