London, Ontario—Use of a common muscle relaxant in patients with very low kidney function can create severe cognitive-related symptoms, a new study warns.

The report in JAMA points out that one in 25 chronic kidney disease (CKD) patients were admitted to the hospital with encephalopathy within a few days after being prescribed baclofen.

The study, led by Canadian researchers from Western University, was also presented at the American Society of Nephrology meeting in Washington, DC.

“When we looked at people with low kidney function (30% or less) who received a high dose of baclofen from their prescriber, approximately one in 25 were being admitted to hospital with severe confusion, typically over the next few days,” said coauthor Amit Garg, MD, PhD. “If you compare that to a group of people who had low kidney function who didn’t get baclofen, that risk is less than one in 500, so it’s quite a dramatic difference between the two groups.”

Researchers launched the study based on observations from nephrologists at London Health Sciences Centre, noting that at least 30 case reports have linked the muscle relaxant baclofen to encephalopathy in patients with CKD.

The study team sought to compare the 30-day risk of encephalopathy in patients with CKD and newly prescribed baclofen at greater than or equal to 20 mg per day versus less than 20 mg per day. Investigators also looked to compare the risk of encephalopathy in baclofen users versus nonusers.

The retrospective, population-based cohort study in Ontario, Canada, was performed using linked healthcare data from 2007 to 2018. Participants were 15,942 adults aged 66 years or older—61% women—with CKD, defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 in patients not receiving dialysis. Although the primary cohort was restricted to patients who were newly prescribed baclofen, participants in the secondary cohort also included new users and nonusers.

The focus was on hospital admission with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, transient cerebral ischemic attack, or unspecified dementia within 30 days of starting baclofen.

For the study, 9,707 (61%) patients were started on baclofen at 20 mg/d or greater, while 6,235 (39%) received the muscle relaxant at less than 20 mg/d. Results indicate that the primary outcome—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; weighted risk ratio (RR), 3.54 (95% CI, 2.24-5.59); weighted risk difference (RD), 0.80% (95% CI, 0.55%-1.04%).

In subgroup analysis, researchers found that the absolute risk increased progressively at lower eGFR (weighted 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]).

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

“Among older patients with CKD who were newly prescribed baclofen, the 30-day incidence of encephalopathy was increased among those prescribed higher doses compared with lower doses,” the authors wrote. “If verified, these risks should be balanced against the benefits of baclofen use.”

Coauthor Peter Blake, MB, pointed out that baclofen is commonly prescribed for muscle spasms and muscle pain, and is also prescribed off-label for alcoholism, gastro-esophageal reflex disease, and trigeminal neuralgia.

In fact, more than 8 million prescriptions were written for the drug in the United States in 2016. This was the first population-based clinical study, however, to look at the link between baclofen and cognitive symptoms in patients with kidney disease, despite past reports.

“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,” Blake noted.

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