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

Cover of Drug Class Review: Skeletal Muscle Relaxants

Drug Class Review: Skeletal Muscle Relaxants: Final Report [Internet].

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Introduction

Skeletal muscle relaxants are a heterogeneous group of medications commonly 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 they have by convention been classified into one group, the Food and Drug Administration (FDA) has approved only a few medications in this class for treatment of spasticity; the remainder are approved for treatment of musculoskeletal conditions. Data from the Third National Health and Nutrition Examination (NHANES III) survey (1988–1994) estimated that 1% of American adults are taking muscle relaxants, often on a chronic basis.1

Spasticity, although difficult to define precisely, is a clinical condition that has been described as "a motor disorder characterized by velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex, as one component of the upper motor neuron syndrome."2 The upper motor neuron syndrome is a complex of signs and symptoms that, in addition to spasticity, can be associated with exaggerated cutaneous reflexes, autonomic hyperreflexia, dystonia, contractures, paresis, lack of dexterity, and fatigability.3 Spasticity from the upper motor neuron syndrome can result from a variety of conditions affecting the cortex or spinal cord. Some of the more common conditions associated with spasticity and requiring treatment include multiple sclerosis,4 spinal cord injury,5 traumatic brain injury, cerebral palsy, and post-stroke syndrome.6 In many patients with these conditions, spasticity can be disabling and painful with a marked effect on functional ability and quality of life.7

Common musculoskeletal conditions causing tenderness and muscle spasms include fibromyalgia,8 tension headaches,9 myofascial pain syndrome, and mechanical low back or neck pain. If muscle spasm is present in these conditions, it is related to local factors involving the affected muscle groups. There is no hypertonicity or hyperreflexia, and the other symptoms associated with the upper motor neuron syndrome are not present. These conditions are commonly encountered in clinical practice and can cause significant disability and pain in some patients. Skeletal muscle relaxants are one of several classes of medications (including antidepressants, neuroleptics, anti-inflammatory agents, and opioids) frequently used to treat these conditions.10–12

Skeletal muscle relaxants have been approved for either treatment of spasticity or for treatment of musculoskeletal conditions. Drugs classified as skeletal muscle relaxants are baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, and tizanidine. Only baclofen, dantrolene, and tizanidine are approved for the treatment of spasticity. These three antispasticity medications act by different mechanisms: baclofen blocks pre- and post-synaptic GABAB receptors,13, 14 tizanidine is a centrally acting agonist of α2 receptors,15, 16 and dantrolene directly inhibits muscle contraction by decreasing the release of calcium from skeletal muscle sarcoplasmic reticulum.17 Medications from other classes have also been used to treat spasticity. Diazepam, a benzodiazepine, was the first medication thought to be effective for spasticity. It acts by central blockade of GABAA receptors.18, 19 Other medications used to treat spasticity but not formally approved for this indication include other benzodiazepines, clonidine, gabapentin, and botulinum toxin.17

The skeletal muscle relaxants carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine have been approved for treatment of musculoskeletal disorders, but not for spasticity. They constitute a heterogeneous group of medications. Cyclobenzaprine is closely related to the tricyclic antidepressants,20 carisoprodol is metabolized to meprobamate,21 methocarbamol is structurally related to mephenesin,20 chlorzoxazone is a benzoxazolone derivative,22 and orphenadrine is derived from diphenhydramine.23 The mechanism of action for most of these agents is unclear, but may be related in part to sedative effects. These drugs are often used for treatment of musculoskeletal conditions whether muscle spasm is present or not.12 Although there is some overlap between clinical usage (tizanidine in particular has been studied for use in patients with musculoskeletal complaints),24 in clinical practice each skeletal muscle relaxant is used primarily for either spasticity or for musculoskeletal conditions.

The purpose of this report is to determine whether there is evidence that one or more skeletal muscle relaxant is superior to others in terms of efficacy or safety. This report was originally submitted in February 2003 and updated annually. Update #1 was completed in January 2004 from searches performed in October 2003. Update #2 is based on searches performed in November 2004. New data for Update #2 are highlighted in the text and tables of this report. Since the last update, the Food and Drug Administration (FDA) has not approved any new skeletal muscle relaxants.

Scope and Key Questions

The scope of the review and key questions were originally developed and refined by the Oregon Evidence-based Practice Center with input from a statewide panel of experts (pharmacists, primary care clinicians, pain care specialists, and representatives of the public). Subsequently, the key questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project (DERP). The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

  1. What is the comparative efficacy of different muscle relaxants in reducing symptoms and improving functional outcomes in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms?
  2. What are the comparative incidence and nature of adverse effects (including addiction and abuse) of different muscle relaxants in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms?
  3. Are there subpopulations of patients for which one muscle relaxant is more effective or associated with fewer adverse effects?

Several aspects of the key questions deserve comment:

Population

The population included in this review is adult or pediatric patients with spasticity or a musculoskeletal condition. We defined spasticity as muscle spasms associated with an upper motor neuron syndrome. Musculoskeletal conditions were defined as peripheral conditions resulting in muscle or soft tissue pain or spasms. We included patients with nocturnal leg cramps. We excluded obstetric and dialysis patients. We also excluded patients with restless legs syndrome or nocturnal myoclonus.

Drugs

We included the following oral drugs classified as skeletal muscle relaxants: baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, and tizanidine. Benzodiazepenes were not considered primary drugs in this report. However, diazepam, clonazepam, and clorazepate were reviewed when they were compared in head-to-head studies with any of the skeletal muscle relaxants listed above. Other medications used for spasticity but considered to be in another drug class, such as gabapentin (a neuroleptic) and clonidine (an antihypertensive), were also only reviewed when they were directly compared to an included skeletal muscle relaxant. Quinine was only included if it was compared to a skeletal muscle relaxant.

The dose of skeletal muscle relaxants used in trials may affect either the efficacy or adverse event profile. One clinical trial25 of cyclobenzaprine, for example, found equivalent efficacy at 10 and 20 mg tid, but increased adverse events with the higher dose. A study on dantrolene also found a `ceiling' effect at doses of 200 mg daily, with no increased efficacy but more side effects above that dose.26 Most trials titrated skeletal muscle relaxants to the maximum tolerated dose or a pre-specified ceiling dose, but there are no standardized methods of titration and determining target doses.

Outcomes

The main efficacy measures were relief of muscle spasms or pain, functional status, quality of life, withdrawal rates, and adverse effects (including sedation, addiction, and abuse). We excluded non-clinical outcomes such as electromyogram measurements or spring tension measurements. There is no single accepted standard on how to measure the included outcomes. Clinical trials of skeletal muscle relaxants have often used different scales to measure important clinical outcomes such as spasticity, pain, or muscle strength.27 Many trials have used unvalidated or poorly described methods of outcome assessment. Studies that use the same scale often report results differently (for example, mean raw scores after treatment, mean improvement from baseline, or number of patients "improved"). All of these factors make comparisons across trials difficult.

Spasticity is an especially difficult outcome to measure objectively. The most widely used standardized scales to measure spasticity in patients with upper motor neuron syndromes are the Ashworth28 and modified Ashworth29 scales. In these scales, the assessor tests the resistance to passive movement around a joint and grades it on a scale of 0 (no increase in tone) to 4 (limb rigid in flexion or extension). The modified Ashworth scale adds a "1+" rating between the 1 and 2 ratings of the Ashworth scale. For both of these scales, the scores are usually added for four lower and four upper limb joints, for a total possible score of 0–32, though scoring methods can vary. Some experts have pointed out that resistance to passive movement may measure tone better than it does spasticity and that the Ashworth scale and other `objective' measures of spasticity may not correlate well with patient symptoms or functional ability.30 Other areas of uncertainty regard the significance of the 1+ rating in the modified Ashworth scale and how a non-continuous ordinal variable should be statistically analyzed.31 An important advantage of the Ashworth scale is that it is a consistent way to measure spasticity or tone across studies, and has been found to have moderate reproducibility.31 Other measures of spasticity include the pendulum test, muscle spasm counts, and patient assessment of spasticity severity on a variety of numerical (e.g., 1–3, 1–4, 0–4) or categorical (e.g., none, mild, moderate, severe) scales. The best technique may be to perform both objective and subjective assessments of spasticity, but validated subjective assessment techniques of spasticity are lacking.

Muscle strength is usually assessed with the time-honored British Medical Research Council Scale, which is based on the observation of resistance provided by voluntary muscle activity and used in everyday clinical practice.16 An assessor grades each muscle or muscle group independently on a scale of 0 (no observed muscle activation) to 5 (full strength). This scale was originally devised to test the strength of polio survivors. Data are not available regarding its reliability and validity in assessing spastic and weak patients.

Most studies measure pain using either visual analogue or categorical pain scales. Visual analogue scales (VAS) consist of a line on a piece of paper labeled 0 at one end, indicating no pain, and a maximum number (commonly 100) at the other, indicating excruciating pain. Patients designate their current pain level on the line. An advantage of VAS is that they provide a continuous range of values for relative severity. A disadvantage is that the meaning of a pain score for any individual patient depends on the patient's subjective experience of pain. This poses a challenge in objectively comparing different patients' scores, or even different scores from the same patient. Categorical pain scales, on the other hand, consist of several pain category options from which a patient must choose (e.g., no pain, mild, moderate, or severe). A disadvantage of categorical scales is that patients must choose between categories that may not accurately describe their pain. The best approach may be to utilize both methods.32 Pain control (improvement in pain) and pain relief (resolution of pain) are also measured using visual analogue and categorical scales.

Studies can evaluate functional status using either disease-specific or non-specific scales. These scales measure how well an individual functions physically, socially, cognitively, and psychologically. Disease-specific scales tend to be more sensitive to changes in status for that particular condition, but non-specific scales allow for some comparisons of functional status between conditions. The most commonly used disease-specific measure of functional and disability status in patients with multiple sclerosis, for example, is the Kurtzke Extended Disability Status Scale (EDSS).33 The EDSS measures both disability and impairment, combining the results of a neurological examination and functional assessments of eight domains into an overall score of 0–10 (in increments of 0.5). The overall score of the EDSS is heavily weighted toward ambulation and the inter-rater reliability has been found to be moderate.33 Disease-specific scales are also available for fibromyalgia,34, 35 low back pain, cerebral palsy, and other musculoskeletal and spastic conditions.

Scales that are not disease-specific include the Medical Outcomes Study Short Form-36 (SF-36), Short Form-12 (SF-12), or another multi-question assessment. Another approach to measuring function is to focus on how well the medication helps resolve problems in daily living that patients with spasticity or musculoskeletal conditions commonly face, such as getting enough sleep or staying focused on the job. Some studies also report effects on mood and the preference for one medication over another.

The following adverse events were specifically reviewed: somnolence or fatigue, dizziness, dry mouth, weakness, abuse, and addiction. We also paid special attention to reports of serious hepatic injury.36 The subcommittee considered these the most common and potentially troubling adverse events in clinical practice. We recorded rates of these adverse events as well as rates of discontinuation of treatment due to a particular adverse effect. In some studies, only "serious" adverse events or adverse events "thought related to treatment medication" are reported. Many studies do not define these terms. We recorded any information about abuse and addiction, and rates of death and hospitalization when available.

Withdrawal rates

Because of inconsistent reporting of outcomes, withdrawal rates may be a more reliable surrogate measure for either clinical efficacy or adverse events in studies of skeletal muscle relaxants. High withdrawal rates probably indicate some combination of poor tolerability and ineffectiveness. An important subset is withdrawal due to any adverse event (those who discontinue specifically because of adverse effects).

Study types

We included controlled clinical trials to evaluate efficacy. The validity of controlled trials depends on how they are designed. Randomized, properly blinded clinical trials are considered the highest level of evidence for assessing efficacy.37–39 Clinical trials that are not randomized or blinded or that have other methodologic flaws are less reliable. These are also discussed in our report with references to specific flaws in study design and data analysis.

Trials comparing one skeletal muscle relaxant to another provided direct evidence of comparative efficacy and adverse event rates. Trials comparing skeletal muscle relaxants to other active medications or placebos provided indirect comparative data.

To evaluate adverse event rates, we included clinical trials and large, high-quality observational cohort studies. Clinical trials are often not designed to assess adverse events, and may select patients at low risk for adverse events (in order to minimize dropout rates) or utilize methodology inadequate for assessing adverse events. Observational studies designed to assess adverse event rates may include broader populations, carry out observations over a longer time, utilize higher quality methodologic techniques for assessing adverse events, or examine larger sample sizes. We did not systematically review case reports and case series in which the proportion of patients suffering an adverse event could not be calculated.

Copyright © 2005, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10693

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