Formulary Drug Listing Decisions SKELETAL MUSCLE RELAXANTS

November 18, 2010

Indications Recommendation Highlights The management of discomfort ± acute muscle n Skeletal muscle relaxants (SMRs) are a spasm associated with painful musculoskeletal heterogeneous group of drugs used to (MSK) conditions (cylcobenzaprine, methocar- treat muscle spasm, pain associated with bamol, and orphenadrine). acute MSK conditions and spasticity associated with spinal cord injuries and neuron The treatment of spasticity associated with disorders. spinal cord injuries and neuron disorders (baclofen, dantrolene, and tizanidine). n Cyclobenzaprine, orphenadrine, and tizanidine have demonstrated significant short- term symptomatic relief and overall improve- DAC Recommendation ment of acute low back pain compared to The DAC recommended that: (i) orphenadrine placebo. Long-term data are unavailable. and cyclobenzaprine be listed in the 25WS Concerns exist in the medical literature formulary ONLY; (ii) baclofen be listed in the regarding their potential for central nervous 03WS formulary ONLY; and (iii) dantrolene, system (CNS) adverse events and drug inter- Drug Profile methocarbamol, and tizanidine NOT BE LISTED actions. Products available in in any WSIB formularies. n Tizanidine does not provide any therapeu- Canada: tic benefit compared to cyclobenzaprine or Baclofen (e.g., Lioresal®, The WSIB Decision orphenadrine in the treatment of acute back various generic) pain; however, tizanidine is associated with Based on the DAC’s recommendations, the Cyclobenzaprine liver and cardiac side effects, an increased WSIB has decided to: (i) LIST cyclobenzaprine (e.g., various generic) risk of abuse and a significantly higher cost. Dantrolene (e.g., and orphenadrine in the initial musculoskel- n Dantrium®) etal (25WS) formulary; (ii) LIST baclofen in the Baclofen has fair to strong evidence of efficacy in muscle spasm and spasticity as- Methocarbamol (e.g., CNS-Brain injury (03WS) formulary; and (iii) Robaxin®, Robaxacet®) NOT LIST dantrolene, methocarbamol, or tizani- sociated with upper motor neuron syndrome Orphenadrine (e.g., dine in any formulary at this time. (based mainly on trials in multiple sclerosis). NorflexTM, various generic) Rigorous evidence in other musculoskeletal TM conditions are lacking. Tizanidine (e.g., Zanaflex , Formulary Status various generic) n There is limited evidence for the use of meth- Cyclobenzaprine and orphenadrine are listed ocarbamol or dantrolene in the treatment in the 25WS formulary ONLY. Baclofen is listed of acute back pain or spasticity. Both drugs in the 03WS formulary ONLY. New requests are associated with CNS side effects and for these drugs outside these formularies WILL potential drug interactions. NOT be approved. Dantrolene, methocarbamol, n Overall, systematic reviews indicate that and tizanidine ARE NOT listed in any WSIB most SMR trials have several methodologi- formularies. cal shortcomings including poor quality, poorly designed and described methods, short duration and heterogeneity of outcome measures. n Relatively few comparative trials involving SMRs are available, making it difficult to assess whether important differences exist between agents.

Page 1 of 4 n Few pharmacoeconomic studies have evaluated the cost-effectiveness of SMRs; those available have major methodological limitations. n The DAC concluded that an independent review of the clinical efficacy, safety, and cost-effectiveness of SMRs in the treatment of acute muscle spasms and painful musculoskeletal conditions demonstrated variable evidence by drug class. Consequently, the DAC recommended that (i) cyclobenzaprine and orphenadrine be listed in the 25WS formulary as they present the best quality evidence; (ii) baclofen be listed in the 03WS formulary for the treatment of spasticity due to CNS-related injury/illness; and (iii) dantrolene, methocarbamol, and tizanidine not be listed in any formularies as these agents do not provide any therapeutic advantage and pose additional risks.

DETAILED DISCUSSION

Background (RCTs). Eight systematic reviews evaluating acute low back pain (2), nonprogressive neu- The term skeletal muscle relaxants (SMRs) rologic disease (2), spasticity and MSK condi- refers to a heterogeneous group of drugs used tions (1), sciatica (1), mechanical neck disorders to treat muscle spasm and pain associated with (1), and fibromyalgia (1) were included in the acute musculoskeletal (MSK) conditions and report. The SMRs investigated were baclofen, spasticity associated with spinal cord injuries cyclobenzaprine, dantrolene, methocarbamol, and neuron disorders (e.g., cerebral palsy, orphenadrine, and tizanidine. multiple sclerosis, paraplegia, etc.). Although SMRs are indicated for the short-term treatment Baclofen is indicated in the treatment of spas- of these symptoms/disorders, they are often ticity from multiple sclerosis and spinal cord prescribed for long-term use. Concerns have injury/disease. There is fair to strong evidence arisen in the medical literature surrounding the that baclofen is effective in alleviating muscle lack of evidence for their long-term use and spasm (non-specific back pain) and spastic- their potential for serious adverse events and ity (mainly in multiple sclerosis). Although drug interactions. balcofen has only been compared to placebo in lower back pain, head-to-head studies evaluat- Summary of Committee ing its use in relief of spasticity suggest that it Considerations is equivalent to tizanidine. Long-term efficacy and safety data are lacking. Baclofen’s efficacy The DAC considered an external, independent in other MSK conditions (e.g., non-progressive review of the clinical efficacy, safety, and cost- neurological diseases, spasticity following effectiveness of SMRs in the treatment of acute spinal cord injury, and mechanical neck or chronic MSK conditions or traumatic nervous disorders) remains unproven in rigorous trials system diseases. The report included system- of adequate duration. Baclofen is associated atic reviews of randomized controlled trials with an elevated risk of abuse, central nervous

Page 2 of 4 system (CNS) adverse events, and exacerbation evidence for the use of methocarbamol in of psychiatric illnesses. Withdrawal reactions muscle spasm or spasticity. Two placebo-con- can occur upon abrupt discontinuation. trolled trials produced inconsistent results and were rated as being of poor quality. Methocar- Cyclobenzaprine is indicated for the short- bamol’s efficacy in other MSK conditions has term treatment of muscle spasm associated not been investigated in rigorous RCTs. Drows- with acute MSK conditions. Two systematic iness, dizziness, and lightheadedness are the reviews concluded that there is strong evidence most frequently reported side effects. Blurred for significant symptomatic relief and overall vision, headache, fever, and nausea may also improvement with short-term cyclobenzaprine occur. use in acute low back pain (ALBP). There is fair to good quality evidence that it is effective in Orphenadrine is indicated in acute skeletal treating acute neck pain compared to placebo. muscle spasm. A systematic review concluded Although fair quality evidence demonstrates that orphenadrine is effective in the treatment improved global functioning and sleep in fibro- of ALBP. Fair evidence demonstrates that myalgia patients, no improvement in fatigue or orphenadrine is effective in general acute tender points has been observed. Furthermore, MSK conditions (e.g., neck pain). Its long-term these studies are limited by their high drop-out efficacy and safety have not been established. rates and short duration. Cyclobenzaprine has Orphenadrine’s efficacy in other MSK condi- not been evaluated in the treatment of spastic- tions has not been investigated in any rigorous ity or spinal cord injuries/diseases. Multiple RCTs. The most commonly reported side adverse events have been reported, including effects include dry mouth, urinary hesitancy or cardiac arrhythmias, urinary retention, dry retention, blurred vision, mydriasis, drowsiness, mouth, sedation, and impairment of physical headache, tachycardia, palpitations, and GI dis- and mental abilities. Additive sedation can turbances. Orphenadrine can impair an individ- occur when taken with other sedating drugs. ual’s ability to engage in potentially hazardous activities, such as operating machinery or Dantrolene is indicated for controlling driving motor vehicles. symptoms of chronic spasticity from neurological conditions. Although there is moderate Tizanidine is indicated for the management of to good evidence that dantrolene reduces spasticity. Similarly to cyclobenzaprine and muscle spasm in ALBP compared to placebo, orphenadrine, systematic reviews have dem- the generalizability of these results is limited onstrated strong evidence for significant relief by the short duration of the trials (4-10 days). and overall short-term improvement in ALBP The evidence for the use of dantrolene in the with tizanidine and fair evidence that it is more treatment of spasticity associated with MSK effective than placebo in MSK conditions, such conditions is also limited and inconsistent, as acute neck pain. Cyclobenzaprine has been calling into question its role in the treatment best studied and has produced the most consis- of these conditions. Although there are no tent evidence, however. Although there is fair well-designed RCTs comparing dantrolene and evidence for the use of tizanidine compared to baclofen, dantrolene appears to be associated placebo in the treatment of spasticity (primarily with more severe adverse events. Side effects in multiple sclerosis), it appears to be roughly most commonly reported include drowsiness, equivalent to baclofen. A single, low quality weakness, malaise, fatigue, and diarrhea. study failed to demonstrate any difference in Fatal and nonfatal cases of hepatitis have also overall improvement for tizanidine compared to been reported. Dantrolene is contraindicated placebo in the treatment of sciatica. The most in individuals with a history of compromised frequently reported side effects appear to be pulmonary function. It should also be used dose-related and include dry mouth, somno- with caution in individuals with a history of lence, asthenia, and dizziness. Tizanidine can myocardial disease. also produce hypotension and has been associated with reports of QT prolongation. Liver Methocarbamol is indicated as an adjunct injury has been reported (regular monitoring in the relief of discomforts associated with of aminotransferase levels is recommended). acute, painful MSK conditions. There is limited

Page 3 of 4 Rebound can occur upon sudden withdrawal. Based on the published and unpublished Reports of abuse and dependence exist, espe- evidence, the DAC concluded that there was no cially with concurrent use of opioids, benzodiaz- compelling evidence demonstrating efficacy epines, and hypnotics. or safety for the long-term use of any SMRs. Evidence is available for the short-term use of Overall, systematic reviews have concluded cyclobenzaprine, orphenadrine, and tizanidine that most SMR studies have numerous in the treatment of acute MSK conditions and methodological shortcomings, are of short for the use of baclofen and dantrolene in spas- duration, and provide limited evidence for their ticity in neurological illness. However, multiple efficacy. Where efficacy has been observed, notable safety concerns exist with tizanidine the magnitude of benefit has generally been and dantrolene. Hence, the DAC recommend- modest to moderate. Furthermore, all SMRs ed that: (i) cyclobenzaprine and orphenadrine are associated with frequent adverse events be listed on the 25WS (initial Musculoskeletal) that may limit their usefulness; many are as- formulary only; (ii) baclofen be listed on the sociated with rare but serious side effects. 03WS (CNS - Brain Injury) formulary only; and Cautious use is recommended. (iii) dantrolene, methocarbamol, and tizanidine Guidelines were reviewed to establish best not be listed on any formularies. practices. In general, the short-term use of Revised: January 29, 2013 SMRs (e.g., cyclobenzaprine) is recommended in the treatment of acute or subacute back pain, when first-and second-line agents (i.e., acet- aminophen and nonsteroidal anti-inflammatory drugs, respectively) have failed to produce sufficient relief. Long-term use is not recommended due to lack of evidence and concerns regarding possible CNS side effects and dependence. The Ontario Drug Benefit Program does not list most SMRs. Diazepam is listed as a psychoac- tive agent. Dantrolene and baclofen are listed for the treatment of spasticity due to neurological illness (e.g., cerebral palsy, spinal cord injury, etc.).

The WSIB will consider all relevant facts and circumstances, and shall make its decision based upon the merits and justice of a particular case.

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