Muscle Relaxants for Pain Management in Rheumatoid Arthritis (Review)

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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

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) 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.

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, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, 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 know from research about the effect of muscle relaxants on pain in patients with rheumatoid arthritis. The review shows that in people with rheumatoid arthritis: - Muscle relaxants may not improve pain when taken as a single dose or for up to a two week period - We are uncertain whether muscle relaxants affect functional status because of the very low quality of the evidence - No trials were found that evaluated whether muscle relaxants affect quality of life - No trials were found that evaluated whether antidepressants affect sleep - We are uncertain whether muscle relaxants affect mood because of the very low quality of the evidence We also do not have precise information about side effects and complications. This is particularly true for rare but serious side effects. Possible side effects may include feeling tired or nauseous, headaches, blurred vision, a dry mouth, sexual dysfunction, or becoming dizzy or constipated. Rare complications may include increased suicidal thinking, liver inflammation, or a reduced white cell count. What is rheumatoid arthritis and what are muscle relaxants? When you have rheumatoid arthritis your immune system, which normally fights infection, attacks the lining of your joints. This makes your joints swollen, stiff, and painful. The small joints of your hands and feet are usually affected first. There is no cure for rheumatoid arthritis at present, so the treatments aim to relieve pain and stiffness and improve your ability to move. Muscle relaxants can be used to treat anxiety and promote sleep, and some people believe they may also reduce pain by acting on the nerves that cause pain, but this remains controversial. Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), Xanax, Ativan and non-benzodiazepines such as Skelaxin, Muscol) and drugs that prevent increased muscle tone (baclofen and dantrolene). Best estimates of what happens to people with rheumatoid arthritis who take muscle relaxants: Pain at 24 hours: - Non-significant result. Pain at 1 to 2 weeks: - Non-significant result.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 2 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Withdrawal due to adverse events, after 2 weeks: - Non-signiﬁcant result. Total adverse events: - 49 more people out of 100 experienced an adverse event, after 1 to 2 weeks, when they took a muscle relaxant (absolute difference 49%), - 52 out of 100 people who took a muscle relaxant suffered an adverse event, - 3 out of 100 people who took a placebo suffered an adverse event. Central nervous system (CNS) adverse events: - 33 more people out of 100 experienced a CNS adverse event, after 1 to 2 weeks, when they took a muscle relaxant (absolute difference 33%), - 39 out of 100 people who took a muscle relaxant suffered a CNS adverse event, - 6 out of 100 people who took a placebo relaxant suffered a CNS adverse event. This record should be cited as: This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in the Cochrane Database of Systematic Reviews [Issue and date] © [year] The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).

Muscle relaxants for pain management in rheumatoid arthritis (Review) 3 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. oyih 02TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The arthrit 2012 rheumatoid © in Copyright management pain for relaxants Muscle SUMMARYOFFINDINGSFORTHEMAINCOMPARISON [Explanation]

Muscle relaxant versus control for pain management in rheumatoid arthritis

Patient or population: patients with pain management in rheumatoid arthritis Settings: Intervention: muscle relaxant versus control

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments (95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Control Muscle Relaxant versus control s(Review) is h ie os Ltd. Sons, & Wiley ohn Pain - 24hrs (Single The mean Pain - 24hrs 104 ⊕⊕ No significant difference. dose) (Single dose) in the inter- (3 studies) low1,2 Absolute risk difference Follow-up: 24 hours vention groups was 2% (6% to 10%) and rela- 0.22 lower tive percent change 8% (- (1.02 lower to 0.58 38% to 22%) higher)

Pain - 1-2 weeks The mean Pain - 1-2 104 ⊕ No significant difference. Follow-up: 1 weeks weeks in the intervention (3 studies) very low2,3,4 Absolute risk difference - groups was 5% (-15% to 5%) and rel- 0.20 standard deviations ative percent change -4% lower (-11% to 3%) (0.59 lower to 0.18 higher)

Withdrawal due to Ad- 0 per 1000 0 per 1000 RR 2.84 180 ⊕ The event rate in the con- verse Events (0 to 0) (0.31 to 26.08) (5 studies5) very low2,3,4 trol group was zero. Ab- Follow-up: 2 weeks solute risk difference 1% (-4% to 6%), relative percent change 184% (-69% to 251%) 4 oyih 02TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The arthrit 2012 rheumatoid © in Copyright management pain for relaxants Muscle

Total Number of Adverse 29 per 1000 117 per 1000 RR 4.03 74 ⊕ Number needed to harm Events - only studies (31 to 438) (1.08 to 15.10) (2 studies) very low2,3,4 (NNTH) was 3 (2 to 8) >24hrs duration . Absolute risk difference Follow-up: 2 weeks 40% (23% to 57%), relative percentage change 303% (8% to 1410%)

Total Number of Adverse 288 per 1000 403 per 1000 RR 1.40 106 ⊕ No significant difference. Events - single dose (167 to 982) (0.58 to 3.41) (3 studies) very low2,3 Absolute risk difference - studies 6% (-23% to 10%) and Follow-up: 24 hours relative percent change - 22% (-59% to 48%)

CNS adverse events 57 per 1000 340 per 1000 RR 5.96 74 ⊕ NNTH was 3 (CI 2 to 11)

s(Review) is 2,3,4

h ie os Ltd. Sons, & Wiley ohn Follow-up: 1-2 weeks (101 to 1000) (1.77 to 20.08) (2 studies) very low . Absolute risk difference 35% (-13% to 83%), relative percent change 496% (77% to 1908%)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

1 Hetergeneous interventions and controls 2 Wide confidence intervals given small number of participants and small event rate 3 All three studies had high risk of bias. 4 Heterogenous interventions, outcomes, study design and length of follow up 5 Three of the five trials hand event rates of 0 5 BACKGROUND for the treatment of painful musculoskeletal conditions that are associated with muscle spasm such as acute low back pain and mus- Description of the condition cle strains (Waldman 1994), their use in RA is less well described. Although these drugs may relieve skeletal muscle pain, their effects Rheumatoid arthritis (RA) is the most common form of inflam- are non-specific and not solely related to muscle relaxation. They matory arthritis, affecting around 1% of the population. How- exhibit modest analgesic activity that may derive from their seda- ever, despite the significant advances in treatment over the past few tive effects and also possibly from suppression of nociceptive input decades, pain management remains a significant issue for many (Hunskaar 1991). All antispasmodic agents can cause significant patients (Heiberg 2002). Progressive disease is characterized by drowsiness, dizziness, confusion, nausea, and vomiting. synovial tissue proliferation and persistent inflammation with re- Antispasticity medications are used to reduce spasticity that inter- sultant cartilage degradation, bone erosion, and damage to ad- feres with therapy or function. Examples of such agents include jacent soft tissue and neural structures (Tak 2000). In the early baclofen and dantrolene. They are not commonly used in patients stages of RA, pain reflects the nociceptive effects of local inflam- with RA. mation (Kidd 2001). Over time, however, the sources of pain are more numerous (Bolay 2002) and the pain is often compounded by associated poor sleep, psychological comorbidity, and muscle How the intervention might work tension (Wolfe 2006). Hypnotic agents or muscle relaxants are widely prescribed in the In recent years we have witnessed dramatic advances in our un- management of insomnia, anxiety, or muscle tension. In a surveyof derstanding of the neuroanatomy of pain pathways and the neu- 242 patients with RA, 60% reported that arthritis pain interfered rophysiology of pain regulation. In RA, pain frequently has mul- with sleep to some degree, with an additional 14% reporting severe tifactorial origins with both central and peripheral components. or very severe interference (Nicassio 1992). When a patient is Pain thresholds are known to be modified by sleep, however few unable to sleep because of pain, a sleep-promoting agent may be current neurobiological hypotheses adequately explain the com- appropriate as increasing sleep may help to increase daytime pain plex relationship between chronic pain and sleep disturbance. To thresholds. date, sleep and pain are known to use common neurotransmitters Poor sleep, independent of mood status, has also been associated (Moldofsky 1975) and alpha wave intrusion into non-rapid eye with fatigue, exhaustion, irritability, poor function, and a cycle of movement (REM) sleep has been suggested as a possible mecha- greater pain (Morin 1998). This may also contribute to muscle nism of sleep disturbance in patients with fibromyalgia (Branco tension, which has also been linked to increased pain in RA ( 1994). Molecular mechanisms linking psychological state and pain Koehler 1985) and osteoarthritis (OA) (Dekker 1992). There is have also been recognized. Patients with pain often report increases also literature to support the notion that elevated levels of anxiety in pain in conjunction with elevations in psychological stress and are seen in patients with RA, also associated with higher levels of the molecular link between psychological stress and pain may be pain (Dickens 2002; Hagland 1989; Smedstad 1996; Smedstad explained by the stress-induced increases in tumour necrosis factor 1997). Muscle relaxants may therefore be useful adjuvant agents (TNF) and interleukin (IL)-1 (Maes 1998). in patients with RA who have persistent pain. Centrally, inhibitory gamma-amino butyric acid (GABA) neurons in the spinal cord are known to act as ’gate keepers’ and to control the relay of pain signals from the periphery to higher areas of the central nervous system. This pivotal role of GABA neurons in Description of the intervention modulating pain signals has been demonstrated in several reports The term ’muscle relaxants’ is very broad and includes a wide which have shown that a loss of such inhibitory capabilities under- range of drugs with different indications and mechanisms of ac- lies several forms of chronic pain (Malan 2002; Moore 2002). In tion. Muscle relaxants can be divided into two main categories, addition, a recent animal study showed that specifically activating antispasmodic and antispasticity medications. The antispasmodic spinal GABA A receptors containing α2 or α3 subunits reduced agents are further subclassified into the benzodiazepines and the nociceptive input and emotional processing of inflammatory and non-benzodiazepines. neuropathic pain (Knabl 2008). Peripheral benzodiazepine recep- Since the introduction of chlordiazepoxide (Librium®) in 1960 tors (PBR) have also been shown to be involved in the regulation (Tobin 1960) and diazepam (Valium®) in 1962 (Randall 1961), of immune responses (Waterfield 1999) and PBR ligands exhibit the benzodiazepines have been widely prescribed for a variety anti-inflammatory properties (Zavala 1990). of medical and psychiatric indications. Non-benzodiazepines in- The analgesic effects of benzodiazepines are predominantly me- clude a variety of drugs that can act at the brain stem or spinal diated through activation of neuronal GABA A receptors (Costa cord level. These include carisoprodol, chlorzoxazone, cycloben- 1979), although benzodiazepines may also act via peripheral mech- zaprine, metaxalone, meprobamate, methocarbamol, tizanidine, anisms in patients with RA. The non-benzodiazepines, however, zopiclone, and orphenadrine. While these agents have been used are structurally unrelated compounds that may indirectly relax

Muscle relaxants for pain management in rheumatoid arthritis (Review) 6 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. skeletal muscle by blocking postsynaptic neurons in the spinal Types of participants cord and the descending reticular formation in the brain. Baclofen Adult patients (aged 18 years or older) with a diagnosis of RA. is a gamma aminobutyric acid (GABA) derivative that inhibits Populations that included a mixed population with RA and other neural transmission at the spinal level and also depresses the cen- causes of musculoskeletal pain were excluded unless results for the tral nervous system. Dantrolene sodium blocks the sarcoplasmic RA population could be separated out from the analysis. reticulum calcium channel thereby diminishing the actin-myosin interaction, causing muscle relaxation. Types of interventions All formulations and doses of muscle relaxants, as monotherapy or in combination, were considered. Why it is important to do this review Comparators could include: 1. placebo; Since their introduction, there has been interest in the therapeu- 2. other analgesics (e.g. paracetamol, non-steroidal anti- tic application of muscle relaxants for the management of pain. inflammatory drugs (NSAIDs), opioids, tramadol, Conclusive data regarding their analgesic activity, however, is lack- neuromodulators etc); ing. There is also conflicting evidence as to whether or not mus- 3. non-pharmacological modalities (e.g. transcutaneous cle relaxants possess analgesic properties that are independent of electrical nerve stimulation (TENS), acupuncture, etc); their effects on sleep. Despite a paucity of evidence to support 4. same drug at differing doses; and their use, muscle relaxants have gained widespread clinical accep- 5. other muscle relaxants. tance as adjuvants in the management of patients with chronic Comparisons with placebo and with other controls were planned musculoskeletal pain (Gordon 1995; Levy 1994). They have also to be reported separately. been advocated for pain associated with anxiety (Fernandez 1987), Drugs that had been withdrawn from the market due to safety muscle injury (Lossius 1980), muscle spasm (Weber 1973), and concerns were excluded from the review. nerve injury (Smirne 1977). This review helps to clarify the risks and benefits associated with using muscle relaxants in the management of pain in patients with RA to aid physicians in making Types of outcome measures a more informed decision about their use. There is considerable variation in the outcome measures reported in clinical trials of interventions for pain. For the purpose of this systematic review, we included outcome measures recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Dworkin 2008. OBJECTIVES As continuous outcome measures in pain trials (such as mean change on a 100 mm visual analogue scale) may not follow a Gaus- The objectives of this review were to evaluate the analgesic efficacy sian distribution, and often a bimodal distribution is seen instead and safety of muscle relaxants in patients with RA. (where patients tend to report either very good or very poor pain relief) (Moore 2010), there is a difficulty in interpreting the mean- ing of average changes in continuous pain measures. For this reason, a dichotomous outcome measure (the proportion of partici- METHODS pants reporting ≥ 30% pain relief) was likely to be more clinically relevant and was the primary efficacy measure in this review. It is recognised, however, that it has been the practice in most trials of interventions for chronic pain to report continuous measures and Criteria for considering studies for this review therefore the mean change in pain score was also included as a secondary efficacy measure. A global rating of treatment satisfaction, such as the Patient Global Impression of Change scale (PGIC), Types of studies which provides an outcome measure that integrates pain relief, changes in function, and side-effects into a single, interpretable All published randomised (RCTs) or quasi-randomised (that is measure, is also recommended by IMMPACT and was included where allocation was not truly random) (CCTs) controlled trials as a secondary outcome measure (Dworkin 2008). which compared muscle relaxant therapy to another therapy (active, including non-pharmacological therapies, or placebo) for RA were considered for inclusion. Only trials that were published as Main outcomes full articles or were available as a full trial report were included. 1. Efficacy: patient reported pain relief of 30% or greater.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 7 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2. Safety: number of withdrawals due to adverse events. 2. EMBASE Classic + EMBASE (Week 44 2010) (Appendix 2); 3. Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010); Minor outcomes 4. PsycINFO (1806 to week 2 November 2010). 3. Pain: No language restrictions were applied. a. patient reported pain relief of 50% or greater; b. patient reported global impression of clinical change (PGIC) much or very much improved; Searching other resources c. proportion of patients achieving pain score below 30/100 mm The American College of Rheumatology (ACR) and European on a visual analogue scale; or League Against Rheumatism (EULAR) conference abstracts from d. mean change in pain score on a visual analogue scale or numer- 2008 and 2009 were searched. Handsearches of references and ical rating scale. relevant reviews were also performed to identify any additional 4. Number and types of adverse events (AEs) and serious adverse trials not retrieved by the above methods. events (SAEs) (defined as AEs that were fatal, life-threatening, or required hospitalisation). 5. Function: as measured by the Health Assessment Questionaire Data collection and analysis (HAQ) or modified HAQ (Fries 1980; Pincus 1983). 6. Quality of life: as measured by either generic instruments (such as the Short Form-36 (SF-36)) or disease-specific tools (such as Selection of studies the Rheumatoid Arthritis Quality of Life instrument (RAQoL)). 7. Participant withdrawals due to inadequate analgesia. All identified studies were assessed independently by two review 8. Sleep as measured by any commonly used sleep scale (eg. In- authors (BR and SW) to identify trials that fulfilled the inclusion somnia Severity Index, Medical Outcomes Study (MOS), Sleep criteria. All possibly relevant articles were retrieved in full text and Scale, Pittsburgh Sleep Diary (PSD), and Pittsburgh Sleep Quality any disagreement in study selection was resolved by consensus or Index (PSQI)). by discussion with a third review author (RB). 9. Depression as measured by any commonly used depression scale (eg. Hamilton Rating Scale for Depression (HRSD), Hospital Data extraction and management Anxiety and Depression (HAD) score, Beck Depression Inventory (BDI), Zung self rating depression score). Two independent review authors (BR and SW) extracted relevant The duration of the trials of interventions for pain varies consid- information from the included trials including study design, char- erably. The efficacy of interventions, and the relative balance of acteristics of study population, treatment regimen and duration, benefits and harms, may vary according to the duration of the outcomes and timing of outcome assessment using predetermined trial and therefore the combination of results from trials of differ- forms. The raw data (means and standard deviations for continu- ent durations may represent a source of bias in systematic reviews ous outcomes and number of events or participants for dichoto- (Moore 2010). For the purpose of this review, trials were grouped mous outcomes) were extracted for outcomes of interest. Differ- into those of duration < 1 week, 1 to 6 weeks, and > 6 weeks. ences in data extraction were resolved by referring back to the Where available, the short and long term outcomes for the propor- original articles and establishing consensus. A third review author tion reporting pain relief of 30% or greater, total number of with- (RB) was consulted to help resolve differences, as necessary. drawals due to adverse effects, number of serious adverse events, function, and quality of life were presented in the summary of Assessment of risk of bias in included studies findings table. Two authors (BR, SW) independently assessed risk of bias for all included studies for the following items: random sequence generation; allocation concealment; blinding of participants, care Search methods for identification of studies provider, and outcome assessor for each outcome measure (see primary and secondary outcome measures); incomplete outcome data; and other biases, conforming to the methods recommended Electronic searches by The Cochrane Collaboration (Higgins 2008). To determine To identify relevant trials for this review, we used computer-aided the risk of bias of a study, for each criterion the presence of suffi- searches of the following databases for RCTs or CCTs using the cient information and the likelihood of potential bias were evalu- search strategies detailed in the appendices: ated. Each criterion was rated as ’yes’ (low risk of bias), ’no’ (high 1. Ovid MEDLINE (1950 to week 1 November 2010) (Appendix risk of bias), or ’unclear’ (either lack of information or uncertainty 1); over the potential for bias). In a consensus meeting, disagreements

Muscle relaxants for pain management in rheumatoid arthritis (Review) 8 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. among the review authors were discussed and resolved. If consen- Assessment of heterogeneity sus could not be reached, a third review author (RB) made the Prior to meta-analysis, we assessed studies for clinical homogene- final decision. ity with respect to type of therapy, control group, and the outcomes. For any studies judged as clinically homogeneous, statistical heterogeneity was estimated using the I2 statistic (Deeks 2008) Measures of treatment effect with the following as a rough guide for interpretation: 0% to 40% The data were summarised in a meta-analysis only if there was suf- might not be important, 30% to 60% may represent moderate ficient clinical and statistical homogeneity. For continuous data, heterogeneity, 50% to 90% may represent substantial heterogene- results were analysed as mean differences between the intervention ity, and 75% to 100% may represent considerable heterogeneity. and comparator groups (MD) with 95% confidence intervals. The mean difference between the treated group and the control group Assessment of reporting biases was weighted by the inverse of the variance in the pooled treatment estimate. However, when different scales were used to measure In order to determine whether reporting bias was present, we the same conceptual outcome (for example functional status or planned to determine whether the protocol of the RCT was pub- pain), standardized mean differences (SMD) were calculated in- lished before recruitment of study patients was started. However as stead. SMDs were calculated by dividing the MD by the standard no studies were published after 1st July 2005, we did not carry out deviation, resulting in a unitless measure of treatment effect. For the preplanned screen of the Clinical Trial Register at the Interna- dichotomous data, a relative risk (RR) with corresponding 95% tional Clinical Trials Registry Platform of the World Health Orga- confidence interval was calculated. nization (http://apps.who.int/trialssearch)(DeAngelis 2004). We also evaluated whether selective reporting of outcomes was present (outcome reporting bias). Unit of analysis issues We compared the fixed-effect model estimate against the random- effects model to assess the possible presence of small sample bias For studies containing more than two intervention groups, making in the published literature (that is in which the intervention effect multiple pair-wise comparisons between all possible pairs of inter- was more beneficial in smaller studies). In the presence of small vention groups possible included the same group of participants sample bias, the random-effects model estimate was used (Sterne only once in the meta-analysis. Cross-over trials were identified, in 2008). The potential for reporting bias was planned to be further which the reporting of continuous outcome data precluded paired explored by funnel plots if ≥10 studies were available, however analysis, however there was no meta-analysis so unit-of-analysis due to the limited number of studies identified this was not done. error was not an issue.

Data synthesis Dealing with missing data Where studies were sufficiently homogeneous that it remained In cases where individuals were missing from the reported results, clinically meaningful for them to be pooled, meta-analysis was per- we assumed the missing values to have a poor outcome. For di- formed using a random-effects model, regardless of the I2 statistic chotomous outcomes that measured adverse events (for example results. Analysis was performed using Review Manager 5 and for- number of withdrawals due to adverse events), the withdrawal rate est plots were produced for all analyses. was calculated using the number of patients that received treatment as the denominator (worst case analysis). For dichotomous Subgroup analysis and investigation of heterogeneity outcomes that measured benefits (for example proportion of participants achieving an American College of Rheumatology 20% If sufficient data had been available, the following subgroup anal- improvement criteria (ACR20) response) the worst case analysis yses were planned: was calculated using the number of randomised participants as 1. patients’ ages (< 65 years versus ≥ 65 years); the denominator. For continuous outcomes (for example pain) 2. gender (male versus female); and we calculated the MD or SMD based on the number of patients 3. duration of RA (≤ 2 years versus > 2 years). analysed at the time point. If the number of patients analysed was not presented for each time point, the number of randomised patients in each group at baseline was used. Where possible, missing Sensitivity analysis standard deviations were computed from other statistics such as If sufficient data had been available, we planned sensitivity analy- standard errors, confidence intervals or P values according to the ses to assess the impact of any bias attributable to inclusion of tri- methods recommended in the Cochrane Handbook for System- als with inadequate treatment allocation concealment (including atic Reviews of Interventions (Higgins 2009). studies with quasi-randomised designs).

Muscle relaxants for pain management in rheumatoid arthritis (Review) 9 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Presentation of key results RESULTS A summary of findings table was produced using GRADEpro software. This table provides key information concerning the quality of evidence, the magnitude of effect of the interventions exam- Description of studies ined, and the sum of available data on the outcomes (short and long term outcomes for pain, total number of withdrawals due See: Characteristics of included studies; Characteristics of excluded to adverse effects, function, and quality of life), as recommended studies. by The Cochrane Collaboration (Schünemann 2008a). The table See: ’Characteristics of included studies’; ’Characteristics of ex- includes an overall grading of the evidence related to each of the cluded studies’. main outcomes, using the GRADE approach. In addition to the absolute and relative magnitudes of effect provided in the summary of findings table, for dichotomous outcomes Results of the search the number needed to treat to benefit (NNTB) or the number The database search yielded a total of 174 articles for review (CEN- needed to treat to harm (NNTH) was calculated from the control TRAL 26, MEDLINE 95, EMBASE 49, and PsycINFO 4) and group event rate (unless the population event rate was known) and no further relevant studies were identified from searching the 2008 the relative risk was calculated using the Visual Rx NNT calcula- and 2009 ACR and EULAR abstracts. tor (Cates 2004). For continuous outcomes, the NNT was calcu- After removal of 42 duplicates, the records were screened and lated using the Wells calculator software, available at the Cochrane nine studies were assessed for detailed review. Six trials (n = 126 Musculoskeletal Group (CMSG) editorial office (http://muscu- participants) met the inclusion criteria of the review (Bayley 1976; loskeletal.cochrane.org/). The minimal clinically important dif- Drewes 1998; Hobkirk 1977; Sharma 1978; Vince 1973; Walsh ference (MCID) for each outcome was determined for input into 1996). No additional studies were identified through reference the calculator. checking (Figure 1).

Muscle relaxants for pain management in rheumatoid arthritis (Review) 11 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Five trials used a cross-over design (Bayley 1976; Hobkirk 1977; Included studies Sharma 1978; Vince 1973; Walsh 1996) and, of these, only one The characteristics of the included studies are described in the included a washout period (Walsh 1996). The remaining study ’Characteristics of included studies’ table. Five trials assessed a ben- used a parallel group design (Drewes 1998). No benzodiazepine zodiazepine and one trial assessed the non-benzodiazepine zopi- trial incorporated more than one week of active treatment and, clone (n = 40) (Drewes 1998). Of the benzodiazepine studies, four overall, no trial was longer than two weeks; the shortest duration evaluated diazepam (n = 71) (Bayley 1976; Hobkirk 1977; Sharma trials were three cross-over studies of single doses of drug given 1978; Vince 1973) and one evaluated triazolam (n = 15) (Walsh for three consecutive nights (Bayley 1976; Hobkirk 1977; Sharma 1996). Five trials included a placebo control (Bayley 1976; Drewes 1978). The other two cross-over studies included two one week 1998; Hobkirk 1977; Vince 1973; Walsh 1996), one compared periods of treatment (Vince 1973; Walsh 1996). diazepam with an NSAID (Bayley 1976), and two studies assessed Three studies evaluated inpatients (Bayley 1976; Hobkirk 1977; whether diazepam in combination with an NSAID was superior Sharma 1978) and three studies (Drewes 1998; Vince 1973; to an NSAID alone (Hobkirk 1977; Sharma 1978). A summary of Walsh 1996) included outpatients. Most participants were women the interventions studied in the six included trials is listed below. (83%), in accordance with the epidemiology of RA, and all patients had active disease with 56% of patients hospitalised at the time of study. One trial incorporated patients who had both RA and sleep 1) Benzodiazepine versus placebo impairment (Walsh 1996). Only 17% (22/127) of patients were 1a) Diazepam versus placebo (Bayley 1976; Vince 1973) receiving corticosteroids and 30% (38/127) were receiving disease 1b) Triazolam versus placebo (Walsh 1996) modifying antirheumatic drugs (DMARDs) (Walsh 1996) (with only 5/38 on methotrexate). No patients were receiving biologi- cal agents. No studies reported any speciﬁc information about the 2) Benzodiazepine versus NSAID type of pain participants were suffering from or whether patients 2a) Diazepam versus Indomethacin (Bayley 1976) suffered from depression.

3) Benzodiazepine + NSAID versus NSAID Excluded studies 3a) Diazepam + sulindac versus sulindac (Sharma 1978) Three studies were excluded from this review (see ’Characteris- 3b) Diazepam + indomethacin versus indomethacin (Hobkirk tics of excluded studies’ table) because they included mixed pop- 1977) ulations and it was not possible to extract data regarding the RA patients alone for analysis (Durrigl 1969; Hardo 1991; Tarpley 1965). 4) Non-benzodiazepine versus placebo 4a) Zopliclone versus placebo (Drewes 1998) Risk of bias in included studies The majority of studies were published in the late 1970s, with the most recent publications being Walsh 1996 and Drewes 1998. See Figure 2.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 12 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 13 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. All studies were rated at high risk of bias (Bayley 1976; Drewes 1998; Hobkirk 1977; Sharma 1978; Vince 1973; Walsh 1996). Incomplete outcome data The most common methodological shortcomings in the studies Only one study failed to describe how incomplete outcome data involved the following, in order of frequency. were addressed. In Vince 1973, 7/24 (29.2%) patients dropped • Inadequate method of randomisation (6, 100% trials scored out without clear reasons or the group allocation being specified. ’unclear’). • Inadequate concealment of the drug allocation procedures Selective reporting (6, 100% trials scored ’unclear’). • Failing to apply intention-to-treat analysis (5, 87% trials All studies reported all prespecified outcomes as defined in their scored ’negative’ or ’unclear’). methods sections. • Non-equivalent co-interventions (4, 67% scored ’unclear’). • Dissimilarity of the baseline characteristics (4, 67% trials Other potential sources of bias scored ’negative’ or ’unclear’). In the five cross-over trials, no information was provided regarding • Failure to blind study personnel (3, 50% trials scored the randomisation of the order of treatments and no assessment ’unclear’). was made of a period effect. Three single dose studies of simi- • Failing to evaluate compliance (3, 50% trials scored lar design each conducted the trial over three consecutive nights, ’negative’ or ’unclear’). without any washout period (Bayley 1976; Hobkirk 1977; Sharma • Inadequate dropouts (2, 33% trials scored ’negative’ or 1978). This may have exposed the trials to the possibility of a ’unclear’). carry-over effect. Another common source of bias was failure to • Failure to address incomplete outcome data (1, 17% trials report co-interventions (Bayley 1976; Drewes 1998; Vince 1973; scored ’negative’ or ’unclear’). Walsh 1996). • Failure to blind participants (1, 17% trials scored ’negative’ or ’unclear’). • Only reporting selective outcomes (no trials scored Effects of interventions ’negative’ or ’unclear’). See: Summary of findings for the main comparison Muscle relaxant versus control for pain management in rheumatoid arthritis Allocation Overall we were able to pool some of the data for three studies of less than one week duration (Bayley 1976; Hobkirk 1977; Sharma No study adequately described how participants were randomised 1978) and for three studies of one to six weeks duration (Drewes and all were deemed ’unclear’. No study provided any information 1998; Vince 1973; Walsh 1996). about whether allocation of treatment was adequately concealed and all were deemed to be ’unclear’. Primary outcomes

Blinding 1) Effectiveness of muscle relaxants - pain intensity All studies described the use of a placebo but did not provide spe- No study reported the primary outcome measure of patient re- cific information about the characteristics of the placebo and in ported pain relief of 30% or greater. Available pain data were con- particular whether the placebo was identical to the active treat- fined to mean pain VAS or means of ordinal outcomes in all trials. ment. No studies audited participants or study personnel on whether they believed the participants were receiving the active treatment. Any muscle relaxant versus placebo None of the included studies provided specific information about When pooled, the short term single dose studies assessing di- whether or not study personnel (including outcome assessors) were azepam (52 participants) (Bayley 1976; Hobkirk 1977; Sharma blinded. This is important and raises the possibility that positive 1978) showed no benefit in mean night pain VAS (0 to 10 cm) results might be an artefact of physician expectations rather than scores over the control arm (SMD -0.22, 95% CI -1.02 to 0.58) a true effect. This was illustrated in the Vince 1973 trial where pa- (Analysis 1.1, Figure 3). The other three studies of between one tient global assessment outcomes were the same in both treatment and two weeks duration (Drewes 1998; Vince 1973; Walsh 1996) groups however the physician global assessment was higher in the also showed no significant improvement in mean pain over control diazepam group than the placebo group. (SMD -0.20, 95% CI -0.59 to 0.18) (Analysis 1.2, Figure 4).

Muscle relaxants for pain management in rheumatoid arthritis (Review) 14 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Forest plot of comparison: 1 Muscle relaxant versus control, outcome: 1.1 Pain 24 hrs.

Figure 4. Forest plot of comparison: 1 Muscle relaxant versus control, outcome: 1.2 Pain 1-2 weeks.

Benzodiazepines versus placebo Non-benzodiazepines versus placebo One small study (1 trial, 41 patients) found no benefit of zopiclone Three studies assessed the efficacy and safety of a benzodiazepine over placebo over two weeks on either present pain intensity (MD versus placebo on pain intensity (Bayley 1976; Vince 1973; Walsh -0.20, 95% CI -0.77 to 0.37) or total pain rating index (MD - 1996)(Analysis 2.1). Two small cross-over trials (Bayley 1976; 6.60, 95% CI -16.25 to 3.05) (Drewes 1998)(Analysis 4.1). Vince 1973) compared diazepam with placebo at different time points and reported conflicting results (2 trials, 35 people). Bayley 1976 reported that a single dose of diazepam was superior to Benzodiazepine versus NSAID placebo in relieving night pain (mean improvement of 0.9 cm, One short term, single dose cross-over study (18 people) reported 95% CI -1.77 to -0.03) on a 10 cm VAS, while Vince 1973 re- no benefit of diazepam over indomethacin in pain outcomes in ported no difference in mean pain scores between diazepam and inpatients with RA (Bayley 1976). However, insufficient data were placebo after one week. provided to extract any data regarding this result. Two studies compared different benzodiazepines with a placebo over one to two weeks (Vince 1973; Walsh 1996). After two weeks, Vince 1973 again found no significant difference in mean pain Benzodiazepine + NSAID versus NSAID scores between diazepam and placebo. Walsh 1996 compared tri- Two small cross-over trials (2 trials, 35 people) evaluated whether azolam with placebo in patients with RA and sleep disturbance or not there was any benefit in the addition of diazepam to an and also found no significant difference in pain outcomes after NSAID over taking an NSAID alone (Hobkirk 1977; Sharma two weeks. Pooling these two one week studies using a random- 1978). Both trials were small and were three consecutive night effects model yielded the same result (SMD -0.19, 95% CI -0.68 trials of inpatients with active disease. Neither trial found an ad- to 0.30) (Analysis 2.1). ditional benefit of the combination in terms of pain reduction

Muscle relaxants for pain management in rheumatoid arthritis (Review) 15 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. compared with NSAID alone. Standard deviations were estimated There was a paucity of data available (n = 70) from the three studies from a conservative estimate of the P values in each of the trials that compared a benzodiazepine with placebo. Overall there was and when data were pooled the results were the same (SMD -0.14, a trend towards more withdrawals in patients receiving a muscle 95% CI -1.65 to 1.36) (Analysis 3.1). relaxant but this did not receive statistical signiﬁcance (RR 2.84, 95% CI 0.31 to 26.08) (Analysis 5.1, Figure 5). No information was provided on withdrawals due to adverse events in Walsh 1996, 2) Safety of muscle relaxants and there were no events reported in the Bayley 1976 study. Vince 1973 only reported adverse events in 17/24 patients that were entered and completed their trial. It was not speciﬁed as to whether the seven patients who did not complete the trial suffered Number of withdrawals due to adverse events an adverse event.

Figure 5. Forest plot of comparison: 5 Muscle relaxant versus control - safety, outcome: 5.1 Withdrawal due to adverse events.

There was only one withdrawal due to adverse events in each of the head-to-head trials (over three consecutive nights only) (Hobkirk Total number of adverse events and serious adverse events 1977; Sharma 1978). In the Hobkirk 1977 trial the patient “felt (SAEs) generally unwell” after one dose of diazepam and indomethacin Five trials reported adverse event data (Bayley 1976; Drewes 1998; and in the Sharma 1978 trial one patient withdrew after two nights Hobkirk 1977; Sharma 1978; Vince 1973). When pooled there having “developed a plethora of minor symptoms”. It was not was a trend towards a significant increase in total adverse events specified as to which two treatments this patient had received only (RR 1.40, 95% CI 0.58 to 3.41) (Analysis 5.2, Figure 6). This however as two arms of the study included diazepam and different was explained by the heterogeneity in the results of the single dose NSAIDs this was included as an experimental event. In the one versus longer duration studies. In the single cross-over studies (3 study of the non-benzodiazepine agent zopiclone versus placebo trials, 106 people) evaluating short term (24 hr) outcomes of di- there were no withdrawals due to adverse events at the end of the azepam versus placebo there was no significant increase in the total two week trial (Drewes 1998). number of adverse events (RR 0.78, 95% CI 0.41 to 1.48) (Bayley 1976; Hobkirk 1977; Sharma 1978)(Analysis 5.4). However, In the longer one or two week trials there were significantly more Secondary outcomes adverse events (RR 4.03, 95% CI 1.08 to 15.10) (Drewes 1998; Vince 1973)(Analysis 5.3, Figure 7). The majority of these were central nervous system effects including drowsiness and dizziness (RR 5.96, 95% CI 1.77 to 20.08) (Analysis 5.5, Figure 8).

Muscle relaxants for pain management in rheumatoid arthritis (Review) 16 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 6. Forest plot of comparison: 5 Muscle relaxant versus control - safety, outcome: 5.2 Total adverse events.

Figure 7. Forest plot of comparison: 5 Muscle relaxant versus control - safety, outcome: 5.3 Total adverse events - trials greater than 24hrs duration.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 17 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 8. Forest plot of comparison: 5 Muscle relaxant versus control - safety, outcome: 5.5 Subgroups adverse events.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 18 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. When added to an NSAID in two small single dose trials (2 trials, 34 participants), there was no significant difference in adverse longer, that is participants less sleepy (11.0 min versus 7.9 min) events (RR 0.77, 95% CI 0.27 to 2.21) (Hobkirk 1977; Sharma (MD 3.10, 95% CI 1.20 to 5.00) (Analysis 2.3), objective mean 1978)(Analysis 5.5.3). Neither trial had a washout period so they total sleep time using polysomnography was significantly longer may have been biased by a carry-over effect. in the triazolam group (408.2 min versus 389.1 min) (MD 19.10, In the one small trial of zopiclone versus placebo, 36% (8/22) 95% CI 5.34 to 32.86) with patients having fewer awakenings of patients were reported to have an adverse event however 5/8 (28.9 versus 21.7) (MD 7.20, 95% CI 0.90 to 13.50) (Analysis of these were described as “bitter taste”. There was a trend to- 2.4). Total sleep latency was not significantly different (MD - wards significance only over two weeks (RR 9.09, 95% CI 0.54 8.40, 95% CI -33.05 to 16.25). In addition, the subjective sleep to 154.07) (Drewes 1998)(Analysis 5.5), which did not change outcome measures showed that patients receiving triazolam had when the patients with bitter taste were removed from the analysis significantly increased total sleep time (434.4 min versus 397 min) (RR 14.04, 95% CI 0.87 to 227.89). The other adverse events (MD 37.40, 95% CI 10.85 to 63.95), shorter sleep latency (time reported included sleepiness and dizziness (3/5). to fall asleep) (20.8 min versus 32.5 min) (MD -11.70, 95% CI - 22.89 to -0.51) and fewer awakenings (2.1 versus 3.3) (MD -1.20, Effectiveness of muscle relaxants versus placebo: functional 95% CI -2.05 to -0.35) (Analysis 2.5), however their daytime status sleepiness score was no different than for those receiving placebo. One non-benzodiazepine trial evaluated sleep outcomes in pa- No trials including benzodiazepines reported a functional status tients receiving zopiclone using polysomnography (Analysis 4.3), outcome. The one trial of zopiclone showed no difference in HAQ the Spiegel Sleep Questionnaire (Analysis 4.4), and the Leeds Sleep scores at the end of the two week trial (RR 0.08, 95% CI -0.54 to Evaluation Questionnaire (Analysis 4.5)(Drewes 1998). There 0.70) (Drewes 1998)(Analysis 4.2). were conflicting results between the objective and subjective sleep outcomes. Patient reported outcomes tended to be in favour of Effectiveness of muscle relaxants: quality of life zopiclone while objective outcomes did not show a significant difference between the two treatments. Using the Spiegel Sleep Ques- Only one trial measured a quality of life outcome, using the Arthri- tionnaire, the authors reported a mean increase of 1.70 units (95% tis Impact Measure Scale (AIMS), and found no significant dif- CI 1.03 to 2.37) (0 to 5 scale) in the overall quality of sleep after ference in any components (insufficient data available to confirm two weeks. The frequency of awakenings was reduced by a mean this result) (Walsh 1996). of 0.60 (95% CI 0.07 to 1.13) (0 to 5 scale) and sleep latency was also significantly decreased, by a mean of 0.70 (95% CI 0.13 Effectiveness of muscle relaxants: participant withdrawals to 1.27) (0 to 5 scale) (Analysis 4.4). With the Leeds Sleep Eval- due to inadequate analgesia uation, there was a significant improvement in mean sleep onset latency of 12 minutes (95% CI 4.73 to 19.27) and mean overall No trials recorded withdrawals due to inadequate analgesia. quality of sleep improvement of 7.53 (on a 100 point scale) (95% CI 2.86 to 12.20) (Analysis 4.5) during zopiclone treatment when Effectiveness of muscle relaxants: sleep compared with placebo. With objective polysomnography measures, total duration of sleep and number of awakenings were not Five trials included a measure of sleep. Three studies evaluating significantly different (Analysis 4.3). Overall there was a positive diazepam used the Wolfe sleep score (Wolff 1974) and reported effect on the subjective assessments of sleep while parameters from no significant short term benefit (at 24 hrs) over placebo (Bayley 1976); or in combination with an NSAID over an NSAID alone conventional sleep staging were not significantly different. Despite the improvements in subjective sleep ratings, clinical parameters (Hobkirk 1977, Sharma 1978). No standard deviations were pro- such as pain, morning stiffness, and sleepiness were unaltered dur- vided in these trials. Data from the Sharma 1978 trial were used ing treatment with zopiclone. to calculate a standard deviation which was then imputed into the similar Hobkirk trial (Analysis 3.2). One trial evaluated the effectiveness of triazolam versus placebo using the multiple sleep latency test (MSLT), polysomnography, Effectiveness of muscle relaxants versus placebo: depression and subjective patient sleep outcomes using the VAS (Walsh 1996). Only one trial recorded a measure of depression (Walsh 1996). In The MSLT is used to measure the time elapsed from the start of this trial there were no significant differences on any of the Profile a daytime nap period to the first signs of sleep. This test is based of Mood States (POMS) scales or on the depression scales of the on the idea that the sleepier people are, the faster they will fall AIMS questionnaire in patients receiving triazolam compared with asleep. After one week, mean MSLT latencies were significantly placebo (Analysis 2.6).

Muscle relaxants for pain management in rheumatoid arthritis (Review) 19 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Preplanned subgroup analyses single dose trial was zero (Bayley 1976). In the other two single There were insufficient data available to carry out the preplanned dose combination studies, there was one event only in each trial sensitivity analyses for age, gender, and duration of RA. (Hobkirk 1977; Sharma 1978). There were no withdrawals due to adverse events after two weeks of treatment in the single study of zopiclone. Other analyses Overall, 34% of patients receiving an intervention and 22% of None of the planned subgroup analyses were performed due to patients in the control groups suffered an adverse event. When insufficient data and high risk of bias in all trials. pooled over all time periods, there was only a trend towards an increase in adverse events in patients receiving muscle relaxants (RR 1.40, 95% CI 0.58 to 3.41). Not surprisingly, the rate of adverse events for diazepam varied greatly between the single dose DISCUSSION trials (11% to 28%) and the two week study (71%). When data from the trials of more than 24 hours duration were pooled there Summary of main results were significantly more adverse events (NNTH 3, 95% CI 2 to 8). Consistent with the literature, these were predominantly cen- This systematic review identified six small double-blind ran- tral nervous system side effects, including dizziness and drowsiness domised trials (including five cross-over trials) investigating the (NNTH 3, 95% CI 2 to 11). In the one small trial of zopiclone, effects of muscle relaxants on pain management in patients with 32% suffered an adverse event with 14% of events related to dizzi- RA. Five trials assessed a benzodiazepine (four trials diazepam, 71 ness and drowsiness. Given the small sample size there was only a participants; one trial triazolam, 15 participants) and one trial used trend towards significance (RR 14.04, 95% CI 0.87 to 227.89). the non-benzodiazepine agent zopiclone (40 participants). Four No trials with benzodiazepines reported functional status as an trials were placebo controlled and two were the benzodiazepine in outcome. One benzodiazepine trial measured quality of life and combination with an NSAID against an active NSAID compara- depression and reported no significant difference for either of tor. All of the trials were deemed to have a high risk of bias. No these after one week (Walsh 1996). The non-benzodiazepine trial trial was longer than two weeks duration with 50% of the included showed no difference in HAQ scores after two weeks but it did trials being single dose studies. No benzodiazepine trial was longer not measure quality of life or depression (Drewes 1998). There than one week in duration. was weak evidence of no short term improvement in any sub- No study reported the primary outcome measure of patient re- jective sleep outcomes in the small, single dose trials of patients ported pain relief of 30% or greater. When pooled, the short term taking benzodiazepines when compared with placebo, NSAID, or single dose studies assessing diazepam showed no benefit over any in combination with an NSAID (Bayley 1976; Hobkirk 1977; of the control arms. When compared with placebo, studies assess- Sharma 1978). Objective and subjective improvements in sleep la- ing pain outcomes at 24 hours had conflicting results. One small, tency, total sleep time and the number of awakenings were seen af- single dose study of inpatients reported a significant benefit of ter two weeks of treatment in one trial evaluating triazolam (Walsh a single dose of diazepam over placebo in improving night pain 1996). Daytime sleepiness was, however, no different than for (Bayley 1976). Patients had a modest mean improvement of only those receiving placebo. 0.9 cm on a 10 cm VAS (95% CI 0.03 to 1.77), which is of ques- In the one non-benzodiazepine trial, there was a positive effect on tionable clinical significance. In this study there was no benefit the subjective assessments of some sleep parameters (sleep latency, of a single dose of diazepam over indomethacin in reducing pain frequency of awakenings) however objective sleep outcomes were levels in inpatients with RA (Bayley 1976). Similarly, there was not significantly different (Drewes 1998). In this trial, despite the weak evidence from two small single dose cross-over studies that improvements in subjective sleep ratings, clinical parameters such there was no additional benefit on pain reduction from adding a as pain, morning stiffness and sleepiness remained unaltered. benzodiazepine to regular NSAID treatment versus NSAID treatment alone (Hobkirk 1977; Sharma 1978) in inpatients with active RA. Three studies evaluated muscle relaxants over one to two Overall completeness and applicability of weeks and found no benefit over placebo (Drewes 1998; Vince evidence 1973; Walsh 1996). Pooling of these trials showed no significant improvement in mean pain levels. There were many limitations of this review. There were no large Reliable conclusions about comparative withdrawals due to ad- trials, limited head-to-head trials and no studies of longer than two verse events and the total adverse event rates could not be drawn weeks duration. There was also a lack of data on many commonly from these short trials. Abuse and addiction were not evaluated used benzodiazepine agents (alprazolam, clonazepam, lorazepam, and no serious adverse events or deaths were reported. Only one oxazepam etc.) as well as no available data on any of the skeletal of the three trials comparing a benzodiazepine with placebo re- muscle relaxants. Physicians are also often concerned about the ported withdrawals due to adverse events and the event rate in this potential problem of addiction and withdrawal associated with

Muscle relaxants for pain management in rheumatoid arthritis (Review) 20 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. these agents, however no study addressed these outcomes so no Reporting of adverse events was also poor. Adverse events were conclusions can be made in regards to this in this patient popula- not consistently reported in these trials and doses of medications tion. and titration methods differed markedly between studies. In the The populations included in this review are not reflective of cur- cross-over studies only one of the five trials included a washout rent day patients with RA. More than half the included trial par- period. This was not likely to have affected the single dose studies ticipants were inpatients who were hospitalised with poorly con- however it may have introduced bias into the Vince 1973 trial. trolled disease. Many were only receiving NSAIDs, or occasion- ally low dose corticosteroids or DMARDs, reflective of practice at the time. The patients selected for inclusion were predominantly Potential biases in the review process women and had various degrees of RA disease severity. It was unclear what other analgesics they were taking at the time of the We believe that all relevant studies were identified. A thorough studies and whether the patients had any co-morbidities. It also search strategy was devised and all major databases were searched remains unclear as to what type of pain these agents were being for relevant studies, with no language restrictions applied. Two used for. The nature and duration of the pain and whether any review authors assessed the trials for inclusion in the review and other analgesics were being used (or were no longer needed) were the risk of bias, with a third review author adjudicating if there not described in any of the studies. No trial reported the primary was any discrepancy. The biggest limitation of the review process efficacy outcome measure of patient reported pain relief of 30% was that many trials did not provide enough published data, or or greater. The mean changes reported were often small and even data in a form that could be extracted for meta-analysis. Although though statistically significant they may not have been clinically several authors were contacted, no further data were obtained. We significant. Functional status, subjective and objective sleep out- did not include the results of unpublished studies. Trials with both comes, depression and quality of life data are known to be im- positive and negative results were identified, making the possibility portant outcomes in this patient population, and any information of publication bias less likely. regarding these outcomes were sparsely reported. Safety and efficacy data are limited to a maximum of one week for the benzodiazepines and two weeks for the only non-benzodi- Agreements and disagreements with other azepine included in this review (zopiclone). Reliable conclusions studies or reviews about withdrawal due to adverse events and total adverse event No systematic review or meta-analysis has assessed the use of mus- rates can not, therefore, be drawn from these short trials. Although cle relaxants in patients with RA or in mixed populations of pa- not identified in our review, chlorzoxazone has been implicated in tients with arthritis that included RA patients. the development of serious (including fatal) hepatocellular toxic- ity. Chlormezanone has also been implicated in causing Stevens- Johnson syndrome and toxic epidermal necrolysis. AUTHORS’ CONCLUSIONS Quality of the evidence Implications for practice All trials were deemed to have a high risk of bias with the major There is currently weak evidence that benzodiazepines (diazepam flaws being that they were too small and of too short duration to and triazolam) do not improve pain as measured by any clinically be able to detect a clinically significant difference. The most com- significant difference over 24 hours or one week in patents with mon methodological flaws included failure to describe randomi- RA. There is also weak evidence that there is no short term benefit sation, allocation concealment, and blinding of study participants of diazepam over indomethacin and no change in pain score with and personnel. In many studies, authors merely stated that the the addition of diazepam to an NSAID over an NSAID alone. trial was randomised, raising concerns about whether or not the Weak evidence exists that diazepam does not improve quality of randomisation procedure was adequate. There was no evaluation life after one week of treatment. There was also no significant short of a carry-over or period effect in any of the cross-over trials, and term benefit over placebo, or in combination with an NSAID over with three trials failing to have a washout period this may have an NSAID alone, in sleep. We are unable to make any conclu- also led to a more conservative estimate of any benefit seen. sions in regard to optimal dosing, whether any muscle relaxant is No study recorded the use of any analgesic co-interventions. Com- superior to another, withdrawals due to inadequate analgesia and pliance gives an indication of the tolerability and acceptability of functional status. the drugs to patients and was also not measured in any of the trials. While not relevant to the controlled inpatient single dose studies, In addition, no reliable conclusions can be made from this data three longer outpatient trials did not address this (Drewes 1998; regarding withdrawals due to adverse events. There was no sig- Vince 1973; Walsh 1996). nificant increase in the total number of adverse events over 24

Muscle relaxants for pain management in rheumatoid arthritis (Review) 21 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. hours, however adverse evenets were significantly increased when should be methodologically sound and involve longer term follow the trials were of one or two weeks duration. The predominant up (six months). Safety data including deaths, withdrawals due to side effects were dizziness and drowsiness with, on average, one adverse events, serious adverse events and total numbers and types adverse event occurring in every three people. The one small non- of adverse events should be evaluated. Compliance data, which benzodiazepine trial that was identified found no benefit of zopi- give an indication of tolerability and acceptability, should also be clone over placebo in outpatients over a two week period. routinely collected. Pain outcomes should be uniformly studied and we recommend that the proportion of patients with reduc- Based on the currently available evidence, we are unable to recom- tions in pain intensity of ≥ 30% and ≥ 50%, which reflect mod- mend the routine use of muscle relaxants for pain management erate and substantial clinically important differences, be reported. in patients with RA. Although conclusions cannot be made about the risk of dependency on the drugs from the trials included in this The routine collection of functional and health-related quality review, there is sufficient indirect evidence from other sources that of life outcomes as well as sleep is also important. Descriptive a substantial risk of dependency can develop when using muscle measures of the type of pain should be included to help readers relaxants. Until better evidence is available regarding their differ- decide if the data are applicable to their particular patients’ pain. ential efficacy and safety, these agents should be used with caution Assessing a variety of muscle relaxants in doses commonly used in particularly in patients who are prone to addiction. current practice is also required to add to the field of knowledge in this area. Implications for research To better assess the efficacy and safety of muscle relaxants in patients with RA, large double-blind placebo controlled and head-to- ACKNOWLEDGEMENTS head RCTs with homogenous RA populations who have pain despite optimal DMARD or bDMARD therapy are required. They Louise Falzon for assistance with the search strategy.

REFERENCES References to studies included in this review References to studies excluded from this review

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Muscle relaxants for pain management in rheumatoid arthritis (Review) 23 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Moore 2002 Smirne 1977 Moore KA, et al.Partial peripheral nerve injury promotes Smirne S, Carlato G. Clonazepam in cranial neuralgias. a selective loss of GABAergic inhibition in the superficial Medical Journal of Australia 1977;1:93–4. dorsal horn of the spinal cord. Journal of Neuroscience 2002; Sterne 2008 22:6724-31. Sterne JAC, Egger M, Moher D (editors). Chapter 10: Moore 2010 Addressing reporting biases. In: Higgins JPT, Green S, Moore RA, Eccleston C, Derry S, Wiffen P,Bell RF, Straube editors. Cochrane Handbook for Systematic Reviews of S, et al.“Evidence” in chronic pain- establishing best practice Intervention. Version 5.0.1 (updated September 2008). in the reporting of systematic reviews. Pain 2010;150(3): The Cochrane Collaboration, 2008. Available from 386–9. www.cochrane-handbook.org. Morin 1998 Tak 2000 Morin CM, Gibson D, Wade J. Self-reported sleep and Tak PP, Bresnihan B. The pathogenesis and prevention of mood disturbance in chronic pain patients. Clinical Journal joint damage in rheumatoid arthritis:advances from synovial of Pain 1998;14:311-4. biopsy and tissue analysis. Arthritis & Rheumatism 2000;43: 2619-33. Nicassio 1992 Tobin 1960 Nicassio PM, Wallston KA. Longitudinal relationships Tobin JM, Lewis NDC. New psychotherapeutic agent: among pain, sleep problems, and depression in rheumatoid chlordiazepoxide. JAMA 1960;174:1242–9. arthritis. Journal of Abnormal Psychology 1992;101:514-20. Waldman 1994 Pincus 1983 Waldman HJ. Centrally acting skeletal muscle relaxants Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon and associated drugs. Journal of Pain Symptom Management NP. Assessment of patient satisfaction in activities of 1994;9:434-41. daily living using a modified Stanford Health Assessment Waterfield 1999 Questionnaire. Arthritis and Rheumatism 1983;26(11): Waterfield JD, McGeer EG, McGeer PL. The peripheral 1346–53. benzodiazepine receptor ligand PK 11195 inhibits arthritis Randall 1961 in the MRL-lpr mouse model. Rheumatology 1999;38: Randall LO, Heise GA, Schallek W, et al.Pharmacologic and 1068–73. clinical studies on Valium, a new psychotherapeutic agent Weber 1973 of the benzodiazepine class. Current Therapeutic Research Weber MB. The treatment of muscle contraction headaches 1961;3:405–25. with diazepam. Current Therapeutic Research 1973;15: 210–6. Schünemann 2008a Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Wolfe 2006 Glasziou P, Guyatt GH. Chapter 11: Presenting results and Wolfe F, Michaud K, Li T. Sleep disturbance in patients ‘Summary of findings’ tables. In: Higgins JPT, Green S, with rheumatoid arthritis: evaluation by medical outcomes editors, Cochrane Handbook for Systematic Reviews of study and visual analog sleep scales. Journal of Rheumatology Interventions Version 5.0.1 (updated September 2008). 2006;33:1942-51. The Cochrane Collaboration, 2008. Available from Wolff 1974 www.cochrane-handbook.org. Wolff B. Evaluation of hypnotics in outpatients with insomnia using a questionnaireand self-rating technique. Smedstad 1996 Clinical Pharmacology and Therapeutics 1974;15:130–40. Smedstad LM, Moum T, Vaglum P, et al.The impact Zavala 1990 of early rheumatoid arthritis on psychological distress. Zavala F, Taupin V, Descamps-Latscha B. In vivo Scandanavian Journal of Rheumatology 1996;25:377–82. treatment with benzodiazepines inhibits murine phagocyte Smedstad 1997 oxidative metabolism and production of interleukin-1, Smedstad LM, Vaglum P, Kvien TK. The relationship tumour necrosis factor and interleukin-6. The Journal of between self-reported pain and sociodemographic variables, Pharmacology and Experimental Therapeutics 1990;255: anxiety, and depressive symptoms in rheumatoid arthritis. 442–50. Journal of Rheumatology 1997;22:514–20. ∗ Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

Bayley 1976

Methods 3 period, single dose double-blind randomised cross-over trial over three consecutive nights

Participants 18 inpatients with rheumatoid arthritis 3 male, 15 female Age 18-75 years with active joint disease Disease 3 months-25 years Inclusion: “classical or deﬁnite rheumatoid arthritis”. “All the patients had been in hospital in order to control active joint disease” Exclusion: any patient taking corticosteroids or more than indomethacin 75 mg/day, known hypersensitivity to study drugs Sample size calculation: not reported

Interventions Indomethacin 100 mg versus diazepam 10 mg versus placebo

Outcomes Primary 1) Sleep (Wolff sleep questionnaire) 2) Night pain (VAS 0-10cm on waking) 3) EMS (minutes) 4) Adverse events Secondary 1) Patient preference

Notes No washout period Conclusion. Outcome: there was no statistically signiﬁcant difference in the preference of patients or sleep score among the three forms of treatment. Both indomethacin and diazepam were more effective than placebo in relieving night pain (P<0.05)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No detailed information provided bias)

Allocation concealment (selection bias) Unclear risk No detailed information provided

Blinding (performance bias and detection Low risk Quote: “double blind nature of the exper- bias) iment was ensured by using appropriate Participants dummies and individual packaged doses” Comment: patients likely to have remained blinded

Blinding (performance bias and detection Low risk No detailed information provided bias) Comment: personnel likely to have re- Personnel mained blinded

Incomplete outcome data (attrition bias) Low risk All patients completed the short trial All outcomes

Selective reporting (reporting bias) Low risk All prespeciﬁed outcomes were reported

Compliance? Low risk Quote: “the trial medication was given in place of any other prescribed analgesic or hypnotic on the night medicine round” Comment: not measured but likely to have been taken

Co-interventions? Unclear risk No speciﬁc information provided Comment: patients hospitalised and given medications so unlikely to have received ex- tra analgesics

Baseline Characteristics/Cross over assess- Unclear risk Quote: “the treatment order being ran- ment? domised” Comment: cross-over trial. No speciﬁc information provided about the presence of a period effect but no wash out. Agents all short acting so carry-over effect unlikely

Intention to treat analysis? Low risk Cross-over trial, no dropouts

Drop Outs? Low risk “all 18 completed the full trial protocol”

Summary Assessment? High risk High risk of bias Study underpowered to detect a signiﬁcant effect

Drewes 1998

Methods 2 week randomised double-blind controlled trial

Participants 41 outpatients with rheumatoid arthritis 11 male, 30 female Mean age 51 years Inclusion: not specified Exclusion: “No subject had any features of fibromyalgia or other medical diseases thought to influence sleep structure” Sample size calculation: not reported

Interventions Zopiclone 7.5 mg versus placebo

Outcomes Outcomes measured at baseline, weeks 1 and 2 Primary 1) Sleep structure - polysomnographic (PSG) studies, daytime sleepiness (VAS 0-100 mm), Spiegel Sleep Questionnaire, Leeds Sleep Evaluation Questionnaire Secondary 1) Clinical outcomes of RA - tender and swollen joint count, HAQ, Richie Articular Index, EMS (mins), Fatigue (ranging from 1 (worst possible) to 7 (best possible)) 2) Pain (Danish version McGill Pain Questionnaire 0-78 (from this Present Pain Intensity and total pain rating index calculated) 3) Adverse events

Notes Conclusion: treatment with zopiclone improves subjective assessments of sleep in RA, but had no effect on pain or other clinical variables

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Pts were randomised” bias) Comment: information not speciﬁed

Allocation concealment (selection bias) Unclear risk Information not speciﬁed

Blinding (performance bias and detection Low risk Quote: “similar placebo tablet” given bias) Comment: information not speciﬁed but Participants likely to have remained blind

Blinding (performance bias and detection Unclear risk Information not speciﬁed bias) Personnel

Incomplete outcome data (attrition bias) Low risk Only 1 drop out at time of ﬁrst sleep study. All outcomes Patient was excluded from the analysis

Selective reporting (reporting bias) Low risk All prespeciﬁed outcomes were reported

Compliance? Unclear risk Information not speciﬁed

Co-interventions? Unclear risk Quote: “Patients were allowed to take their regular drugs during the study, but they were not permitted any changes in the medication” Comment: information not speciﬁed

Baseline Characteristics/Cross over assess- Low risk Baseline characteristics were similar ment?

Intention to treat analysis? High risk Completers only analysis was performed

Drop Outs? Low risk 1/41 patients dropped out due to technical difﬁculties with sleep study

Summary Assessment? High risk High risk of bias Study underpowered and designed to assess sleep structure

Hobkirk 1977

Methods 3 period, single dose randomised, double-blind cross-over

Participants 18 patients with active rheumatoid arthritis 4 male, 14 female Age 43-77 years Disease duration 4 mo to 22 years Inclusion: patients hospitalised for treatment of rheumatoid arthritis Exclusion: corticosteroid use, >75 mg indomethacin daily, allergy to study drugs Sample size calculation: not reported

Interventions Diazepam 10mg + indomethacin 100mg versus indomethacin 100 mg versus placebo

Outcomes Primary 1) Sleep (Wolff sleep questionnaire) 2) Night pain (VAS 0-10cm on waking) 3) EMS (mins) 4) Adverse events Secondary Patient preference

Notes No washout period Conclusion: indomethacin plus diazepam was superior to placebo but not indomethacin alone. Patient preference was for the combination treatment

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Information not speciﬁed bias)

Allocation concealment (selection bias) Unclear risk Information not speciﬁed

Blinding (performance bias and detection Low risk quote: “double blind nature of the exper- bias) iment was ensured by using appropriate Participants dummies and individual packaged doses” Comment: patients likely to have remained blinded

Blinding (performance bias and detection Low risk Information not speciﬁed bias) Comment: personnel likely to have re- Personnel mained blinded

Incomplete outcome data (attrition bias) Low risk 1 patient excluded from the analysis who All outcomes suffered adverse event

Selective reporting (reporting bias) Low risk All prespeciﬁed outcomes were reported

Compliance? Low risk Quote: “The trial drugs replaced any analgesic or hypnotic given at the 10 p.m. medicine round” Comment: likely to have been taken

Co-interventions? Low risk Information not speciﬁed Comment: patients hospitalised and given medications so unlikely to have received ex- tra analgesics

Baseline Characteristics/Cross over assess- Unclear risk quote: “the treatment order being ran- ment? domised” Comment: cross-over trial. No speciﬁc information provided about the presence of a period effect

Intention to treat analysis? High risk Completers only analysis was performed

Drop Outs? Low risk 1/18 dropped out due to an adverse event

Summary Assessment? High risk High risk of bias Underpowered study

Sharma 1978

Methods 3 period, single dose randomised double-blind cross-over trial

Participants 18 inpatients with rheumatoid arthritis with active disease 2 male, 16 female Age 24-68 years Inclusion: patients hospitalised for treatment of rheumatoid arthritis Exclusion: corticosteroid use, >75 mg indomethacin daily, allergy to study drugs Sample size calculation: not reported

Interventions Indomethacin 100mg + diazepam 10mg versus sulindac 200mg versus sulindac 200mg + 10mg diazepam

Outcomes Primary 1) Sleep (Wolff sleep questionnaire) 2) Night pain (VAS 0-10cm on waking) 3) EMS (mins) 4) Adverse events Secondary Patient preference

Notes No washout period Conclusion: there was no signiﬁcant difference in pain or sleep between the different groups

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Information not speciﬁed bias)

Allocation concealment (selection bias) Unclear risk Information not speciﬁed

Blinding (performance bias and detection Low risk Information not speciﬁed bias) Comment: personnel likely to have re- Personnel mained blinded

Incomplete outcome data (attrition bias) Low risk 1 patient dropped out after two nights and All outcomes was excluded from the analysis

Selective reporting (reporting bias) Low risk All prespeciﬁed outcomes reported

Compliance? Low risk Quote: “The trial medication replaced any analgesic or hypnotic given at the 22.00 hours” Comment: medication likely to have been taken

Co-interventions? Low risk Information not speciﬁed Comment: patients hospitalised and given medications so unlikely to have received ex- tra analgesics

Baseline Characteristics/Cross over assess- Unclear risk Quote: “the treatment order being ran- ment? domised” Comment: Cross-over trial. No speciﬁc information provided about the presence of a period effect

Intention to treat analysis? High risk Completers only analysis was performed

Drop Outs? High risk Quote: 1/18 dropped out after 2 nights with a “plethora of minor symptoms” Comment: it is likely they did not suf- fer withdrawal due to an adverse event, although it was not clear which treatments they had received

Summary Assessment? High risk High risk of bias Underpowered

Vince 1973

Methods 2 period, 1 week double-blind cross-over trial

Participants 17 outpatients with rheumatoid arthritis 1 male, 16 females Mean age 47yr (31-73yrs) Mean duration 5.8yrs (2-20yrs) 15/17 Steinbroker III, 5/24 receiving <10mg oral corticosteroids, all receiving NSAIDs Inclusion: nil speciﬁed Exclusion: nil speciﬁed Sample size calculation: not reported

Interventions Diazepam 15 mg daily versus placebo

Outcomes Baseline, weeks 1 and 2 Primary 1) Pain (none = 0, slight =1, moderate = 2, and severe = 3) 2) EMS (mins), Ritchie articular index, grip strength, function, 3) Adverse events. 4) Patient’s and doctor’s global assessment (much better = 2, better = I, no change = 0, worse = - I and much worse = -2)

Notes No washout period Conclusion: no signiﬁcant dIfferences were noted in the patients’ pain, joint tenderness or grip strength. Morning stIffness was signiﬁcantly reduced during placebo therapy

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Treatment with diazepam and bias) placebo was allocated randomly.” Information not speciﬁed

Allocation concealment (selection bias) Unclear risk Information not speciﬁed

Blinding (performance bias and detection Unclear risk Authors refer to “placebo”, no details pro- bias) vided Participants Comment: it is likely patients were blinded

Blinding (performance bias and detection Unclear risk Information not speciﬁed bias) Personnel

Incomplete outcome data (attrition bias) High risk 7 patients dropped out and it was not spec- All outcomes iﬁed how they were dealt with

Selective reporting (reporting bias) Low risk All prespeciﬁed outcomes were reported

Compliance? Unclear risk Information not speciﬁed

Co-interventions? Unclear risk Information not speciﬁed

Baseline Characteristics/Cross over assess- High risk Cross-over trial. No washout and no infor- ment? mation provided about the presence of a period effect

Intention to treat analysis? Unclear risk Information not speciﬁed

Drop Outs? High risk 7/24 (29.2%) patients dropped out without clear reasons speciﬁed

Summary Assessment? High risk High risk of bias

Walsh 1996

Methods 2 period, 1 week double-blind cross-over study 1-3 week washout period

Participants 15 outpatients with rheumatoid arthritis 1 male, 14 female Mean age 53.5yrs Mean disease duration 12.1yrs, duration sleep complaint 6.5yrs, EMS 76.1min 10/15 patients receiving prednisone Inclusion: subjective complaint of daytime fatigue and sleepiness and difﬁcult with sleep

onset (>60mins) or sleep maintenance (<6hrs or ≥3 awakenings at least 3 days per week Exclusion: sleep apnoea, taking other CNS sedating medications, signiﬁcant psy- chopathology, uncontrolled medical disorders Sample size calculation: not reported

Interventions Triazolam 0.25mg ﬁrst two nights (age 30-59) or 0.125mg (age 60-70). Dose doubled after 2nd night if poor clinical response

Outcomes Assessments were made at baseline and daily for seven days Primary 1) Daytime somnolescence (VAS 100mm) 2) Insomnia (polysomnography, subjective sleep assessments (time to fall asleep (min), sleep duration (min), number of awakenings, morning sleepiness VAS 100mm) Secondary 1) Pain (0-4 scale), daytime arthritis symptom severity (VAS 100mm) 2) EMS (VAS 100mm) on waking and at 30, 60,90,180mins 3) Arthritis impact measurement scale (AIMS) 6.5-8.5hrs post waking 4) Arthritis disturbed sleep (VAS 100mm) 5) Tender joint count (TJC), swollen joint count (SJC), grip strength 6) Mood - Proﬁle of Mood states (POMS), AIMS

Notes Patients were paid for their involvement Conclusions: short term treatment with triazolam increased sleep duration and decreased EMS. There was no signiﬁcant difference in mood, pain or other measures of RA clinical symptoms

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Information not speciﬁed bias)

Allocation concealment (selection bias) Unclear risk Information not speciﬁed

Blinding (performance bias and detection Low risk quote: “double blind”, “placebo” bias) Comment: no detailed information pro- Participants vided, participants likely to have remained blind

Blinding (performance bias and detection Unclear risk Information not speciﬁed bias) Personnel

Incomplete outcome data (attrition bias) Low risk 1 patient withdrew in the ﬁrst week “for All outcomes personal reasons unrelated to study procedures or drug” Comment: it is unlikely this patient suffered an event that was related to the study

Selective reporting (reporting bias) Low risk All prespeciﬁed outcomes were reported

Compliance? Unclear risk Information not speciﬁed

Co-interventions? Unclear risk Information not speciﬁed

Baseline Characteristics/Cross over assess- Low risk Cross-over study with 1-3 week washout ment? period. No evidence of period effect and carry-over unlikely

Intention to treat analysis? High risk Cross-over study with one patient excluded from the analysis after dropping out in ﬁrst week

Drop Outs? Low risk 1 patient dropped out in the ﬁrst week, it is unclear from which group

Summary Assessment? High risk High risk of bias, underpowered

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Durrigl 1969 Mixed population, unable to extract data

Hardo 1991 Mixed population, unable to extract data

Tarpley 1965 Mixed population, unable to extract data

Comparison 1. Muscle relaxant versus control

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pain 24hrs 3 104 Mean Difference (IV, Random, 95% CI) -0.22 [-1.02, 0.58] 2 Pain 1-2 weeks 3 104 Std. Mean Difference (IV, Random, 95% CI) -0.20 [-0.59, 0.18]

Comparison 2. Benzodiazepine versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pain 24hrs 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 1.1 24hrs (Single dose) 1 36 Mean Difference (IV, Fixed, 95% CI) -0.90 [-1.77, -0.03] 2 Pain 1 week 2 64 Std. Mean Difference (IV, Random, 95% CI) -0.19 [-0.68, 0.30] 3 Sleep (MSLT) 1 30 Mean Difference (IV, Fixed, 95% CI) 3.10 [1.20, 5.00] 4 Sleep (Polysomnography) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.1 Sleep Latency 1 30 Mean Difference (IV, Fixed, 95% CI) -8.40 [-33.05, 16.25] 4.2 Total Sleep Time (mins) 1 30 Mean Difference (IV, Fixed, 95% CI) 19.10 [5.34, 32.86] 4.3 Number of awakenings 1 30 Mean Difference (IV, Fixed, 95% CI) 7.20 [0.90, 13.50] (>15sec) 5 Sleep (Patient reported outcome 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only measures) 5.1 Sleep Latency (mins) 1 30 Mean Difference (IV, Fixed, 95% CI) -11.7 [-22.89, -0.51] 5.2 Duration Sleep (mins) 1 30 Mean Difference (IV, Fixed, 95% CI) 37.40 [10.85, 63.95] 5.3 Number of awakenings 1 30 Mean Difference (IV, Fixed, 95% CI) -1.20 [-2.05, -0.35] 6 Depression 1 30 Std. Mean Difference (IV, Random, 95% CI) 0.17 [-0.55, 0.88]

Comparison 3. Benzodiazepine + NSAID versus NSAID - pain

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pain 24hrs 2 68 Std. Mean Difference (IV, Random, 95% CI) -0.14 [-1.65, 1.36] 2 Sleep (Wolff Sleep Score) 2 68 Std. Mean Difference (IV, Random, 95% CI) 0.37 [-0.11, 0.85]

Muscle relaxants for pain management in rheumatoid arthritis (Review) 35 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Comparison 4. Non-benzodiazepine versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pain 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only 1.1 Present Pain Intensity (2 1 40 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.77, 0.37] weeks) 1.2 Total Pain Rating Index (2 1 40 Mean Difference (IV, Fixed, 95% CI) -6.60 [-16.25, 3.05] weeks) 2 Functional Status 1 40 Std. Mean Difference (IV, Random, 95% CI) 0.08 [-0.54, 0.70] 3 Sleep (Polysomnography) 1 80 Mean Difference (IV, Fixed, 95% CI) -0.42 [-1.73, 0.89] 3.1 Total sleep 1 40 Mean Difference (IV, Fixed, 95% CI) -16.0 [-53.73, 21.73] 3.2 Number of awakenings 1 40 Mean Difference (IV, Fixed, 95% CI) -0.40 [-1.71, 0.91] (>2min) 4 Sleep (Patient reported 1 160 Mean Difference (IV, Fixed, 95% CI) -0.11 [-0.38, 0.17] outcomes) Spiegel Sleep Questionnaire 4.1 Sleep Latency (0-5) 1 40 Mean Difference (IV, Fixed, 95% CI) -0.70 [-1.27, -0.13] 4.2 Duration Sleep (0-5) 1 40 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.69, 0.29] 4.3 Frequency of awakenings 1 40 Mean Difference (IV, Fixed, 95% CI) -0.60 [-1.13, -0.07] 4.4 Patient Global Sleep 1 40 Mean Difference (IV, Fixed, 95% CI) 1.70 [1.03, 2.37] 5 Sleep (Patient reported 1 120 Mean Difference (IV, Fixed, 95% CI) -7.53 [-12.20, -2.86] outcomes) Leeds Sleep Evaluation 5.1 Sleep Latency 1 40 Mean Difference (IV, Fixed, 95% CI) -12.0 [-19.27, -4.73] 5.2 Frequency awakenings 1 40 Mean Difference (IV, Fixed, 95% CI) 0.90 [-7.88, 9.68] 5.3 Patient Global Sleep 1 40 Mean Difference (IV, Fixed, 95% CI) -9.30 [-17.76, -0.84]

Comparison 5. Muscle relaxant versus control - safety

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Withdrawal due to adverse 5 180 Risk Ratio (M-H, Random, 95% CI) 2.84 [0.31, 26.08] events 2 Total Adverse Events 5 180 Risk Ratio (M-H, Random, 95% CI) 1.40 [0.58, 3.41] 3 Total Adverse events - trials 2 74 Risk Ratio (M-H, Random, 95% CI) 4.03 [1.08, 15.10] greater than 24hrs duration 4 Total adverse events - trials 24hr 3 106 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.41, 1.48] duration only 5 Subgroups Adverse Events 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only 5.1 Benzodiazepine vs Placebo 3 106 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.40, 1.48] 24hrs 5.2 Benzodiazepine vs Placebo 1 34 Risk Ratio (M-H, Random, 95% CI) 3.00 [1.21, 7.45] 1-2 weeks

Muscle relaxants for pain management in rheumatoid arthritis (Review) 36 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5.3 Benzodiazepine + NSAID 2 68 Risk Ratio (M-H, Random, 95% CI) 0.77 [0.27, 2.21] vs NSAID 5.4 Non Benzodiazepine vs 1 40 Risk Ratio (M-H, Random, 95% CI) 14.04 [0.87, 227.89] Placebo 5.5 CNS effects 2 74 Risk Ratio (M-H, Random, 95% CI) 5.96 [1.77, 20.08] 5.6 Gastrointestinal events 5 180 Risk Ratio (M-H, Random, 95% CI) 0.25 [0.03, 2.20]

Analysis 1.1. Comparison 1 Muscle relaxant versus control, Outcome 1 Pain 24hrs.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 1 Muscle relaxant versus control

Outcome: 1 Pain 24hrs

Mean Mean Studyorsubgroup Musclerelaxant Control Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Bayley 1976 18 1.85 (1.33) 18 2.75 (1.33) 28.4 % -0.90 [ -1.77, -0.03 ]

Hobkirk 1977 17 0.83 (0.48) 17 1.28 (0.48) 40.0 % -0.45 [ -0.77, -0.13 ]

Sharma 1978 17 4.76 (1.08) 17 4.07 (1.08) 31.6 % 0.69 [ -0.04, 1.42 ] Total (95% CI) 52 52 100.0 % -0.22 [ -1.02, 0.58 ] Heterogeneity: Tau2 = 0.39; Chi2 = 9.77, df = 2 (P = 0.01); I2 =80% Test for overall effect: Z = 0.53 (P = 0.59) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours muscle relaxant Favours control

Muscle relaxants for pain management in rheumatoid arthritis (Review) 37 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.2. Comparison 1 Muscle relaxant versus control, Outcome 2 Pain 1-2 weeks.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 1 Muscle relaxant versus control

Outcome: 2 Pain 1-2 weeks

Std. Std. Mean Mean Studyorsubgroup Musclerelaxant Control Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Drewes 1998 22 1.9 (0.8) 18 2.1 (1) 38.2 % -0.22 [ -0.84, 0.41 ]

Vince 1973 17 1.88 (0.78) 17 1.94 (0.75) 33.0 % -0.08 [ -0.75, 0.60 ]

Walsh 1996 15 5.2 (1.6) 15 5.6 (0.54) 28.7 % -0.33 [ -1.05, 0.40 ] Total (95% CI) 54 50 100.0 % -0.20 [ -0.59, 0.18 ] Heterogeneity: Tau2 = 0.0; Chi2 = 0.25, df = 2 (P = 0.88); I2 =0.0% Test for overall effect: Z = 1.03 (P = 0.30) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours muscle relaxant Favours control

Analysis 2.1. Comparison 2 Benzodiazepine versus placebo, Outcome 1 Pain 24hrs.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 2 Benzodiazepine versus placebo

Outcome: 1 Pain 24hrs

Mean Mean Studyorsubgroup Benzodiazepine Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 24hrs (Single dose) Bayley 1976 18 1.85 (1.33) 18 2.75 (1.33) 100.0 % -0.90 [ -1.77, -0.03 ] Subtotal (95% CI) 18 18 100.0 % -0.90 [ -1.77, -0.03 ] Heterogeneity: not applicable Test for overall effect: Z = 2.03 (P = 0.042)

-100 -50 0 50 100 Favours Benzodiazepine Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 38 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.2. Comparison 2 Benzodiazepine versus placebo, Outcome 2 Pain 1 week.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 2 Benzodiazepine versus placebo

Outcome: 2 Pain 1 week

Std. Std. Mean Mean Studyorsubgroup Benzodiazepine Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Vince 1973 17 1.88 (0.78) 17 1.94 (0.75) 53.5 % -0.08 [ -0.75, 0.60 ]

Walsh 1996 15 5.2 (1.6) 15 5.6 (0.54) 46.5 % -0.33 [ -1.05, 0.40 ] Total (95% CI) 32 32 100.0 % -0.19 [ -0.68, 0.30 ] Heterogeneity: Tau2 = 0.0; Chi2 = 0.25, df = 1 (P = 0.62); I2 =0.0% Test for overall effect: Z = 0.77 (P = 0.44) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours Benzodiazepine Favours control

Analysis 2.3. Comparison 2 Benzodiazepine versus placebo, Outcome 3 Sleep (MSLT).

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 2 Benzodiazepine versus placebo

Outcome: 3 Sleep (MSLT)

Mean Mean Studyorsubgroup Benzodiazepine Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Walsh 1996 15 11 (2.66) 15 7.9 (2.66) 100.0 % 3.10 [ 1.20, 5.00 ] Total (95% CI) 15 15 100.0 % 3.10 [ 1.20, 5.00 ] Heterogeneity: not applicable Test for overall effect: Z = 3.19 (P = 0.0014) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours Triazolam Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 39 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.4. Comparison 2 Benzodiazepine versus placebo, Outcome 4 Sleep (Polysomnography).

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 2 Benzodiazepine versus placebo

Outcome: 4 Sleep (Polysomnography)

Mean Mean Studyorsubgroup Benzodiazepine Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Sleep Latency Walsh 1996 15 24 (16.3) 15 32.4 (45.9) 100.0 % -8.40 [ -33.05, 16.25 ] Subtotal (95% CI) 15 15 100.0 % -8.40 [ -33.05, 16.25 ] Heterogeneity: not applicable Test for overall effect: Z = 0.67 (P = 0.50) 2 Total Sleep Time (mins) Walsh 1996 15 408.2 (19.23) 15 389.1 (19.23) 100.0 % 19.10 [ 5.34, 32.86 ] Subtotal (95% CI) 15 15 100.0 % 19.10 [ 5.34, 32.86 ] Heterogeneity: not applicable Test for overall effect: Z = 2.72 (P = 0.0065) 3 Number of awakenings (>15sec) Walsh 1996 15 28.9 (8.7) 15 21.7 (8.9) 100.0 % 7.20 [ 0.90, 13.50 ] Subtotal (95% CI) 15 15 100.0 % 7.20 [ 0.90, 13.50 ] Heterogeneity: not applicable Test for overall effect: Z = 2.24 (P = 0.025)

-100 -50 0 50 100 Favours experimental Favours control

Muscle relaxants for pain management in rheumatoid arthritis (Review) 40 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.5. Comparison 2 Benzodiazepine versus placebo, Outcome 5 Sleep (Patient reported outcome measures).

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 2 Benzodiazepine versus placebo

Outcome: 5 Sleep (Patient reported outcome measures)

Mean Mean Studyorsubgroup Benzodiazepine Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Sleep Latency (mins) Walsh 1996 15 20.8 (15.64) 15 32.5 (15.64) 100.0 % -11.70 [ -22.89, -0.51 ] Subtotal (95% CI) 15 15 100.0 % -11.70 [ -22.89, -0.51 ] Heterogeneity: not applicable Test for overall effect: Z = 2.05 (P = 0.040) 2 Duration Sleep (mins) Walsh 1996 15 434.4 (37.1) 15 397 (37.1) 100.0 % 37.40 [ 10.85, 63.95 ] Subtotal (95% CI) 15 15 100.0 % 37.40 [ 10.85, 63.95 ] Heterogeneity: not applicable Test for overall effect: Z = 2.76 (P = 0.0058) 3 Number of awakenings Walsh 1996 15 2.1 (1.19) 15 3.3 (1.19) 100.0 % -1.20 [ -2.05, -0.35 ] Subtotal (95% CI) 15 15 100.0 % -1.20 [ -2.05, -0.35 ] Heterogeneity: not applicable Test for overall effect: Z = 2.76 (P = 0.0058)

-100 -50 0 50 100 Favours Triazolam Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 41 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.6. Comparison 2 Benzodiazepine versus placebo, Outcome 6 Depression.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 2 Benzodiazepine versus placebo

Outcome: 6 Depression

Std. Std. Mean Mean Studyorsubgroup Benzodiazepine Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Walsh 1996 15 5.9 (7.4) 15 4.7 (6.7) 100.0 % 0.17 [ -0.55, 0.88 ] Total (95% CI) 15 15 100.0 % 0.17 [ -0.55, 0.88 ] Heterogeneity: not applicable Test for overall effect: Z = 0.45 (P = 0.65) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours experimental Favours control

Analysis 3.1. Comparison 3 Benzodiazepine + NSAID versus NSAID - pain, Outcome 1 Pain 24hrs.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 3 Benzodiazepine + NSAID versus NSAID - pain

Outcome: 1 Pain 24hrs

Std. Std. Mean Mean Studyorsubgroup Experimental Control Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Hobkirk 1977 17 0.83 (0.48) 17 1.28 (0.48) 49.8 % -0.92 [ -1.63, -0.20 ]

Sharma 1978 17 4.76 (1.08) 17 4.07 (1.08) 50.2 % 0.62 [ -0.07, 1.31 ] Total (95% CI) 34 34 100.0 % -0.14 [ -1.65, 1.36 ] Heterogeneity: Tau2 = 1.06; Chi2 = 9.26, df = 1 (P = 0.002); I2 =89% Test for overall effect: Z = 0.19 (P = 0.85) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours experimental Favours control

Muscle relaxants for pain management in rheumatoid arthritis (Review) 42 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.2. Comparison 3 Benzodiazepine + NSAID versus NSAID - pain, Outcome 2 Sleep (Wolff Sleep Score).

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 3 Benzodiazepine + NSAID versus NSAID - pain

Outcome: 2 Sleep (Wolff Sleep Score)

Std. Std. Benzodiazepine Mean Mean Study or subgroup + NSAID NSAID Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Hobkirk 1977 17 1.8 (5.68) 17 -1.5 (5.68) 49.0 % 0.57 [ -0.12, 1.25 ]

Sharma 1978 17 1.8 (5.68) 17 0.71 (5.68) 51.0 % 0.19 [ -0.49, 0.86 ] Total (95% CI) 34 34 100.0 % 0.37 [ -0.11, 0.85 ] Heterogeneity: Tau2 = 0.0; Chi2 = 0.60, df = 1 (P = 0.44); I2 =0.0% Test for overall effect: Z = 1.52 (P = 0.13) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours experimental Favours control

Analysis 4.1. Comparison 4 Non-benzodiazepine versus placebo, Outcome 1 Pain.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 4 Non-benzodiazepine versus placebo

Outcome: 1 Pain

Mean Mean Studyorsubgroup Zopiclone Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Present Pain Intensity (2 weeks) Drewes 1998 22 1.9 (0.8) 18 2.1 (1) 100.0 % -0.20 [ -0.77, 0.37 ] Subtotal (95% CI) 22 18 100.0 % -0.20 [ -0.77, 0.37 ] Heterogeneity: not applicable Test for overall effect: Z = 0.69 (P = 0.49) 2 Total Pain Rating Index (2 weeks) Drewes 1998 22 13.8 (14.3) 18 20.4 (16.4) 100.0 % -6.60 [ -16.25, 3.05 ] Subtotal (95% CI) 22 18 100.0 % -6.60 [ -16.25, 3.05 ] Heterogeneity: not applicable Test for overall effect: Z = 1.34 (P = 0.18) Test for subgroup differences: Chi2 = 1.68, df = 1 (P = 0.19), I2 =41%

-100 -50 0 50 100 Favours Zopiclone Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 43 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.2. Comparison 4 Non-benzodiazepine versus placebo, Outcome 2 Functional Status.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 4 Non-benzodiazepine versus placebo

Outcome: 2 Functional Status

Std. Std. Mean Mean Studyorsubgroup Zopiclone Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Drewes 1998 22 6.3 (4.5) 18 5.9 (5.2) 100.0 % 0.08 [ -0.54, 0.70 ] Total (95% CI) 22 18 100.0 % 0.08 [ -0.54, 0.70 ] Heterogeneity: not applicable Test for overall effect: Z = 0.26 (P = 0.80) Test for subgroup differences: Not applicable

-100 -50 0 50 100 Favours Zopiclone Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 44 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.3. Comparison 4 Non-benzodiazepine versus placebo, Outcome 3 Sleep (Polysomnography).

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 4 Non-benzodiazepine versus placebo

Outcome: 3 Sleep (Polysomnography)

Mean Mean Studyorsubgroup Zopiclone Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Total sleep Drewes 1998 22 419.2 (60.3) 18 435.2 (60.8) 0.1 % -16.00 [ -53.73, 21.73 ] Subtotal (95% CI) 22 18 0.1 % -16.00 [ -53.73, 21.73 ] Heterogeneity: not applicable Test for overall effect: Z = 0.83 (P = 0.41) 2 Number of awakenings (>2min) Drewes 1998 22 2.3 (2.1) 18 2.7 (2.1) 99.9 % -0.40 [ -1.71, 0.91 ] Subtotal (95% CI) 22 18 99.9 % -0.40 [ -1.71, 0.91 ] Heterogeneity: not applicable Test for overall effect: Z = 0.60 (P = 0.55) Total (95% CI) 44 36 100.0 % -0.42 [ -1.73, 0.89 ] Heterogeneity: Chi2 = 0.66, df = 1 (P = 0.42); I2 =0.0% Test for overall effect: Z = 0.63 (P = 0.53) Test for subgroup differences: Chi2 = 0.66, df = 1 (P = 0.42), I2 =0.0%

-100 -50 0 50 100 Favours Zopiclone Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 45 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.4. Comparison 4 Non-benzodiazepine versus placebo, Outcome 4 Sleep (Patient reported outcomes) Spiegel Sleep Questionnaire.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 4 Non-benzodiazepine versus placebo

Outcome: 4 Sleep (Patient reported outcomes) Spiegel Sleep Questionnaire

Mean Mean Studyorsubgroup Zopiclone Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Sleep Latency (0-5) Drewes 1998 22 3.1 (0.6) 18 3.8 (1.1) 23.6 % -0.70 [ -1.27, -0.13 ] Subtotal (95% CI) 22 18 23.6 % -0.70 [ -1.27, -0.13 ] Heterogeneity: not applicable Test for overall effect: Z = 2.42 (P = 0.015) 2 Duration Sleep (0-5) Drewes 1998 22 3.1 (0.6) 18 3.3 (0.9) 32.1 % -0.20 [ -0.69, 0.29 ] Subtotal (95% CI) 22 18 32.1 % -0.20 [ -0.69, 0.29 ] Heterogeneity: not applicable Test for overall effect: Z = 0.81 (P = 0.42) 3 Frequency of awakenings Drewes 1998 22 2.7 (0.6) 18 3.3 (1) 27.4 % -0.60 [ -1.13, -0.07 ] Subtotal (95% CI) 22 18 27.4 % -0.60 [ -1.13, -0.07 ] Heterogeneity: not applicable Test for overall effect: Z = 2.24 (P = 0.025) 4 Patient Global Sleep Drewes 1998 22 3.8 (0.9) 18 2.1 (1.2) 16.9 % 1.70 [ 1.03, 2.37 ] Subtotal (95% CI) 22 18 16.9 % 1.70 [ 1.03, 2.37 ] Heterogeneity: not applicable Test for overall effect: Z = 4.97 (P < 0.00001) Total (95% CI) 88 72 100.0 % -0.11 [ -0.38, 0.17 ] Heterogeneity: Chi2 = 35.68, df = 3 (P<0.00001); I2 =92% Test for overall effect: Z = 0.76 (P = 0.45) Test for subgroup differences: Chi2 = 35.68, df = 3 (P = 0.00), I2 =92%

-100 -50 0 50 100 Favours Zopiclone Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 46 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.5. Comparison 4 Non-benzodiazepine versus placebo, Outcome 5 Sleep (Patient reported outcomes) Leeds Sleep Evaluation.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 4 Non-benzodiazepine versus placebo

Outcome: 5 Sleep (Patient reported outcomes) Leeds Sleep Evaluation

Mean Mean Studyorsubgroup Zopiclone Placebo Difference Weight Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Sleep Latency Drewes 1998 22 37.8 (15.8) 18 49.8 (6.6) 41.2 % -12.00 [ -19.27, -4.73 ] Subtotal (95% CI) 22 18 41.2 % -12.00 [ -19.27, -4.73 ] Heterogeneity: not applicable Test for overall effect: Z = 3.23 (P = 0.0012) 2 Frequency awakenings Drewes 1998 22 49.6 (16.9) 18 48.7 (11.3) 28.3 % 0.90 [ -7.88, 9.68 ] Subtotal (95% CI) 22 18 28.3 % 0.90 [ -7.88, 9.68 ] Heterogeneity: not applicable Test for overall effect: Z = 0.20 (P = 0.84) 3 Patient Global Sleep Drewes 1998 22 36.6 (15.1) 18 45.9 (12.2) 30.5 % -9.30 [ -17.76, -0.84 ] Subtotal (95% CI) 22 18 30.5 % -9.30 [ -17.76, -0.84 ] Heterogeneity: not applicable Test for overall effect: Z = 2.15 (P = 0.031) Total (95% CI) 66 54 100.0 % -7.53 [ -12.20, -2.86 ] Heterogeneity: Chi2 = 5.16, df = 2 (P = 0.08); I2 =61% Test for overall effect: Z = 3.16 (P = 0.0016) Test for subgroup differences: Chi2 = 5.16, df = 2 (P = 0.08), I2 =61%

-100 -50 0 50 100 Favours Zopiclone Favours Placebo

Muscle relaxants for pain management in rheumatoid arthritis (Review) 47 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.1. Comparison 5 Muscle relaxant versus control - safety, Outcome 1 Withdrawal due to adverse events.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 5 Muscle relaxant versus control - safety

Outcome: 1 Withdrawal due to adverse events

Studyorsubgroup MuscleRelaxant Control RiskRatio RiskRatio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Bayley 1976 0/18 0/18 0.0 [ 0.0, 0.0 ]

Drewes 1998 0/22 0/18 0.0 [ 0.0, 0.0 ]

Hobkirk 1977 1/18 0/17 2.84 [ 0.12, 65.34 ]

Sharma 1978 1/18 0/17 2.84 [ 0.12, 65.34 ]

Vince 1973 0/17 0/17 0.0 [ 0.0, 0.0 ] Total (95% CI) 93 87 2.84 [ 0.31, 26.08 ] Total events: 2 (Muscle Relaxant), 0 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.92 (P = 0.36) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours Muscle Relaxant Favours control

Muscle relaxants for pain management in rheumatoid arthritis (Review) 48 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.2. Comparison 5 Muscle relaxant versus control - safety, Outcome 2 Total Adverse Events.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 5 Muscle relaxant versus control - safety

Outcome: 2 Total Adverse Events

Studyorsubgroup MuscleRelaxant Control RiskRatio Weight Risk Ratio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Bayley 1976 5/18 8/18 26.6 % 0.63 [ 0.25, 1.55 ]

Drewes 1998 8/22 0/18 7.9 % 14.04 [ 0.87, 227.89 ]

Hobkirk 1977 2/18 3/17 16.1 % 0.63 [ 0.12, 3.32 ]

Sharma 1978 5/18 4/17 22.9 % 1.18 [ 0.38, 3.67 ]

Vince 1973 12/17 4/17 26.5 % 3.00 [ 1.21, 7.45 ] Total (95% CI) 93 87 100.0 % 1.40 [ 0.58, 3.41 ] Total events: 32 (Muscle Relaxant), 19 (Control) Heterogeneity: Tau2 = 0.56; Chi2 = 9.77, df = 4 (P = 0.04); I2 =59% Test for overall effect: Z = 0.75 (P = 0.45) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours Muscle Relaxant Favours control

Muscle relaxants for pain management in rheumatoid arthritis (Review) 49 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.3. Comparison 5 Muscle relaxant versus control - safety, Outcome 3 Total Adverse events - trials greater than 24hrs duration.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 5 Muscle relaxant versus control - safety

Outcome: 3 Total Adverse events - trials greater than 24hrs duration

Studyorsubgroup MuscleRelaxant Control RiskRatio Weight Risk Ratio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Drewes 1998 8/22 0/18 19.2 % 14.04 [ 0.87, 227.89 ]

Vince 1973 12/17 4/17 80.8 % 3.00 [ 1.21, 7.45 ] Total (95% CI) 39 35 100.0 % 4.03 [ 1.08, 15.10 ] Total events: 20 (Muscle Relaxant), 4 (Control) Heterogeneity: Tau2 = 0.35; Chi2 = 1.31, df = 1 (P = 0.25); I2 =24% Test for overall effect: Z = 2.07 (P = 0.038) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours Muscle Relaxant Favours control

Analysis 5.4. Comparison 5 Muscle relaxant versus control - safety, Outcome 4 Total adverse events - trials 24hr duration only.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 5 Muscle relaxant versus control - safety

Outcome: 4 Total adverse events - trials 24hr duration only

Studyorsubgroup MuscleRelaxant Control RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Bayley 1976 5/18 8/18 52.6 % 0.63 [ 0.25, 1.55 ]

Hobkirk 1977 2/18 3/17 20.3 % 0.63 [ 0.12, 3.32 ]

Sharma 1978 5/18 4/17 27.1 % 1.18 [ 0.38, 3.67 ] Total (95% CI) 54 52 100.0 % 0.78 [ 0.41, 1.48 ] Total events: 12 (Muscle Relaxant), 15 (Control) Heterogeneity: Chi2 = 0.80, df = 2 (P = 0.67); I2 =0.0% Test for overall effect: Z = 0.77 (P = 0.44) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours Muscle Relaxant Favours control

Muscle relaxants for pain management in rheumatoid arthritis (Review) 50 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.5. Comparison 5 Muscle relaxant versus control - safety, Outcome 5 Subgroups Adverse Events.

Review: Muscle relaxants for pain management in rheumatoid arthritis

Comparison: 5 Muscle relaxant versus control - safety

Outcome: 5 Subgroups Adverse Events

Studyorsubgroup MuscleRelaxant Placebo RiskRatio RiskRatio M- M- H,Random,95% H,Random,95% n/N n/N CI CI 1 Benzodiazepine vs Placebo 24hrs Bayley 1976 5/18 8/18 0.63 [ 0.25, 1.55 ]

Hobkirk 1977 2/18 3/17 0.63 [ 0.12, 3.32 ]

Sharma 1978 5/18 4/17 1.18 [ 0.38, 3.67 ] Subtotal (95% CI) 54 52 0.77 [ 0.40, 1.48 ] Total events: 12 (Muscle Relaxant), 15 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.80, df = 2 (P = 0.67); I2 =0.0% Test for overall effect: Z = 0.78 (P = 0.44) 2 Benzodiazepine vs Placebo 1-2 weeks Vince 1973 12/17 4/17 3.00 [ 1.21, 7.45 ] Subtotal (95% CI) 17 17 3.00 [ 1.21, 7.45 ] Total events: 12 (Muscle Relaxant), 4 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 2.37 (P = 0.018) 3 Benzodiazepine + NSAID vs NSAID Hobkirk 1977 1/17 3/17 0.33 [ 0.04, 2.89 ]

Sharma 1978 4/17 4/17 1.00 [ 0.30, 3.36 ] Subtotal (95% CI) 34 34 0.77 [ 0.27, 2.21 ] Total events: 5 (Muscle Relaxant), 7 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.77, df = 1 (P = 0.38); I2 =0.0% Test for overall effect: Z = 0.49 (P = 0.63) 4 Non Benzodiazepine vs Placebo Drewes 1998 8/22 0/18 14.04 [ 0.87, 227.89 ] Subtotal (95% CI) 22 18 14.04 [ 0.87, 227.89 ] Total events: 8 (Muscle Relaxant), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.86 (P = 0.063) 5 CNS effects Drewes 1998 3/22 0/18 5.78 [ 0.32, 105.12 ]

Vince 1973 12/17 2/17 6.00 [ 1.58, 22.86 ]

0.01 0.1 1 10 100 Favours Benzodiazepine Favours control (Continued ... )

Muscle relaxants for pain management in rheumatoid arthritis (Review) 51 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (... Continued) Studyorsubgroup MuscleRelaxant Placebo RiskRatio RiskRatio M- M- H,Random,95% H,Random,95% n/N n/N CI CI Subtotal (95% CI) 39 35 5.96 [ 1.77, 20.08 ] Total events: 15 (Muscle Relaxant), 2 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 0.98); I2 =0.0% Test for overall effect: Z = 2.88 (P = 0.0040) 6 Gastrointestinal events Bayley 1976 0/18 1/18 0.33 [ 0.01, 7.68 ]

Drewes 1998 0/22 0/18 0.0 [ 0.0, 0.0 ]

Hobkirk 1977 0/18 0/17 0.0 [ 0.0, 0.0 ]

Sharma 1978 0/18 0/17 0.0 [ 0.0, 0.0 ]

Vince 1973 0/17 2/17 0.20 [ 0.01, 3.88 ] Subtotal (95% CI) 93 87 0.25 [ 0.03, 2.20 ] Total events: 0 (Muscle Relaxant), 3 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0% Test for overall effect: Z = 1.24 (P = 0.21)

0.01 0.1 1 10 100 Favours Benzodiazepine Favours control

APPENDICES

Appendix 1. MEDLINE search strategy 1. exp arthritis, rheumatoid/ 2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw. 3. (felty$ adj2 syndrome).tw. 4. (caplan$ adj2 syndrome).tw. 5. (sjogren$ adj2 syndrome).tw. 6. (sicca adj2 syndrome).tw. 7. still$ disease.tw. 8. or/1-7 9. exp Muscle Relaxants, Central/ 10. exp Neuromuscular Nondepolarizing Agents/ 11. exp Neuromuscular Blocking Agents/ 12. exp Benzodiazepines/ 13. muscle relaxant$.tw. or benzodiazepine$.tw. 14. (Alprazolam or Xanax or Xanor or Taﬁl or Alprox or Frontal).tw. 15. (Bromazepam or Lexotanil or Lexotan or Lexomil or Somalium or Bromam).tw. 16. (Chlordiazepoxide or Librium or Tropium or Risolid or Klopoxid).tw. 17. (Cinolazepam or Gerodorm).tw.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 52 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18. (Clonazepam or Klonopin or Rivotril or Iktorivil).tw. 19. (Cloxazolam or Olcadil).tw. 20. (Clorazepate or Tranxene).tw. 21. (Diazepam or Valium or Pax or Apzepam or Stesolid).tw. 22. (Estazolam or ProSom).tw. 23. (Flunitrazepam or Rohypnol or Fluscand or Flunipam or Rona or Rohydorm).tw. 24. (Flurazepam or Dalmadorm or Dalmane).tw. 25. (Flutoprazepam or Restas).tw. 26. (Halazepam or Paxipam or Ketazolam or Anxon or Loprazolam or Dormonoct or lorazepam or Ativan or Temesta or Tavor or Lorabenz or Lormetazepam or Loramet or Noctamid or Pronoctan or Medazepam or Nobrium or Midazolam or Dormicum or Versed or Hypnovel or Dormonid or Nimetazepam or Erimin or Nitrazepam or Mogadon or Alodorm or Pacisyn or Dumolid or Nordazepam or Madar or Stilny or Oxazepam or Seresta or Serax or Serenid or Serepax or Sobril or Pinazepam or Domar or Prazepam or Lysanxia or Centrax or Quazepam or Doral or Temazepam or Restoril or Normison or Euhypnos or Tenox or Tetrazepam or Mylostan or Triazolam or Halcion or Rilamir).tw. 27. (Orphenadrine or Norflex or Mephenamin or Disipal or Banflex or Flexon or Tizanidine or Zanaflex or Sirdalud or Flupirtine or Dantrolene or Dantrium or Dantrolen or Baclofen or Kemstro or Lioresal).tw. 28. or/9-27 29. randomized controlled trial.pt. 30. controlled clinical trial.pt. 31. randomized.ab. 32. placebo.ab. 33. drug therapy.fs. 34. randomly.ab. 35. trial.ab. 36. groups.ab. 37. or/29-36 38. exp animals/ not humans.sh. 39. 37 not 38 40. 8 and 28 and 39

Appendix 2. EMBASE search strategy 1. exp arthritis, rheumatoid/ 2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw. 3. (felty$ adj2 syndrome).tw. 4. (caplan$ adj2 syndrome).tw. 5. (sjogren$ adj2 syndrome).tw. 6. (sicca adj2 syndrome).tw. 7. still$ disease.tw. 8. or/1-7 9. exp Muscle Relaxants, Central/ 10. exp Neuromuscular Nondepolarizing Agents/ 11. exp Neuromuscular Blocking Agents/ 12. exp Benzodiazepines/ 13. muscle relaxant$.tw. 14. benzodiazepine$.tw. 15. (Alprazolam or Xanax or Xanor or Taﬁl or Alprox or Frontal).tw. 16. (Bromazepam or Lexotanil or Lexotan or Lexomil or Somalium or Bromam).tw. 17. (Chlordiazepoxide or Librium or Tropium or Risolid or Klopoxid).tw. 18. (Cinolazepam or Gerodorm).tw. 19. (Clonazepam or Klonopin or Rivotril or Iktorivil).tw.

Muscle relaxants for pain management in rheumatoid arthritis (Review) 53 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20. (Cloxazolam or Olcadil).tw. 21. (Clorazepate or Tranxene).tw. 22. (Diazepam or Valium or Pax or Apzepam or Stesolid).tw. 23. (Estazolam or ProSom).tw. 24. (Flunitrazepam or Rohypnol or Fluscand or Flunipam or Rona or Rohydorm).tw. 25. (Flurazepam or Dalmadorm or Dalmane).tw. 26. (Flutoprazepam or Restas).tw. 27. (Halazepam or Paxipam or Ketazolam or Anxon or Loprazolam or Dormonoct or lorazepam or Ativan or Temesta or Tavor or Lorabenz or Lormetazepam or Loramet or Noctamid or Pronoctan or Medazepam or Nobrium or Midazolam or Dormicum or Versed or Hypnovel or Dormonid or Nimetazepam or Erimin or Nitrazepam or Mogadon or Alodorm or Pacisyn or Dumolid or Nordazepam or Madar or Stilny or Oxazepam or Seresta or Serax or Serenid or Serepax or Sobril or Pinazepam or Domar or Prazepam or Lysanxia or Centrax or Quazepam or Doral or Temazepam or Restoril or Normison or Euhypnos or Tenox or Tetrazepam or Mylostan or Triazolam or Halcion or Rilamir).tw. 28. (Orphenadrine or Norflex or Mephenamin or Disipal or Banflex or Flexon or Tizanidine or Zanaflex or Sirdalud or Flupirtine or Dantrolene or Dantrium or Dantrolen or Baclofen or Kemstro or Lioresal).tw. 29. or/9-28 30. (random$ or placebo$).ti,ab. 31. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab. 32. controlled clinical trial$.ti,ab. 33. RETRACTED ARTICLE/ 34. or/30-33 35. (animal$ not human$).sh,hw. 36. 34 not 35 37. 8 and 29 and 36

WHAT’S NEW Last assessed as up-to-date: 6 September 2011.

Date Event Description

28 September 2010 Amended CMSG ID A058-P

HISTORY Protocol ﬁrst published: Issue 1, 2011 Review ﬁrst published: Issue 1, 2012

Muscle relaxants for pain management in rheumatoid arthritis (Review) 54 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. CONTRIBUTIONSOFAUTHORS BR wrote the protocol and review. SW contributed to the search strategy, study selection, data extraction, risk of bias analysis and provided comments and suggestions on draft versions of the protocol and review. RB contributed to the search strategy, adjudicated on study selection, risk of bias assessments and data extraction, and provided comments and suggestions on draft versions of the protocol and review. All authors approved the current version.

DECLARATIONSOFINTEREST None known

SOURCES OF SUPPORT

Internal sources • Royal Prince Alfred Hospital, Australia. In kind support • The Queen Elizabeth Hospital, Australia. In kind support • Cabrini Hospital, Australia. In kind support • School of Public Health & Preventive Medicine, Monash University, Australia. In kind support

External sources • No sources of support supplied