What evidence exists for capping doses of cyclobenzaprine to 5 mg (single dose) and 15 mg (daily dose) in the acute inpatient space?

Comment by InpharmD Researcher

Evidence supporting a maximum cyclobenzaprine dose of 5 mg (single dose) and 15 mg (daily dose) in the acute inpatient setting is scarce. However, available data indicate that 5 mg administered three times daily (15 mg/day) may provide pain relief comparable to higher doses while being associated with less sedation. In older inpatients, a retrospective study found that patients receiving 5 mg experienced shorter hospital stays and required fewer injectable antipsychotics or benzodiazepines than those receiving 10 mg, with no difference in 30-day readmission. Overall, dose capping at these levels appears to be driven primarily by safety and tolerability considerations rather than robust inpatient efficacy data.

Background

Available review articles suggest cyclobenzaprine may provide a modest benefit for acute back pain. A systematic review of 14 randomized controlled trials (3,023 patients) found greater global improvement with cyclobenzaprine than placebo at about 10 days (number needed to treat [NNT] 3). In pooled data from four additional trials (1,389 patients), 50% of patients taking cyclobenzaprine 5 mg three times daily (TID) reported pain relief at 7 days compared with 38% on placebo (NNT 9; p<0.001). Across studied regimens, 5 mg TID was comparable in effectiveness to 10 mg, but with less somnolence; no difference was observed between 2.5 mg and placebo, or between 30 mg extended release once daily and 10 mg immediate release TID. Additionally, experts suggest that if cyclobenzaprine is used specifically for pain management, 5 mg at bedtime may be considered as a starting dose, with titration based on response and tolerability up to a maximum of 15 mg per day, for no longer than one week. Despite these findings, evidence specifically supporting the use of cyclobenzaprine at 5 mg per dose and a maximum of 15 mg per day in the acute inpatient setting remains limited. [1], [2]

A 2024 retrospective cohort study evaluated the impact of lower versus higher cyclobenzaprine dosing in inpatients 65 years of age and older. The study compared outcomes for patients who received either 5 mg or 10 mg doses over a 2.5-year period. The primary outcome was hospital length of stay, adjusted using multivariate linear regression, while secondary outcomes included 30-day readmission rates and use of injectable antipsychotics or benzodiazepines. The study also assessed the effect of implementing a geriatric prescribing context (GEM-CON) on dose selection. Results showed that patients receiving the higher 10 mg dose had an adjusted hospital length of stay that was 32.7% longer (95% confidence interval [CI] 25.9% to 39.9%) compared with those receiving 5 mg. The higher-dose group also had significantly greater use of injectable antipsychotics and benzodiazepines (p<0.001 and p= 0.025, respectively). Cyclobenzaprine dose was not significantly associated with 30-day readmission (odds ratio [OR] 0.93; 95% CI 0.45 to 1.93). After GEM-CON implementation, there was a significant increase in use of the lower recommended dose (p<0.001). Overall, the authors concluded that lower cyclobenzaprine dosing in older inpatients was associated with reduced hospital length of stay and decreased need for injectable psychotropic medications. However, only the abstract of the study was available for scrutiny, limiting a complete analysis of the study findings. [3]

References:

[1] Braschi E, Garrison S, Allan GM. Cyclobenzaprine for acute back pain. Can Fam Physician. 2015;61(12):1074.
[2] Perry T, editor. Therapeutics Letter. Vancouver (BC): Therapeutics Initiative; 1994-. Letter 105, Is cyclobenzaprine useful for pain? 2017 Apr. Available from: https://www.ncbi.nlm.nih.gov/books/NBK598501/
[3] Coli KG, Yuksel JM, McCall KL, Guan J, Ulen KR, Noviasky J. Utilization of Lower-Dose Cyclobenzaprine in the Older Inpatient. Sr Care Pharm. 2024;39(7):249-258. doi:10.4140/TCP.n.2024.249
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What evidence exists for capping doses of cyclobenzaprine to 5 mg (single dose) and 15 mg (daily dose) in the acute inpatient space?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Efficacy of a Low-Dose Regimen of Cyclobenzaprine Hydrochloride in Acute Skeletal Muscle Spasm: Results of Two Placebo-Controlled Trials
Design

Two randomized, double-blind, placebo-controlled, parallel-group trials

N= 1405
Objective To assess the efficacy and tolerability of cyclobenzaprine 2.5, 5, and 10 mg TID compared with placebo in patients with acute musculoskeletal spasm
Study Groups

Study 1: Cyclobenzaprine 5 mg (n= 242), Cyclobenzaprine 10 mg (n= 249), Placebo (n= 246)

Study 2: Cyclobenzaprine 2.5 mg (n= 223), Cyclobenzaprine 5 mg (n= 222), Placebo (n= 223)
Inclusion Criteria Age ≥18 years; acute, physician-rated moderate or moderately severe painful muscle spasm of the lumbar and/or cervical region; normal neurologic examination; ability to discontinue all analgesics, NSAIDs, and other muscle relaxants for duration of study; willingness to participate and provide written informed consent
Exclusion Criteria Duration of current episode > 14 days (study 1) or >7 days (study 2); inability to discontinue analgesics, muscle relaxants, or NSAIDs 24 hours before start of study; vertebral body or spinous process, percussive tenderness; unexplained constipation, diarrhea, or urinary retention; contraindications to use of cyclobenzaprine; depression, psychosis, alcohol or drug abuse; worker's compensation case related to muscle spasm; pregnancy or breast-feeding; systolic blood pressure > 160 mm Hg or diastolic blood pressure > 105 mm Hg; myocardial infarction within 1 year of study; participation in any drug study within 30 days of present trial; any situation or condition that might interfere with study participation
Methods

Patients were randomized to receive cyclobenzaprine 2.5, 5, or 10 mg or placebo TID for 7 days. The method of blinding the study drug differed between the 2 trials. In study 1, patients received 2 bottles marked A and B and were instructed to take 1 tablet from each bottle at each dose. In study 2, patients received 1 bottle of medication and were instructed to take the tablet on awakening, another at 2 PM, and the last at bedtime. In each treatment group, the bottle contained cyclobenzaprine 2.5 mg, cyclobenzaprine 5 mg, or a matching placebo.
Duration 7 days of treatment over an 8-day study period
Outcome Measures

Primary: Patient-rated clinical global impression of change, medication helpfulness, relief from starting backache

Secondary: Degree of relief from starting backache before the evening dose, physician's rating of muscle spasm
Baseline Characteristics

 

   Study 1 Study 2
Cyc 5 mg (n= 242) Cyc 10 mg (n= 249) Placebo (n= 246) Cyc 2.5 mg (n= 223) Cyc 5 mg (n= 222) Placebo (n= 223)
Female 57% 57% 59% 60% 55% 56%
Mean age, years 42.3 41.5 42.3 43.6 42.6 41.5
White 86% 88% 86% 86% 91% 90%

Location of muscle spasm

          Lumbar

          Cervical

          Both

 

66%

31%

3%

 

65%

33%

3%

 

63%

36%

1%

 

55%

39%

5%

 

64%

27%

9%

 

62%

35%

3%
Results   Study 1  Study 2
Cyc 5 mg (n= 242) Cyc 10 mg (n= 249) Placebo (n= 246) Cyc 2.5 mg (n= 223) Cyc 5 mg (n= 222) Placebo (n= 223)

Patient-rated clinical global impression of change* 

          Visit 2

          Visit 3

 

2.29γ

2.88γ

 

2.30γ

2.82γ

 

1.91

2.47

 

2.05

2.63

 

2.19

2.82≡

 

1.97

2.41

Patient-rated medication helpfulness*

          Visit 2

          Visit 3

 

1.62γ

2.09γ

 

1.62γ

2.13γ

 

1.24

1.65

 

1.25

1.72

 

1.49

2.00≡

 

1.20

1.50

Relief from starting backacheδ 

          Day 3

          Day 7

 

1.74≡

2.37≡

 

1.83≡

2.38≡

 

1.41

2.00

 

1.63≡

2.03

 

1.62

2.24≡

 

1.29

1.72

* Mean score on a scale from 0 = worsening to 4 = marked improvement. 

δ Mean score on a scale from 0 = no relief to 3 = a lot of relief.

γ p < 0.001 versus placebo. 

≡ p < 0.03 versus placebo. 
Adverse Events Somnolence and dry mouth were the most common adverse effects, mild and dose-related. Overall, >1 adverse event was reported in 54.1%, 61.8%, and 35.4% of patients receiving cyclobenzaprine 5 or 10 mg or placebo, respectively, in study 1 and by 43.9%, 55.9%, and 35.4% of patients receiving cyclobenzaprine 2.5 or 5 mg or placebo, respectively, in study 2. Adverse events were the primary reason for discontinuation of treatment in the cyclobenzaprine 5- and 10-mg groups in both studies.
Study Author Conclusions Cyclobenzaprine 2.5 mg TID was not significantly more effective than placebo. The cyclobenzaprine 5- and 10-mg TID regimens were associated with significantly higher mean efficacy scores compared with placebo. Cyclobenzaprine 5 mg TID was as effective as 10 mg TID, and was associated with a lower incidence of sedation.
Critique The study's strengths include its large sample size and rigorous design with randomized, double-blind, placebo-controlled trials. However, the exclusion of NSAIDs as an active control limits the ability to assess the benefit of cyclobenzaprine over standard analgesic therapy. The short duration of the study (7 days) may not reflect long-term efficacy and safety. Additionally, the study did not include patients with chronic pain, limiting the generalizability of the findings to this population.
References:

Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Clin Ther. 2003;25(4):1056-1073. doi:10.1016/s0149-2918(03)80067-x

 

Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial
Design

Prospective, randomized, open-label, multicenter, community-based study

N= 867
Objective To compare cyclobenzaprine 5 mg three times daily (TID; CYC5) as monotherapy or in combination with ibuprofen 400 mg TID (IBU400) or 800 mg TID (IBU800) in adults with acute neck or back pain with muscle spasm
Study Groups

CYC5 (n= 288)

CYC5/IBU400 (n= 286)

CYC5/IBU800 (n= 293)
Inclusion Criteria Male or female outpatients 18 to 65 years of age with physician-diagnosed acute muscle spasm of the cervical or thoracolumbar region, pain for ≤ 14 days, and cervical and/or thoracolumbar muscle spasm
Exclusion Criteria Allergy to aspirin, NSAIDs, or cyclobenzaprine; use of a muscle relaxant or narcotic < 12 h before baseline; use of monoamine oxidase inhibitors or selegiline within 2 weeks prior to baseline; current use of tricyclic antidepressants, lithium, anticoagulants, or tramadol; history of cervical or thoracolumbar muscle spasm or myocardial infarction within 12 months; neck or back pain radiating to arms or legs; drug or alcohol abuse; liver impairment; renal failure; pregnant or breast-feeding
Methods

Patients were randomized 1:1:1 to receive cyclobenzaprine 5 mg TID, cyclobenzaprine 5 mg plus ibuprofen 400 mg TID, or cyclobenzaprine 5 mg plus ibuprofen 800 mg TID for 7 days. 
Duration

February 2, 2004, to July 30, 2004
Outcome Measures

Primary: Patient global impression of change (PGIC) after 7 days of treatment

Secondary: PGIC after 3 days, change from baseline in patient-rated pain intensity, muscle spasm intensity, and functional disability (Oswestry Disability Index [ODI]), medication helpfulness, proportion of responders
Baseline Characteristics   CYC5 (n= 288) CYC5/IBU400 (n= 286) CYC5/IBU800 (n= 293)
Age, years, mean ± SD (range) 42.4 ± 12.7 (18–71) 41.3 ± 12.5 (18–80) 40.1 ± 12.4 (18–66)
Male  117 (40.6%) 111 (38.8%) 92 (31.4%)
Cause of pain episode - Twisting  61 (21.2%) 39 (13.6%) 65 (22.2%)
Cause of pain episode - Lifting  71 (24.7%) 86 (30.1%) 79 (27.0%)
Cause of pain episode - Motor vehicle accident 34 (11.8%) 39 (13.6%) 23 (7.8%)
Duration of pain episode > 0–5 days  146 (50.7%) 174 (60.8%) 152 (51.9%)
Location of spasm - Cervical muscles  90 (31.3%) 89 (31.1%) 89 (30.4%)
Location of spasm - Thoracolumbar muscles  158 (54.9%) 158 (55.2%) 170 (58.0%)
Physician rating of spasm intensity - Moderate 154 (53.5%) 154 (53.8%) 163 (55.6%)
Patient rating of pain intensity 7.0 ± 1.8 7.0 ± 1.7 6.7 ± 1.9
Patient rating of spasm intensity 6.3 ± 2.6 6.0 ± 2.6 5.8 ± 2.8
Percentage ODI score 37.5 ± 18.2 37.2 ± 17.6 36.4 ± 18.5
Results

A total of 867 patients provided postbaseline data and were included in the ITT population (CYC5, n= 288; CYC5/IBU400, n= 286; CYC5/IBU800, n= 293). All three groups showed significant improvements from baseline in PGIC, spasm, pain, ODI, and medication helpfulness (p< 0.001 for all) after 3 and 7 days. There were no significant differences in mean PGIC among groups after 3 days (p = 0.65) or 7 days (primary endpoint; p= 0.41). PGIC responder analysis showed that 88% of patients reported at least mild improvement after 3 days, and 93% after 7 days; these findings were provided in figures in the study.
Adverse Events The most common adverse events were fatigue, somnolence, dizziness, sedation, and nausea. There were no significant differences between treatments regarding the number of adverse events reported or number of patients reporting adverse events.
Study Author Conclusions This randomized, community-based clinical trial demonstrated that combination therapy with cyclobenzaprine 5 mg TID plus ibuprofen was not superior to cyclobenzaprine 5 mg TID alone in adult patients with acute neck and back pain with muscle spasm. All treatments were well tolerated.
Critique The study was open-label, which may introduce bias into efficacy and safety results. The use of a voluntary telephone reporting system may have led to underreporting of adverse events. Additionally, the study did not record the use of concomitant physical therapy, topical rubs, and ice/heat therapy, which could have affected the results. The findings may not be applicable to other NSAIDs or muscle relaxants beyond cyclobenzaprine.
References:

Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21(9):1485-1493. doi:10.1185/030079905X61938