Abstract
BACKGROUND:
The growth of oral muscle relaxant prescriptions among older adults in the United States is concerning due to the drugs’ adverse sedative effects. Baclofen is a gamma-aminobutyric acid (GABA) agonist muscle relaxant that is associated with encephalopathy. We characterized the risk of fall and fracture associated with oral baclofen against other muscle relaxants (tizanidine or cyclobenzaprine) in older adults.
METHODS:
We designed a new-user, active-comparator study using tertiary health system data from Geisinger Health, Pennsylvania (January 2005 through December 2018). Older adults (aged ≥65 years) newly treated with baclofen, tizanidine, or cyclobenzaprine were included. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance the treatment groups on 58 baseline characteristics. Fine-Gray competing risk regression was used to estimate the risk of fall and fracture.
RESULTS:
The study cohort comprised of 2,205 new baclofen users, 1,103 new tizanidine users, and 9,708 new cyclobenzaprine users. During a median follow-up of 100 days, baclofen was associated with a higher risk of fall compared to tizanidine (IPTW incidence rate, 108.4 versus 61.9 per 1,000 person-years; subdistribution hazard ratio [SHR], 1.68 [95% CI, 1.20-2.36]). The risk of fall associated with baclofen was comparable to cyclobenzaprine (SHR, 1.17 [95% CI, 0.93-1.47]) with a median follow-up of 106 days. The risk of fracture was similar among patients treated with baclofen versus tizanidine (SHR, 0.85 [95% CI, 0.63-1.14]) or cyclobenzaprine (SHR, 0.85 [95% CI, 0.67-1.07]).
CONCLUSIONS:
The risk of fall associated with baclofen was greater than tizanidine, but not compared to cyclobenzaprine in older adults. The risk of fracture was comparable among the older users of baclofen, tizanidine, and cyclobenzaprine. Our findings may inform risk-benefit considerations in the increasingly common clinical encounters where oral muscle relaxants are prescribed.
Keywords: Baclofen, muscle relaxant, fall, fracture
INTRODUCTION
Oral muscle relaxant prescriptions are becoming increasingly common among older adults in the United States. Ambulatory care visits by older adults with a new or continued muscle relaxant therapy rose more than 3-fold from 1.3 per 100 office visits in 2005 to 4.3 per 100 office visits in 2016.1 Muscle relaxants, including baclofen, tizanidine, and cyclobenzaprine, are among the 200 most dispensed medications.2 With the growth driven by continued prescriptions, the extended use of the muscle relaxants raises safety concerns due to the drugs’ adverse sedative effects.1,3 Baclofen is a commonly used oral muscle relaxant that is a gamma-aminobutyric acid (GABA) agonist and excreted by kidneys.4 Initially approved for spasms and pain in the setting of spinal cord diseases or multiple sclerosis,5,6 it has been used on an off-label basis for common musculoskeletal conditions, such as non-specific back pain.1,3,7
Prescription drugs can adversely increase risk of falls in older adults.8 An association between baclofen and falls was previously demonstrated in a cohort study of older adults with chronic kidney disease (CKD) in Ontario, Canada, where a higher dose baclofen conferred a greater risk of fall compared to a lower dose baclofen during a 30-day follow-up period.9 Given that baclofen is a drug cleared by kidneys, older adults with CKD may be more susceptible to its adverse effects.4 However, it is equally important to characterize the risk of fall and fracture associated with commonly used muscle relaxants in a broader population of older adults inclusive of those without CKD over a longer duration than 30 days.
With an increase of clinical encounters prescribing oral muscle relaxants among older adults, data on the comparative risk of fall and fracture associated with baclofen against other commonly used muscle relaxants would have the potential to inform clinical practice.1 A more recent cohort study of older adults receiving care at an integrated health system in California, United States showed a higher risk of injury associated with baclofen compared to tizanidine.10 Given cyclobenzaprine is the most commonly prescribed oral muscle relaxant accounting for more than half of all oral muscle relaxant prescriptions in the United States, an assessment of the comparative risk between baclofen and cyclobenzaprine would further inform prescribing practice and shared decision making with older patients.11 Therefore, we conducted a real-world cohort study to quantify the risk of fall and fracture associated with new baclofen use versus new tizanidine or cyclobenzaprine use in older adults.
METHODS
Design and Setting
We designed a new-user, active-comparator cohort study using electronic health record data from Geisinger Health between January 1, 2005 and December 31, 2018.12,13 Geisinger Health is a tertiary health system that serves a stable patient population in 45 counties of central and northeastern Pennsylvania, United States.14 The electronic health record data contain patient-level information on demographics, drug prescriptions, diagnoses, healthcare encounters, and laboratory measurements.
The study was approved by the institutional review board of Geisinger Medical Center and Johns Hopkins University. The reporting of the study followed the STROBE and RECORD guidelines (Table S1).15,16
Study Cohort and Exposure
Older adults (aged 65 years or older) with a new prescription for baclofen, tizanidine, or cyclobenzaprine were included in the study cohort. Study drug exposure was ascertained through the prescription information available in the electronic health records. The date of the first study muscle relaxant prescription served as the date of cohort entry (i.e., index date). Patients were required not to have any prior prescription for study muscle relaxants for at least one year, thereby restricting the cohorts to new users of the muscle relaxants. We excluded those (i) with less than one year engagement with Geisinger Health, (ii) without a serum creatinine laboratory measurement in the year prior to the index date, (iii) with evidence of end-stage kidney disease as defined by dialysis initiation or kidney transplantation prior to or on the index date, or (iv) with fall or fracture on or prior to the index date (Figure S1). We made two comparisons: (i) new users of baclofen versus new users of tizanidine and (ii) new users of baclofen versus new users of cyclobenzaprine.
Outcomes and Follow-Up
The primary outcome was a clinical encounter (defined as an emergency department visit, hospitalization, or outpatient visit) with fall. The secondary outcome was a clinical encounter with fracture. Both outcomes were defined by the presence of the International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnosis codes (Table S2).9,17 The information on the visit type and ICD diagnosis codes associated with a clinical encounter was derived from the electronic health records.
We followed the patients for the primary and secondary outcomes using an as-treated approach. The follow-up for the study outcomes began from the index date (i.e., date of study muscle relaxant initiation) until the occurrence of prespecified study outcome, discontinuation of treatment drug, initiation of comparator drug, end-stage kidney disease, last encounter with Geisinger Health, or end of study period (December 31, 2018), whichever came first. Drug discontinuation was defined as the absence of recurring prescription within 60 days from the end of days’ supply of the previous prescription.14,18-21 Information on the duration of drug prescriptions and time gaps (in days) between the drug prescriptions was obtained from electronic health records.
Patient Characteristics
Baseline demographic characteristics included age, sex, and race. The time of cohort entry was reported in years. Comorbidities and coprescriptions that may predispose to the study drug exposure or outcomes were considered.22-24 We assessed the following comorbidities using the ICD-9 and ICD-10 diagnosis codes: alcohol use disorder, chronic liver disease, chronic lung disease, cerebrovascular disease, dementia, depression, fibromyalgia, gastrointestinal reflux disease, heart failure, cancer, multiple sclerosis, musculoskeletal conditions, rheumatic disease, spasms/nystagmus, paralysis/spinal cord injury, psychosis, substance use disorder, diabetes mellitus, dyslipidemia, coronary artery disease, hypertension, hypotension, benign prostatic hyperplasia, osteoporosis, and Parkinson disease. Coding definitions for these comorbidities are presented in Table S3. Overall patient-level comorbidity burden was summarized using the Charlson comorbidity index.25 The following concomitant prescriptions were examined on the index date: antiepileptics, antipsychotics, benzodiazepines/barbiturates, non-benzodiazepine sedative hypnotics, lithium, serotonin norepinephrine reuptake inhibitors/atypical antidepressants, selective serotonin reuptake inhibitors, tricyclic antidepressants, opioid analgesics, lipid-lowering agents, antihypertensives/diuretics, antidiabetics, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, non-study muscle relaxants, alpha-blockers, 5-alpha reductase inhibitors, overactive bladder medications, bisphosphonates, proton pump inhibitors, anticoagulants, and aromatase inhibitors. Individual drug information for the drug classes is presented in Table S4.
As frailty is an important risk factor for adverse health outcomes in older adults, a validated frailty index was used to measure patient-level frailty.26 Estimated glomerular filtration rate (eGFR) was calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation from the patient’s most recent serum creatinine measurement in the year prior to the index date.27 Information on healthcare encounters was also identified. The number of outpatient visits, emergency department visits, and hospitalizations in the year prior to the index date was examined.
Statistical Analysis
We used propensity score-based inverse probability treatment weighting (IPTW) as the principal method to address confounding in this observational study. The propensity score for the probability of receiving baclofen (versus a comparator drug) was derived using a logistic regression model with 58 characteristics including demographics, comorbidities, and coprescriptions (see Patient Characteristics). We used stabilized weights and trimmed weights at 1st and 99th percentiles to mitigate influence of extreme weights.28
Baseline characteristics before and after IPTW were described using means with standard deviations (SD) or medians with interquartile intervals (IQI) for continuous variables and counts with percentages for categorical variables. Standardized mean differences (SMDs) were used to evaluate the between-group differences in the baseline characteristics before and after IPTW.29 An absolute SMD greater than or equal to 0.10 (10%) indicated a meaningful imbalance in a given characteristic. An unbalanced characteristic after IPTW was further controlled as a covariate in the regression analysis for outcomes.30
We estimated the risks of primary and secondary outcomes in both absolute and relative terms. IPTW Poisson regression was used to estimate the incidence rate difference and 95% confidence intervals (95% CIs) between the baclofen and comparator groups. In relative terms, we used IPTW Fine-Gray competing risk regression to estimate the risk of fall and fracture, while considering death as a competing risk.31 Subdistribution hazard ratios (SHRs) and 95% CIs were reported.
We additionally examined whether the risk of fall associated with baclofen versus comparator drug differed by the following three subgroups: (i) eGFR (<60 ml/min/1.73 m2 or ≥60 ml/min/1.73 m2), (ii) concomitant opioid use (yes or no), and (iii) concomitant benzodiazepine/barbiturate use (yes or no).
Sensitivity Analysis
We performed a negative control outcome analysis to evaluate the robustness of our findings.32 We selected nephrolithiasis as the negative control outcome a priori because there was no known association with the study muscle relaxants. We repeated the analyses using two different definitions of study drug discontinuation: the absence of recurring prescription within 30 days and 90 days from the end of days’ supply of the previous prescription. We conducted all analyses using Stata 17 (StataCorp, College Station, TX).
RESULTS
Study Cohort
The study cohort comprised of 2,205 new baclofen users, 1,103 new tizanidine users, and 9,708 new cyclobenzaprine users from 2005 to 2018. The median (IQI) duration of prescription was 111 (49-253) days for baclofen, 114 (50-290) days for tizanidine, and 114 (46-275) days for cyclobenzaprine.
Select baseline characteristics of the baclofen and tizanidine groups are presented in Table 1 (full data presented in Table S5). Before IPTW, the baclofen group was less likely to have musculoskeletal conditions and less likely to use NSAIDs than the tizanidine group. After IPTW, all baseline characteristics were well balanced between the baclofen and tizanidine groups (all absolute SMDs <0.10) (Table S5).
Table 1.
Select baseline characteristics of new baclofen users and tizanidine users
| Before IPTW | After IPTW | |||||
|---|---|---|---|---|---|---|
| Characteristics a | Baclofen (Unweighted N=2205) |
Tizanidine (Unweighted N=1103) |
Absolute SMD b |
Baclofen (Weighted N=2206) |
Tizanidine (Weighted N=1094) |
Absolute SMD b |
| Age in years, mean (SD) | 74.2 (6.6) | 74.2 (6.4) | 0.01 | 74.2 (6.6) | 74.2 (6.4) | 0.00 |
| Female | 1210 (54.9) | 648 (58.7) | 0.08 | 1242 (56.3) | 625 (57.2) | 0.02 |
| White race | 2128 (96.5) | 1071 (97.1) | 0.03 | 2133 (96.7) | 1058 (96.7) | 0.00 |
| Comorbidities | ||||||
| Cerebrovascular disease | 426 (19.3) | 199 (18) | 0.03 | 417 (18.9) | 205 (18.7) | 0.01 |
| Dementia | 43 (2.0) | 21 (1.9) | 0.00 | 43 (1.9) | 21 (1.9) | 0.00 |
| Multiple sclerosis | 20 (0.9) | 12 (1.1) | 0.02 | 21 (0.9) | 11 (1.0) | 0.00 |
| Musculoskeletal condition | 1513 (68.6) | 824 (74.7) | 0.14 | 1562 (70.8) | 783 (71.6) | 0.02 |
| Paralysis/Spinal cord injury | 86 (3.9) | 27 (2.4) | 0.08 | 75 (3.4) | 34 (3.1) | 0.02 |
| Spasm/Nystagmus | 305 (13.8) | 153 (13.9) | 0.00 | 307 (13.9) | 153 (13.9) | 0.00 |
| Hypotension | 135 (6.1) | 52 (4.7) | 0.06 | 124 (5.6) | 58 (5.3) | 0.01 |
| Osteoporosis | 584 (26.5) | 307 (27.8) | 0.03 | 598 (27.1) | 301 (27.5) | 0.01 |
| Parkinson disease | 59 (2.7) | 19 (1.7) | 0.07 | 52 (2.4) | 25 (2.3) | 0.01 |
| Charlson comorbidity index, mean (SD) | 2.6 (2.6) | 2.6 (2.6) | 0.00 | 2.6 (2.6) | 2.6 (2.6) | 0.01 |
| Frailty index, median (IQI) c | 0.19 (0.16–0.24) | 0.19 (0.16–0.24) | – | 0.19 (0.16–0.24) | 0.19 (0.15–0.23) | – |
| Coprescriptions | ||||||
| Antiepileptic | 412 (18.7) | 228 (20.7) | 0.05 | 428 (19.4) | 213 (19.5) | 0.00 |
| Antipsychotic | 57 (2.6) | 29 (2.6) | 0.00 | 58 (2.6) | 29 (2.6) | 0.00 |
| Benzodiazepine/Barbiturate | 503 (22.8) | 251 (22.8) | 0.00 | 503 (22.8) | 250 (22.9) | 0.00 |
| Non-benzodiazepine sedative hypnotic | 52 (2.4) | 32 (2.9) | 0.03 | 57 (2.6) | 29 (2.6) | 0.01 |
| Opioid | 903 (41) | 508 (46.1) | 0.10 | 942 (42.7) | 470 (43) | 0.01 |
| SSRI | 422 (19.1) | 210 (19) | 0.00 | 421 (19.1) | 208 (19) | 0.00 |
| Antihypertensive/Diuretic | 1779 (80.7) | 888 (80.5) | 0.00 | 1779 (80.6) | 882 (80.6) | 0.00 |
| Corticosteroid | 561 (25.4) | 241 (21.8) | 0.09 | 534 (24.2) | 261 (23.9) | 0.01 |
| Selective alpha-1 blocker | 196 (8.9) | 76 (6.9) | 0.07 | 180 (8.2) | 85 (7.7) | 0.02 |
| Bisphosphonate | 173 (7.8) | 98 (8.9) | 0.04 | 183 (8.3) | 92 (8.4) | 0.01 |
| Proton pump inhibitor | 867 (39.3) | 425 (38.5) | 0.02 | 864 (39.2) | 428 (39.1) | 0.00 |
| Anticoagulant | 330 (15.0) | 148 (13.4) | 0.04 | 317 (14.4) | 155 (14.1) | 0.01 |
| Aromatase inhibitor | 8 (0.4) | 9 (0.8) | 0.06 | 10 (0.5) | 6 (0.6) | 0.01 |
| Mean eGFR (SD) d, ml/min/1.73 m2 | 68.0 (18.1) | 67.4 (17.7) | 0.03 | 67.7 (18.1) | 67.6 (17.7) | 0.01 |
| Median number of outpatient visits in the past year (IQI) | 7 (4–11) | 7 (4–11) | – | 7 (4–11) | 7 (4–11) | – |
| Median number of ED visits and hospitalizations in the past year, (IQI) | 0 (0–1) | 0 (0–1) | – | 0 (0–1) | 0 (0–1) | – |
Abbreviations: IPTW, inverse probability of treatment weighting; SMD, standardized mean difference; SD, standard deviation; IQI, interquartile interval; SSRI, Selective serotonin reuptake inhibitor; eGFR, estimated glomerular filtration rate; ED, emergency department
Data are presented as count (percentage) unless otherwise noted.
The absolute difference between the groups divided by the pooled standard deviation; a value greater than 0.10 is interpreted as a meaningful difference.
A validated frailty index was derived using the International Classification of Diseases (ICD), Current Procedural Terminology (CPT), and Healthcare Common Procedure Coding System (HCPCS) codes.26 A score of <0.15 is considered robust, 0.15–0.24 is considered pre-frail, and ≥0.25 is considered frail.
Calculated from the most recent serum creatinine in the one year prior to cohort entry using 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Comparison was also made between the baclofen and cyclobenzaprine groups. Before IPTW, baclofen users had later years of cohort entry and a higher mean Charlson comorbidity index compared to cyclobenzaprine users. Furthermore, the baclofen group was more likely to have cerebrovascular disease, paralysis/spinal cord injury, and Parkinson disease compared to the cyclobenzaprine group. Musculoskeletal condition was less common in the baclofen group compared to the cyclobenzaprine group. The baclofen users were more likely to use non-study muscle relaxant but less likely to use NSAIDs compared to the cyclobenzaprine users. After IPTW, all baseline characteristics were well balanced between the baclofen and cyclobenzaprine groups (all absolute SMDs <0.10), except the year of cohort entry. Absolute SMD for years 2008-2010 was 0.15, for years 2011-2013 was 0.12, and for years 2014-2016 was 0.18 (Table S6).
Primary Outcome: Fall
The median (IQI) follow-up was 100 (40-245) days for fall in the weighted cohort of baclofen and tizanidine users. In IPTW analyses, the risk of fall was higher in older adults newly treated with baclofen (incidence rate, 108.4 [95% CI, 91.3-129.4] per 1,000 person-years) compared to those treated with tizanidine (incidence rate, 61.9 [95% CI, 46.1-84.8] per 1,000 person-years) with SHR of 1.68 (95% CI, 1.20-2.36) (Table 2). The cumulative incidence of fall in the weighted cohort of baclofen and tizanidine users is depicted in Figure 1A.
Table 2.
Risk of fall associated with baclofen compared to tizanidine or cyclobenzaprine
| Comparison a | Unweighted n (%) of events |
IPTW incidence rate, per 1,000 person-years (95% CI) |
IPTW incidence rate difference, per 1,000 person-years (95% CI) |
IPTW SHR (95% CI) b, c |
|
|---|---|---|---|---|---|
| Baclofen vs. tizanidine | Baclofen (N=2,205) | 141 (6.4) | 108.4 (91.3, 129.4) | 46.5 (20.0, 73.0) | 1.68 (1.20, 2.36) |
| Tizanidine (N=1,103) | 45 (4.1) | 61.9 (46.1, 84.8) | |||
| Baclofen vs. cyclobenzaprine | Baclofen (N=2,205) | 141 (6.4) | 78.3 (63.6, 97.0) | 13.2 (−4.6, 31.0) | 1.17 (0.93, 1.47) |
| Cyclobenzaprine (N=9,708) | 365 (3.8) | 65.1 (58.5, 72.5) | |||
Abbreviations: CI, confidence interval; IPTW, inverse probability of treatment weighting; SHR, subhazard ratio
The median (IQI) durations of prescription for baclofen, tizanidine, and cyclobenzaprine were 111 (49-253), 114 (50-290), and 114 (46-275) days, respectively.
Fine-Gray competing risk regression was used to estimate the risk of fall.
Year of cohort entry was included as a covariate in the regression model for the comparison of baclofen vs. cyclobenzaprine.
Figure 1.
Cumulative incidence of fall. (A) The weighted cohort of baclofen and tizanidine users. (B) The weighted cohort of baclofen and cyclobenzaprine users.
Abbreviations: IPTW, inverse probability of treatment weighting
The median (IQI) follow-up was 106 (41-257) days for fall in the weighted cohort of baclofen and cyclobenzaprine users. In IPTW analyses, the risk of fall was similar between new baclofen users (incidence rate, 78.3 [95% CI, 63.6-97.0] per 1,000 person-years) and new cyclobenzaprine users (incidence rate, 65.1 [95% CI, 58.5-72.5] per 1,000 person-years) with SHR of 1.17 (95% CI, 0.93-1.47]. The cumulative incidence of fall in the weighted cohort of baclofen and cyclobenzaprine users is depicted in Figure 1B.
Secondary Outcome: Fracture
The median (IQI) duration of follow-up for fracture was 99 (39-246) days in the weighted cohort of baclofen and tizanidine users and 106 (40-256) days in the weighted cohort of baclofen and cyclobenzaprine users. Older adults newly treated with baclofen had a similar risk of fracture as those newly treated with tizanidine (SHR, 0.85 [95% CI, 0.63-1.14]) (Table 3). Similarly, the risk of fracture was not different between new baclofen users and cyclobenzaprine users (SHR, 0.85 [95% CI, 0.67-1.07]).
Table 3.
Risk of fracture associated with baclofen compared to tizanidine or cyclobenzaprine
| Comparison a | Unweighted n (%) of events |
IPTW incidence rate, per 1,000 person-years (95% CI) |
IPTW incidence rate difference, per 1,000 person-years (95% CI) |
IPTW SHR (95% CI) b, c |
|
|---|---|---|---|---|---|
| Baclofen vs. tizanidine | Baclofen (N=2,205) | 121 (5.5) | 92.2 (76.5, 111.8) | −12.4 (−43.0, 18.2) | 0.85 (0.63, 1.14) |
| Tizanidine (N=1,103) | 74 (6.7) | 104.6 (82.6, 134.0) | |||
| Baclofen vs. cyclobenzaprine | Baclofen (N=2,205) | 119 (5.4) | 68.0 (54.4, 85.8) | −12.2 (−29.5, 5.1) | 0.85 (0.67, 1.07) |
| Cyclobenzaprine (N=9,708) | 450 (4.6) | 80.2 (72.8, 88.6) | |||
Abbreviations: CI, confidence interval; IPTW, inverse probability of treatment weighting; SHR, subhazard ratio
The median (IQI) durations of prescription for baclofen, tizanidine, and cyclobenzaprine were 111 (49-253), 114 (50-290), and 114 (46-275) days, respectively.
Fine-Gray competing risk regression was used to estimate the risk of fracture.
Year of cohort entry was included as a covariate in the regression model for the comparison of baclofen vs. cyclobenzaprine.
Subgroup Analyses
The risk of fall in older adults treated with baclofen versus tizanidine was consistent across the subgroups defined by eGFR, concomitant opioid use, and concomitant benzodiazepine/barbiturate use (all interactions P >0.10; Figure 2A). Similarly, the risk of fall was comparable between the baclofen and cyclobenzaprine groups across the three subgroups (all interactions P >0.10; Figure 2B).
Figure 2.
Risk of fall in subgroups by estimated glomerular filtration rate, concomitant opioid use, and concomitant benzodiazepine/barbiturate use. (A) Baclofen vs. tizanidine. (B) Baclofen vs. cyclobenzaprine.
Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate
Sensitivity Analysis
Negative control outcome analysis was performed using nephrolithiasis as the outcome. The risk of nephrolithiasis was similar between older adults newly treated with baclofen versus tizanidine (SHR, 1.18 [95% CI, 0.71-1.96]). Similarly, the risk of nephrolithiasis was similar between the baclofen and cyclobenzaprine groups (SHR, 1.12 [95% CI, 0.79-1.60]).
Varying the definition of study drug discontinuation to the absence of recurrent prescription within 30 days and 90 days demonstrated congruent results to the main analysis (Tables S7 and S8).
DISCUSSION
In this real-world cohort study of older adults, we found that new treatment with baclofen compared to tizanidine was associated with a greater risk of fall. The risk of fall associated with baclofen was not significantly higher than cyclobenzaprine. The comparative risk of fall associated with baclofen versus tizanidine or cyclobenzaprine was consistent across the subgroups by eGFR (≥60 versus <60 ml/min/1.73 m2) and concomitant opioid or benzodiazepine/barbiturate use. The risk of fracture associated with baclofen was similar to tizanidine or cyclobenzaprine.
We quantified the comparative risk of fall and fracture among older adults newly treated with baclofen versus tizanidine or cyclobenzaprine in a routine care setting. The oral muscle relaxants were prescribed for a median duration of approximately 3 to 4 months in our cohorts. Consistent with prior studies that demonstrated the chronic use of oral muscle relaxants in older adults, such a finding motivates real-world evaluations of the medications.1,7,33 Our findings support the safety concerns for baclofen-associated fall risks in a previous cohort study of older adults with CKD using a 30-day follow-up period.9 Our investigation expanded to include older adults with and without CKD, and used longer durations of follow-up to reflect the chronic nature of muscle relaxant prescriptions.1,7 Moreover, we performed an assessment of comparative risk associated with baclofen against other commonly used muscle relaxants, tizanidine and cyclobenzaprine. Musculoskeletal diagnoses were prevalent at approximately 80% in the older users of the muscle relaxants, and our findings may facilitate risk-benefit considerations in common clinical encounters involving musculoskeletal complaints.
Baclofen has been newly added as a drug that should be avoided or have its dosage reduced with decreased kidney function (eGFR <60 ml/min/1.73 m2) in the American Geriatrics Society 2023 updated AGS Beers Criteria® based on its encephalopathy risk.34-36 Falls are extremely common, occurring in more than one in four older adults annually in United States.37 Falls in older adults are also costly to the health system, with estimated attributable medical costs of $50 billion in 2015.38 The present study suggests the risk of fall should also be considered among potential harms associated with baclofen in older adults regardless of impairment in kidney function. Given the growing evidence highlighting the fall risk with baclofen use, future prescribing guidelines could consider the inclusion of fall as potential baclofen-associated harm in older adults.9,10
To our knowledge, this study was the first real-world comparative assessment for the fall and fracture risks among the three commonly used oral muscle relaxants – baclofen, tizanidine, and cyclobenzaprine. In addition to allowing for the evaluation of comparative risk, the active-comparator design mitigated confounding by indication.13 The use of new-user design allowed removal of bias that may arise from comparing patients at different time point during the course of pharmacotherapy.12 We used propensity-score based IPTW as the primary approach to address confounding.
There are limitations to our study. Despite our rigorous IPTW approach, there might still exist residual or unmeasured confounding. While we used two active comparators (i.e., tizanidine and cyclobenzaprine) to mitigate confounding by indication, baclofen might be used for indications not shared by the two comparator medications. Given drug exposure was ascertained based on prescriptions, actual drug intake and adherence by patients could not be guaranteed. Our study cohort was comprised of predominantly White patients and derived from a single integrated health system in the United States. Larger pharmacoepidemiologic investigations involving more diverse racial and ethnic groups would be needed to evaluate the generalizability of the fall risk to a wider range of patient populations. More well-designed real-world studies would be warranted to assess the comparative safety of central nervous system drugs among older adults, with increasing central nervous system polypharmacy in the vulnerable population.
In conclusion, baclofen was associated with a higher risk of fall compared to tizanidine, but not compared to cyclobenzaprine. The risk of fracture associated with baclofen was similar to tizanidine and cyclobenzaprine. Our findings have the potential to inform prescribing practice in the increasingly common clinical encounters where risks of muscle relaxants should be weighed against their potential benefits in the care of older adults.
Supplementary Material
Table S1. STROBE and RECORD Checklists.
Table S2. Coding definition for outcomes.
Table S3. Coding definition for comorbidities.
Table S4. Individual drug information for concomitant prescriptions.
Table S5. Full baseline characteristics of new baclofen users and tizanidine users.
Table S6. Full baseline characteristics of new baclofen users and cyclobenzaprine users.
Table S7. Risk of fall and fracture when drug discontinuation is defined as the absence of recurring prescription within 30 days from the end of days’ supply of the previous prescription.
Table S8. Risk of fall and fracture when drug discontinuation is defined as the absence of recurring prescription within 90 days from the end of days’ supply of the previous prescription. Figure S1. Derivation schematic for study cohort.
Key Points.
Baclofen is associated with a higher risk of fall compared to tizanidine, but a similar risk of fall compared to cyclobenzaprine
The risk of fracture associated with baclofen is similar to tizanidine or cyclobenzaprine
Why does this paper matter?
Use of muscle relaxants in older adults raises safety concerns given the drugs’ sedative effects. Quantifying the risk of fall and fracture among commonly used oral muscle relaxants have the potential to inform prescribing practice in older adults.
Funding Sources:
Dr. Morgan E. Grams was supported by R01DK115534 and K24HL155861 from the National Institute of Diabetes and Digestive and Kidney Diseases for this work. Dr. Jung-Im Shin was supported by K01DK121825 from the National Institute of Diabetes and Digestive and Kidney Disease for this work.
Footnotes
Conflict of Interest
Authors have no relevant disclosures.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. STROBE and RECORD Checklists.
Table S2. Coding definition for outcomes.
Table S3. Coding definition for comorbidities.
Table S4. Individual drug information for concomitant prescriptions.
Table S5. Full baseline characteristics of new baclofen users and tizanidine users.
Table S6. Full baseline characteristics of new baclofen users and cyclobenzaprine users.
Table S7. Risk of fall and fracture when drug discontinuation is defined as the absence of recurring prescription within 30 days from the end of days’ supply of the previous prescription.
Table S8. Risk of fall and fracture when drug discontinuation is defined as the absence of recurring prescription within 90 days from the end of days’ supply of the previous prescription. Figure S1. Derivation schematic for study cohort.