Association of baclofen with encephalopathy in patients with chronic kidney disease

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

Objectives — The primary objective was to compare the 30-day risk of encephalopathy in patients with chronic kidney disease newly prescribed baclofen at ≥20 mg/day vs <20 mg/day. The secondary objective was to compare the risk in baclofen users vs non-users.

Design, Setting, and Participants — Retrospective population-based cohort study in Ontario, Canada (2007–2018) using linked healthcare data. Participants included 15,942 older adults (aged 66 years or 34 older) with chronic kidney disease (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis). The primary cohort was restricted to new baclofen users; the secondary cohort included both new users and non-users.

Exposure — Oral baclofen ≥20 mg/day vs <20 mg/day.

Main Outcome and Measure — 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 (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. Pre-specified subgroup analyses were conducted by eGFR category.

Results — The primary cohort included 15,942 patients with chronic kidney disease (61% women; median age 77 [IQR 71-82]; 9707 (61%) patients started baclofen at ≥20 mg/day and 6235 (39%) at <20 mg/day). The primary outcome, hospitalization with encephalopathy, occurred in 108/9707 (1.11%) patients who started baclofen at ≥20 mg/day and in 26/6235 (0.42%) who started at <20 mg/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 non-users, both groups of baclofen users (<20 mg/day and ≥20 mg/day) had a higher risk of encephalopathy: weighted RRs: 5.90 (95% CI, 3.59 to 9.70) and 19.8 (95% CI, 14.0 to 28.0), respectively.

Conclusions and Relevance — Among older patients with chronic kidney disease starting baclofen, the 30-day incidence of encephalopathy was increased among those prescribed higher compared with lower doses. If verified, these risks should be balanced against the benefits of baclofen use.