Table 10Summary of evidence

Key QuestionConditionLevel of EvidenceConclusions
Efficacy
1. What is the comparative efficacy of different muscle relaxants in reducing symptoms and improving functional outcomes in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms?Spasticity: comparative efficacyFAIR for tizanidine vs. baclofen

FAIR for tizanidine, baclofen, and dantrolene vs. diazepam

POOR for dantrolene vs. tizanidine, baclofen or other skeletal muscle relaxants
9 fair-quality head-to-head trials and a fair-quality meta-analysis of unpublished trials consistenly found that tizanidine and baclofen are roughly equivalent for various measures of efficacy including spasms, functional status, and patient preference. Most of these trials evaluated patients with multiple sclerosis. Interpretation of trials was limited by lack of good-quality trials and heterogeneity in outcomes assessed, unvalidated methods to measure outcomes, and unstandardized methods of reporting results. 8 fair-quality head-to-head trials of dantrolene, tizandine, or baclofen compared to diazepam provide some evidence that each of these medications is similar in efficacy to diazepam, but judgments about comparative efficacy could not be made from these trials. Placebo-controlled trials were not helpful in assessing comparative efficacy. Findings of other recent systematic reviews are similar to our report.
Spasticity: efficacy vs. placeboFAIR for tizanidine, baclofen, and dantrolene vs. placeboTizanidine, baclofen, and dantrolene (all FDA-approved for use in patients with spasticity) have consistently been found to be more effective than placebo in fair- quality clinical trials. Other skeletal muscle relaxants (not FDA-approved for use in patients with spasticity) have not been adequately assessed for this condition.
Musculoskeletal conditions: comparative efficacyFAIR for cyclobenzaprine vs. diazepam

POOR for comparative efficacy of other skeletal muscle relaxants
2 fair-quality head-to-head trials and 1 fair-quality meta-analysis of unpublished trials found that cyclobenzaprine and diazepam are roughly equivalent for various measures of efficacy including pain, spasm, and global response, but 3 other fair- quality trials found that cyclobenzaprine was superior to diazepam for most (2 trials) or some (1 trial) clinical outcomes. Most of these trials evaluated patients with neck or back pain or spasms. For other comparisons, one fair-quality trial found that carisoprodol was superior to diazepam and another fair-quality trial found that chlorzoxazone was superior to diazepam for several measures of efficacy, but both used unstandardized outcomes scales. Other skeletal muscle relaxants have been directly compared in only 1 fair-quality trial or have been compared to diazepam, and comparative efficacy could not be accurately assessed. Placebo- controlled trials were not helpful in assessing comparative efficacy. Findings of other recent systematic reviews were similar to our report.
Musculoskeletal conditions: efficacy vs. placeboFAIR for cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine vs. placebo

POOR for other skeletal muscle relaxants vs. placebo
21 fair-quality trials consistently found cyclobenzaprine to be more effective than placebo for various measures of efficacy (pain relief, muscle spasms, functional status) in patients with musculoskeletal conditions. 2 good-quality systematic reviews reported similar findings. The body of evidence is not as robust for carisoprodol (4 trials), orphenadrine (4), and tizanidine (7), but these medications were also consistently found to be more effective than placebo. Tizanidine is the only skeletal muscle relaxant with at least fair-quality evidence of effectiveness for both spasticity and musculoskeletal conditions. There is very limited data regarding the effectiveness of methocarbamol, dantrolene, chlorzoxazone, or baclofen compared to placebo. Data on efficacy from five trials of metaxalone are mixed. A good-quality systematic review of 5 placebo-controlled trials of cyclobenzaprine in patients with fibromyalgia found no clear differences for specific assessed outcomes (sleep quality, pain, trigger points, fatigue), though patients were more likely to report `improvement.'
Adverse events
2. What are the comparative safety of different muscle relaxants?Spasticity:
comparative safety
FAIR for tizanidine vs. baclofen

FAIR for risk of hepatotoxicity from dantrolene and tizanidine

POOR for other skeletal muscle relaxants
7 of 7 head-to-head trials of tizanidine vs. baclofen reporting rates of weakness found that tizanidine was associated with lower rates of weakness, while 5 of 7 head-to-head trials of tizanidine vs. baclofen reporting rates of dry mouth found that baclofen was associated with lower rates of dry mouth. Overall tolerability appears to be similar, as withdrawals due to adverse events (a marker of intolerable adverse events) were similar in all head-to-head trials except one. There was insufficient evidence from head-to-head or placebo-controlled trials to judge the comparative adverse event rates of other skeletal muscle relaxants. Serious hepatotoxicity with dantrolene has been found in observational studies, and tizanidine is associated with usually asymptomatic and reversible (rarely serious) hepatotoxicity.
Musculoskeletal conditions: comparative safetyPOOR overall

FAIR for risk of hepatoxicity from tizanidine and chlorzoxazone
There is insufficient evidence to accurately judge comparative adverse event rates from skeletal muscle relaxants in patients with musculoskeletal conditions. Direct comparisons of skeletal muscle relaxants in head-to-head trials were too limited in quantity and quality. Placebo-controlled trials showed no pattern of one skeletal muscle relaxant being superior to others and were generally of inferior quality compared to head-to-head trials. There are no data to judge comparative abuse or addiction risk, though there are numerous case reports, almost all associated with carisoprodol use . Tizanidine and chlorzoxazone are associated with usually reversible (rarely serious or fatal) hepatotoxicity, but data to estimate comparative event rates are not available. Other serious adverse events appear to be rare, but no assessment of comparative risk could be made.
Subpopulations
3. Are there subpopulations of patients for which one muscle relaxant is more effective or associated with fewer adverse effects?POORThere is almost no information to judge the comparative efficacy or safety of skeletal muscle relaxants in subpopulations defined by age, race, or gender. Almost all head-to-head trials have been done either in patients with multiple sclerosis or in patients with neck or low back syndromes, and there is insufficient evidence to judge the relative effectiveness or safety of skeletal muscle relaxants for other conditions. There are no studies to estimate the comparative risk of addiction or abuse in patients with prior substance abuse. Special populations (e.g. chronic liver disease, renal failure, or patients with seizures) have usually been excluded from clinical trials.

From: Summary

Cover of Drug Class Review: Skeletal Muscle Relaxants
Drug Class Review: Skeletal Muscle Relaxants: Final Report [Internet].
Chou R, Peterson K.
Portland (OR): Oregon Health & Science University; 2005 May.
Copyright © 2005, Oregon Health & Science University, Portland, Oregon.

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