Muscle Relaxant Use and Risk for Adverse Outcomes in Patients Receiving Hemodialysis

Muscle relaxants are used by individuals in the United States for a variety of conditions, including musculoskeletal and spastic disorders, despite lack of clear evidence of their efficacy and safety. Associations between use of muscle relaxants and central nervous system side effects such as drowsiness and sedation have been seen in the general population, as well as increased risk for falls and fracture among older adults.

Patients on maintenance hemodialysis often report musculoskeletal pain and cramping, but there are few epidemiologic data on the prevalence, indications, and harms of use of muscle relaxants in that patient population. Due to risk factors for falls and fractures, patients on hemodialysis may be predisposed to the known adverse effects of muscle relaxants. Further, mescal relaxants or their metabolites may build up in the setting of decreased kidney function. Case reports have shown higher baclofen blood levels and symptoms and signs of baclofen toxicity, included altered mental status, in patients with acute kidney injury, chronic kidney disease, and end-stage renal disease.

Diana Mina, MD, and colleagues recently conducted an observational cohort study to examine the prevalence of the use of muscle relaxants and the diagnoses associated with use in hemodialysis patients. The researchers also sought to assess the association of this class of agents with adverse outcomes in patients on maintenance hemodialysis, and to test the hypothesis that there would be an association between the use of muscle relaxants and altered mental status, falls, and fractures. Results of the study were reported in the American Journal of Kidney Diseases [2019;73(4):525-532].

The researchers utilized data from the US Renal Data System to identify 159,467 adults ≥18 years of age receiving maintenance in-center hemodialysis. Following application of exclusion criteria, including death, receipt of a kidney transplant, change in dialysis modality, uncertain/unrecovered kidney function, loss to follow-up, withdrawal from dialysis therapy, or loss of Part D coverage in January 2011, the final study population included 140,899 patients with Medicare coverage receiving hemodialysis therapy in 2011.

Primary outcomes of interest were time to first emergency department visit or hospitalization for altered mental status, fall, or fracture. Secondary outcomes included death and composites of death with each of the primary outcomes.

In the overall cohort, median age was 61 years, 52% were men, and 50%  were white. Censoring occurred for the following reasons: death (13%), transplantation (2%), withdrawal from dialysis therapy (1.7%), change in modality (1.5%), and loss of Part D coverage (0.6%). Muscle relaxant prescriptions were more prevalent in patients who were younger, women, black, or had comorbid conditions (depression, seizures, hypertension, congestive heart failure, chronic obstruction pulmonary disease, liver disease, or dependence on alcohol, tobacco, drugs, or opioids) and higher body mass index.

In 2011, 10% (n=14,312) of patients received a prescription for muscle relaxants. The prevalence of individual agents of interest was: cyclobenzaprine (6.8%), carisoprodol (1.4%), methocarbamol (1.2%), baclofen (0.7%), tizanidine (0.7%), orphenadrine citrate (0.2%), metaxalone (0.2%), chlorzoxazone (0.08%), and dantrolene sodium (0.02%). Median duration of exposure to any muscle relaxant was 31 days, and median duration of exposure to cyclobenzaprine was 31 days.

Among patients who received at least one muscle relaxant, 86% had an association of interest (14% did not have an association of interest). Among the patients with at least one muscle relaxant prescription in 2011, the most common associated diagnoses were musculoskeletal pain other than back or neck pain (72%), back pain (48%), muscle spasticity (25%), neck pain (19%), headache (14%), fibromyalgia (8%), cramps (2%), cerebral palsy (1%), and multiple sclerosis (0.4%).

There were episodes of altered mental status, fall, fracture, and death in 11%, 6%, 3%, and 13% of the cohort, respectively, during study follow-up. The rates of the adverse outcomes were higher during periods of muscle relaxant exposure compared with periods of nonexposure for altered mental status (18 vs 15 per 100 person-years; P<.001), and fall (11 vs 7 per 100 person-years; P<.001). For fracture, rates were slightly higher during periods of muscle relaxant exposure compared with nonexposure (4.4 vs 3.8 per 100 person-years; P<.001).

There was an association between use of muscle relaxant agents and 39% higher hazard of altered mental status (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.29-1.51; P<.001) and a 18% higher hazard of fall (HR, 1.18; 95% C I, 1.05-1.33; P=.004). There was a nominal association between use of a muscle relaxant agent and a 17% higher hazard of fracture (HR, 1.17; 95% CI, 0.98-1.39) that did not reach statistical significance.

There was an association between shorter duration of muscle relaxant exposure (<30 days) and significantly higher hazard of altered mental status (HR, 1.59; 95% CI, 1.35-1.86) than longer exposure. Compared with no use, there was an association between shorter duration of muscle relaxant exposure and a higher hazard of altered mental status (HR, 1.65; 95% CI, 1.50-1.81), fall (HR. 1.26; 95% CI, 1.09-1.46), and fracture (HR, 1.28; 95% CI, 1.03-1.59). Compared with longer duration of exposure, there was no association of higher hazard of altered mental status, fall, or fracture.

There was no association between use of muscle relaxants and gastrointestinal bleeding. There was an association between muscle relaxant exposure and lower hazard of death (HR, 0.85; 95% CI, 0.76-0.94), but higher hazard of altered mental status or death (HR, 1.17; 95% CI, 1.10-1.,25), fall or death (HR, 1.14; 95% CI, 1.06-1.22), and fracture or death (HR, 1.10; 95% CI, 1.01-1.20). In the cohort of 108,901 (77%) who received the low-income subsidy, the magnitude of associations was similar.

Study limitations included the observational design, limiting the ability to infer a causal association between muscle relaxant use and adverse outcomes; limitations on the ability to determine potential unmeasured confounders; and lack of data on the clinical scenario surrounding the prescription for muscle relaxants.

“In summary, muscle relaxant use was common in US hemodialysis patients, and muscle relaxant use was associated with risk for altered mental status and fall. Our data are insufficient to make definitive recommendations about whether and how to use muscle relaxants in hemodialysis patients. It is possible that for some patients, muscle relaxant use may improve quality of life at the expense of higher hospitalization rates or other complications. Further research regarding the appropriate use of these medications (i.e., indications, selection of agent, and dose) in patients receiving hemodialysis is warranted,” the researchers said.

Takeaway Points

1. Results of an observational study designed to assess the prevalence of use of muscle relaxants among US patients on hemodialysis and the risks associated with that use are reported.
2. Compared with no use, use of muscle relaxant agents was associated with an increased risk for altered mental status and fall; the risk for fracture did not reach statistical significance.
3. Use of muscle relaxants was associated with lower hazard of death; however, hazards were higher for the composites of altered mental status or death, fall or death, and fracture or death.