Reviewing the Evidence of the Association Between Baclofen and Encephalopathy.

In the United States, baclofen, a centrally acting γ-aminobutyric acid (GABA) agonist with renal elimination, was prescribed more than 6 million times in 2020.1The top 200 drugs of 2020.https://clincalc.com/DrugStats/Top200Drugs.aspxDate accessed: February 26, 2023Google Scholar Whereas it is primarily used as a muscle relaxant to treat spasticity, baclofen is also prescribed off-label for conditions such as alcoholism, gastroesophageal reflux disease, nystagmus, and trigeminal neuralgia.2Baclofendrug information—UpToDate.https://www.uptodate.com/contents/baclofen-drug-information?search=baclofen&source=panel_search_result&selectedTitle=1∼81&usage_type=panel&kp_tab=drug_general&display_rank=1#F138868Date accessed: February 26, 2023Google Scholar More than 30 case reports and two recent population-based studies conducted in Ontario (Canada) have linked baclofen use to encephalopathy in patients with renal disease.3Muanda F.T. Weir M.A. Bathini L. et al.Association of baclofen with encephalopathy in patients with chronic kidney disease.JAMA. 2019; 322: 1987-1995Crossref PubMed Scopus (22) Google Scholar,4Chauvin K.J. Blake P.G. Garg A.X. et al.Baclofen has a risk of encephalopathy in older adults receiving dialysis.Kidney Int. 2020; 98: 979-988Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar In the first population-based study, researchers evaluated the risk of encephalopathy in a cohort of 15,942 older adults with chronic kidney disease not receiving dialysis who were new users of baclofen.3Muanda F.T. Weir M.A. Bathini L. et al.Association of baclofen with encephalopathy in patients with chronic kidney disease.JAMA. 2019; 322: 1987-1995Crossref PubMed Scopus (22) Google Scholar The study found that patients who initiated baclofen at 20 mg/d or more vs less than 20 mg/d had a significantly higher risk of hospitalization with encephalopathy within 30 days. In the second population-based study, the researchers examined the risk of encephalopathy in 6469 older adults receiving maintenance dialysis. They found that those who started baclofen had a significantly higher risk of hospitalization with encephalopathy within 30 days compared with those who did not use baclofen.4Chauvin K.J. Blake P.G. Garg A.X. et al.Baclofen has a risk of encephalopathy in older adults receiving dialysis.Kidney Int. 2020; 98: 979-988Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar These two population-based studies considered comparisons with alternative muscle relaxants, including cyclobenzaprine and tizanidine; however, these drugs were prescribed infrequently in Ontario (Canada).3Muanda F.T. Weir M.A. Bathini L. et al.Association of baclofen with encephalopathy in patients with chronic kidney disease.JAMA. 2019; 322: 1987-1995Crossref PubMed Scopus (22) Google Scholar,4Chauvin K.J. Blake P.G. Garg A.X. et al.Baclofen has a risk of encephalopathy in older adults receiving dialysis.Kidney Int. 2020; 98: 979-988Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The study by Hwang et al. published in this issue of Mayo Clinic Proceedings fills this knowledge gap by comparing the risk of encephalopathy associated with oral baclofen vs other muscle relaxants, including tizanidine and cyclobenzaprine.5Hwang Y.J. Chang A.R. Brotman D.J. Inker L.A. Grams M.E. Shin J.I. Baclofen and the risk of encephalopathy: a real-world, active-comparator cohort study.Mayo Clin Proc. 2023; 98: 676-688Abstract Full Text Full Text PDF Scopus (1) Google Scholar The study used data from the Geisinger Health System in Pennsylvania, which included adults aged 18 years and older newly treated with baclofen or tizanidine in two cohorts. The study used a propensity score–based inverse probability of treatment weighting technique to balance the cohorts on 45 patient characteristics and Fine-Gray competing risk regression to estimate the risk of encephalopathy. The study also conducted four prespecified subgroup analyses based on age, estimated glomerular filtration rate, sex, concomitant opioid use, and multiple sensitivity analyses. In the cohort of patients treated with baclofen or tizanidine, the 30-day risk of encephalopathy was 64.7 (95% CI, 52.5 to 80.8) per 1000 person-years for baclofen users compared with 28.3 (95% CI, 18.8 to 44.5) per 1000 person-years for tizanidine users (subdistribution hazard ratio of 2.29 [95% CI, 1.43 to 3.67]). In the cohort of patients treated with baclofen or cyclobenzaprine, the 30-day risk of encephalopathy was 52.6 (95% CI, 38.5 to 73.9) per 1000 person-years for baclofen vs 22.3 (95% CI, 18.0 to 28.0) per 1000 person-years for cyclobenzaprine (inverse probability of treatment weighting subdistribution hazard ratio of 2.35 [95% CI, 1.59 to 3.48]). The results study showed that the 30-day risk of encephalopathy was at least 2-fold higher in patients treated with baclofen than with tizanidine or cyclobenzaprine. The study also found that the risk of encephalopathy persisted through the first year of treatment and remained consistent in subgroup analyses and across multiple sensitivity analyses. Hwang's study confirms and extends the findings of 30 international case reports and the previous population-based cohort study of 15,942 older adults with chronic kidney disease (defined by estimated glomerular filtration rate <60 mL/min per 1.73 m2) in Ontario, Canada, that linked baclofen to encephalopathy. Contrary to prior studies that apply to patients with renal disease, Hwang's study results may apply to a broader range of patients, including younger patients (i.e, adults <65 years old); those with normal renal function; those co-prescribed opioids; and patients without a history of multiple sclerosis, paralysis, or spinal cord injury. Hwang's study also confirms that the risk of encephalopathy is higher within the first 30 days of treatment initiation, which may persist for up to 1 year. Although the mechanism of action of baclofen-induced encephalopathy is not entirely understood, it is believed to be related to its effect on GABAB receptors.6Romito J.W. Turner E.R. Rosener J.A. et al.Baclofen therapeutics, toxicity, and withdrawal: a narrative review.SAGE Open Med. 2021; 920503121211022197Crossref PubMed Scopus (20) Google Scholar, 7Bowery N.G. GABAB receptor pharmacology.Annu Rev Pharmacol Toxicol. 1993; 33: 109-147Crossref PubMed Scopus (563) Google Scholar, 8Molderings G.J. Boomsma F. Göthert M. The enigma of baclofen toxicity.Trends Pharmacol Sci. 2004; 25: 255-257Google Scholar Baclofen activates GABAB receptors in the brain and spinal cord, decreasing excitatory neurotransmitter release and increasing the inhibitory neurotransmitter GABA. This results in muscle relaxation and a decrease in spasticity. However, excessive activation of GABAB receptors by baclofen can reduce the release of neurotransmitters critical for cognitive function and mood regulation, resulting in neurologic symptoms such as confusion, disorientation, and cognitive impairment. In addition, baclofen can decrease cerebral blood flow and metabolic activity, leading to more severe symptoms, such as seizures, coma, and even death. Taken together, Hwang's study and others have important clinical implications. Acknowledging that these studies did not consider the risk-benefit profile, the findings suggest that physicians should consider alternative drugs, such as tizanidine or cyclobenzaprine, for the indication for which they are considering baclofen. When baclofen is prescribed, it should be initiated at a low dose, especially in patients with kidney disease, and patients should be counseled and monitored for signs of toxic effects. If a patient is admitted to the hospital with encephalopathy, physicians should review the patient's medication list to determine whether baclofen is a potential cause. Prescribing references can cite these study findings, and computerized medication-order entry warnings can be updated.9Erler A. Beyer M. Petersen J.J. et al.How to improve drug dosing for patients with renal impairment in primary care—a cluster-randomized controlled trial.BMC Fam Pract. 2012; 13: 91Crossref PubMed Scopus (35) Google Scholar,10Tawadrous D. Shariff S.Z. Haynes R.B. Iansavichus A.V. Jain A.K. Garg A.X. Use of clinical decision support systems for kidney-related drug prescribing: a systematic review.Am J Kidney Dis. 2011; 58: 903-914Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Finally, regulatory agencies such as Health Canada and the US Food and Drug Administration should consider issuing warning labels to alert prescribers about the potential risk of encephalopathy associated with baclofen, particularly in patients with chronic kidney disease. The authors report no competing interests. Baclofen and the Risk of Encephalopathy: A Real-World, Active-Comparator Cohort StudyMayo Clinic ProceedingsVol. 98Issue 5PreviewTo quantify the risk of encephalopathy associated with oral baclofen compared with other muscle relaxants—tizanidine or cyclobenzaprine. Full-Text PDF