My patient on chronic oral baclofen began having mental status changes and hallucinations soon after hospitalization while still receiving baclofen. Could a lower than home-dose of baclofen have caused his withdrawal symptoms?

Absolutely! Although we usually think of withdrawal symptoms in the setting of complete discontinuation of certain CNS depressants, even a reduced dose of baclofen1,2 in a patient who has been on a higher dose chronically can precipitate full-blown withdrawal symptoms, such as delirium, fevers, hallucinations, hyperspasticity, autonomic instability and even respiratory failure, multiorgan failure, cardiac arrest and death.1-5

Recall that baclofen is a GABA-B agonist and a potent inhibitor of neuronal synapses with resultant decreased excitation of muscle spindles and muscle spasticity.6 Similar to other benzodiazepines, baclofen is also a CNS depressant and bears many similarities with alcohol in its physiologic effects.  For example, baclofen and alcohol both produce unsteady gait, dizziness, mood alterations and impairment in attention and memory and reduce anxiety, among others.  Not surprisingly, abrupt withdrawal from baclofen may produce similar symptoms as those associated with alcohol withdrawal, such as confusion, hallucination and delirium (observed in our patient) as well as seizures.3 Withdrawal symptoms typically occur 24-48 hours after discontinuation or reduction in the dose of baclofen.1,2

Of course, many of our hospitalized patients are already at risk of mental status changes or sedation from their underlying conditions or from medications needed to treat them.  In this setting, consideration in reducing the home dose of certain CNS depressants, such as baclofen, is understandable and reasonable. However, we should also keep in mind that even a reduction in the chronic dose of baclofen carries a risk of withdrawal!  Unfortunately, healthcare facilities often lack established management protocols for anticipated interruption of oral baclofen.7

In our patient, the home dose of baclofen had been reduced by one-half following his admission. Worsening delirium and new onset visual and auditory hallucinations were noted within a few days of hospitalization. Thankfully, no further bouts of confusion or hallucination was observed after resuming his home dose.

Bonus Pearl:

Did you know that baclofen is often used (off label) to treat intractable hiccups of central origin? 8,9

Contributed by Fahad Tahir, MD, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Terrence CF, Fromm GH. Complications of Baclofen Withdrawal. Arch Neurol. 1981;38(9):588–589. doi:10.1001/archneur.1981.00510090082011. https://jamanetwork.com/journals/jamaneurology/article-abstract/580084
  1. O’Rourke, F., Steinberg, R., Ghosh, P., & Khan, S. (2001). Withdrawal of baclofen may cause acute confusion in elderly patients. BMJ (Clinical research ed.), 323(7317), 870.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1121408/ 
  1. de Beaurepaire R. A review of the potential mechanisms of action of baclofen in alcohol use disorder. Front. Psychiatry 2018; 9:506). In fact, baclofen may be a promising treatment for alcohol use disorder. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232933/pdf/fpsyt-09-00506.pdf
  2. Cardoso AL, Quintaneiro C, Seabra H, Teixeira C. Cardiac arrest due to baclofen withdrawal syndrome. BMJ Case Rep. 2014;2014:bcr2014204322. Published 2014 May 14.doi:10.1136/bcr-2014-204322 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025399/pdf/bcr-2014-204322.pdf
  1. Green LB, Nelson VS. Death after acute withdrawal of intrathecal baclofen: case report and literature review. Arch Phys Med Rehabil. 1999 Dec;80(12):1600-4. doi: 10.1016/s0003-9993(99)90337-4. PMID: 10597813. https://www.archives-pmr.org/article/S0003-9993(99)90337-4/pdf
  1. Allerton CA, Boden PR, Hill RG. Actions of the GABAB agonist, (-)-baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro. Br J Pharmacol. 1989;96(1):29-38. doi:10.1111/j.1476-5381.1989.tb11780.x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1854300/
  1. Schmitz NS, Krach LE, Coles LD, Schrogie J, Cloyd JC, Kriel RL. Characterizing Baclofen Withdrawal: A National Survey of Physician Experience. Pediatr Neurol. 2021 Sep;122:106-109. doi: 10.1016/j.pediatrneurol.2021.06.007. Epub 2021 Jul 28. PMID: 34330615. https://www.pedneur.com/article/S0887-8994(21)00129-6/fulltext
  1. Zhang, C., Zhang, R., Zhang, S. et al. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial. Trials 15, 295 (2014). https://doi.org/10.1186/1745-6215-15-295
  1. Jeon YS, Kearney AM, Baker PG Management of hiccups in palliative care patients BMJ Supportive & Palliative Care 2018;8:1-6. https://spcare.bmj.com/content/8/1/1.long

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My patient on chronic oral baclofen began having mental status changes and hallucinations soon after hospitalization while still receiving baclofen. Could a lower than home-dose of baclofen have caused his withdrawal symptoms?

My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

Hepatic encephalopathy (HE) may be precipitated by a variety of factors including infection, hypovolemia, electrolyte imbalance (eg, hyponatremia, hypokalemia), metabolic alkalosis, sedatives, and of course UGIB. 1-3

Ammonia is often considered to play a central role in the the pathogenesis of HE, particularly when associated with UGIB. The ammoniagenic potential of UGIB is primarily attributed to the presence of hemoglobin protein in the intestinal tract. One-half of the ammoniagenesis originates from amino acid metabolism (mainly glutamine) in the mucosa of the small bowel, while the other half is due to the splitting of urea by the resident bacteria in the colon (eg, Proteus spp., Enterobacteriaceae, and anerobes).1,2

A large protein load in the GI tract, as occurs in UGIB, may result in hyperammonemia in patients with cirrhosis due to the limited capacity of the liver to convert ammonia to urea through the urea cycle as well as by the shunting of blood around hepatic sinusoids. Recent studies, however, also implicate the kidneys as an important source of ammonia in this setting, further compounding HE.3

It’s important to stress that ammonia is not likely to be the only mediator of HE. Enhanced production of cytokines due to infection or other inflammatory states, neurosteroids, endogenous benzodiazepines, and other bacterial byproducts may also play an important role in precipitating HE.2,4-6  So stay tuned!

Bonus pearl: Did you know that proinflammatory cytokines tumor necrosis factor-alpha and inerleukin-6 increase ammonia permeability across central nervous system-derived endothelial cells? 7

 

References

  1. Olde Damink SWM, Jalan R, Deutz NEP, et al. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 2003;37:1277-85.
  2. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol 2011;7:222-233.
  3. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90:646-58.
  4. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.
  5. Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with grade ¾ hepatic encephalopathy, but not mortality in controls. J Hepatol 2011;54:640-49.
  6. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci 2005;62:2295-2304.
  7. Duchini A, Govindarajan S, Santucci M, et al. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996;44:474-82.

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My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?