Drug Class Review on Skeletal Muscle Relaxants Final Report Update 2 May 2005 Original Report Date: April 2003 Update 1 Report Date: January 2004 A literature scan of this topic is done periodically The purpose of this report is to make available information regarding the comparative effectiveness and safety profiles of different drugs within pharmaceutical classes. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Roger Chou, MD Kim Peterson, MS Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright © 2005 by Oregon Health & Science University Portland, Oregon 97201. All rights reserved. Note: A scan of the medical literature relating to the topic is done periodically (see http://www.ohsu.edu/ohsuedu/research/policycenter/DERP/about/methods.cfm for scanning process description). Upon review of the last scan, the Drug Effectiveness Review Project governance group elected not to proceed with another full update of this report. Some portions of the report may not be up to date. Prior versions of this report can be accessed at the DERP website. Final Report Update 2 Drug Effectiveness Review Project TABLE OF CONTENTS Introduction........................................................................................................................4 Scope and Key Questions ........................................................................................5 Methods...............................................................................................................................8 Literature Search......................................................................................................8 Study Selection........................................................................................................9 Data Abstraction....................................................................................................10 Quality Assessment................................................................................................10 Data Synthesis........................................................................................................11 Results ...............................................................................................................................12 Key Question 1. Symptoms and functional outcomes...........................................14 Key Question 2. Incidence and nature of adverse effects......................................21 Key Question 3. Subpopulations............................................................................28 Summary...........................................................................................................................29 References.........................................................................................................................30 Tables Table 1. Overview of included systematic reviews on skeletal muscle relaxants.........................................................................41 Table 2. Overview of head-to-head trials of skeletal muscle relaxants for spasticity............................................................................................47 Table 3. Overview of placebo-controlled trials of included skeletal muscle relaxants.........................................................................51 Table 4. Overview of head-to-head trials of skeletal muscle relaxants for musculoskeletal conditions .....................................................................54 Table 5. Overview of placebo-controlled trials of skeletal muscle relaxants for musculoskeletal conditions .....................................................................57 Table 6. Adverse events, head-to-head trials of skeletal muscle relaxants for spasticity............................................................................................62 Table 7. Adverse events, placebo-controlled trials of skeletal muscle relaxants for spasticity............................................................................................66 Table 8. Adverse events, head-to-head trials of skeletal muscle relaxants for musculoskeletal conditions .....................................................................69 Table 9. Adverse events, placebo-controlled trials of skeletal muscle relaxants for musculoskeletal conditions ...............................................................71 Table 10. Summary of evidence ............................................................................75 Skeletal Muscle Relaxants Page 2 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Tables Evidence Table 1. Included systematic reviews and meta-analyses of skeletal muscle relaxants in patients with spasticity.............................79 Evidence Table 2. Included systematic reviews and meta-analyses of skeletal muscle relaxants in patients with musculoskeletal conditions.................................................................................89 Evidence Table 3. Head-to-head trials of skeletal muscle relaxants in patients with spasticity ..........................................................................95 Evidence Table 4. Placebo-controlled trials of skeletal muscle relaxants in patients with spasticity...........................................................125 Evidence Table 5. Head-to-head trials of skeletal muscle relaxants in patients with musculoskeletal conditions............................................165 Evidence Table 6. Placebo-controlled trials of skeletal muscle relaxants in patients with musculoskeletal conditions ..........................185 Appendix A: Search Strategy...........................................................................................225 Appendix B: Clinical Trials Search Results ....................................................................231 Appendix C: Methods for Drug Class Reviews...............................................................232 Appendix D: Abstraction Tool for Adverse Effects ........................................................236 Skeletal Muscle Relaxants Page 3 of 237 Final Report Update 2 Drug Effectiveness Review Project 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 13, 14 mechanisms: baclofen blocks pre- and post-synaptic GABAB receptors, tizanidine is a centrally acting agonist of α2 receptors,15, 16 and dantrolene directly