Association of Baclofen With Encephalopathy in Patients With Chronic Kidney Disease

Abstract

Importance: At least 30 case reports have linked the muscle relaxant baclofen to encephalopathy in patients with chronic kidney disease (CKD).

Objective: 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 vs less than 20 mg per day. The secondary objective was to compare the risk of encephalopathy in baclofen users vs nonusers.

Design, setting, and participants: Retrospective population-based cohort study in Ontario, Canada (2007-2018) using linked health care data. Participants comprised 15 942 older adults (aged 66 years or older) with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis). The primary cohort was restricted to patients who were newly prescribed baclofen; participants in the secondary cohort were new users and nonusers.

Exposures: Prescription for oral baclofen greater than or equal to 20 mg per day vs less than 20 mg per day.

Main outcomes and measures: 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. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RRs) were obtained using modified Poisson regression and weighted risk differences (RDs) using binomial regression. Prespecified subgroup analyses were conducted by eGFR category.

Results: The primary cohort comprised 15 942 patients with CKD (9699 [61%] women; median age, 77 years [interquartile range, 71-82]; 9707 [61%] patients started baclofen at ≥20 mg/d and 6235 [39%] at <20 mg/d). The primary outcome, hospitalization with encephalopathy, occurred in 108/9707 (1.11%) patients who started baclofen at greater than or equal to 20 mg per day and in 26/6235 (0.42%) who started baclofen at less than 20 mg per day; weighted RR, 3.54 (95% CI, 2.24 to 5.59); weighted RD, 0.80% (95% CI, 0.55% to 1.04%). In subgroup analysis, 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, both groups of baclofen users had a higher risk of encephalopathy (<20 mg/d weighted 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]).

Conclusions and relevance: 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. If verified, these risks should be balanced against the benefits of baclofen use.

Figure.. Subgroup Analysis for Risk of Encephalopathy by eGFR Category (Weighted Risk Difference and Weighted Risk Ratio)

The 30-day risk of a hospital admission with encephalopathy, defined as main diagnosis of delirium, disorientation, transient alteration of awareness, transient cerebral ischemic attack, or unspecified dementia. To improve the specificity of this outcome, we only considered codes that were entered in the main diagnosis field of the database; this field contains a single diagnosis that most influences the patient’s length of hospital stay and/or is responsible for the greatest proportion of resource use. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health.^,, The propensity score was estimated using multivariable logistic regression with 164 covariates chosen a priori (defined in eTable 7 in the Supplement). Patients in the reference group were weighted (propensity score/[1−propensity score]).^,, This method produces a weighted pseudo sample of patients in the reference group with the same distribution of measured covariates as the exposed group.^, Weighted risk ratios and 95% CIs were obtained using modified Poisson regression, and weighted risk differences and 95% CIs were obtained using a binomial regression model with an identity link function. eGFR indicates estimated glomerular filtration rate.