What skeletal muscle relaxants/spasticity agents are safest to use in elderly patients post-operatively s/p spinal surgery? Which agents have the highest potential for confusion or adverse drug events in older patients?

What is the safest/most effective muscle relaxant to use in older adults aged >65 years old?

Comment by InpharmD Researcher

There is a lack of comparative clinical data indicating the safest and most effective muscle relaxant to use in the elderly population, not only in the setting of spinal surgery but also in general. The 2023 Beers Criteria recommend avoiding muscle relaxants, specifically carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, and benzodiazepines in older adults due to increased risk for adverse events. Given the declined renal and hepatic functions with advanced age, each agent's pharmacokinetic and pharmacodynamic parameters should be closely considered before choosing an agent (see Table 1). One retrospective study observed similar rates of delirium among patients receiving baclofen, cyclobenzaprine, or both medications following spinal surgery in elderly patients (Table 3). However, another retrospective study reported baclofen to be associated with higher incidences of injury and delirium compared to tizanidine for managing musculoskeletal pain in older adults (Table 2). Overall, muscle relaxants should be limited to short-term, with the lowest effective dose, and individualized to patient needs, regardless of the setting.

Background

According to the 2023 American Geriatrics Society Beers Criteria, skeletal muscle relaxants, including carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, are generally poorly tolerated by the elderly population due to anticholinergic adverse effects, sedation, and increased risk of fractures, particularly when used for the treatment of musculoskeletal complaints. The effectiveness of these agents at tolerable doses for older adults remains unclear. Given the potential risks for adverse events, the updated Beers Criteria recommends avoiding muscle relaxants in the elderly (Quality of evidence: moderate; Strength of recommendation: Strong). Of note, this statement does not apply to skeletal muscle relaxants typically used to manage spasticity (i.e., baclofen and tizanidine), as those agents may also lead to substantial adverse effects. Additionally, benzodiazepines should be avoided due to the increased risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in older adults (Quality of evidence: moderate; Strength of recommendation: Strong). [1]

A 2014 review discussed clinical considerations for the appropriate use of skeletal muscle relaxants for managing acute low back pain, with special instructions for elderly patients based on the pharmacokinetic and pharmacodynamic characteristics of each agent. Due to anticholinergic and central nervous system (CNS) side effects, such as dizziness, drowsiness, and light-headedness, orphenadrine and chlorzoxazone should be avoided in patients of advanced age. Carisoprodol and its active metabolites are known for their enhanced CNS depression with long-term use. With a declined renal function, elderly patients are more prone to experience CNS depression due to decreased renal function and potential accumulation of the metabolites. Primarily metabolized by CYP3A4 and CYP1A2, cyclobenzaprine exhibits a patient-specific half-life ranging from 8 to 36 hours. As such, use in the elderly should be cautioned due to decreased hepatic metabolism and, consequently, higher steady-state concentration at more than 1.7 times greater than those in younger adults. Overall, the use of muscle relaxants for the management of acute low back pain should be limited to short-term only for temporary pain relief and tailored to individual patient needs. [2]

According to the Pharmacist’s Letter/Prescriber’s Letter, the following muscle relaxants are known to cause sedation/drowsiness: carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, tizanidine, diazepam (central nervous system side effects), and orphenadrine (anticholinergic adverse effects). Of these, it is stated that tizanidine is “very sedating”, while methocarbamol is less sedating than other muscle relaxants. For chlorzoxazone and metaxalone, it is suggested they can also cause sedation, but this effect is likely related to their mechanisms of action. Sedation is not listed as either an unusual or significant adverse effect of chlorzoxazone, while metaxalone is noted to have a relatively low risk of drowsiness or cognitive effects. Finally, sedation is not specifically listed as an adverse effect of baclofen and dantrolene. [3]

A review article states that tizanidine and cyclobenzaprine are more sedating than methocarbamol and metaxalone. Therefore, it is suggested that methocarbamol and metaxalone can be used in patients intolerable to the stronger sedative properties of tizanidine and cyclobenzaprine. [4]

Another review article also suggests that methocarbamol can be useful for patients intolerable to the sedative effects of other muscle relaxants. [5]

The Palliative Care Network of Wisconsin's Fast Facts and Concepts on skeletal muscle relaxants states that patients less than 65 years old with insomnia due to muscle spasms are recommended to use the muscle relaxants that are most sedating, such as cyclobenzaprine, tizanidine, or diazepam. It also states that methocarbamol and metaxalone have the least sedative effects. [6]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the safest/most effective muscle relaxant to use in older adults aged >65 years old?

Please see Tables 1-3 for your response.

Relevant Recommendations From Prescribing Information Regarding Use in Geriatric, Renal, and Hepatic Impaired Patients
Antispasmodic muscle relaxing agent	Impaired renal function	Impaired hepatic function	Geriatric use
Baclofen	Because baclofen is primarily excreted unchanged through the kidneys, it should be given with caution, and it may be necessary to reduce the dosage.	N/A	N/A
Carisoprodol	Safety and pharmacokinetics have not been evaluated. Excreted by kidneys. Use with caution. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis.	Safety and pharmacokinetics have not been evaluated. Metabolized by the liver. Use with caution.	Efficacy, safety, and pharmacokinetics in patients over 65 years old have not been established.
Chlorzoxazone	There is no evidence that the drug will cause renal damage. Rarely, a patient may note discoloration of the urine resulting from a phenolic metabolite of chlorzoxazone. This finding is of no known clinical significance.	Serious (including fatal) hepatocellular toxicity has rarely been reported in patients receiving chlorzoxazone. The mechanism is unknown but appears to be idiosyncratic and unpredictable. Factors predisposing patients to this rare event are not known. Patients should be instructed to report early signs and/or symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, or jaundice. Chlorzoxazone should be discontinued immediately and a physician consulted if any of these signs or symptoms develop. Chlorzoxazone use should also be discontinued if a patient develops abnormal liver enzymes (e.g., AST, ALT, alkaline phosphatase and bilirubin).	N/A
Cyclobenzaprine	Extensively metabolized via the kidney. No recommendations are provided.	Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine HCl in subjects with moderate to severe impairment is not recommended. Pharmacokinetics study in patients with mild hepatic impairment observed double AUC and Cmax values compared to healthy control groups.	Initiate at 5 mg dose and titrate up slowly. In a pharmacokinetic study in elderly individuals (≥65yrs old), mean (n= 10) steady-state cyclobenzaprine AUC values were approximately 1.7 fold (171.0 ng.hr/mL, range 96.1-255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1-182.9) from another study.
Dantrolene	N/A	BOXED WARNING Potential for hepatotoxicity, including serious hepatic injury and liver dysfunction. Use only in conjunction with appropriate monitoring. The lowest effective dose should be used. Discontinue after 45 if no improvement is seen.	Insufficient clinical data; use with caution due to greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Use the lowest effective dose. Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving dantrolene sodium, but complicated with other confounding factors.
Metaxalone	The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, metaxalone tablets should be used with caution in patients with hepatic and/or renal impairment.		Elderly patients may be especially susceptible to CNS effect.
Methocarbamol	Clearance in 8 renally impaired patients was reduced by ~40% compared to 17 normal patients. The mean elimination half-life was similar: 1.2 ± 0.6 vs. 1.1 ± 0.3 hours, respectively.	In 8 patients with cirrhosis secondary to alcohol abuse, the mean total clearance was reduced by ~70% compared to 8 normal patients. The mean elimination half-life was 3.38 ± 1.62 vs. 1.11 ± 0.27 hours, respectively.	Prolonged half-life vs. younger population: 1.5 ± 0.4 hrs vs. 1.1 ± 0.27 hrs Decreased fraction of bound vs. younger population: 41 to 43% vs. 46 to 50%
Orphenadrine	N/A	N/A	Elderly patients may experience some degree of mental confusion. These adverse reactions can usually be eliminated by reduction in dosage.
Tizanidine	Extensively excreted by the kidney. Patients with renal insufficiency had > 50% reduced clearance. Individual doses should be reduced during titration and patients should be monitored for potential overdose.	Has not been evaluated. However, tizanidine is extensively metabolized by the liver. Hepatic impairment is expected to have significant effects on pharmacokinetics of tizanidine.	Use with caution due to decreased clearance by four-fold. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased.

References:

Baclofen tablet. Prescribing information. Advagen Pharma Limited; 2022
SOMA (carisoprodol tablet). Prescribing information. Meda Pharmaceuticals; 2019.
Chlorzoxazone tablet. Prescribing information. Par Pharmaceutical, Inc.; 2020.
Cyclobenzaprine hydrochlroide tablet. Prescribing information. Cipla USA Inc.; 2021.
Dantrolene sodium capsule. Prescribing information. Amneal Pharmaceuticals of New York LLC; 2022.
Metaxalone tablet. Prescribing information. Eon Labs, Inc.; 2022.
Methocarbamol tablet. Prescribing information. Camber Pharmaceuticals, Inc.; 2021.
Orphenadrine citrate tablet, extended-release. Prescribing information. Eon Labs, Inc.; 2022.
Tizanidine tablet. Prescribing information. AvPAK.; 2022.

Safety of Baclofen Versus Tizanidine For Older Adults With Musculoskeletal Pain
Design	Retrospective cohort study N= 18,128
Objective	To investigate the relative risk between baclofen and tizanidine in causing injury and delirium in older adults
Study Groups	Baclofen (n= 12,101) Tizanidine (n= 6,027)
Inclusion Criteria	Older adults aged ≥ 65 years who filled a prescription for baclofen or tizanidine during the study period; diagnosed with musculoskeletal pain (muscle spasms/cramps, dorsalgia, and cervicalgia); had continuous Kaiser Permanente Health Plan membership within the 6 months prior to the index date
Exclusion Criteria	Received intrathecal baclofen during the study period or were initiated on both study drugs on the index date; diagnosis of alcohol or substance use disorder, dementia, or multiple sclerosis (or other types of spinal involvement) within the 2 years prior to the index date
Methods	Patients' health data, including outpatient visits, hospital admissions, emergency department visits, laboratory, and drug prescriptions, were retrospectively collected from the electronic healthcare record database. Outcomes of interest were identified through both outpatient and inpatient encounters during the study period. Only the initial visits for the treatment of episodes were included for new cases of injury.
Duration	Treatment initiation: Between January 2016 and December 2018 Follow-up: Up to the first occurrence of end of the index drug exposure based on days' supply of the last prescription, end of membership, death, or the study end date (December 31, 2019)
Outcome Measures	New incidence of injury (i.e., concussion, contusion, dislocation, fall, and fracture) and new incidence of delirium (i.e., altered mental status/awareness, and disorientation)
Baseline Characteristics		Baclofen (n= 12,101)	Tizanidine (n= 6,027)
	Age, years	72.1 ± 6.1	72.4 ± 6.4
	Female	59.3%	58.2%
	White African American Hispanic Asian	58.6% 9.2% 19.9% 8.7%	65.4% 7.4% 12.3% 10.6%
	Chronic kidney disease Stage 1 Stage 2 Stage 3 Stage 4 Stage 5	25.3% 55.7% 18.2% 0.5% 0.2%	16.4% 65.6% 16.9% 0.7% 0.4%
	Recent injury within 100 days prior to index date	5.7%	4.7%
	Skeletal muscle relaxants prescription within 100 days prior to index date	2.7%	2.8%
Results	Endpoint	Baclofen (n= 12,101)	Tizanidine (n= 6,027)	Hazard ratio (95% confidence interval [CI]); p-value
	Incidence of injury Events Per 100 person-years (95% CI)	333 15.1 (13.6 to 16.3)	101 11.4 (9.3 to 13.5)	1.56 (1.21 to 1.96); < 0.001
	Incidence of delirium Events Per 100 person-years (95% CI)	165 7.2 (6.1 to 8.3)	23 2.5 (1.5 to 3.5)	3.33 (2.11 to 5.26); < 0.001
	Other significant risk factors for injury included age over 76, having CKD stages 3–5, or having a history of a recent injury. Other significant risk factors for the delirium outcome included being age over 76, having CKD stage 3–5, recent injury, recent antidepressant use, and recent antipsychotic use.
Adverse Events	See results
Study Author Conclusions	The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.
InpharmD Researcher Critique	Use of a retrospective chart review of prescriptions may not accurately capture the exact adherence to either agent, limiting the reliability of the study findings. Additionally, unadjusted confounding factors, such as mobility status and degree of cognitive function, may increase the overall risk of bias.

References:

Su Zhang VR, Niu F, Lee EA, et al. Safety of baclofen versus tizanidine for older adults with musculoskeletal pain [published online ahead of print, 2023 Mar 29]. J Am Geriatr Soc. 2023;10.1111/jgs.18349. doi:10.1111/jgs.18349

Postoperative Use of the Muscle Relaxants Baclofen and/or Cyclobenzaprine Associated with an Increased Risk of Delirium Following Lumbar Fusion
Design	Retrospective, single-center, cohort study N= 530
Objective	To investigate whether the incidence of postoperative delirium in older adults undergoing spinal fusion surgery is associated with postoperative muscle relaxant administration
Study Groups	No muscle relaxant (n= 280) Muscle relaxant (n= 250)
Inclusion Criteria	Age > 65 years; underwent posterior lumbar fusion for degenerative spine disease
Exclusion Criteria	Non-elective cases; developed delirium on postoperative day 1 (i.e., muscle relaxant exposure unlikely to have contributed to delirium)
Methods	Patients were stratified into two groups based on whether they received oral baclofen and/or cyclobenzaprine after surgery as part of a multimodal analgesia (MMA) regimen on postoperative day 1 (muscle relaxant group) or did not receive muscle relaxants on postoperative day 1 (no muscle relaxant group). Patients who initiated muscle relaxants after postoperative day 1 were considered as crossovers from the control group. The decision to administer muscle relaxants and other MMA components was based on surgeon preference. The MMA regimen varied between surgeons but typically consisted of 600 mg gabapentin and 975 mg acetaminophen 30 minutes prior to surgery followed by administration of intravenous (IV) fentanyl or hydromorphone intraoperatively and in the postoperative care unit. Postoperatively, all patients received acetaminophen followed by a combination of opioids, acetaminophen, gabapentin, and baclofen or cyclobenzaprine as needed for pain.
Duration	Surgery: January 1, 2017 to February 1, 2021 Follow-up: 7 days postoperatively
Outcome Measures	Primary: occurrence of delirium during admission for up to the first seven PODs (diagnosed using the "Delirium Observational Screening Scale" when patients were admitted to the general neurosurgical or orthopedic ward and "Confusion Assessment Method for ICU" when patients were admitted to the Surgical Intensive Care Unit) Secondary: day of delirium onset, length of delirium episode, length of stay, morphine equivalent dosing, visual analog scale (VAS) pain, and disposition on discharge
Baseline Characteristics		No muscle relaxant (n= 280)	Muscle relaxant (n= 250)	p-value
	Age, years	72.3 ± 5.2	71.6 ± 5.0
	Gender (unspecified male or female)	50.7%	53.6%
	Body mass index, kg/m²	31 ± 6.7	30.1 ± 5.3
	ASA class 1 2 3 4	0.7% 41.8% 56.1% 1.4%	0 47.2% 51.6% 1.2%
	Surgical specifications Levels fused, n Interbody spacers, n Procedure length, minutes Anesthesia length, minutes	3.9 ± 2.5 0.7 ± 1.0 223.1 ± 87.8 330.4 ± 80.4	4.0 ± 2.3 0.9 ± 1.0 241.7 ± 97.0 340.7 ± 74.3	0.388 < 0.001 0.023 0.029
	MMA protocol Gabapentin 30 minutes preop Paracetamol 30 minutes preop Postoperative gabapentin Postoperative PCA	71.4% 82.0% 71.1% 64.6%	71.2% 79.2% 76.8% 62.4%
	Preoperative medication use Opioid Gabapentinoid Muscle relaxant Acetaminophen Benzodiazepine Antihistamine Non-benzodiazepines Antidepressants	38.6% 41.1% 12.1% 53.9% 7.9% 10.7% 3.6% 41.4%	45.6% 49.2% 24.0% 61.2% 12.0% 8.4% 5.6% 38.0%
	ICU admission	18.9%	15.2%
	ASA, American Society of Anesthesiologists; PCA, patient-controlled analgesia
Results	Endpoint	No muscle relaxant (n= 280)	Muscle relaxant (n= 250)	p-value
	Patients who experienced delirium, n	22 (7.9%)	44 (17.6%)	0.001
	Postoperative day of delirium onset	2.4 ± 0.6	3.1 ± 1.4	0.051
	Delirium, days	1.6 ± 0.7	2.5 ± 1.5	0.008
	Length of stay, days	4.6 ± 3.7	5.1 ± 5.0	0.090
	Length of stay in ICU, hours	49.5 ± 35.3	61.1 ± 53.1	0.466
	Pain average, VAS	3.6 ± 1.6	4.7 ± 1.6	< 0.001
	Morphine Equivalent Dosing average	53.3 ± 48.6	65.6 ± 58.4	< 0.001
	Discharge disposition Home Other (SNF, acute rehab)	179 (63.9%) 101 (36.1%)	161 (64.4%) 89 (35.6%)	0.982
	SNF, skilled nursing facility Patients who became delirious were found to have received significantly higher doses of baclofen on postoperative day 2 (p= 0.03) and postoperative day 5 (p= 0.006). The association between cyclobenzaprine dose and delirium was not evaluated; however, univariate comparison found the rates of delirium to be similar between patients who received baclofen, cyclobenzaprine, or both medications (17.3% vs. 18.2% vs. 18.4%, p= 0.9796, respectively). Factors found to be significantly associated with delirium were muscle relaxant use (p= 0.015), age (p= 0.006), day of surgical admission gabapentin (p= 0.033), day of surgical admission acetaminophen (p < 0.001), and ICU admission risk on POD2 (p < 0.001).
Adverse Events	See results
Study Author Conclusions	Postoperative use of muscle relaxants as part of a multi-modal analgesia regimen was associated with an increased risk of delirium in older adults after lumber fusion surgery. Although muscle relaxants may be beneficial in select patients, they should be used with caution in individuals at high risk for postoperative delirium. Additional work is needed to further examine the risks and benefits of postoperative muscle relaxant administration.
InpharmD Researcher Critique	The external validity of this study is limited due to the single-center, retrospective design. Additionally, this study does not provide conclusions on whether the risk of delirium is higher with certain muscle relaxants, only that use of muscle relaxants, in general, following spinal surgery may be associated with delirium.

References:

Perez EA, Ray E, Gold CJ, et al. Postoperative Use of the Muscle Relaxants Baclofen and/or Cyclobenzaprine Associated with an Increased Risk of Delirium Following Lumbar Fusion [published online ahead of print, 2023 Feb 15]. Spine (Phila Pa 1976). 2023;10.1097/BRS.0000000000004606. doi:10.1097/BRS.0000000000004606