140 Journal of Pain and Symptom Management Vol. 28 No. 2 August 2004 Review Article Comparative Efficacy and Safety of Skeletal Muscle Relaxants for Spasticity and Musculoskeletal Conditions: A Systematic Review Roger Chou, MD, Kim Peterson, MS, and Mark Helfand, MD, MPH Department of Medicine (R.C., M.H.) and Oregon Evidence-Based Practice Center (R.C., K.P., M.H.), Oregon Health & Science University, Portland; and Portland Veterans Affairs Medical Center (M.H.), Portland, Oregon, USA Abstract Skeletal muscle relaxants are a heterogeneous group of medications used to treat two different types of underlying conditions: spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Although widely used for these indications, there appear to be gaps in our understanding of the comparative efficacy and safety of different skeletal muscle relaxants. This systematic review summarizes and assesses the evidence for the comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. Randomized trials (for comparative efficacy and adverse events) and observational studies (for adverse events only) that included oral medications classified as skeletal muscle relaxants by the FDA were sought using electronic databases, reference lists, and pharmaceutical company submissions. Searches were performed through January 2003. The validity of each included study was assessed using a data abstraction form and predefined criteria. An overall grade was allocated for the body of evidence for each key question. A total of 101 randomized trials were included in this review. No randomized trial was rated good quality, and there was little evidence of rigorous adverse event assessment in included trials or observational studies. There is fair evidence that baclofen, tizanidine, and dantrolene are effective compared to placebo in patients with spasticity (primarily multiple sclerosis). There is fair evidence that baclofen and tizanidine are roughly equivalent for efficacy in patients with spasticity, but insufficient evidence to determine the efficacy of dantrolene compared to baclofen or tizanidine. There is fair evidence that although the overall rate of adverse effects between tizanidine and baclofen is similar, tizanidine is associated with more dry mouth and baclofen with more weakness. There is fair evidence that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared to placebo in patients with Address reprint requests to: Roger Chou, MD, 3181 SW PMPD_hrc.htm#drugclass1 last updated January 2004; Sam Jackson Park Rd., Mail Code: BICC, Portland, OR Web site checked on June 7, 2004 or from the authors 97239, USA. (updated January 2004). Although the Oregon Evi- dence-based Practice Center receives support from Accepted for publication: November 22, 2003. the Agency for Healthcare Research and Quality Note: Evidence tables and appendices are available (AHRQ), this report has not been reviewed or ap- on the Web site http://www.ohppr.state.or.us/hrc/ proved by AHRQ. 2004 U.S. Cancer Pain Relief Committee 0885-3924/04/$–see front matter Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2004.05.002
Transcript
140 Journal of Pain and Symptom Management Vol. 28 No. 2 August 2004
Review Article
Comparative Efficacy and Safetyof Skeletal Muscle Relaxants for Spasticityand Musculoskeletal Conditions:A Systematic ReviewRoger Chou, MD, Kim Peterson, MS, and Mark Helfand, MD, MPHDepartment of Medicine (R.C., M.H.) and Oregon Evidence-Based Practice Center (R.C., K.P.,M.H.), Oregon Health & Science University, Portland; and Portland Veterans Affairs MedicalCenter (M.H.), Portland, Oregon, USA
AbstractSkeletal muscle relaxants are a heterogeneous group of medications used to treat twodifferent types of underlying conditions: spasticity from upper motor neuron syndromes andmuscular pain or spasms from peripheral musculoskeletal conditions. Although widely usedfor these indications, there appear to be gaps in our understanding of the comparativeefficacy and safety of different skeletal muscle relaxants. This systematic review summarizesand assesses the evidence for the comparative efficacy and safety of skeletal muscle relaxantsfor spasticity and musculoskeletal conditions. Randomized trials (for comparative efficacyand adverse events) and observational studies (for adverse events only) that included oralmedications classified as skeletal muscle relaxants by the FDA were sought using electronicdatabases, reference lists, and pharmaceutical company submissions. Searches wereperformed through January 2003. The validity of each included study was assessed usinga data abstraction form and predefined criteria. An overall grade was allocated for thebody of evidence for each key question. A total of 101 randomized trials were included inthis review. No randomized trial was rated good quality, and there was little evidence ofrigorous adverse event assessment in included trials or observational studies. There is fairevidence that baclofen, tizanidine, and dantrolene are effective compared to placebo inpatients with spasticity (primarily multiple sclerosis). There is fair evidence that baclofenand tizanidine are roughly equivalent for efficacy in patients with spasticity, butinsufficient evidence to determine the efficacy of dantrolene compared to baclofen ortizanidine. There is fair evidence that although the overall rate of adverse effects betweentizanidine and baclofen is similar, tizanidine is associated with more dry mouth andbaclofen with more weakness. There is fair evidence that cyclobenzaprine, carisoprodol,orphenadrine, and tizanidine are effective compared to placebo in patients with
Address reprint requests to: Roger Chou, MD, 3181 SWSam JacksonPark Rd.,Mail Code: BICC, Portland, OR97239, USA.Accepted for publication: November 22, 2003.Note: Evidence tables and appendices are availableon the Web site http://www.ohppr.state.or.us/hrc/
� 2004 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.
PMPD_hrc.htm#drugclass1 last updated January 2004;Web site checked on June 7, 2004 or from the authors(updated January 2004). Although the Oregon Evi-dence-based Practice Center receives support fromthe Agency for Healthcare Research and Quality(AHRQ), this report has not been reviewed or ap-proved by AHRQ.
0885-3924/04/$–see front matterdoi:10.1016/j.jpainsymman.2004.05.002
Vol. 28 No. 2 August 2004 141Comparative Efficacy and Safety of Skeletal Muscle Relaxants
musculoskeletal conditions (primarily acute back or neck pain). Cyclobenzaprine has beenevaluated in the most clinical trials and has consistently been found to be effective. Thereis very limited or inconsistent data regarding the effectiveness of metaxalone,methocarbamol, chlorzoxazone, baclofen, or dantrolene compared to placebo in patients withmusculoskeletal conditions. There is insufficient evidence to determine the relative efficacyor safety of cyclobenzaprine, carisoprodol, orphenadrine, tizanidine, metaxalone,methocarbamol, and chlorzoxazone. Dantrolene, and to a lesser degree chlorzoxazone, havebeen associated with rare serious hepatotoxicity. J Pain Symptom Manage2004;28:140–175. � 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc.All rights reserved.
IntroductionSkeletal muscle relaxants are a heteroge-
neous group of medications commonly used totreat two different types of underlying condi-tions: spasticity from upper motor neuron syn-dromes and muscular pain or spasms fromperipheral musculoskeletal conditions.
Spasticity from the upper motor neuron syn-drome (a complex of signs and symptoms thatcan be associated with exaggerated reflexes, au-tonomic hyperreflexia, dystonia, contractures,paresis, lack of dexterity, and fatigability, in ad-dition to spasticity) can result from a variety ofconditions affecting the cortex or spinal cord.1
Some of the more common conditions associ-ated with spasticity include multiple sclerosis,2
spinal cord injury,3 traumatic brain injury, cere-bral palsy, and post-stroke syndrome.4 In manypatients with these conditions, spasticity can bedisabling and painful, with a marked effect onfunctional ability and quality of life.5
Common musculoskeletal conditions causingtenderness and muscle spasms include fibromy-algia,6 tension headaches,7 myofascial pain syn-drome, and mechanical low back or neck pain. Ifmuscle spasm is present in these conditions,it is related to local factors involving affectedmuscle groups. These conditions are commonlyencountered in clinical practice and can causesignificant disability and pain in some patients.Skeletal muscle relaxants are one of severalclasses of medications frequently used to treatthese conditions.8–10
Drugs classified as skeletal muscle relaxantsinclude baclofen, carisoprodol, chlorzoxazone,cyclobenzaprine, dantrolene, metaxalone, meth-ocarbamol, orphenadrine, and tizanidine. Only
baclofen, dantrolene, and tizanidine are ap-proved for the treatment of spasticity. Thesethree medications act by different mechanisms:baclofen blocks pre- and post-synaptic GABABreceptors,11,12 tizanidine is a centrally-acting ag-onist of α2 receptors,13,14 and dantrolene di-rectly inhibits muscle contraction by decreasingthe release of calcium from skeletal muscle sar-coplasmic reticulum.15 Other medications usedto treat spasticity but not formally approved forthis indication include benzodiazepines, cloni-dine, gabapentin, and botulinum toxin.15–17
The skeletal muscle relaxants carisoprodol,chlorzoxazone, cyclobenzaprine, metaxalone,methocarbamol, and orphenadrine have beenapproved for the treatment of musculoskeletaldisorders. Cyclobenzaprine is closely related tothe tricyclic antidepressants,18 carisoprodol ismetabolized to meprobamate,19 methocarba-mol is structurally related to mephenesin,18
chlorzoxazone is a benzoxazolone derivative,20
and orphenadrine is derived from diphenhydra-mine.21 The mechanism of action for most ofthese agents is unclear, but may be related inpart to sedative effects. These drugs are oftenused for treatment of musculoskeletal condi-tions, whether muscle spasm is present or not.10
Although there is some overlap between clinicalusage (tizanidine in particular has been studiedin patients with musculoskeletal conditions),22
in clinical practice each skeletal muscle relax-ant is used primarily for either spasticity or formusculoskeletal conditions.
There is little data regarding the comparativeefficacy and safety of different skeletal musclerelaxants. In 2001, Senate Bill 819 was passedby the Oregon Legislature and signed into law
142 Vol. 28 No. 2 August 2004Chou et al.
by the Governor. The law mandates develop-ment of a Practitioner-Managed PrescriptionDrug Plan (PMPDP) for the Oregon HealthPlan (OHP) and evidence-based reviews of thestate’s most expensive drug classes. The OregonHealth Resources Commission (OHRC) re-quested such a review of the skeletal musclerelaxant drug class. In consultation with a multi-disciplinary committee of experts, we selectedthe following key questions to guide the review:
What is the comparative efficacy of differentmuscle relaxants?What is the comparative safety of differentmuscle relaxants?Are there subpopulations of patients forwhich one muscle relaxant is more effectiveor associated with fewer adverse effects?
MethodsLiterature Search
To identify articles relevant to each key ques-tion, we searched (in this order): the Evidence-Based Medicine Library (2003, Issue 1) (fromtheCochrane Collaboration), MEDLINE(1966–January 2003), EMBASE (1980–January 2003),andreference listsofreviewarticles. In electronicsearches wecombinedtermsforspasticity, condi-tions associated with spasticity, and musculo-skeletal disorders with included skeletal musclerelaxants (see Appendix A on the Web site forcomplete search strategy). In addition, the Stateof Oregon created and disseminated a protocolto pharmaceutical manufacturers for submit-ting data. All citations were imported into anelectronic database (EndNote 6.0).
Study SelectionAll English-language titles and abstracts and
suggested additional citations that met the fol-lowing eligibility criteria were included:
Population. The population included in thisreview is adult or pediatric patients withspasticity or a musculoskeletal condition. Wedefined spasticity as muscle spasms associatedwith an upper motor neuron syndrome. Muscu-loskeletal conditions were defined as peripheralconditions resulting in muscle or soft tissuepain or spasms. We excluded obstetric and dial-ysis patients, and patients with restless legs syn-drome or nocturnal myoclonus. Senate Bill 819
specifically excludes patients with HIV and pa-tients with cancer.
Drugs. We included the following oral drugsclassified as skeletal muscle relaxants: baclofen,carisoprodol, chlorzoxazone, cyclobenzaprine,dantrolene, metaxalone, methocarbamol, or-phenadrine, and tizanidine. Other medicationsused for spasticity but considered to be in an-other drug class, such as benzodiazepines, qui-nine, tricyclic antidepressants, gabapentin, andclonidine, were not considered primary drugsin this report, but were reviewed when they weredirectly compared to an included skeletalmuscle relaxant. We excluded trials20,23–27 inwhich an included skeletal muscle relaxant wascombined with an analgesic medication unlessthe comparison arm included the same analgesicmedication and dose, trials28 which evaluatedskeletal muscle relaxants not approved in theUnited States, and trials29 which only comparedone dose of an included skeletal muscle relax-ant with another dose.
Outcomes. The main efficacy measures wererelief of muscle spasms or pain, functionalstatus, quality of life, withdrawal rates, and ad-verse effects (including sedation, weakness,addiction, and abuse). We excluded non-clini-cal outcomes such as electromyogram measure-ments or spring tension measurements.
There is no single accepted standard on howto measure the included outcomes. Spasticityis an especially difficult outcome to measureobjectively. The most widely used standardizedscales to measure spasticity are the Ashworth30
and modified Ashworth31 scales. In these scales,the assessor tests the resistance to passive move-ment around a joint and grades it on a scale of0 (no increase in tone) to 4 (limb rigid inflexion or extension). The modified Ashworthscale adds a “1�” rating between the 1 and 2ratings of the Ashworth scale. For both of thesescales, the scores are usually added for fourlower and four upper limb joints, for a totalpossible score of 0–32, though scoring methodscan vary. Other measures of spasticity includethe pendulum test, muscle spasm counts, andpatient assessment of spasticity severity on a vari-ety of numerical (e.g., 1–3, 1–4, 0–4) or categor-ical (e.g., none, mild, moderate, severe) scales.Many of these scales have not been validated.
Vol. 28 No. 2 August 2004 143Comparative Efficacy and Safety of Skeletal Muscle Relaxants
Muscle strength is usually assessed with theBritish Medical Research Council (BMRC)scale, which is based on the observation of resis-tance provided byvoluntary muscle activity.14 Anassessor grades each muscle or muscle groupindependently on a scale of 0 (no observedmuscle activation) to 5 (full strength).
Most studies measure pain using either visualanalogue or categorical pain scales. Visual ana-logue scales (VAS) consist of a line on a pieceof paper labeled 0 at one end, indicating nopain, and a maximum number (commonly 100)at the other, indicating excruciating pain. Pa-tients designate their current pain level on theline. Categorical pain scales, on the other hand,consist of several pain category options fromwhich a patient must choose (e.g., no pain,mild, moderate, or severe). Pain control (im-provement in pain) and pain relief (resolutionof pain) are also measured using visual ana-logue and categorical scales.
Studies can evaluate functional status usingeither disease-specific or non-specific scales.Disease-specific scales tend to be more sensitiveto changes in status for that particular condition,but non-specific scales allow for some compari-sons of functional status between conditions.The most commonly used disease-specific mea-sure of functional and disability status inpatients with multiple sclerosis, for example,is the Kurtzke Extended Disability Status Scale(EDSS).32 The EDSS measures both disabilityand impairment, combining the results of aneurological examination and functional as-sessments of eight domains into an overall scoreof 0–10 (in increments of 0.5). Disease-specificscales are also available for other musculoskele-tal and spastic conditions.33, 34 Scales that are notdisease-specific include the Medical OutcomesStudy Short Form-36 (SF-36), Short Form-12(SF-12), and other multi-question assessments.Another approach to measuring function is tofocus on how well the medication helps resolveproblems in daily living that patients with spas-ticity or musculoskeletal conditions commonlyface, such as getting enough sleep or stayingfocused on the job. Some studies also reporteffects on mood and the preference for onemedication over another.
We focused on the following common ad-verse events: somnolence or fatigue, dizziness,dry mouth, and weakness. We also paid specialattention to reports of serious hepatic injury,
abuse, and addiction.35 In some studies, only“serious” adverse events or adverse events“thought related to treatment medication” arereported. Many studies do not define theseterms. We included information on hospitaliza-tions and deaths when available.
Because of inconsistent reporting of out-comes, withdrawal rates may be a more reliablesurrogate measure for either clinical efficacyor adverse events in studies of skeletal musclerelaxants. High withdrawal rates probably indi-cate some combination of poor tolerability andineffectiveness. An important subset is with-drawal due to any adverse event (those who discon-tinue specifically because of adverse effects),which may indicate an intolerable adverse event.
Study Types. We included the following studytypes:
Systematic reviews of the clinical efficacy oradverse event rates of skeletal muscle relax-ants for spasticity or musculoskeletal condi-tions, OR
Randomized controlled trials that comparedone of the included skeletal muscle relaxantslisted to another included skeletal musclerelaxant, an antispasticity medication froma different drug class, or placebo in adultpatients with spasticity or musculoskeletalconditions, OR
Randomized controlled trials and large, highquality observational studies that reportedadverse event rates for an included skeletalmuscle relaxant.
We did not systematically review case re-ports and case series in which the proportionof patients suffering an adverse event couldnot be calculated. We excluded “single-dose”studies, abstracts and unpublished trials unlessa pharmaceutical company submitted thefull data.
Data AbstractionOne reviewer abstracted the following data
from included trials: study design, setting, pop-ulation characteristics (including sex, age, race,diagnosis), eligibility and exclusion criteria, in-terventions (dose and duration), comparisons,numbers screened, eligible, enrolled, and lost tofollow-up, method of outcome ascertainment
144 Vol. 28 No. 2 August 2004Chou et al.
(e.g., scales used), and results for each outcome.We recorded intention-to-treat results if avail-able and the trial did not report high overall lossto follow-up. In crossover trials, outcomes for thefirst intervention were recorded if available tominimize potential bias in results due to differ-ential withdrawal prior to crossover. We alsowanted to screen out the possibility of a “car-ryover” effect from the first treatment in studieswithout a washout period or “rebound” spasticityfrom withdrawal of the first intervention.36 Asecond reviewer checked all data.
Quality AssessmentWe assessed the quality of included trials using
predefined criteria (detailed methods availableon the Web37 or from the authors). Random-ized, properly blinded clinical trials are consid-ered the highest level of evidence for assessingefficacy.38–40 Clinical trials that are not random-ized or blinded or that have other methodo-logic flaws are less reliable. These are discussedin our report with references to specific flawsin study design and data analysis.
We rated the internal validity of each trialbased on methods used for randomization; allo-cation concealment and blinding; the similarityof compared groups at baseline; maintenanceof comparable groups; adequate reporting ofdropouts, attrition, crossover, adherence, andcontamination; loss to follow-up; and the useof intention-to-treat analysis. External validityof trials was assessed based on: adequate de-scription of the study population, similarity ofpatients to other populations to whom the inter-vention would be applied, control group receiv-ing comparable treatment, funding source, andthe role of the funder.
Overall quality was assigned based on criteriadeveloped by the US Preventive Services TaskForce and the National Health Service Centrefor Reviews and Dissemination (UK).39,40 Trialswith a fatal flaw in one or more categories wererated poor-quality. Trials that met all criteriawere rated “good quality.” The remainder wasrated fair quality. As the “fair-quality” categoryis broad, studies with this rating vary in theirstrengths and weaknesses. The results of somefair-quality studies are unlikely to be valid,while others are probably or likely to be valid. A“poor-quality” trial is not valid. The results areat least as likely to reflect flaws in the study
design as they are true differences between thecompared drugs.
Many of the studies we reviewed were con-ducted in the 1970s and early 1980s whenstandards for reporting clinical trial methodol-ogy were generally less stringent. Authors ofthese trials often did not discuss their methodsin what would today be considered adequatedetail.41 In general, not reporting specific areasof methodology (such as randomization, alloca-tion concealment, or blinding technique) wasnot considered a “fatal flaw,” but did prevent atrial from achieving a “good” rating for thatparticular criterion.
A particular randomized trial might receivetwo different ratings: onefor efficacy andoneforadverse events. Appendix D on the Web siteshows the criteria we used to rate studiesreporting adverse events. These criteria reflectaspects of the study design that are particularlyimportant for assessing adverse event rates. Werated studies as good-quality for adverse eventassessment if they adequately met six or moreof the seven pre-defined criteria, fair if they metthree to five criteria, and poor if they met twoor fewer criteria.
After assignment of quality ratings by the ini-tial reviewer, a second reviewer independentlyassigned a quality rating. Overall quality ratingand quality rating scores (for studies on adverseevent assessment) were compared betweenreviewers. If overall quality ratings differed, thetwo reviewers came to consensus prior to as-signing a final quality rating.
Data SynthesisWe constructed evidence tables showing
study characteristics, quality ratings, and resultsfor all included studies. To assess the overallstrength of evidence for a body of literatureabout a particular key question, we examinedthe consistency of study designs, patient popula-tions, interventions, and results. Consistent re-sults from good-quality studies across a broadrange of populations suggest a high degree ofcertainty that the results of the studies were true(that is, the entire body of evidence wouldbe considered “good quality.”) For a body offair-quality studies, however, consistent resultsmay indicate that similar biases are operatingin all the studies. Unvalidated assessment tech-niques or heterogeneous reporting methodsfor important outcomes may weaken the overall
Vol. 28 No. 2 August 2004 145Comparative Efficacy and Safety of Skeletal Muscle Relaxants
body of evidence for that particular outcome ormake it difficult to accurately estimate the truemagnitude of benefit or harm.
ResultsSearches identified 3,847 citations: 335 from
the Evidence-Based Medicine (Cochrane) Li-brary, 1,155 from MEDLINE, 2,314 fromEMBASE, and 43 from reference lists. We re-ceived no pharmaceutical company submis-sions. We identified 377 reports of clinicaltrials and excluded 227 of these (see AppendixB on the Web site for detailed search results).Sixty-seven were excluded because they did notevaluate an included population, 148 were ex-cluded because they did not evaluate an in-cluded intervention (skeletal muscle relaxant),seven were excluded because they did not evalu-ate an included outcome (spasms, pain,strength, functional ability, or adverse events),one was excluded because it was a single-dosestudy, and four were excluded because theywere not English-language. We retrieved 150reports on clinical trials for more detailed evalu-ation. After this second review, we excluded 52:39 because they did not evaluate an includedintervention, one because it did not evaluatean included population, one because it did notcontain original data, two because they didnot evaluate an included outcome, six becauseof study design (results published in anotherreviewed trial, not a controlled trial, or no data),and three because they were not in the En-glish language.
Ninety-eight reports presenting data for 101randomized controlled trials of patients withspasticity (55 trials reported in 54 publications)or musculoskeletal conditions (46 trials re-ported in 44 publications) provided usable dataand were included. We also identified four rele-vant systematic reviews41–44 and three relevantmeta-analyses (not systematic).45–47 In all trials,external validity was difficult to assess. Num-bers screened and enrolled were usually notreported, eligibility and exclusion criteria wereoften poorly specified, and funding sourceswere often not stated. When exclusion criteriawere reported, numbers of patients excludedfor each criterion were not reported.
Comparative Efficacy: Spasticity
Systematic Reviews and Meta-Analyses. Three sys-tematic reviews evaluated skeletal muscle relax-ants used to treat patients with spasticity (Table1). One was a good-quality systematic review41 ofvarious anti-spasticity agents, including skeletalmuscle relaxants, for treating symptoms ofmultiple sclerosis (Table 1 and Evidence Table1). It identified 11 head-to-head and 12 pla-cebo-controlled trials (five trials of baclofen,four dantrolene, and three tizanidine) ofincluded skeletal muscle relaxants. Seven of thehead-to-head trials compared tizanidine tobaclofen (including one German-languagetrial, one unpublished trial and one abstract thatwere not included in our search). Four othertrials compared baclofen, dantrolene, or tizani-dine to diazepam. No evaluated trial was ratedgood quality, and many trials used unvali-dated measures of spasticity or muscle strengthand inconsistent reporting methods. The au-thors found no pattern to suggest that one in-cluded skeletal muscle relaxant was any betterthan the others.Meta-analysis was not possible be-cause of marked heterogeneity in study designs,interventions used, and outcomes measured.
One systematic review evaluated pharmaco-logic interventions for spasticity followingspinal cord injury.44 It was rated fair qualitybecause the authors had not yet assessed 15identified potentially relevant studies. Of thenine studies included, two were placebo-con-trolled trials evaluating baclofen or tizanidine.There were no head-to-head trials, and no studywas rated good quality. There was insufficientevidence to judge the comparative efficacy oftizanidine versus baclofen.
One systematic review43 evaluated 20 studiesof tizanidine versus baclofen (14 studies) ordiazepam (6 studies) in patients with spasticity.This systematic review included both publishedand unpublished trials and was rated poor qual-ity (see Table 1). Although this systematicreview found some evidence of increased ef-fectiveness of tizanidine compared to baclofenand diazepam, it is not possible to determinewhether these conclusions are valid.
Two fair-quality meta-analyses (not systematicreviews) evaluated unpublished trials on tizani-dine versus baclofen or diazepam.45,46 Authorsof these trials were employed by Athena Neuro-sciences (San Francisco, CA), a pharmaceutical
146Vol.
28N
o.2
August
2004C
houet
al.
Au Main Findings
SysBro Included studies of generally
2 fair quality.
Cyclobenzaprine moderately effectivein improving symptoms compared toplacebo. No information on compar-ative efficacy and safety.
Sh Included studies of fair or poor2 quality.
Tizanidine more effective than baclo-fen for muscle strength in 2 out of 7head-to-head trials, otherwise no sig-nificant differences in efficacy. Nodifferences in efficacy between tizani-dine, baclofen, and dantrolene com-pared to diazepam; diazepamassociated with more sedation andless preferred.
Ta Included studies of fair or poor2 . quality.
Tizanidine more effective than placebofor Ashworth score but not for func-tional status. No difference betweenbaclofen and placebo.
La rch Unable to assess quality of included1 qual- studies.
suffi-uded No significant differences between ti-
zanidine and baclofen or diazepamfor muscle tone, muscle spasms,clonus, muscle strength, functionalstatus, or overall antispastic effect.Tizanidine slightly better toleratedthan diazepam and baclofen. With-drawals due to adverse events 4% ontizanidine vs. 9% on baclofen ordiazepam.
(continued)
Table 1Overview of Included Systematic Reviews on Skeletal Muscle Relaxants
Skeletal Muscle Number of Includedthor/Year Purpose of Study Relaxants Evaluated Studies and Patients Quality
tematic Reviewswning Assess the effectiveness Cyclobenzaprine 14 trials Good.00142 of cyclobenzaprine
in low back pain.3315 patients
on cyclobenzaprine
akespeare Assess the comparative Tizanidine 36 trials (7 tizanidine Good.00141 effectiveness and Baclofen vs. baclofen, 2 tizanidine
tolerability of Dantrolene vs. diazepam, 1 baclofenanti-spasticity agents Diazepama vs. diazepam, 1 dantro-in multiple sclerosis lene vs. diazepam)patients.
1359 patients overall
ricco Assess the Tizanidine 9 trials (2 baclofen vs. Fair. Some identified00044 effectiveness and Baclofen placebo, 1 tizanidine studies not assessed
safety of drugs for vs. placebo)spasticity in spinalcord injury patients. 218 patients overall
taste Assess the comparative Tizanidine 20 trials (14 vs. baclofen, Poor. Methods of sea99443 efficacy of tizanidine Baclofen 6 vs. diazepam) not reported, study
compared to other Diazepama ity not assessed, inanti-spastic agents. 385 patients on tizanidine, cient detail of incl
392 on baclofen or studies.diazepam
Vol.28
No.
2A
ugust2004
147C
omparative
Efficacyand
Safetyof
SkeletalM
uscleR
elaxants
Author/ Quality Main Findings
Meta-anaGroves ufficient detail of No significant differences between
199846 ed studies and not tizanidine and baclofen or diazepamf data combined for spasticity by Ashworth score orpriately. mean change in muscle strength.
“Global tolerability to treatment”favored tizanidine compared tobaclofen (P � 0.008) and diazepam(P � 0.001).
Wallace ufficient detail of See results for Groves 1998 for results199445 ed studies and not of head-to-head studies.
f data combinedpriately. In placebo-controlled studies, there
were increased withdrawals due toadverse events (44/284 vs. 15/277)on tizanidine. Frequent adverseevents on tizanidine were dry mouth(49%), somnolence (48%), asthenia(41%), dizziness (16%), head-ache (12%).
Nibbelin ufficient detail of ‘Global response’ equivalent for197847 ed studies and not cyclobenzaprine and diazepam and
f data combined significantly better than placebo.priately. Muscle spasms, tenderness on palpa-
tion, limitation of motion, and limi-tation of daily living (but not localpain) significantly better in patientson cyclobenzaprine compared to di-azepam at Week 2 using unvalidatedmethods.
aCompara
Table 1Continued
Skeletal Muscle Number of IncludedYear Purpose of Study Relaxants Evaluated Studies and Patients
lysesAssess the efficacy Tizanidine 10 trials (7 vs. baclofen, 3 Fair. Ins
and tolerability of Baclofen vs. diazepam) includtizanidine using Diazepama clear iunpublished trials held 270 patients overall approby the manufacturer.
Assess the efficacy Tizanidine 3 placebo-controlled trials Fair. Insand tolerability of Baclofen with 525 patients includtizanidine using Diazepama clear iunpublished trials 11 head-to-head studies (8 approheld by the vs. baclofen, 3 vs. diaze-manufacturer. pam) with 270 patients
k Assess the efficacy of Cyclobenzaprine 20 randomized trials Fair. Inscyclobenzaprine using Diazepama includunpublished trials. Placebo 434 patients on cyclobenza- clear i
prine, 280 on diazepam, appro439 on placebo
tor
148 Vol. 28 No. 2 August 2004Chou et al.
company marketing tizanidine in the U.S., andanalyzed the same trials (ten trials in one meta-analysis46 and eleven in the other45). Both stud-ies found no significant differences betweentizanidine compared to diazepam orbaclofenfor outcomes of tone (Ashworth scale) or musclestrength (summed BMRC strength scores).
Head-to-Head Trials. Of 55 trials evaluating in-cluded skeletal muscle relaxants in patients withspasticity, 17 (total enrolled � 654) were head-to-head trials of two skeletal muscle relaxantsor a skeletal muscle relaxant versus anothermedication used to treat spasticity (Table 2).The majority (10) of the trials focused on pa-tients with multiple sclerosis, but other clinicalconditions (children with cerebral palsy,48 post-stroke or head trauma,49 spinal cord injury,50
and spasticity from various causes51–54) were alsoevaluated. Except for one study lasting oneyear,51 all of the head-to-head trials were of rela-tively short duration, ranging from 2 to 8 weeksper intervention. All of the trials except one50
were published before 1990. Although elderlypatients were included in most trials, no trialspecifically evaluated only elderly patients. Onetrial included only children.48
None of the 17 head-to-head trials was ratedgood quality. All studies had at least two of thefollowing methodological flaws: randomizationtechnique not described, eligibility criteria notdescribed, blinding technique not described,allocation concealment technique not de-scribed, or high loss to follow-up (EvidenceTable 3). Adequate blinding is an especiallyimportant factor in studies using subjective out-comes, such as patient preference, global assess-ments, spasm severity, or pain. One trialcomparing baclofen to clonidine that found nodifferences for spasticity was rated poor qualitybecause it was not randomized and did not per-form blinding, and was excluded from thetables.55 The remainder were rated fair quality.Possible confounding factors in these trials in-cluded different methods of medication titra-tion or target doses, differential withdrawalsduring the first intervention period in crossovertrials, and previous use of an intervention orother muscle relaxant, which was inconsistentlyreported. In crossover trials, results of the firstintervention were usually not reported.
In eight trials of tizanidine vs. baclofen, theaverage dose of tizanidine ranged from 11 mg/
day53 to 24 mg/day56–58 and the dose of baclo-fen ranged from 15 mg/day57 to 90 mg/day.58
Most of these trials evaluated patients with mul-tiple sclerosis. In each of these eight trials, tizan-idine and baclofen appeared to have roughlyequivalent efficacy (Table 2). Outcomes mea-sured included muscle tone, muscle spasm,clonus, functional assessments, patient or physi-cian global assessments, and patientor physicianpreference. These outcomes were assessed usinga variety of methods, including unvalidated orunspecified scales. Six trials36,51,53,56,57,59 usedtheAshworth scale to measure spasticity or tone,but methods of reporting these results were in-consistent and raw scores were usually not pre-sented. In most trials, regardless of the methodused to assess outcomes, patients receivingeither baclofen or tizanidine reported signifi-cant improvements compared to baseline. Thelongest trial (52 weeks compared to 8 weeksor less for the other trials) reported results simi-lar to shorter trials.51 The overall withdrawalrate was higher with baclofen than with tizani-dine in three out of seven trials51,57,60 androughly equivalent in the other four. Of thethree trials with differential withdrawal rates,two had low numbers of overall withdrawals (fivein each trial), making the significance ofthese differential rates difficult to assess. In twoof the trials,51,60 withdrawals due to adverseevents accounted for most of the observed dif-ferences in overall withdrawal rates (see sectionon adverse events).
There were no trials directly comparing dan-trolene to baclofen or tizanidine. In the eighttrials48,49,52–54,61–63 of tizanidine, baclofen, ordantrolene versus diazepam, there was no pat-tern to suggest that any of these skeletal musclerelaxants was superior to the others for assessedclinical outcomes including spasm, strength,functional status, or patient preference (Table2 and Evidence Table 3). Differences in studydesign, patient populations, outcomes evalu-ated, and roughly similar efficacy of each skele-tal muscle relaxant compared to diazepam inindividual trials made it impossible to make ac-curate judgments about the comparative effi-cacy of tizanidine, baclofen, and dantrolenefrom these trials as a whole.
Placebo-Controlled Trials. In addition to onehead-to-head trial54 that also included a placeboarm, we identified an additional 38 additional
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WithdrawalsMain Results (overall)
No significant differences 11% (5/46)between interventions 28% (13/46)for main outcomes.
le
No significant differences 16% (8/50)between interventions. 12% (6/50)
dsort No significant differences 6% (1/16)
between interventions 25% (4/16)(Ashworth scale scoresnot reported).
sty
ort No significant differences 7% (1/15)between interventions 27% (4/15)(Ashworth scale scoresnot reported).
lity
No significant differences 11% (4/36)les between interventions 17% (6/36)
Disability: Kurtzke ExpandedDisability Status ScaleFunctional status: Kurtzke Functional SystemIncapacity status: Minimal record of disabilifor multiple sclerosisAmbulation: Ambulation indexClonus and reflexes: Unspecified methodsMuscle strength and pain: 5-point scalesEfficacy and tolerance: �3 to �3 scales
Tizanidine mean Medici 198951 Spasticity due to Spasticity: Ashworth scale and patient self-rep20 mg/day various causes (4-point scale)
Tizanidine Smith 199496 Multiple sclerosis No significantFair 220 daily counts.
Tizanidine UK Tizanidine Trial Multiple sclerosis Tizanidine supGroup 199497 187
FairChlorzoxazone Losin 196698 Various spasticity (children) Outcomes not
Poor 30Cyclobenzaprine Ashby 1972100 Various spasticity No significant
Fair 15Methocarbamol Bjerre 197199 Cerebral palsy (children) No significant
Poor 44 methocarbamJohnson scalfor upper ex
Vol. 28 No. 2 August 2004 153Comparative Efficacy and Safety of Skeletal Muscle Relaxants
placebo-controlled trials (Table 3). Fourteenevaluated baclofen,64–77 15 dantrolene,78–92 sixtizanidine,55,93–97 one chlorzoxazone,98 onemethocarbamol,99 and one cyclobenzaprine.100
Conditions evaluated in these studies weremultiple sclerosis, cervical myelopathy, cerebralpalsy, post-stroke, traumatic brain injury,spinal cord injury, and spasticity from variouscauses. Nine placebo-controlled trials evaluatedchildren72,74,79,80,83,84,89,98,99 and one specificallyevaluated elderly post-stroke patients.70 Weidentified no placebo-controlled trials of cari-soprodol, metaxalone, or orphenadrine in pa-tients with spasticity.
None of the placebo-controlled trials wasrated good quality (Evidence Table 4). Mainresults from placebo-controlled trials for spas-ticity are summarized in Table 3. Most of theplacebo-controlled trials found either signifi-cant benefits or trends towards benefit frombaclofen, dantrolene, and tizanidine comparedto placebo for spasticity, functional ability,and strength. However, because of the use ofunvalidated outcomes scales and inconsistentmethods for reporting outcomes, the relativemagnitude of benefit for each of these medica-tions could not be compared across studies.There was inadequate evidence from onetrial98 of chlorzoxazone (rated poor quality),one trial100 of cyclobenzaprine (no significantdifferences), and one trial99 of methocarbamolin children with cerebral palsy (rated poorquality) to show that these skeletal muscle relax-ants are effective for treatment of spasticity.These three medications are not approved forthis indication.
Meta-analysis could not be performed on theplacebo-controlled trials because of marked dif-ferences in interventions (doses used and meth-ods of titration), trial designs, populationsstudied, outcomes scales, and methods for re-porting outcomes. No reliable conclusionsabout comparative efficacy can be drawn fromthese placebo-controlled trials.
Comparative Efficacy: MusculoskeletalConditions
Systematic Reviews and Meta-Analyses. We identi-fied no systematic reviews comparing differentskeletal muscle relaxants in patients with mus-culoskeletal conditions.
One good-quality systematic review evaluatedthe efficacy of cyclobenzaprine versus placebofor treatment of back pain (Table 1 and Evi-dence Table 2).42 This systematic review exam-ined 14 trials of fair overall quality and foundthat cyclobenzaprine was associated with better‘global improvement’ scores at Day 14 (oddsratio 4.7; 95% confidence interval (CI), 2.7–8.1). For individual symptoms, the systematicreview found a modest magnitude of improve-ment (effect size 0.38–0.58) compared to pla-cebo by Day 14 for five outcomes: local pain,muscle spasm, tenderness to palpation, rangeof motion, and activities of daily living. Informa-tion regarding other skeletal muscle relaxantsevaluated in included trials was specifically ex-cluded from analysis in this systematic review.
One fair-quality meta-analysis evaluated thecomparative efficacy of cyclobenzaprine, diaz-epam and placebo.47 This study summarizedresults of 20 unpublished short-term (2-week)trials performed in the U.S. in 1153 patientswith muscle spasm; the authors were employedby Merck Laboratories. It included patients withpost-traumatic injury, musculoskeletal strain,radiculopathy, and osteoarthritis. This studyfound that the unvalidated outcome measure‘global response’ was equivalent for cyclobenza-prine and diazepam (66% marked or moderateimprovement) and significantly better than pla-cebo (40%).
Head-to-Head Trials. Of 46 trials of includedskeletal muscle relaxants in patients with muscu-loskeletal conditions, 11 (total enrolled � 724)were head-to-head trials (Table 4). All of thehead-to-head trials focused on patients withback or neck pain and spasms. One trial101 fo-cused on patients with chronic symptoms andthe remainder evaluated patients with acutesymptoms. The duration of all head-to-headtrials ranged from seven18 to 18102 days. All ofthe trials were published before 1985. Althoughelderly patients were included in most trials, notrial specifically evaluated only elderly patientsand none included children.
None of the 11 head-to-head trials was ratedgood-quality; all had at least two importantmethodological flaws (Evidence Table 5). Alltrials were rated fair except one trial of cycloben-zaprine versus diazepam that was rated poorbecause in addition to other flaws, it only re-ported results for 52 of the 105 enrollees and
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OverallIntervent Main Results Withdrawals
TizanidinTizanidin No significant differences between 0% (0/14)Chlorzox interventions. 8% (1/13)
500 mg
CyclobenzaCycloben No significant differences between in- 14% (12/87)
10 mg terventions except slightly greater 13% (12/94)Methoca proportion of patients with improve-
1500 m ment in local pain with cyclobenza-prine (48% vs. 40%).
CyclobenzaCycloben No significant differences between 24% (9/37)
10 mg interventions. 28% (11/39)Carisopro
CarisoprodCarisopro Carisoprodol superior to diazpeam for 10% (4/40)
P � 0.015) and functional assessment (P � 0.04)fference for sleep impairment using 4-point scale
r pain, tenderness, limitation of motion, daily� 0.05) at end of Week 2 using 5-point scales.
r spasm, limitation of motion, daily activities (all); and global evaluation (P not reported) using
scle spasm (P � 0.01) and pain (P � 0.01) using
rmance time or muscle spasms using 5-point scale.
scle spasm, or functional measurements using
0.02) using 1–10 visual analogue scale and sleepe (P � 0.02).tion using 5-point scale (P not reported).
clobenzaprine superior to placebo for musclemotion, and global evaluation (all P � 0.01) and
o naprosyn alone for functional capacity usingspasm using 4 point scale (P � 0.05), no differenced 4-point scales).r global evaluation using 5-point scale (P not
mprovement using 0–10 visual analogue scale, painctional disability, or psychological status.ale (P not reported).
itation of motion; favors cyclobenzaprine for localted) using 9-point scales.ale for patient-rated stiffness and aching, patient-rating (P � 0.05), no difference using 5-point scale
ain.
(continued)
Table 5Overview of Placebo-Controlled Trials of Skeletal Muscle Relaxants for Musculoske
Medication Trials Population/Number Enrolled Main Outcomes (Included
Carisoprodol Baratta 1976121 Low back syndrome No significant difference for pain usingFair 105 various functional measurements and
Carisoprodol Cullen 1976122 Acute back or neck syndrome Carisoprodol superior for pain, spasm,Fair 65 methods (all P � 0.01).
Carisoprodol Hindle 1972123 Low back syndrome (Mexican migrant Carisoprodol superior for pain, spasm,Fair workers) P � 0.01) and pain intensity using 0–
48Carisoprodol Soyka 1979124 Acute neck or low back syndrome Favors carisoprodol for muscle spasm (
Fair 414 using 5-point scales, no significant dior pain using 5-point scale.
Cyclobenzaprine Aiken 1978a125 Acute neck or low back syndrome Cyclobenzaprine superior to placebo foFair 117 (including diazepam arm) activities, and global evaluation (all P
Cyclobenzaprine Aiken 1978b125 Acute neck or low back syndrome Cyclobenzaprine superior to placebo foFair 50 P � 0.01); pain/tenderness (P � 0.05
5-point scales.Cyclobenzaprine Baratta 1982126 Various acute muscle spasm Cyclobenzaprine superior for local mu
Fair 120 5-point scale.Cyclobenzaprine Basmajian 1978102 Various acute muscle spasm No significant differences for task perfo
Fair 120 (including diazepam arm)Cyclobenzaprine Basmajian 1989127 Various acute muscle spasm No significant differences for pain, mu
Fair 175 unspecified methods.Cyclobenzaprine Bennett 1988114 Fibromyalgia Cyclobenzaprine superior for pain (P �
Fair 120 quality and fatigue using 5-point scalCyclobenzaprine Bercel 1977128 Neck or back pain � 30 days Favors cyclobenzaprine for spasm dura
Fair 54Cyclobenzaprine Bianchi 1978129 Acute neck or low back syndrome No significant differences at Day 14; cy
Fair 48 consistency, tenderness, limitation ofdaily activities (P � 0.05) at Day 7.
Cyclobenzaprine Borenstein 1990110 Acute low back syndrome Cyclobenzaprine � naprosyn superior t(�naprosyn Poor 40 4-point scale (P � 0.05) and musclein both arms) for resolution of pain (using 0–20 an
Cyclobenzaprine Brown 1978101 Chronic (�12 months) neck or low Cyclobenzaprine superior to placebo foFair back pain reported).
Cyclobenzaprine Carette 1994115 Fibromyalgia No significant difference for 6-month iFair 208 using McGill Pain Questionnaire, fun
Cyclobenzaprine Preston 198418 Acute local muscle spasm No differences for muscle spasm or limFair 227 (includes methocarbamol arm) pain and daily activities (P not repor
Cyclobenzaprine Quimby 1989130 Fibromyalgia Favors cyclobenzaprine using 5-point scFair 40 rated poor sleep, and overall patient
for patient rated fatigue or muscle p
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rity count using 5-point scale, pain using 7-point scale,ess using Stanford Sleepiness Rating Scale.for muscle spasm, local pain, tenderness, limitation
bal evaluation (P � 0.01) using 5-point scales.for muscle spasm, local pain, tenderness, limitation
bal evaluation (P � 0.01) using 5-point scales.evaluation, pain, muscle spasm, or functionalethods.
m, local pain, limitation of normal motion, anding unspecified scales.
nt scale for muscle spasm or 4-point scale for pain.
apeutic response using 4-point scale, range of motionpasm using 5-point scale.apeutic response using 4-point scale, range of motionpasm using 5-point scale.ors cyclobenzaprine for local pain, limitation ofreported) using 9-point scales.spasm and local pain at 48 hours using 5-point scales;tion of motion and daily activities at 1 WeekP � 0.10) or muscle spasm (NS) using 5-point scales.nsity (P � 0.01) and pain relief (P � 0.01)using
of nocturnal leg cramps in one-month period.
ss and function using 4-point scales (P not reported).
nt scale for ‘overall effect’.
enderness, spasm, functional assessments using
m using “manual semiotic maneuvers” (P � 0.001)logue scale (P � 0.001).racture using 4-point scale (P � 0.04), strength using
ence for pain on movement using 4-point scale.
n movement (P � 0.029), and pain at nighto differences for pain at rest or restriction of
(continued)
Table 5Continued
Medication Trials Population/Number Enrolled Main Outcomes (Include
Cyclobenzaprine Reynolds 1991113 Fibromyalgia No differences for tender point seveFair 12 fatigue using 7-point scale, sleepin
Cyclobenzaprine Scheiner 1978 (1)106 Acute back or neck spasm Cyclobenzaprine superior to placeboFair 96 of motion, daily activities, and glo
Cyclobenzaprine Scheiner 1978 (2)106 Acute back or neck spasm Cyclobenzaprine superior to placeboFair 75 of motion, daily activities, and glo
Cyclobenzaprine Steingard 1980131 Back or neck spasm No significant differences for globalFair 121 measurements using unspecified m
Metaxalone Dent 1975133 Acute skeletal muscle disorders Metaxolone superior for muscle spasPoor (not specified) interference with daily activities us
228Metaxalone Diamond 1966135 Muscle pain and spasm, unspecified No significant difference using 5-poi
Fair locations100
Metaxalone Fathie 1964 (1)134 Low back pain Metaxolone superior for global therFair 100 using 5-point scale, and palpable s
Metaxalone Fathie 1964 (2)134 Low back pain Metaxolone superior for global therFair 100 using 5-point scale, and palpable s
Methocarbamol Preston 198418 Acute local muscle spasm No differences for muscle spasm; favFair 227 (includes cyclobenzaprine arm) motion, and daily activities (P not
Methocarbamol Tisdale 1975141 Acute local muscle spasm Methocarbamol superior for muscleFair 180 methocarbamol superior for limita
(P � 0.05) but not for local pain (Orphenadrine Gold 197821 Acute low back syndrome Orphenadrine superior for pain inte
Poor 60 unspecified methods.Orphenadrine Latta 1989120 Nocturnal leg cramps (elderly) Orphenadrine superior for number
Fair 59Orphenadrine McGuinness 1983111 Various musculoskeletal conditions Favors orphenadrine for pain, stiffne
(�paracetamol Fair 32in both arms)
Orphenadrine Valtonen 1975132 Low back or neck pain No significant difference using 3-poiFair 200
Baclofen Dapas 1985140 Acute back syndrome Baclofen superior for lumbar pain, tFair 200 unspecifie methods (P � 0.05).
Dantrolene Casale 1988142 Chronic low back syndrome Dantrolene superior for muscle spasFair 20 and pain behavior using visual ana
Dantrolene Salvini 198612 Neck or low back syndromes Dantrolene superior for muscle cont(� ibuprofen Fair 60 5-point scale (P � 0.05), no differin both arms)
Tizanidine Berry 1988a137 Acute low back syndrome Cyclobenzaprine superior for pain oPoor 105 (P � 0.025) using 4-point scales, n
movement using 4-point scales.
158 Vol. 28 No. 2 August 2004Chou et al.
Tab
le5
Con
tinu
ed
Med
icat
ion
Tri
als
Popu
lati
on/N
umbe
rE
nro
lled
Mai
nO
utco
mes
(In
clud
edSk
elet
alM
uscl
eR
elax
ant
vers
usPl
aceb
o)
Tiz
anid
ine
Ber
ry19
88b13
6A
cute
low
back
syn
drom
eN
osi
gnif
ican
tdi
ffer
ence
sfo
rpa
inat
nig
ht,
pain
atre
st,
orre
stri
ctio
nof
mov
emen
tus
ing
Fair
112
4-po
int
scal
es.
Tiz
anid
ine
Foge
lhol
m19
9211
6T
ensi
onh
eada
che
(all
wom
en)
Tiz
anid
ine
supe
rior
for
hea
dach
ese
veri
tyus
ing
0–10
0vi
sual
anal
ogue
(P�
0.01
8)sc
ale
Fair
45an
d5-
poin
tve
rbal
rati
ng
scal
e(P
�0.
012)
and
for
anal
gesi
cus
eus
ing
pill
coun
ts(P
�0.
001)
.T
izan
idin
eL
epis
to19
7913
8L
owba
cksy
ndr
ome
Tiz
anid
ine
supe
rior
for
pain
,m
uscl
ete
nsi
on,
ten
dern
ess
usin
g4-
poin
tsc
ales
(P�
0.05
),Fa
ir30
no
diff
eren
ces
for
limit
atio
non
mov
emen
tus
ing
4-po
int
scal
e.T
izan
idin
eM
urro
s20
0011
8T
ensi
onh
eada
che
No
stat
isti
cal
diff
eren
ces
for
hea
dach
ese
veri
tyus
ing
100
mm
visu
alan
alog
uesc
ale,
days
Fair
201
free
ofh
eada
che,
daily
dura
tion
ofh
eada
che,
orus
eof
para
ceta
mol
.T
izan
idin
eSa
per
2002
119
Dai
lyh
eada
ches
Tiz
anid
ine
supe
rior
for
hea
dach
ein
dex
(hea
dach
eda
ysx
aver
age
inte
nsi
tyx
dura
tion
),Fa
ir13
6ra
ndo
miz
edm
ean
hea
dach
eda
ys/w
eek,
aver
age
hea
dach
edu
rati
on,
aver
age
hea
dach
ein
ten
sity
usin
g5-
poin
tsc
ale,
pain
usin
g10
0m
mvi
sual
anal
ogue
scal
e,n
odi
ffer
ence
for
fun
ctio
nal
stat
usus
ing
Mig
rain
eD
isab
ility
Ass
essm
ent
ques
tion
nai
re.
Tiz
anid
ine
Sird
alud
Ter
nel
inA
sia-
Acu
ten
eck
orlo
wba
cksy
ndr
omes
Tiz
anid
ine
supe
rior
for
pain
usin
g4-
poin
tsc
ale
(P�
0.05
),sp
asm
usin
g4-
poin
tsc
ale
Paci
fic
Stud
yG
roup
405
(P�
0.00
1),
rest
rict
ion
ofbo
dym
ovem
ent
usin
g4-
poin
tsc
ale
(P�
0.00
1),
no
1988
139
diff
eren
cefo
rsl
eep
qual
ity
usin
g4-
poin
tsc
ale.
Fair
did not account for the other patients.102 Avariety of methods was used for measuring out-comes, including various scales for pain (4-, 5-,or 9- point scales and visual analogue scales),tenderness, and functional status. Most assess-ment scales were unvalidated, and methods ofreporting these outcomes were inconsistent.Functional status was either not measured orassessed using unstandardized and unvalidatedmethods. Doses of medications varied betweentrials.
There was no clear evidence from head-to-head trials that one skeletal muscle relaxant wassuperior to any other. Three trials evaluatedone included skeletal muscle relaxant versusanother, but each evaluated a different compar-ison. In a trial comparing tizanidine andchlorzoxazone in patients with back pain,103
there were no significant differences betweentreatments for muscle pain, muscle tension,tenderness, and activity. More patients reported‘excellent’ overall results with tizanidine (57%)compared to chlorzoxazone (23%), but similarproportions of patients reported ‘good or excel-lent’ results (79% vs. 69%). A trial of cycloben-zaprine versus methocarbamol in patients withlocalized muscle spasm found that there wereno significant differences in the proportion ofpatients reporting absent or mild muscle spasm,limitation of motion, or limitation of daily activi-ties.18 In a trial of cyclobenzaprine versus car-isoprodol in patients with acute back pain andspasms,104 there were no significant differencesfor pain, muscle stiffness, activity impairment,sleep impairment, tension, or relief scores com-pared to baseline.
Eight other head-to-head trials compared anincluded skeletal muscle relaxant to diazepam.Of these, the trial that appeared to be of bestquality compared carisoprodol and diaze-pam.105 This trial was still rated fair qualitybecause the authors did not describe allocationconcealment techniques and used unvalidatedmethods for assessing outcomes. Carisoprodolwas significantly superior to diazepam for stiff-ness, tension, and relief, with average differ-ences about 0.5 on a 1–5 scale.105 No significantdifferences were seen for pain, activity impair-ment, or sleep impairment.
Of five trials101,102,106,107 comparing cycloben-zaprine to diazepam, two106,107 found signifi-cant differences (using unvalidated measures)for most measurements of pain, muscle spasm,
Vol. 28 No. 2 August 2004 159Comparative Efficacy and Safety of Skeletal Muscle Relaxants
functional status, and ‘global evaluations’ thatfavored cyclobenzaprine. One other trial106 re-ported decreased tenderness, decreased limita-tion of motion and better ‘global evaluation’for cyclobenzaprine versus diazepam, but notfor other measures (muscle spasm, pain, func-tional ability). All three of these trials had somesupport from a manufacturer (Merck Sharp &Dohme, West Point, Pennsylvania, USA) andwere published in the same book. For mostoutcomes that favored cyclobenzaprine, themagnitude of difference between treatmentswas greater at the end of Week 1 than at theend of Week 2. Two other trials comparingcyclobenzaprine to diazepam101,102 and twotrials108,109 comparing tizanidine to diazepamfound no significant differences for any clinicaloutcomes including pain, stiffness, or func-tional ability.
The trial101 focusing on patients with chronicback or neck symptoms reported results similarto the other trials. The overall withdrawal ratesin all head-to-head trials ranged from 0% to35%. In one trial,106 the overall withdrawal rateappeared significantly higher on cyclobenza-prine (12/34 [35%]) compared to diazepam(3/32 [9%]), but there was no significant differ-ence in the withdrawal rate between interven-tions in other trials.
We identified no head-to-head trials of orphe-nadrine, metaxalone, dantrolene, or baclofenin patients with musculoskeletal conditions.
Placebo-Controlled Trials. In addition to sixhead-to-head trials (from five publications)18,
101,102,106,107 with a placebo arm, we identifiedanadditional35placebo-controlled trials(Table5). Three trials evaluated a skeletal muscle relax-ant with an equivalent analgesic in each arm.110–112
Most trialsevaluatedlowbackornecksyndromesalone or mixed with other musculoskeletal con-ditions. Other conditions evaluated were fibro-myalgia,113–115 tension headaches or mixedheadache conditions,116–119 and nocturnal legcramps.120 No trial included children.
In general, placebo-controlled trials were nothelpful in assessing comparative efficacy. Noneof the placebo-controlled trials involving pa-tients with musculoskeletal conditions was ratedgood quality (Table 5 and Evidence Table 6).The comparative efficacy of each skeletalmuscle relaxant was also difficult to assess be-cause of marked heterogeneity in study design,
interventions, populations studied, and out-comes assessed.
Carisoprodol (four trials121–124), cyclobenza-prine (18 trials reported in 17 publications18,
101,102,106,107,110,113–115,117,125–131 including five head-to-head trials with a placebo arm), orphena-drine (four trials21,111,120,132), metaxalone (fourtrials in three publications133–135), and tizani-dine (six trials116,118,119,136–139) were evaluatedin the highest number of trials. A smallernumber of trials evaluated baclofen (1 trial140),methocarbamol (2 trials18,141), and dantrolene(2 trials112,142). Although most of these trialsfound significant benefits or trends towardsbenefit on active treatment compared to pla-cebo, cyclobenzaprine has been evaluated andconsistently found effective in substantiallymore trials than the other skeletal muscle relax-ants. The data on metaxalone, on the otherhand, was mixed. The best fair-quality trialfound no differences compared to placebo,135
but a poor-quality trial133 and two lesser fair-quality trials134 reported some benefits com-pared to placebo using unvalidated outcomemeasures. We identified no placebo-controlledtrials evaluating chlorzoxazone.
Comparative Safety: Spasticity
Systematic Reviews and Meta-Analyses. We identi-fied no systematic reviews that evaluated com-parative adverse event rates from skeletalmuscle relaxants in patients with spasticity. Onemeta-analysis of three placebo-controlled trialswas rated poor quality for adverse eventassessment because no information about ad-verse event assessment methods was reported(Table 1).45 Adverse events included 49% drymouth, 48% somnolence, 41% asthenia, 16%dizziness, and 12% headache in patients on ti-zanidine compared to 10%, 10%, 16%, 4%, and13% on placebo. Two patients had liver func-tion abnormalities and three had hallucina-tions. No deaths were reported. Abuse oraddiction was not evaluated. Withdrawal ratesdue to adverse events were 17% for tizanidineand 7% for placebo.
Head-to-Head Trials. No head-to-head trial wasrated good quality for adverse event assessment.In general, there was little evidence of rigorous
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iness or Withdrawals DueStud eadedness Dry Mouth to Adverse Events
TizaBas orted 23% 9% (4/46)
orted 14% 26% (12/46)Eyse orted 28% 6% (3/49)
orted Infrequent (data 6% (3/49)not reported)
Hoo 14% 36% 11% (1/9)14% 14% 14% (1/7)
Med 0% 7% 0% (0/15)7% 0% 20% (3/15)
New 8% 0% 6% (2/36)15% 4% 17% (6/36)
Rin % severe) 50% 6% (1/16)3% severe) 27% 6% (1/16)
Smo eported 9% 0% (0/11)eported 10% 0% (0/10)
Stie orted Not reported 6% (1/18)separately
orted Not reported 4% (1/20)separately
TizaBes eported 11% 12% (6/51)
eported 3% 28% (15/54)Rin 7% 33% 0% (0/15)
13% 0% 27% (4/15)Car 3% 3% 30% (11/37)
0% 0% 38% (14/37)Fro 6% Not reported 6% (1/16)
6% Not reported 0% (0/16)Rou orted Not reported 0% (0/13)
orted Not reported 0% (0/13)Gla orted Not reported 19% (3/16)
orted Not reported 6% (1/16)Nog orted Not reported None reported
orted Not reported None reportedSch 19% Not reported Not clear
19% Not reported Not clear
Table 6Adverse Events, Head-to-Head Trials of Skeletal Muscle Relaxants for S
Dizzy Interventions Somnolence or Fatigue Weakness Lighth
nidine versus Baclofens 198860 Tizanidine mean 17 mg/day 29% 21% Not rep
Baclofen mean 35 mg/day 19% 35% Not reptte 198858 Tizanidine 24 mg/day 30% Infrequent (data Not rep
n 198736 Tizanidine mean 23/day 33% (also includes Not reported Not repweakness and dry separatelymouth)
Baclofen mean 59 mg/day 25% (also includes Not reported Not repweakness and dry separatelymouth)
nidine, Baclofen, or Dantrolene versus Diazepam198849 Tizanidine mean 17 mg/day 44% 2% None r
Diazepam mean 20 mg/day 44% 18% None rne 1980 (1)53 Tizanidine mean 14 mg/day 53% (0% severe) 13% (8% severe)
Diazepam mean 15 mg/day 87% (47% severe) 53% (27% severe)tlidge 197463 Baclofen 30 mg/day and 60 mg/day 14% 11%
Diazepam 15 mg/day and 30 mg/day 11% 16%m 197561 Baclofen mean 61 mg/day 31% 19%
Diazepam mean 21 mg/day 69% 12%ssan 198552 Baclofen mean 47 mg/day 8% Not reported Not rep
Diazepam mean 28 mg/day 38% Not reported Not repss 197454 Dantrolene 100 mg qid Not reported Not reported Not rep
Diazepam 5 mg qid Not reported Not reported Not repen 197648 Dantrolene titrated to 75 mg qid Not clear Not reported Not rep
Diazepam titrated to 12 mg/day Not clear Not reported Not repmidt 197662 Dantrolene 75 mg qid 31% 67%
Diazepam 5 mg qid 67% 76%
Vol. 28 No. 2 August 2004 161Comparative Efficacy and Safety of Skeletal Muscle Relaxants
adverse event assessment in these trials (Evi-dence Table 3). No trial appeared to have signif-icantly better adverse event reporting methodsthan the others. The most frequently reportedadverse event rates were for somnolence, weak-ness, dizziness, and dry mouth. For the samemedication, adverse event rates varied betweentrials (Table 6). For example, rates of somno-lence from baclofen in head-to-head trials ofbaclofen and tizanidine ranged from 0%56 to80%,53 and weakness ranged from 7%51 to57%.57 The observed ranges of adverse eventrates could reflect differences in populations,dosing of medications in trials, use of a run-inperiod, the rigor of adverse event assessment,or other factors. No deaths or serious adverseevents were reported in these trials. Rates ofabuse and addiction were not evaluated.
For each skeletal muscle relaxant evaluatedin head-to-head trials, rates across trials forcommon adverse events overlapped with ratesfound for other skeletal muscle relaxants(Table 6). In individual head-to-head trials oftizanidine and baclofen, however, several pat-terns emerged. In these eight trials, dry mouthwas reported more frequently on tizanidine infive studies (roughly equivalent or not reportedin the other three), but weakness was re-ported more frequently on baclofen in all sevenstudies in which it was reported. No consistentpatterns were seen for somnolence or dizziness.Withdrawal rates due to adverse events, an indi-cator of intolerable adverse events, were higheron baclofen than tizanidine (12/46 [26%] vs.4/46 [9%]) in only one trial with significantnumbers of withdrawals. Other trials had verylow numbers of withdrawals due to adverseevents or found no differences.
It was not possible to use trials comparingbaclofen, dantrolene, or tizanidine with diaze-pam to assess comparative adverse event ratesbetween these three medications. Adverseevents data were not reported or poorlyreported in three trials.48, 52, 54 In the remainingtrials, no clear pattern of differential adverseevents was apparent for any skeletal musclerelaxant. Withdrawals due to adverse events fa-vored tizanidine over diazepam in one trial49
(28% [15/54] vs. 12% [6/51]), but in othertrials withdrawal rates were equivalent, not re-ported, or very few in number. The smallnumber (two or three) of trials for each skele-tal muscle relaxant, the wide ranges for ad-verse events (somnolence 11–67%, weakness
12–53%) on diazepam (the common compara-tor) in different trials, and the limited qualityof adverse event assessment limit further inter-pretation of these data.
Placebo-Controlled Trials. Most placebo-con-trolled trials showed little evidence of rigorousadverse event assessment. Abuse or addictionwas not evaluated. Three trials appeared to havemore rigorous adverse event assessment95–97
and were rated good quality. All three of thesetrials evaluated tizanidine. Rates of somno-lence (41–54%) were similar in these trials butrates for other adverse events (dry mouth, dizzi-ness, weakness, and withdrawal due to adverseevents) ranged widely or were not consistentlyreported (Table 7). In one of the good-qualitytrials,95 3 patients (18%) developed elevationsof transaminases (highest alanine transaminase90) that were not thought to be clinicallysignificant.
In general, placebo-controlled trials gavelittle additional information to compare ad-verse events of skeletal muscle relaxants in pa-tients with spasticity. For each evaluatedmedication, adverse event rates overlapped fordifferent skeletal muscle relaxants and had wideranges across trials. We were unable to definenarrower ranges for adverse events by stratifyingtrials according to dose because most trials ti-trated the medication, and it was not clear onwhich dose adverse events occurred. With-drawal rates due to adverse events and rates ofweakness were not consistently reported.
Observational Studies. We identified two obser-vational studies assessing rates of hepatic com-plications in patients on dantrolene.35, 143 Onestudy35 published in 1990 collected all cases ofdantrolene-associated hepatic injury that werereported to the manufacturer, regulatory au-thorities, or in the published literature, usingpre-specified inclusion criteria. It found 122cases of dantrolene-associated hepatic injury,with 27 fatalities. Fifty-two percent (14/27) ofthe fatalities occurred in multiple sclerosis pa-tients. Fatalities were associated with a highermean dantrolene dose (582 mg/dL) than non-fatal cases (263 mg/dL). The risk of hepaticcomplications was estimated to be less than9.0 cases per 100,000 prescriptions written fordantrolene, and fatal hepatic reactions 0.83cases per 100,000 prescriptions. An earlier study
162Vol.
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or Spasticity
Withdrawals Due Any AdverseInt Dry Mouth to Adverse Events Events
Ba 0% 0% None reportedBa Not reported 12% Not reportedBa Not reported Not reported by Not reported
interventionBa 12% 0% 60%Ba 22% 0% Not reportedBa Not reported Not reported Not reportedBa Not reported 56% 78%Ba None reported None reported Not reportedBa None reported 0% 40%
Ba None reported None reported 50%Ba Not reported 0% 25%
6Ba None reported None reported 64%Ba Not reported Not reported Not reported
(36% overall)Ba 5% Not clear 71%Da Not reported Not reported by Not reported
intervention groupDa Not reported 0% Not reportedDa Not reported None reported 57%Da Not reported 9% 54%Da Not reported None reported Not reportedDa Not reported 0% Not reportedDa Not reported 9% 91%Da Not reported Not reported by Not reported
intervention groupDa Not reported 25% 75%Da Not reported Not reported by 100%
intervention groupDa Not clear Not clear (27% Not reported
withdrawals over-all)
Da Not reported None reported Not reportedDa Not clear Not reported Not reportedDa Not clear 17% Not reported
8
(continued)
Table 7Adverse Events, Placebo-Controlled Trials of Skeletal Muscle Relaxants f
Dizziness orervention Study and Year Somnolence or Fatigue Lightheadedness
clofen 5 mg tid Basmajian 197464 0% 0%clofen unclear dose Basmajian 197565 Not reported Not reportedclofen 5–20 mg/day Brar 199166 Not reported Not reported
clofen 5 mg tid to 100 mg/day Duncan 197666 12% 24%clofen 15–80 mg/day Feldman 197868 17% Not reportedclofen 40–80 mg/day Hinderer 199069 Not reported Not reportedclofen 10 mg tid Hulme 198570 78% Not reportedclofen 15–60 mg/day Jones 197071 Not clear None reportedclofen 0.5 mg/kg/day titrated to McKinlay 198072 60% Not clear
maximum 60 mg/dayclofen 30 mg/day Medaer 199173 5% 30%clofen 10 mg/day titrated up to Milla 197774 20% None reported0 mg/day
clofen 5 mg tid titrated to 15 mg tid Orsnes 200075 36% 21%clofen 5 mg tid titrated to 80 mg/day Sachais 197776 71% 22%
clofen 5 mg tid titrated to 60 mg/day Sawa 197977 29% 10%ntrolene unclear dose Basmajian 197378 ‘Almost all’ ‘Several’
ntrolene 25–100 mg qid Chyatte 197379 Not reported Not reportedntrolene 1–3 mg/kg qid Denhoff 197580 Not reported Not reportedntrolene 25 mg bid to 350 mg/day Gambi 198381 29% Not reportedntrolene 50–800 mg/day Gelenberg 197382 15% 55%ntrolene 4–12 mg/kg/day Haslam 197483 Not reported Not reportedntrolene 4–12 mg/kg/day Joynt 198084 Not reported Not reportedntrolene 25 mg bid to 50 mg qid Katrak 199285 70% Not reported
ntrolene mean 165 mg/day Ketel 198486 Not reported Not reportedntrolene 75 mg tid to 400 mg qid Luisto 198287 88% 24%
ntrolene 50–100 mg qid Monster 197488 Not clear Not clear
ntrolene 6–8 mg/kg/day Nogen 197989 82% Not reportedntrolene titrated to maximum 200 mg qid Sheplan 197590 Not clear Not clearntrolene 100 mg/day titrated to Tolosa 197591 Not clear Not clear00 mg/day
Vol. 28 No. 2 August 2004 163Comparative Efficacy and Safety of Skeletal Muscle Relaxants
Tab
le7
Con
tinu
ed
Diz
zin
ess
orW
ith
draw
als
Due
An
yA
dver
seIn
terv
enti
onSt
udy
and
Year
Som
nol
ence
orFa
tigu
eL
igh
thea
dedn
ess
Dry
Mou
thto
Adv
erse
Eve
nts
Eve
nts
Dan
trol
ene
titr
ated
to10
0m
gqi
dW
eise
r19
7892
23%
Incl
uded
inso
mn
olen
ceN
otre
port
ed11
%N
otre
port
edT
izan
idin
e10
mg/
day
Kn
utss
on19
8293
33%
Non
ere
port
ed17
%0%
Not
repo
rted
Tiz
anid
ine
2–32
mg/
day
Lap
ierr
e19
8794
48%
3%48
%U
ncl
ear
Not
repo
rted
Tiz
anid
ine
12-3
6m
g/da
yM
eyth
aler
2001
a95
41%
Not
repo
rted
12%
0%N
otre
port
edT
izan
idin
e4-
36m
g/da
yN
ance
1994
5541
%17
%39
%25
%81
%T
izan
idin
eti
trat
edto
max
imum
36m
g/da
ySm
ith
1994
a96
48%
19%
57%
13%
91%
Tiz
anid
ine
mea
n25
mg/
day
UK
Tiz
anid
ine
Tri
alN
otre
port
edby
Not
repo
rted
45%
13%
87%
Gro
up19
94a9
7in
terv
enti
on(5
4%ov
eral
l)C
hlo
rzox
azon
e20
mg/
lb/d
ayL
osin
1966
98N
one
repo
rted
Not
repo
rted
Not
repo
rted
Not
repo
rted
Not
repo
rted
Cyc
lobe
nza
prin
e60
mg/
day
Ash
by19
7210
0N
one
repo
rted
7%7%
7%N
otre
port
edM
eth
ocar
bam
olm
ean
85m
g/kg
/day
Bje
rre
1971
995%
Not
repo
rted
Not
repo
rted
Not
repo
rted
Not
repo
rted
a Rat
edgo
odqu
alit
yfo
rad
vers
eev
ent
asse
ssm
ent.
(1977), which included results from placebo-controlled trials as well as spontaneously re-ported cases, estimated rates of 1.8% (16/1044)for any hepatic injury and 0.3% (3/1044) fora fatal outcome.143 Differences between the twostudies may be related in part to higher dosesof dantrolene in earlier studies, increasingly se-lective use of dantrolene, or different methodsused to find cases.
Tizanidine has been associated with hepaticaminotransaminase elevations that are usuallyasymptomatic and reversible with discontinua-tion of the medication. Postmarketing surveil-lance data submitted to the FDA indicate thattizanidine is associated with elevations ofaminotransaminases greater than three timesthe upper limit of normal in 5% of patients,compared to 0.4% in placebo.144 Of threedeaths associated with liver failure in patientstreated with tizanidine, one case was thoughtprobably related to tizanidine and the othertwo occurred in patients on other hepatotoxicagents. We found one other case report thatreported a case of symptomatic jaundice associ-ated with tizanidine that resolved after drugdiscontinuation.145
We identified no other large, good-qualityobservational trials on adverse events from skel-etal muscle relaxants in patients with spasticity.Although other serious adverse events (seriouswithdrawal symptoms,146–150 overdose,151–153
and seizure154) have been reported in case re-ports and series, rates cannot be estimated fromthese reports.
Comparative Safety: Musculoskeletal Conditions
Systematic Reviews and Meta-Analyses. No sys-tematic review or meta-analysis compared ad-verse events between different skeletal musclerelaxants in patients with musculoskeletal con-ditions. Adverse events from cyclobenzaprinehave been evaluated in one systematic reviewand one meta-analysis (not systematic) (Evi-dence Table 2). Neither study rated the qualityof included trials for adverse event assessment.The systematic review42 evaluated rates of ad-verse events for cyclobenzaprine versus placebo(Table 1). As expected, it found significantlyincreased rates of drowsiness, dry mouth, dizzi-ness, and any adverse event in patients on cyclo-benzaprine versus placebo. Withdrawals due
164 Vol. 28 No. 2 August 2004Chou et al.
to adverse events were not reported. The meta-analysis reported comparative rates of adverseevents for cyclobenzaprine versus diazepam.47
Rates of drowsiness (38%) and dry mouth(24%) were higher for cyclobenzaprine com-pared to diazepam (33% and 8%). Dizzinesswas reported more frequently in patients ondiazepam (17%) compared to cyclobenzaprine(10%). Other adverse events and withdrawalsdue to adverse events were not reported.
Head-to-Head Trials. There was very limiteddata from head-to-head trials to assess compara-tive safety of skeletal muscle relaxants in patientswith musculoskeletal conditions (Table 8). Of11 head-to-head trials, three trials reportedalmost no adverse event information.102, 103, 109
Of the remainder, quality of adverse event as-sessment was generally poor. Reliable conclu-sions about the comparative adverse event ratescould not be drawn from these trials. In allhead-to-head trials, withdrawals due to adverseevents were roughly equal or none werereported. Abuse and addiction were not evalu-ated, and no deaths were reported.
In the head-to-head trial of cyclobenzaprineversus methocarbamol, cyclobenzaprine was as-sociated with more somnolence (58% vs. 31%),but the rate of withdrawals due to adverse eventswas equivalent (7% vs. 6%).18 In the head-to-head trial of cyclobenzaprine and carisoprodol,dry mouth was more frequent with cyclobenza-prine (38% vs. 10%) and dizziness less frequent(8% vs. 26%).104
The five head-to-head trials with adverse eventdata comparing cyclobenzaprine, carisoprodol,or tizanidine to diazepam are difficult to inter-pret because the rate of adverse events for diaze-pam varied greatly between trials. Rates ofsomnolence on diazepam, for example, were13%,101 30%,105 and 50%,108 while respectiverates for dizziness were 12%, 8%, and 50%despite similar doses of diazepam.
Placebo-Controlled Trials. There was no patternfrom placebo-controlled trials to suggest thatany one muscle relaxant was superior to othersfor adverse events (Table 9). Quality of adverseevent assessment was generally poor. Abuse andaddiction were not evaluated. No deathsthought related to medication were reported,and serious adverse events were rare.
Adverse events were not reported consistentlyin these trials, and doses of medications andtitration methods differed markedly betweenstudies. For example, for baclofen, dosesranged from 5 mg tid up to 80 mg daily, withvarious methods for titrating doses. Wide andoverlapping ranges for all commonly reportedadverse events (somnolence, dizziness, drymouth, withdrawals due to adverse events) wereseen for carisoprodol, cyclobenzaprine, and ti-zanidine. There were extremely limited adverseevents data for orphenadrine (2 trials120, 132 re-ported almostno adverseeventsandtwo21,111 didnot report adverse event data), metaxalone, (noadverseevent data from3trials134,135 andunclearadverse event rates from 1 other133) baclofen(only 1 trial140), methocarbamol (poor qualityand very limited adverse event data from oneplacebo-controlled trial141) or dantrolene (nei-ther of 2 trials112,142 reported adverse events).
Observational Studies. We found no observa-tional studies evaluating abuse risk of carisopro-dol or other skeletal muscle relaxants usingvalidated measures, though one study used anunvalidated questionnaire to estimate abuse“risk.”19 Reports of abuse and addiction are fromcase reports and series.155 A French studyfrom 1997 noted that meprobamate (a metabo-lite of carisoprodol) was the most frequentlycited drug in fatal pharmaceutical overdoses(19 cases, or 15.3%), but we were unable tofind similar data on meprobamate or carisop-rodol in the U.S.156
We identified one large, fair-quality observa-tional study evaluating safety of cyclobenzaprinein 6311 patients.157 This study enrolled about2,000 physicians and asked each to report anyadverse events in five patients with musculoskel-etal conditions. Rates of somnolence (16%), drymouth (7%), dizziness (3%), and other adverseevents were about 50% lower than in clinicaltrials and might not be reliable for estimatingtrue adverse events rates.
We identified one observational study of hep-atotoxicity associated with chlorzoxazone.158
The authors of this study reported on one caseof reversible hepatotoxicity associated withchlorzoxazone, and also found 23 additionalcases of hepatotoxicity reported to the FDAsince 1970. Eight cases (two fatal) were judgedto be probably related to chlorzoxazone, while
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elaxants
laxants for Musculoskeletal Conditions
Dizziness or Withdrawals DueStudy Lightheadedness to Adverse Events Any Adverse Event
Head-to-head TBragstad 1979 Not reported None reported 0%
Not reported None reported 15%Preston, 1984 Included in somnolence 7% (6/87) 42%
Included in somnolence 6% (6/94) 31%Rollings, 1983 8% 8% (3/37) 65%
sky, 1981108 Tizanidine 4-8 mg tid 10% 10%Diazepam 5-10 mg tid 50% 10%
109 Tizanidine 4 mg tid None reported None reporteDiazepam 5 mg tid None reported None reporte
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eletal Conditions
Withdrawals Due Any Adverseto Adverse Events Event
Not reported Not reported3% Not reported
None reported Not reported1% Not reported4% 96%0% 43%
None reported Not reported8% 89%
0% Not reportedNone reported 42%None reported 20%
14% 98%
0% Not reported4% Not reported
0% Not reportedNone reported 54%
9% 14%None reported Not clearNot reported Not reportedNot reported Not reported
3% Not clear
None reported 25%None reported 3%
7% Not reported
Not reported Not reported17% 68%
None reported Not reported0% 3%
Not reported Not reportedby intervention
8% 41%5% Not reported
Not reported 33%Not reported 11% (tolerated ‘poorly’)
by intervention13% Not reported
0% Not reported
Table 9Adverse Events, Placebo-Controlled Trials of Skeletal Muscle Relaxants for Musculosk
Somnolence or Dizziness orIntervention Trials Fatigue Lightheadedness Dry Mouth
Carisoprodol 350 mg qid Baratta 1976121 Not reported Not reported Not reportedCarisoprodol 350 mg qid Cullen 1976122 12% 19% Not reportedCarisoprodol 350 mg tid Hindle 1972123 Not reported Not reported Not reportedCarisoprodol 400 mg qid Soyka 1979124 8% 18% 0%Cyclobenzaprine 10–20 mg tid Aiken 1978b125 84% 36% 4%Cyclobenzaprine 10 mg tid Baratta 1982126 31% 36% 10%Cyclobenzaprine 10 mg bid Basmajian 1989127 Not reported Not reported Not reportedCyclobenzaprine 10 mg qpm Bennett 1988114 55% 11% 92%
titrated to 40 mg/dayCyclobenzaprine 20–40 mg/day Bercel 1977128 33% 11% 4%Cyclobenzaprine 10 mg tid Bianchi 1978129 29% 4% 8%Cyclobenzaprine 10 mg tid Borenstein 1990110 0% 5% Not reported
(�naprosyn in both arms)Cyclobenzaprine 10 mg qD Carette 1994115 4% 6% None reported
titrated to 30 mg qDCyclobenzaprine 30–60 mg/day Lance 1972117 20% 5% 16%Cyclobenzaprine 10 mg qhs titrated Quimby 1989130 Not reported Not reported 68%
to 30 mg qhs � 10 mg qamCyclobenzaprine 10 mg tid Reynolds 1991113 Not reported Not reported Not reportedCyclobenzaprine 30 mg/day Steingard 1980131 24% 5% 12%Metaxalone 400 or 800 mg qid Dent 1975a133 4% 3% Not reportedMetaxalone 800 mg qid Diamond 1966135 Not reported Not reported Not reportedMetaxalone 800 mg qid Fathie 1964 (1)134 Not reported Not reported Not reportedMetaxalone 800 mg qid Fathie 1964 (2)134 Not reported Not reported Not reportedMethocarbamol 2000 mg qid initially, Tisdale 1975141 Not reported 11% Not reported
then 1000–1500 mg qidOrphenadrine 100 mg bid Gold 197821 Not clear Not clear Not clearOrphenadrine 100 mg qhs Latta 1989120 0% 0% 0%Orphenadrine dose unclear McGuinness 1983111 Not reported Not reported Not reported
(�paracetamol in both arms)Orphenadrine 100 mg bid Valtonen 1975132 5% 4% 0%Baclofen 30–80 mg/day Dapas 1985140 49% 28% 5%Dantrolene 25 mg/day Casale 1988142 Not reported Not reported Not reportedDantrolene 25 mg/day Salvini 1986112 None reported None reported None reported
(� ibuprofen in both arms)Tizanidine 4 mg tid Berry 1988 (1)137 22% 6% 6%
(�ibuprofen both arms)Tizanidine 4 mg tid Berry 1988 (2)136 22% Not reported Not reportedTizanidine 6–18 mg/day Fogelholm 1992116 ‘Frequent’ ‘Frequent’ Not reportedTizanidine 2 mg/day Lepisto 1979138 33% 0% 0%Tizanidine 6–12 mg/day Murros 2000118 17% Not reported 22%
(�diclofenac in both arms) Asia-PacificStudy Group1988139
aUnclear sample size, based on intervention sample of 90 patients.
Vol. 28 No. 2 August 2004 167Comparative Efficacy and Safety of Skeletal Muscle Relaxants
the rest were possibly or doubtfully related.Most cases were mild and resolved after discon-tinuation of the medication, but a few wereassociated with very high elevations of serumtransaminases, severe hepatitis, or permanentliver damage. We found no data estimating ratesof serious hepatotoxicity in patients treatedwith chlorzoxazone.
The hepatotoxic potential of tizanidine, amedication used for both spasticity and muscu-loskeletal conditions, was previously discussed.We identified no other large- or good-qualityobservational studies of comparative adverseevent rates for skeletal muscle relaxants.
SubpopulationsNo clinical trials or observational studies were
designed to compare the efficacy of skeletalmuscle relaxants for different races, age groups,or genders. There is almost no information tojudge the relative effectiveness or safety of skele-tal muscle relaxants in these subpopulations.Race was rarely reported in the trials. Whenit was reported, the overwhelming majority ofpatients were white. Women, older patients, andchildren were all included in some studies, butthe effect of gender or age on comparative effi-cacy was not evaluated in any study or groupof studies.
Most trials were in adult patients with multi-ple sclerosis or acute neck and low back pain.Small numbers of trials, lack of high-qualitystudies, and heterogeneous designs and meth-ods severely limit our ability to systematicallyevaluate skeletal muscle relaxants for other pa-tient populations and underlying conditions.
No study has assessed the comparative riskof abuse and addiction from skeletal musclerelaxants in patients with a prior history of sub-stance abuse. In trials that specified exclusioncriteria, patients with prior or suspected sub-stance abuse were usually excluded.
Patients with renal and hepatic disease havetypically been excluded from clinical trials. Incase reports, baclofen toxicity has been seenin patients with impaired renal function.151 Wefound no trials involving patients with chronicliver disease. In one trial involving children withspasticity and epilepsy, dantrolene did not in-crease the frequency of seizures.89
Summary of ResultsResults for each of the key questions are sum-
marized in Table 10. Only tizanidine was found
effective in a substantial number of trials forboth spasticity and musculoskeletal conditions.Most of the head-to-head trials were performedin patients with multiple sclerosis or patientswith acute neck or low back pain; almost all ofthe evidence regarding efficacy and safety inpatients with other conditions comes from pla-cebo-controlled trials.
In general, there was insufficient evidence toprove that different skeletal muscle relaxantsare associated with different overall efficacy.Dantrolene, baclofen, and tizanidine all appeareffective in patients with spasticity. The bestavailable evidence suggests that tizanidine isroughly equivalent to baclofen for most clinicaloutcomes in patients with spasticity. The com-parative efficacy for other skeletal muscle relax-ants and other conditions has not beenestablished. In patients with musculoskeletalconditions, cyclobenzaprine has consistentlybeen found to be effective in the most clinicaltrials. There is little published data demonstra-ting the effectiveness of chlorzoxazone, metax-alone, methocarbamol, dantrolene, or baclofenfor musculoskeletal conditions.
The data on adverse events is insufficient todistinguish any skeletal muscle relaxant withregard to overall safety, though the adverseevent profile may differ between medicationsand some medications are associated with rarebut serious adverse events. There is a small risk ofserious (including fatal) hepatic injury associatedwith dantrolene and chlorzoxazone. Tizanidineappears to be associated with asymptomatic,reversible elevations of aminotransferases. De-spite concerns about the potential risk of abusefrom carisoprodol because of its metabolism tomeprobamate, the available literature providesno data regarding the comparative risk of abuseand addiction from skeletal muscle relaxants.
Essentially no data are available to assess com-parative efficacy and adverse event risks in sub-populations of patients with spasticity ormusculoskeletal conditions.
DiscussionUnlike other drug classes such as statins, an-
giotensin-converting enzyme inhibitors, orbeta-blockers, the skeletal muscle relaxants area heterogeneous group of medications thatare not chemically related. Because of this,
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ad trials and a fair-quality meta-analysis of unpub-tly found that tizanidine and baclofen are roughlymeasures of efficacy including spasms, functional
eference. Most of these trials evaluated patients witherpretation of trials was limited by lack of good-qual-eneity in outcomes assessed, unvalidated methods tond unstandardized methods of reporting results. 8ad trials of dantrolene, tizandine, or baclofen com-ovide some evidence that each of these medicationso diazepam, but judgments about comparative effi-from these trials. Placebo-controlled trials were not
omparative efficacy.
d dantrolene have consistently been found to belacebo in fair-quality clinical trials. Other skeletalnot been adequately assessed for this condition.
ad trials and 1 fair-quality meta-analysis of unpub-at cyclobenzaprine and diazepam are roughly equiva-ures of efficacy including pain, spasm, and global
fair-quality trials found that cyclobenzaprine was su-r most (2 trials) or some (1 trial) clinical outcomes.e 3 trials is unclear because they all used unvalidatedad the same manufacturer support, and were pub-ok. Most of these trials evaluated patients with necks. For other comparisons, the best fair-quality trialol was superior to diazepam for several measures oftandardized outcomes scales. Other skeletal muscleirectly compared in only 1 fair-quality trial or have
azepam, and comparative efficacy cannot be accu-hese data. Placebo-controlled trials were not helpfulive efficacy.sistently found cyclobenzaprine to be more effectiveous measures of efficacy (pain relief, muscle spasms,patients with musculoskeletal conditions. A good-qual-f 14 trials reported similar findings. The body of evi-
t for carisoprodol (4 trials), orphenadrine (4 trials),ls), but these medications were also consistentlyective than placebo. There is very limited or inconsis-he effectiveness of methocarbamol, metaxalone, dan-e, or baclofen compared to placebo.
(continued)
Table 10Summary of Evidence
Key Question Condition Level of Evidence
Efficacy1. What is the comparative efficacy of different Spasticity: FAIR for tizanidine 8 fair-quality head-to-he
muscle relaxants in reducing symptoms and comparative vs. baclofen lished trials consistenimproving functional outcomes in patients efficacy FAIR for tizanidine, baclo- equivalent for variouswith a chronic neurologic condition associ- fen, and dantrolene status, and patient prated with spasticity, or a chronic or acute vs. multiple sclerosis. Intmusculoskeletal condition with or without diazepam ity trials and heterogmuscle spasms? POOR for dantrolene vs. measure outcomes, a
tizanidine or baclofen fair-quality head-to-heand other skeletal pared to diazepam prmuscle relaxants is similar in efficacy t
cacy cannot be madehelpful in assessing c
Spasticity: efficacy FAIR for tizanidine, baclo- Tizanidine, baclofen, anvs. placebo fen, and dantrolene vs. more effective than p
placebo muscle relaxants have
Musculoskeletal FAIR for cyclobenzaprine 2 fair-quality head-to-heconditions: vs. diazepam lished trials found thcomparative POOR for comparative lent for various measefficacy efficacy of other skel- response, but 3 other
etal muscle relaxants perior to diazepam foInterpretation of thesoutcome measures, hlished in the same boor back pain or spasmfound that carisoprodefficacy, but used unsrelaxants have been dbeen compared to dirately assessed from tin assessing comparat
Musculoskeletal FAIR for cyclobenza- 17 fair-quality trials conconditions: efficacy prine, carisoprodol, or- than placebo for varivs. placebo phenadrine, and functional status) in
tizanidine vs. placebo ity systematic review odence is not as robus
POOR for other skeletal and tizanidine (6 triamuscle relaxants found to be more effvs. placebo tent data regarding t
trolene, chlorzoxazon
Vol.28
No.
2A
ugust2004
169C
omparative
Efficacyand
Safetyof
SkeletalM
uscleR
elaxants
Key Qu Conclusions
Adverse2. Wha d-to-head trials of tizanidine vs. baclofen reporting rates of weak-
musc nd that tizanidine was associated with lower rates of weakness,of 7 head-to-head trials of tizanidine vs. baclofen reporting rates ofth found that baclofen was associated with lower rates of dryOverall tolerability appears to be similar, as withdrawals due to ad-ents (a marker of intolerable adverse events) were similar in all-head trials except one. There was insufficient evidence from head-or placebo-controlled trials to judge the comparative adverse eventother skeletal muscle relaxants. Serious hepatotoxicity with dantro-
s been found in observational studies, and tizanidine is associatedally asymptomatic and reversible (rarely serious) hepatotoxicity.
nsufficient evidence to accurately judge comparative adverse eventm skeletal muscle relaxants in patients with musculoskeletal condi-irect comparisons of skeletal muscle relaxants in head-to-headre too limited in quantity and quality. Placebo-controlled trialsno pattern of one skeletal muscle relaxant being superior tond were generally of inferior quality compared to head-to-headhere are no data to judge comparative abuse or addiction risk. Ti-
and chlorzoxazone are associated with usually reversible (rarely se-fatal) hepatotoxicity, but data to estimate comparative event rates
available. Other serious adverse events appear to be rare, but noent of comparative risk could be made.
Subpopu3. Are lmost no information to judge the comparative efficacy or safety of
whic muscle relaxants in subpopulations defined by age, race, oror as Almost all head-to-head trials have been done either in patients
ltiple sclerosis or in patients with neck or low back syndromes, andinsufficient evidence to judge the relative effectiveness or safety ofmuscle relaxants for other conditions. There are no studies to esti-e comparative risk of addiction or abuse in patients with prior sub-buse. Special populations (e.g., chronic liver disease, renal failure,nts with seizures) have usually been excluded from clinical trials.
Table 10Continued
estion Condition Level of Evidence
eventst are the comparative safety of different Spasticity FAIR for tizanidine 7 of 7 heale relaxants? vs. baclofen ness fou
FAIR for risk of hepato- while 5toxicity from dan- dry moutrolene and tizanidine mouth.
POOR for other skeletal verse evmuscle relaxants head-to
to-headrates oflene hawith usu
Musculoskeletal POOR overall There is iconditions FAIR for risk of hepatoxi- rates fro
city from tizanidine tions. Dand chlorzoxazone trials we
lationsthere subpopulations of patients for POOR There is ah one muscle relaxant is more effective skeletalsociated with fewer adverse effects? gender.
with muthere isskeletalmate thstance aor patie
170 Vol. 28 No. 2 August 2004Chou et al.
there may be important differences in efficacyor safety that need to be considered in choosinga medication to treat patients with spasticity ormusculoskeletal conditions. The current avail-able literature provides only limited evidenceto guide the prescribing physician in choosingan initial skeletal muscle relaxant, particularlyfor patients with musculoskeletal conditions.For these patients, clinicians might choose toavoid medications (chlorzoxazone, methocar-bamol, metaxalone, dantrolene, and baclofen)for which there is very limited published evi-dence regarding their clinical effectiveness.
A major limitation of the literature is thatclinical trials of skeletal muscle relaxants haveoften used unvalidated or poorly describedmethods to measure important clinical out-comes such as spasticity, pain, or musclestrength.41 Studies that have used the samescale often reported results differently (for ex-ample, mean raw scores after treatment, meanimprovement from baseline, or number of pa-tients “improved”). All of these factors makecomparisons across trials difficult.
Even if standardized methods of reportingoutcomes were adopted, the optimal methodsto measure important clinical outcomes are notclear. The most common standardized methodsfor measuring spasticity, for example, are theAshworth and modified Ashworth scales. An im-portant advantage of the Ashworth scale is thatit is a consistent way to measure spasticity ortone across studies, and has been found to havemoderate reproducibility.159 Some experts,however, have suggested that resistance topassive movement may measure tone betterthan it does spasticity and that the Ashworthscale and other ‘objective’ measures of spasticitymay not correlate well with patient symptomsor functional ability.160 The best technique maybe to perform both objective and subjective as-sessments of spasticity, as well as for other im-portant clinical outcomes such as pain andweakness. Validated subjective assessment tech-niques, however, are currently lacking. Stan-dardized methods for measuring and reportingimportant clinical outcomes would be helpfulin facilitating meaningful comparisons acrossstudies.
Other limitations of the literature are rela-tively small numbers of head-to-head trials, lackof high-quality studies, generally poor quality
of adverse event assessment, typically short du-ration of follow-up, and heterogeneity in studydesignandinterventions. Inaddition, fewstudieshave adequately evaluated functional outcomes.
Other specific areas have not been ade-quately investigated. For example, patients whoare still ambulatory might do better with oneskeletal muscle relaxant compared to another,because of differential risk profiles. There arealso no data to judge the comparative efficacyor safety of skeletal muscle relaxants in patientsfor whom one agent has failed or who havehad intolerable side effects. There may be otherreasons (convenience, improved compliance,better sleep, or more consistent pain relief) forchoosing a specific skeletal muscle relaxant,but these outcomes have not been adequatelyassessed.
The lack of high-quality evidence regardingthis class of medications is concerning giventheir wide use. Without better evidence regard-ing differential efficacy or safety, payers may beforced to rely disproportionately upon cost asa differentiating factor in choosing betweenmedications in this class. We hope this reporthelps to highlight remaining gaps in our under-standing of this important class of medicationand that studies to fill these gaps will be sup-ported and undertaken.
AcknowledgmentsThe authors wish to acknowledge the Oregon
Department of Human Services for its fundingsupport. They also wish to acknowledge theadministrative support provided by KathrynPyle Krages, AMLS, MA; Susan Wingenfeld; andPatty Davies, MS. Additional information regard-ing Oregon’s Practitioner-Managed Prescrip-tion Drug Plan is available online at http://www.ohpr.state.or.us.
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