Higher doses of baclofen in patients with chronic kidney disease (CKD) may be associated with an increased risk of encephalopathy, according to a study published in JAMA.

Although primarily used as a muscle relaxant for patients with spasticity, baclofen is also prescribed off-label for conditions such as alcoholism, gastroesophageal reflux disease, nystagmus, and trigeminal neuralgia. However, instead of being metabolized by the liver, baclofen is eliminated primarily unchanged in the urine, with a step-wise prolongation in the elimination of half-life as kidney function declines, according to the authors.

Although at least 30 case reports have linked baclofen use to encephalopathy in patients with CKD within days of initiating the drug, there have been no clinical studies assessing the risk of baclofen-associated encephalopathy.

“It came to my clinical attention dealing with patients with advanced kidney failure, that this drug that is generally thought to be relatively harmless, appeared to be the precipitant of severe confusion,” co-author Peter Blake, MB, FRCPC, professor at Schulich Medicine & Dentistry, said in a press release. “These are patients who had previously been very oriented, and they were suddenly extremely confused and when you took a history, we understood that they had recently started this drug, baclofen.”

Baclofen was prescribed more than 8.3 million times in the United States in 2016, according to the study. Because the drug has not been previously associated with serious adverse effects, it has become widely prescribed.

For the study, the authors compared the 30-day risk of encephalopathy in approximately 16,000 patients with CKD and newly-prescribed baclofen at greater than or equal to 20 mg per day versus less than 20 mg per day. Patients who started a new dose of baclofen between 2007 and 2018 were included.

Overall, hospitalization with encephalopathy occurred in 1.11% of patients who started baclofen at greater than or equal to 20 mg per day and in 0.42% who started baclofen at less than 20 mg per day. A subgroup analysis showed that the absolute risk increased progressively at lower estimated glomerular filtration rate (eGFR) (weighted risk difference [RD] eGFR 45-59, 0.42% [95% CI, 0.19%-0.64%]; eGFR 30-44, 1.23% [95% CI, 0.62%-1.84%]; eGFR <30, 2.90% [95% CI, 1.30%-4.49%]; P for interaction, <.001]).

Additionally, 3.75% of patients with kidney function less than 30% were hospitalized with cognitive-related symptoms after starting a high dose of baclofen, the authors found.

Starting baclofen at the higher dose was also associated with a higher risk of hospitalization with delirium and all-cause hospitalization, but not all-cause mortality, according to the results.

According to the secondary comparison with 284,263 nonusers, both groups of baclofen users had a higher risk of encephalopathy (<20 mg/d weighted risk ratio [RR], 5.90 [95% CI, 3.59 to 9.70] and ≤20 mg/d weighted RR, 19.8 [95% CI, 14.0 to 28.0]).

The authors noted that the findings will better inform physicians and pharmacists about the use of baclofen for patients with CKD.

“If verified, these risks should be balanced against the benefits of baclofen use,” the authors wrote.


REFERENCES

Common muscle relaxant linked to severe confusion in patients with kidney disease [news release]. Western University’s website. https://mediarelations.uwo.ca/2019/11/09/common-muscle-relaxant-linked-to-severe-confusion-in-patients-with-kidney-disease/. Accessed November 11, 2019.

Muanda FT, Weir MA, Bathini L, et al. Association of baclofen with encephalopathy in patients with chronic kidney disease. JAMA. 2019. doi:https://doi.org/10.1001/jama.2019.17725