Muscle relaxants for pain management in rheumatoid arthritis (Review) Richards BL, Whittle SL, Buchbinder R This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 1 http://www.thecochranelibrary.com Muscle relaxants for pain management in rheumatoid arthritis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 3 BACKGROUND .................................... 6 OBJECTIVES ..................................... 7 METHODS ...................................... 7 RESULTS....................................... 10 Figure1. ..................................... 11 Figure2. ..................................... 13 Figure3. ..................................... 15 Figure4. ..................................... 15 Figure5. ..................................... 16 Figure6. ..................................... 17 Figure7. ..................................... 17 Figure8. ..................................... 18 DISCUSSION ..................................... 20 AUTHORS’CONCLUSIONS . 21 ACKNOWLEDGEMENTS . 22 REFERENCES ..................................... 22 CHARACTERISTICSOFSTUDIES . 24 DATAANDANALYSES. 35 Analysis 1.1. Comparison 1 Muscle relaxant versus control, Outcome 1 Pain 24hrs. 37 Analysis 1.2. Comparison 1 Muscle relaxant versus control, Outcome 2 Pain 1-2 weeks. 38 Analysis 2.1. Comparison 2 Benzodiazepine versus placebo, Outcome 1 Pain 24hrs. 38 Analysis 2.2. Comparison 2 Benzodiazepine versus placebo, Outcome 2 Pain 1 week. 39 Analysis 2.3. Comparison 2 Benzodiazepine versus placebo, Outcome3Sleep(MSLT). 39 Analysis 2.4. Comparison 2 Benzodiazepine versus placebo, Outcome 4 Sleep (Polysomnography). 40 Analysis 2.5. Comparison 2 Benzodiazepine versus placebo, Outcome 5 Sleep (Patient reported outcome measures). 41 Analysis 2.6. Comparison 2 Benzodiazepine versus placebo, Outcome 6 Depression. 42 Analysis 3.1. Comparison 3 Benzodiazepine + NSAID versus NSAID - pain, Outcome 1 Pain 24hrs. 42 Analysis 3.2. Comparison 3 Benzodiazepine + NSAID versus NSAID - pain, Outcome 2 Sleep (Wolff Sleep Score). 43 Analysis 4.1. Comparison 4 Non-benzodiazepine versus placebo, Outcome 1 Pain. 43 Analysis 4.2. Comparison 4 Non-benzodiazepine versus placebo, Outcome 2 Functional Status. 44 Analysis 4.3. Comparison 4 Non-benzodiazepine versus placebo, Outcome 3 Sleep (Polysomnography). 45 Analysis 4.4. Comparison 4 Non-benzodiazepine versus placebo, Outcome 4 Sleep (Patient reported outcomes) Spiegel SleepQuestionnaire. 46 Analysis 4.5. Comparison 4 Non-benzodiazepine versus placebo, Outcome 5 Sleep (Patient reported outcomes) Leeds Sleep Evaluation.................................... 47 Analysis 5.1. Comparison 5 Muscle relaxant versus control - safety, Outcome 1 Withdrawal due to adverse events. 48 Analysis 5.2. Comparison 5 Muscle relaxant versus control - safety, Outcome 2 Total Adverse Events. 49 Analysis 5.3. Comparison 5 Muscle relaxant versus control - safety, Outcome 3 Total Adverse events - trials greater than 24hrsduration. ................................. 50 Analysis 5.4. Comparison 5 Muscle relaxant versus control - safety, Outcome 4 Total adverse events - trials 24hr duration only...................................... 50 Analysis 5.5. Comparison 5 Muscle relaxant versus control - safety, Outcome 5 Subgroups Adverse Events. 51 APPENDICES ..................................... 52 WHAT’SNEW..................................... 54 HISTORY....................................... 54 CONTRIBUTIONSOFAUTHORS . 54 DECLARATIONSOFINTEREST . 55 Muscle relaxants for pain management in rheumatoid arthritis (Review) i Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. SOURCESOFSUPPORT . 55 Muscle relaxants for pain management in rheumatoid arthritis (Review) ii Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Muscle relaxants for pain management in rheumatoid arthritis Bethan L Richards1, Samuel L Whittle2, Rachelle Buchbinder3 1Institute of Rheumatology and Orthopedics, Royal Prince Alfred Hospital, Camperdown, Australia. 2Rheumatology Unit, The Queen Elizabeth Hospital, Woodville, Australia. 3Monash Department of Clinical Epidemiology at Cabrini Hospital, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Malvern, Australia Contact address: Bethan L Richards, Institute of Rheumatology and Orthopedics, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales, 2050, Australia. [email protected]. Editorial group: Cochrane Musculoskeletal Group. Publication status and date: New, published in Issue 1, 2012. Review content assessed as up-to-date: 6 September 2011. Citation: Richards BL, Whittle SL, Buchbinder R. Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD008922. DOI: 10.1002/14651858.CD008922.pub2. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT Background Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. Objectives The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlor- diazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, ha- lazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, ox- azepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). Search methods We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. Selection criteria We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Data collection and analysis Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Muscle relaxants for pain management in rheumatoid arthritis (Review) 1 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Main results Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non- benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Authors’ conclusions Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness. PLAIN LANGUAGE SUMMARY Muscle relaxants for pain management in rheumatoid arthritis This summary of a Cochrane review presents what we