- Baclofen toxicity
- Baclofen withdrawal
- Questions & discussion
- Oral baclofen has a bioavailability of 70-85%, with absorption occurring within a few hours. It distributes to both the brain (where it causes sedation) and also the spinal cord (where it causes muscle relaxation).(32436697) Clinical effects of baclofen occur slowly (beginning over 3-4 days, with peak effect after 5-10 days), possibly due to slow penetration of the central nervous system.(20717751)
- Baclofen is excreted mostly by the kidneys, with a half-life of ~3 hours. Renal insufficiency may cause baclofen accumulation, with resultant toxicity.
- Intrathecal baclofen administration allows for greater concentrations in the spinal cord (achieving greater muscle relaxation) without higher levels in the brain (which would cause sedation). Intrathecal baclofen has a half-life of ~5 hours.(34158937)
mechanism of action
- Baclofen acts as an agonist of the GABA-B receptor. It is the only GABA-B agonist currently available.(32436697)
- Distribution of the GABA-B receptor includes the following:(32436697)
- GABA-B receptors are present in the brain (especially the cerebral cortex, thalamic nuclei, cerebellum, and amygdala).
- GABA-B receptors are also found in the ventral and dorsal horns of the spinal cord.
- GABA-B receptors occur outside the blood-brain barrier, within the sympathetic nervous system and some visceral tissues (including the heart).
- Oral baclofen
- For treatment of spasticity, dosing starts at ~5 mg PO TID. The dose may be gradually escalated as tolerated (e.g., increasing by 5 mg/dose every 3 days). The package insert recommends a maximal dose of 80 mg/day, but in practice patients may be treated with up to ~300 mg/day.(34158937)
- Acute ingestion of >200-400 mg baclofen is associated with a higher risk of coma, seizure, or intubation. However, patients on chronic baclofen therapy develop tolerance.(34358487)
- Intrathecal baclofen
- The dose range extends from roughly 50 – 1,000 mcg/day.(22006082)
- For spasticity of spinal cord origin, typical doses are 300 – 800 mcg/day.
- For spasticity of cerebral origin, typical doses are 90 – 700 mcg/day.
baclofen toxicity – diagnosis
relationship of renal failure with baclofen toxicity
- Renal dysfunction is the major risk factor for inadvertent baclofen intoxication. Kidney failure causes the half-life of baclofen to extend in an unpredictable fashion, so baclofen should be avoided in patients with GFR <30 ml/min.(28899601) Even relatively low doses may precipitate encephalopathy among patients with renal insufficiency (graphical abstract below).
- Patients on a chronic and stable dose of baclofen may develop toxicity due to the development of acute kidney injury (which causes acute accumulation of baclofen).
- In practice, encephalopathy frequently results from a synergistic combination of baclofen accumulation, uremic encephalopathy, and the accumulation of other centrally acting medications (e.g., gabapentin).
- 💡 Among intensivists and nephrologists, baclofen is notorious for the havoc it wreaks among patients with renal insufficiency. In a deep field of highly deliriogenic medications, baclofen is uniquely problematic.
symptoms of systemic baclofen toxicity
- Dysautonomia, most often:
- Usually depression of mental status (e.g., confusion, lethargy, somnolence, catatonia).(34158937) Less often, hallucinations, agitation, or mania may occur.
- Coma occurs at higher doses. With large intoxications, brainstem reflexes may be lost (causing baclofen intoxication to mimic brain death).
- Seizures (generalized tonic/clonic or myoclonic seizures) and/or nonconvulsive status epilepticus.(34158937)
- Hypotonia, hyporeflexia, and flaccid paralysis. With intrathecal baclofen intoxication, ascending hypotonia may occur.(27434299)
- Nystagmus, tremor.
- Respiratory suppression.
The differential diagnosis may vary depending on any individual patient's presentation. In cases of obvious overdose an extensive investigation may be unnecessary. Some differential diagnostic considerations may include:(22006082)
- Intracranial catastrophe (e.g., intracranial hemorrhage).
- Adrenal crisis.
- Decompensated hypothyroidism.
- Opioid intoxication (especially among patients who are receiving a combination of intrathecal opioid plus intrathecal baclofen).
baclofen toxicity – management
- For patients with a baclofen pump, the specialist managing the pump must be consulted immediately. The pump should be interrogated and generally stopped for 48 hours.
- ⚠️ Once symptoms of intoxication resolve, patients must often be restarted on a lower dose of baclofen, to prevent withdrawal.
- Intubation may be needed for airway protection.
- Hemodynamic support as needed.
- In acute baclofen poisoning, guidelines generally suggest that dialysis shouldn't be performed. However, the guideline is based largely upon patients with preserved renal function. There may be situations where dialysis is useful for acute poisoning (e.g., critical intoxication in a patient with severe renal failure).(34358487) 📄
- In subacute baclofen toxicity in the context of kidney impairment, dialysis is suggested if there is coma requiring mechanical ventilation. Multiple sessions are usually required. Dialysis may also be helpful in patients with marked somnolence/obtundation, with a goal of reducing hospital length of stay and avoiding nosocomial complications.(34358487) 📄
- ⚠️ The goal of hemodialysis is to remove enough baclofen for the patient to be extubated and be safely protecting their airway (i.e., not obtunded). For patients on chronic baclofen therapy, excessive removal of baclofen could precipitate withdrawal.
baclofen withdrawal – symptoms & investigation
- Dysautonomia, most often:
- Tachycardia, hypotension or hypertension.
- Anxiety, agitation, hallucinations, delusions, disorientation, and/or insomnia. In severe cases this may lead to stupor or coma.(31930325)
- Recrudescence of any underlying spasticity (rebound spasticity).
- Hyperreflexia, tremor, myoclonus, hypertonia, rigidity.
- Pruritus, paresthesia.(27434299)
- Nausea/vomiting, diarrhea.
oral vs. intrathecal baclofen withdrawal
- Intrathecal baclofen withdrawal tends to be more severe. This may rapidly progress to a multiorgan failure state resembling neuroleptic malignant syndrome (with tachycardia, rigidity, hypotension, fever, seizures, and rhabdomyolysis).(35314493)
- Oral baclofen withdrawal may be more notable for agitated delirium (given the distribution of oral baclofen to both the brain and spinal cord). Alternatively, intrathecal baclofen withdrawal may cause more pronounced spasticity (since there is predominantly a deficiency of baclofen within the spinal cord).
- Septic shock.
- Meningitis (which could relate to an infected pump).
- Autonomic dysreflexia (in patients with spinal cord injury).📖
- Serotonin syndrome.📖
- Neuroleptic malignant syndrome (NMS).📖
- Malignant hyperthermia.📖
- Malignant catatonia.📖
- Alcohol withdrawal.📖
- Sympathomimetic intoxication.📖
- Evaluation for competing diagnoses (e.g., sepsis).
- For patients with baclofen pumps, plain radiography may sometimes reveal catheter kinking, migration, or disconnection (with a series of films including several views). Baclofen pumps should also be interrogated to determine if they are functioning properly. More sophisticated imaging may be needed (e.g., with contrast injection into the pump's catheter).
- Investigation of the duration and timing of baclofen administration may be helpful. Baclofen withdrawal should occur within ~1-4 days of stopping oral baclofen (or <48 hours after stopping intrathecal baclofen, although the precise timing of pump malfunction may be unknown).(31930325; 27434299) If the patient was started on baclofen within <1 month, this would make baclofen withdrawal unusual.(34358487)
management of oral baclofen withdrawal
- General supportive care (e.g., hemodynamic support, management of rhabdomyolysis 📖, management of hyperthermia 📖, fluid resuscitation due to insensible losses).
- Resumption of oral baclofen therapy is the definitive therapy. However, even with resumption of oral baclofen, complete clinical resolution may be delayed by as long as 4 days.(31930325) This delay may be explained by the slow onset of action of oral baclofen (with onset after 3-4 days and peak effect after 5-10 days).(20717751)
- Dexmedetomidine may be useful, especially for immediate therapy (since IV dexmedetomidine will have a faster onset than oral baclofen). As a titratable agent that doesn't suppress respiration, dexmedetomidine may be especially well positioned to safely manage agitation.(31930325) Intravenous benzodiazepines may be helpful as well. If these are ineffective, then some of the therapies outlined below for intrathecal baclofen withdrawal could be added on.📖
management of intrathecal baclofen withdrawal
causes of intrathecal baclofen withdrawal
- Pump malfunction.
- Dosing error.
- Depletion of the pump's battery or baclofen reservoir.
- Intrathecal catheter migration or fracture.
- Intentional pump removal due to infection.
why management of intrathecal baclofen withdrawal is difficult
- Intrathecal baclofen selectively delivers a high concentration of baclofen to the spinal cord, while avoiding excess baclofen delivery to the brain. It can be nearly impossible to replace this activity using systemic medications. For example, oral baclofen will tend to cause respiratory suppression before reaching very high levels in the spinal cord. Downregulation of spinal GABA-B receptors make it even more impossible to use systemic baclofen to achieve control of spasticity.
optimal management: resumption of intrathecal baclofen
- The ideal management is to immediately resume intrathecal baclofen.
- Pump revision is best achieved by a surgical team in the operating room.
- Temporary replacement of intrathecal baclofen may be achieved by infusion into a lumbar drain (which may be placed by neurosurgeons or anesthesiologists). This may be used as a bridge to stabilize the patient, until more durable pump revision is possible.
- A single bolus of intrathecal baclofen may be administered via lumbar puncture, but this is only a temporizing measure.(27434299)
management of intrathecal baclofen withdrawal without intrathecal baclofen
- Withdrawal may need to be managed without intrathecal baclofen; for example, in the following situations:
- (1) Infection or coagulopathy renders it dangerous to place a lumbar drain.
- (2) Lack of immediate access to neurosurgical or anesthesiology expertise required to administer intrathecal baclofen.
- (3) The patient was on an extremely low dose of intrathecal baclofen, which might be expected to be manageable without resumption of intrathecal baclofen.
- There is no high-level evidence regarding the optimal strategy to manage this. The challenge is to provide adequate symptomatic relief without causing respiratory suppression.
- There is no silver bullet. Multimodal therapy is generally needed, with the use of several antispasmodic agents acting upon different receptor sites. The use of several agents at low doses might achieve synergistic efficacy, while avoiding toxicity due to high doses of any single agent. Consensus guidelines recommend that oral baclofen, benzodiazepines, and cyproheptadine may be considered as front-line agents.(27434299) However, dexmedetomidine is arguably the front-line agent for management of agitation (due to its rapid action, titratability, and lack of respiratory suppression).
- ⚠️ If this strategy fails (and it may!), the need for intrathecal baclofen should be reconsidered. Note that intrathecal baclofen is the definitive therapy.
- General supportive care is essential (e.g., hemodynamic support, management of rhabdomyolysis 📖, management of hyperthermia 📖, fluid resuscitation due to insensible losses).
- For management of hypertension combined with agitation, consider dexmedetomidine (more on this below).(31759793)
oral baclofen 💊
- A moderate dose of oral baclofen is generally administered (e.g., 10-20 mg PO q8hr).(35314493)
- As discussed above, it's impossible to fully treat intrathecal baclofen withdrawal using oral baclofen.
- High doses of oral baclofen will cause sedation, without much additional benefit for spasticity. Patients may be poorly tolerant of oral baclofen, despite previously being exposed to high doses of intrathecal baclofen (because intrathecal baclofen causes desensitization of the spinal cord – but not the brain).(27434299)
- ⚠️ Oral baclofen has a slow onset of action (~3-4 days), due to slow penetration of the central nervous system.(31759793) You shouldn't expect oral baclofen to cause any immediate clinical benefit!
- Benzodiazepines might theoretically be the most effective agent, albeit with a risk of sedation at higher doses. Stimulation of spinal GABA-A receptors by benzodiazepines may circumvent a deficiency of spinal GABA-B activity.(34158937) Benzodiazepines may also reduce the risk of seizure.
- A reasonable dose might be lorazepam 0.5-2 mg IV Q6hr, or midazolam 1-4 mg IV Q6hr.(34158937)
- ⚠️ There is no good data on optimal dosing, so the best approach might be to provide titrated IV doses while carefully observing the patient's responses (both to determine whether the benzodiazepine is improving symptoms, and whether sedation is occurring).
- If the patient is becoming increasingly somnolent, doses should be reduced or held. It may be useful to combine a moderate scheduled dose plus a small additional PRN dose, to avoid excessive dosing.
- Diazepam may be also used (e.g., 2-10 mg IV q6hr). Diazepam has a half-life of 20-50 hours, so this will accumulate over time.(34158937) Accumulation may be beneficial, as this prevents patients from experiencing marked withdrawal of benzodiazepine between doses. However, accumulation may also be dangerous if diazepam is scheduled and doses are continued despite increasing somnolence.
central alpha-2 agonists (dexmedetomidine, tizanidine)
- Dexmedetomidine may be a useful agent, since it is highly titratable and doesn't cause respiratory suppression.(31759793) Dexmedetomidine is an excellent agent to use for management of agitation. Dexmedetomidine is also helpful to suppress sympathetic activation (e.g., tachycardia and hypertension).
- Oral tizanidine 💉 is another central alpha-2 agonist, with greater antispasmodic activity and less sedative activity (compared to dexmedetomidine). Tizanidine may be useful as an adjunctive agent to treat spasticity (often beginning at a dose of 4 mg PO q8hr).(20717751)
- Cyproheptadine is an antihistamine and antiserotonin agent, with some antispasmodic activity. Unfortunately, it does have sedative properties.
- A reasonable dose might be 4 mg PO q6hr, with gradual uptitration to 8 mg q6hr if tolerated.(27434299; 20717751)
- Dantrolene is a ryanodine receptor antagonist, with antispasmodic properties.
- Low-dose dantrolene may provide some efficacy against spasms, without causing respiratory sedation (e.g., 25 mg/day, with gradual uptitration if tolerated).
- The role of dantrolene in baclofen withdrawal is unclear, but it could be used for spasticity refractory to other therapies.(20717751)
- If other treatments fail, then intubation and sedation may be utilized (e.g., with a propofol infusion).
- In highly unstable patients, intubation with chemical paralysis may be used as a temporary strategy to achieve control of refractory rigidity or extreme hyperthermia.
- The strongest indication for intubation with paralysis is profound hyperthermia. Elimination of skeletal muscle activity may be required for prompt temperature control.
Follow us on iTunes
questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Failure to consider the possibility of baclofen intoxication or withdrawal, especially among patients with intrathecal baclofen pumps (who may not have “baclofen” listed on the medication list).
- The specialist managing the baclofen pump should be contacted immediately for assistance in managing these crises.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
- RebelEM: Baclofen Withdrawal (by Anand Swaminathan)
- 20717751 Ross JC, Cook AM, Stewart GL, Fahy BG. Acute intrathecal baclofen withdrawal: a brief review of treatment options. Neurocrit Care. 2011 Feb;14(1):103-8. doi: 10.1007/s12028-010-9422-6 [PubMed]
- 22006082 Watve SV, Sivan M, Raza WA, Jamil FF. Management of acute overdose or withdrawal state in intrathecal baclofen therapy. Spinal Cord. 2012 Feb;50(2):107-11. doi: 10.1038/sc.2011.112 [PubMed]
- 27434299 Saulino M, Anderson DJ, Doble J, Farid R, Gul F, Konrad P, Boster AL. Best Practices for Intrathecal Baclofen Therapy: Troubleshooting. Neuromodulation. 2016 Aug;19(6):632-41. doi: 10.1111/ner.12467 [PubMed]
- 28899601 Wolf E, Kothari NR, Roberts JK, Sparks MA. Baclofen Toxicity in Kidney Disease. Am J Kidney Dis. 2018 Feb;71(2):275-280. doi: 10.1053/j.ajkd.2017.07.005 [PubMed]
- 31759793 Gottula AL, Gorder KL, Peck AR, Renne BC. Dexmedetomidine for Acute Management of Intrathecal Baclofen Withdrawal. J Emerg Med. 2019 Nov 20:S0736-4679(19)30827-3. doi: 10.1016/j.jemermed.2019.09.043 [PubMed]
- 31930325 Defayette A, Perrello A, Brewer T, Picano J, Ahmed S. Enteral baclofen withdrawal managed with intravenous dexmedetomidine: A case report. Am J Health Syst Pharm. 2020 Feb 19;77(5):352-355. doi: 10.1093/ajhp/zxz332 [PubMed]
- 32204996 Parker-Pitts CK, Weymouth CW, Frawley MT. Intrathecal Baclofen Overdose With Paradoxical Autonomic Features Mimicking Withdrawal. J Emerg Med. 2020 Apr;58(4):616-619. doi: 10.1016/j.jemermed.2019.12.031 [PubMed]
- 32436697 Kent CN, Park C, Lindsley CW. Classics in Chemical Neuroscience: Baclofen. ACS Chem Neurosci. 2020 Jun 17;11(12):1740-1755. doi: 10.1021/acschemneuro.0c00254 [PubMed]
- 34158937 Romito JW, Turner ER, Rosener JA, Coldiron L, Udipi A, Nohrn L, Tausiani J, Romito BT. Baclofen therapeutics, toxicity, and withdrawal: A narrative review. SAGE Open Med. 2021 Jun 3;9:20503121211022197. doi: 10.1177/20503121211022197 [PubMed]
- 34358487 Ghannoum M, Berling I, Lavergne V, Roberts DM, Galvao T, Hoffman RS, Nolin TD, Lewington A, Doi K, Gosselin S; EXTRIP workgroup. Recommendations from the EXTRIP workgroup on extracorporeal treatment for baclofen poisoning. Kidney Int. 2021 Oct;100(4):720-736. doi: 10.1016/j.kint.2021.07.014 [PubMed]
- 35314493 Balaratnam MS, Stevenson VL. Intrathecal baclofen pumps: what the neurologist needs to know. Pract Neurol. 2022 Mar 21:practneurol-2021-003184. doi: 10.1136/practneurol-2021-003184. Epub ahead of print [PubMed]