Muscle relaxants for pain management in rheumatoid arthritis2012/01/18 · Muscle relaxants can be...

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 Library2012, Issue 1

http://www.thecochranelibrary.com

Muscle relaxants for pain management in rheumatoid arthritis (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

20DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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, Outcome 3 Sleep (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

Sleep Questionnaire. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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

24hrs duration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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

52APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iMuscle relaxants for pain management in rheumatoid arthritis (Review)


55SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiMuscle relaxants for pain management in rheumatoid arthritis (Review)


[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 Databaseof Systematic Reviews 2012, Issue 1. Art. No.: CD008922. DOI: 10.1002/14651858.CD008922.pub2.


A B S T R A C T

Background

Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle

spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines

such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle

tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants

have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain.

Objectives

The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA.

The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlor-

diazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, ha-

lazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, ox-

azepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine,

carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity

drugs (baclofen and dantrolene sodium).

Search methods

We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010),

MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also

searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts

and performed a handsearch of reference lists of relevant articles.

Selection criteria

We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological

therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome.

Data collection and analysis

Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine

the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety.

1Muscle relaxants for pain management in rheumatoid arthritis (Review)


mailto:[email protected]

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.

P L A I N L A N G U A G E S U M M A R Y

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:




Withdrawal due to adverse events, after 2 weeks:


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).



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [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

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Control Muscle Relaxant versus

control

Pain - 24hrs (Single

dose)

Follow-up: 24 hours

The mean Pain - 24hrs

(Single dose) in the inter-

vention groups was

0.22 lower

(1.02 lower to 0.58

higher)

104

(3 studies)

⊕⊕©©

low1,2

No significant difference.

Absolute risk difference

2% (6% to 10%) and rela-

tive percent change 8% (-

38% to 22%)

Pain - 1-2 weeks

Follow-up: 1 weeks

The mean Pain - 1-2

weeks in the intervention

groups was

0.20 standard deviations

lower

(0.59 lower to 0.18

higher)

104

(3 studies)

⊕©©©

very low2,3,4


Absolute risk difference -

5% (-15% to 5%) and rel-

ative percent change -4%

(-11% to 3%)

Withdrawal due to Ad-

verse Events

Follow-up: 2 weeks

0 per 1000 0 per 1000

(0 to 0)

RR 2.84

(0.31 to 26.08)

180

(5 studies5)

⊕©©©

very low2,3,4

The event rate in the con-

trol group was zero. Ab-

solute risk difference 1%

(-4% to 6%), relative per-

cent change 184% (-69%

to 251%)

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Total Number of Adverse

Events - only studies

>24hrs duration

Follow-up: 2 weeks

29 per 1000 117 per 1000

(31 to 438)

RR 4.03

(1.08 to 15.10)

74

(2 studies)

⊕©©©

very low2,3,4

Number needed to harm

(NNTH) was 3 (2 to 8)

. Absolute risk difference

40% (23% to 57%), rel-

ative percentage change

303% (8% to 1410%)

Total Number of Adverse

Events - single dose

studies

Follow-up: 24 hours

288 per 1000 403 per 1000

(167 to 982)

RR 1.40

(0.58 to 3.41)

106

(3 studies)

⊕©©©

very low2,3


Absolute risk difference -

6% (-23% to 10%) and

relative percent change -

22% (-59% to 48%)

CNS adverse events

Follow-up: 1-2 weeks

57 per 1000 340 per 1000

(101 to 1000)

RR 5.96

(1.77 to 20.08)

74

(2 studies)

⊕©©©

very low2,3,4

NNTH was 3 (CI 2 to 11)

. Absolute risk difference

35% (-13% to 83%), rela-

tive 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 controls2 Wide confidence intervals given small number of participants and small event rate3 All three studies had high risk of bias.4 Heterogenous interventions, outcomes, study design and length of follow up5 Three of the five trials hand event rates of 0

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B A C K G R O U N D

Description of the condition

Rheumatoid arthritis (RA) is the most common form of inflam-

matory arthritis, affecting around 1% of the population. How-

ever, despite the significant advances in treatment over the past few

decades, pain management remains a significant issue for many

patients (Heiberg 2002). Progressive disease is characterized by

synovial tissue proliferation and persistent inflammation with re-

sultant cartilage degradation, bone erosion, and damage to ad-

jacent soft tissue and neural structures (Tak 2000). In the early

stages of RA, pain reflects the nociceptive effects of local inflam-

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

tension (Wolfe 2006).

Hypnotic agents or muscle relaxants are widely prescribed in the

management of insomnia, anxiety, or muscle tension. In a survey of

242 patients with RA, 60% reported that arthritis pain interfered

with sleep to some degree, with an additional 14% reporting severe

or very severe interference (Nicassio 1992). When a patient is

unable to sleep because of pain, a sleep-promoting agent may be

appropriate as increasing sleep may help to increase daytime pain

thresholds.

Poor sleep, independent of mood status, has also been associated

with fatigue, exhaustion, irritability, poor function, and a cycle of

greater pain (Morin 1998). This may also contribute to muscle

tension, which has also been linked to increased pain in RA (

Koehler 1985) and osteoarthritis (OA) (Dekker 1992). There is

also literature to support the notion that elevated levels of anxiety

are seen in patients with RA, also associated with higher levels of

pain (Dickens 2002; Hagland 1989; Smedstad 1996; Smedstad

1997). Muscle relaxants may therefore be useful adjuvant agents

in patients with RA who have persistent pain.

Description of the intervention

The term ’muscle relaxants’ is very broad and includes a wide

range of drugs with different indications and mechanisms of ac-

tion. Muscle relaxants can be divided into two main categories,

antispasmodic and antispasticity medications. The antispasmodic

agents are further subclassified into the benzodiazepines and the

non-benzodiazepines.

Since the introduction of chlordiazepoxide (Librium®) in 1960

(Tobin 1960) and diazepam (Valium®) in 1962 (Randall 1961),

the benzodiazepines have been widely prescribed for a variety

of medical and psychiatric indications. Non-benzodiazepines in-

clude a variety of drugs that can act at the brain stem or spinal

cord level. These include carisoprodol, chlorzoxazone, cycloben-

zaprine, metaxalone, meprobamate, methocarbamol, tizanidine,

zopiclone, and orphenadrine. While these agents have been used

for the treatment of painful musculoskeletal conditions that are as-

sociated with muscle spasm such as acute low back pain and mus-

cle strains (Waldman 1994), their use in RA is less well described.

Although these drugs may relieve skeletal muscle pain, their effects

are non-specific and not solely related to muscle relaxation. They

exhibit modest analgesic activity that may derive from their seda-

tive effects and also possibly from suppression of nociceptive input

(Hunskaar 1991). All antispasmodic agents can cause significant

drowsiness, dizziness, confusion, nausea, and vomiting.

Antispasticity medications are used to reduce spasticity that inter-

feres with therapy or function. Examples of such agents include

baclofen and dantrolene. They are not commonly used in patients

with RA.

How the intervention might work

In recent years we have witnessed dramatic advances in our un-

derstanding of the neuroanatomy of pain pathways and the neu-

rophysiology of pain regulation. In RA, pain frequently has mul-

tifactorial origins with both central and peripheral components.

Pain thresholds are known to be modified by sleep, however few

current neurobiological hypotheses adequately explain the com-

plex relationship between chronic pain and sleep disturbance. To

date, sleep and pain are known to use common neurotransmitters

(Moldofsky 1975) and alpha wave intrusion into non-rapid eye

movement (REM) sleep has been suggested as a possible mecha-

nism of sleep disturbance in patients with fibromyalgia (Branco

1994). Molecular mechanisms linking psychological state and pain

have also been recognized. Patients with pain often report increases

in pain in conjunction with elevations in psychological stress and

the molecular link between psychological stress and pain may be

explained by the stress-induced increases in tumour necrosis factor

(TNF) and interleukin (IL)-1 (Maes 1998).

Centrally, inhibitory gamma-amino butyric acid (GABA) neurons

in the spinal cord are known to act as ’gate keepers’ and to con-

trol the relay of pain signals from the periphery to higher areas of

the central nervous system. This pivotal role of GABA neurons in

modulating pain signals has been demonstrated in several reports

which have shown that a loss of such inhibitory capabilities under-

lies several forms of chronic pain (Malan 2002; Moore 2002). In

addition, a recent animal study showed that specifically activating

spinal GABA A receptors containing α2 or α3 subunits reduced

nociceptive input and emotional processing of inflammatory and

neuropathic pain (Knabl 2008). Peripheral benzodiazepine recep-

tors (PBR) have also been shown to be involved in the regulation

of immune responses (Waterfield 1999) and PBR ligands exhibit

anti-inflammatory properties (Zavala 1990).

The analgesic effects of benzodiazepines are predominantly me-

diated through activation of neuronal GABA A receptors (Costa

1979), although benzodiazepines may also act via peripheral mech-

anisms in patients with RA. The non-benzodiazepines, however,

are structurally unrelated compounds that may indirectly relax



skeletal muscle by blocking postsynaptic neurons in the spinal

cord and the descending reticular formation in the brain. Baclofen

is a gamma aminobutyric acid (GABA) derivative that inhibits

neural transmission at the spinal level and also depresses the cen-

tral nervous system. Dantrolene sodium blocks the sarcoplasmic

reticulum calcium channel thereby diminishing the actin-myosin

interaction, causing muscle relaxation.

Why it is important to do this review

Since their introduction, there has been interest in the therapeu-

tic application of muscle relaxants for the management of pain.

Conclusive data regarding their analgesic activity, however, is lack-

ing. There is also conflicting evidence as to whether or not mus-

cle relaxants possess analgesic properties that are independent of

their effects on sleep. Despite a paucity of evidence to support

their use, muscle relaxants have gained widespread clinical accep-

tance as adjuvants in the management of patients with chronic

musculoskeletal pain (Gordon 1995; Levy 1994). They have also

been advocated for pain associated with anxiety (Fernandez 1987),

muscle injury (Lossius 1980), muscle spasm (Weber 1973), and

nerve injury (Smirne 1977). This review helps to clarify the risks

and benefits associated with using muscle relaxants in the man-

agement of pain in patients with RA to aid physicians in making

a more informed decision about their use.

O B J E C T I V E S

The objectives of this review were to evaluate the analgesic efficacy

and safety of muscle relaxants in patients with RA.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All published randomised (RCTs) or quasi-randomised (that is

where allocation was not truly random) (CCTs) controlled trials

which compared muscle relaxant therapy to another therapy (ac-

tive, including non-pharmacological therapies, or placebo) for RA

were considered for inclusion. Only trials that were published as

full articles or were available as a full trial report were included.

Types of participants

Adult patients (aged 18 years or older) with a diagnosis of RA.

Populations that included a mixed population with RA and other

causes of musculoskeletal pain were excluded unless results for the

RA population could be separated out from the analysis.

Types of interventions

All formulations and doses of muscle relaxants, as monotherapy

or in combination, were considered.

Comparators could include:

1. placebo;

2. other analgesics (e.g. paracetamol, non-steroidal anti-

inflammatory drugs (NSAIDs), opioids, tramadol,

neuromodulators etc);

3. non-pharmacological modalities (e.g. transcutaneous

electrical nerve stimulation (TENS), acupuncture, etc);

4. same drug at differing doses; and

5. other muscle relaxants.

Comparisons with placebo and with other controls were planned

to be reported separately.

Drugs that had been withdrawn from the market due to safety

concerns were excluded from the review.

Types of outcome measures

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.

As continuous outcome measures in pain trials (such as mean

change on a 100 mm visual analogue scale) may not follow a Gaus-

sian distribution, and often a bimodal distribution is seen instead

(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 rea-

son, a dichotomous outcome measure (the proportion of partici-

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

therefore the mean change in pain score was also included as a sec-

ondary efficacy measure. A global rating of treatment satisfaction,

such as the Patient Global Impression of Change scale (PGIC),

which provides an outcome measure that integrates pain relief,

changes in function, and side-effects into a single, interpretable

measure, is also recommended by IMMPACT and was included

as a secondary outcome measure (Dworkin 2008).

Main outcomes

1. Efficacy: patient reported pain relief of 30% or greater.



2. Safety: number of withdrawals due to adverse events.

Minor outcomes

3. Pain:

a. patient reported pain relief of 50% or greater;

b. patient reported global impression of clinical change (PGIC)

much or very much improved;

c. proportion of patients achieving pain score below 30/100 mm

on a visual analogue scale; or

d. mean change in pain score on a visual analogue scale or numer-

ical rating scale.

4. Number and types of adverse events (AEs) and serious adverse

events (SAEs) (defined as AEs that were fatal, life-threatening, or

required hospitalisation).

5. Function: as measured by the Health Assessment Questionaire

(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

the Rheumatoid Arthritis Quality of Life instrument (RAQoL)).

7. Participant withdrawals due to inadequate analgesia.

8. Sleep as measured by any commonly used sleep scale (eg. In-

somnia Severity Index, Medical Outcomes Study (MOS), Sleep

Scale, Pittsburgh Sleep Diary (PSD), and Pittsburgh Sleep Quality

Index (PSQI)).

9. Depression as measured by any commonly used depression scale

(eg. Hamilton Rating Scale for Depression (HRSD), Hospital

Anxiety and Depression (HAD) score, Beck Depression Inventory

(BDI), Zung self rating depression score).

The duration of the trials of interventions for pain varies consid-

erably. The efficacy of interventions, and the relative balance of

benefits and harms, may vary according to the duration of the

trial and therefore the combination of results from trials of differ-

ent durations may represent a source of bias in systematic reviews

(Moore 2010). For the purpose of this review, trials were grouped

into those of duration < 1 week, 1 to 6 weeks, and > 6 weeks.

Where available, the short and long term outcomes for the propor-

tion reporting pain relief of 30% or greater, total number of with-

drawals due to adverse effects, number of serious adverse events,

function, and quality of life were presented in the summary of

findings table.

Search methods for identification of studies

Electronic searches

To identify relevant trials for this review, we used computer-aided

searches of the following databases for RCTs or CCTs using the

search strategies detailed in the appendices:

1. Ovid MEDLINE (1950 to week 1 November 2010) (Appendix

1);

2. EMBASE Classic + EMBASE (Week 44 2010) (Appendix 2);

3. Cochrane Central Register of Controlled Trials (CENTRAL)

(The Cochrane Library, 4th quarter 2010);

4. PsycINFO (1806 to week 2 November 2010).

No language restrictions were applied.

Searching other resources

The American College of Rheumatology (ACR) and European

League Against Rheumatism (EULAR) conference abstracts from

2008 and 2009 were searched. Handsearches of references and

relevant reviews were also performed to identify any additional

trials not retrieved by the above methods.

Data collection and analysis

Selection of studies

All identified studies were assessed independently by two review

authors (BR and SW) to identify trials that fulfilled the inclusion

criteria. All possibly relevant articles were retrieved in full text and

any disagreement in study selection was resolved by consensus or

by discussion with a third review author (RB).

Data extraction and management

Two independent review authors (BR and SW) extracted relevant

information from the included trials including study design, char-

acteristics of study population, treatment regimen and duration,

outcomes and timing of outcome assessment using predetermined

forms. The raw data (means and standard deviations for continu-

ous outcomes and number of events or participants for dichoto-

mous outcomes) were extracted for outcomes of interest. Differ-

ences in data extraction were resolved by referring back to the

original articles and establishing consensus. A third review author

(RB) was consulted to help resolve differences, as necessary.

Assessment of risk of bias in included studies

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

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

by The Cochrane Collaboration (Higgins 2008). To determine

the risk of bias of a study, for each criterion the presence of suffi-

cient information and the likelihood of potential bias were evalu-

ated. Each criterion was rated as ’yes’ (low risk of bias), ’no’ (high

risk of bias), or ’unclear’ (either lack of information or uncertainty

over the potential for bias). In a consensus meeting, disagreements



among the review authors were discussed and resolved. If consen-

sus could not be reached, a third review author (RB) made the

final decision.

Measures of treatment effect

The data were summarised in a meta-analysis only if there was suf-

ficient clinical and statistical homogeneity. For continuous data,

results were analysed as mean differences between the intervention

and comparator groups (MD) with 95% confidence intervals. The

mean difference between the treated group and the control group

was weighted by the inverse of the variance in the pooled treatment

estimate. However, when different scales were used to measure

the same conceptual outcome (for example functional status or

pain), standardized mean differences (SMD) were calculated in-

stead. SMDs were calculated by dividing the MD by the standard

deviation, resulting in a unitless measure of treatment effect. For

dichotomous data, a relative risk (RR) with corresponding 95%

confidence interval was calculated.

Unit of analysis issues

For studies containing more than two intervention groups, making

multiple pair-wise comparisons between all possible pairs of inter-

vention groups possible included the same group of participants

only once in the meta-analysis. Cross-over trials were identified, in

which the reporting of continuous outcome data precluded paired

analysis, however there was no meta-analysis so unit-of-analysis

error was not an issue.

Dealing with missing data

In cases where individuals were missing from the reported results,

we assumed the missing values to have a poor outcome. For di-

chotomous outcomes that measured adverse events (for example

number of withdrawals due to adverse events), the withdrawal rate

was calculated using the number of patients that received treat-

ment as the denominator (worst case analysis). For dichotomous

outcomes that measured benefits (for example proportion of par-

ticipants achieving an American College of Rheumatology 20%

improvement criteria (ACR20) response) the worst case analysis

was calculated using the number of randomised participants as

the denominator. For continuous outcomes (for example pain)

we calculated the MD or SMD based on the number of patients

analysed at the time point. If the number of patients analysed was

not presented for each time point, the number of randomised pa-

tients in each group at baseline was used. Where possible, missing

standard deviations were computed from other statistics such as

standard errors, confidence intervals or P values according to the

methods recommended in the Cochrane Handbook for System-

atic Reviews of Interventions (Higgins 2009).

Assessment of heterogeneity

Prior to meta-analysis, we assessed studies for clinical homogene-

ity with respect to type of therapy, control group, and the out-

comes. For any studies judged as clinically homogeneous, statisti-

cal heterogeneity was estimated using the I2 statistic (Deeks 2008)

with the following as a rough guide for interpretation: 0% to 40%

might not be important, 30% to 60% may represent moderate

heterogeneity, 50% to 90% may represent substantial heterogene-

ity, and 75% to 100% may represent considerable heterogeneity.

Assessment of reporting biases

In order to determine whether reporting bias was present, we

planned to determine whether the protocol of the RCT was pub-

lished before recruitment of study patients was started. However as

no studies were published after 1st July 2005, we did not carry out

the preplanned screen of the Clinical Trial Register at the Interna-

tional Clinical Trials Registry Platform of the World Health Orga-

nization (http://apps.who.int/trialssearch) (DeAngelis 2004). We

also evaluated whether selective reporting of outcomes was present

(outcome reporting bias).

We compared the fixed-effect model estimate against the random-

effects model to assess the possible presence of small sample bias

in the published literature (that is in which the intervention effect

was more beneficial in smaller studies). In the presence of small

sample bias, the random-effects model estimate was used (Sterne

2008). The potential for reporting bias was planned to be further

explored by funnel plots if ≥10 studies were available, however

due to the limited number of studies identified this was not done.

Data synthesis

Where studies were sufficiently homogeneous that it remained

clinically meaningful for them to be pooled, meta-analysis was per-

formed using a random-effects model, regardless of the I2 statistic

results. Analysis was performed using Review Manager 5 and for-

est plots were produced for all analyses.

Subgroup analysis and investigation of heterogeneity

If sufficient data had been available, the following subgroup anal-

yses were planned:

1. patients’ ages (< 65 years versus ≥ 65 years);

2. gender (male versus female); and

3. duration of RA (≤ 2 years versus > 2 years).

Sensitivity analysis

If sufficient data had been available, we planned sensitivity analy-

ses to assess the impact of any bias attributable to inclusion of tri-

als with inadequate treatment allocation concealment (including

studies with quasi-randomised designs).



http://apps.who.int/trialssearch




Presentation of key results

A summary of findings table was produced using GRADEpro soft-

ware. This table provides key information concerning the quality

of evidence, the magnitude of effect of the interventions exam-

ined, and the sum of available data on the outcomes (short and

long term outcomes for pain, total number of withdrawals due

to adverse effects, function, and quality of life), as recommended

by The Cochrane Collaboration (Schünemann 2008a). The table

includes an overall grading of the evidence related to each of the

main outcomes, using the GRADE approach.

In addition to the absolute and relative magnitudes of effect pro-

vided in the summary of findings table, for dichotomous outcomes

the number needed to treat to benefit (NNTB) or the number

needed to treat to harm (NNTH) was calculated from the control

group event rate (unless the population event rate was known) and

the relative risk was calculated using the Visual Rx NNT calcula-

tor (Cates 2004). For continuous outcomes, the NNT was calcu-

lated using the Wells calculator software, available at the Cochrane

Musculoskeletal Group (CMSG) editorial office (http://muscu-

loskeletal.cochrane.org/). The minimal clinically important dif-

ference (MCID) for each outcome was determined for input into

the calculator.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

See: ’Characteristics of included studies’; ’Characteristics of ex-

cluded studies’.

Results of the search

The database search yielded a total of 174 articles for review (CEN-

TRAL 26, MEDLINE 95, EMBASE 49, and PsycINFO 4) and

no further relevant studies were identified from searching the 2008

and 2009 ACR and EULAR abstracts.

After removal of 42 duplicates, the records were screened and

nine studies were assessed for detailed review. Six trials (n = 126

participants) met the inclusion criteria of the review (Bayley 1976;

Drewes 1998; Hobkirk 1977; Sharma 1978; Vince 1973; Walsh

1996). No additional studies were identified through reference

checking (Figure 1).



Figure 1. Study flow diagram.



Included studies

The characteristics of the included studies are described in the

’Characteristics of included studies’ table. Five trials assessed a ben-

zodiazepine and one trial assessed the non-benzodiazepine zopi-

clone (n = 40) (Drewes 1998). Of the benzodiazepine studies, four

evaluated diazepam (n = 71) (Bayley 1976; Hobkirk 1977; Sharma

1978; Vince 1973) and one evaluated triazolam (n = 15) (Walsh

1996). Five trials included a placebo control (Bayley 1976; Drewes

1998; Hobkirk 1977; Vince 1973; Walsh 1996), one compared

diazepam with an NSAID (Bayley 1976), and two studies assessed

whether diazepam in combination with an NSAID was superior

to an NSAID alone (Hobkirk 1977; Sharma 1978). A summary of

the interventions studied in the six included trials is listed below.

1) Benzodiazepine versus placebo

1a) Diazepam versus placebo (Bayley 1976; Vince 1973)

1b) Triazolam versus placebo (Walsh 1996)

2) Benzodiazepine versus NSAID

2a) Diazepam versus Indomethacin (Bayley 1976)

3) Benzodiazepine + NSAID versus NSAID

3a) Diazepam + sulindac versus sulindac (Sharma 1978)

3b) Diazepam + indomethacin versus indomethacin (Hobkirk

1977)

4) Non-benzodiazepine versus placebo

4a) Zopliclone versus placebo (Drewes 1998)

The majority of studies were published in the late 1970s, with

the most recent publications being Walsh 1996 and Drewes 1998.

Five trials used a cross-over design (Bayley 1976; Hobkirk 1977;

Sharma 1978; Vince 1973; Walsh 1996) and, of these, only one

included a washout period (Walsh 1996). The remaining study

used a parallel group design (Drewes 1998). No benzodiazepine

trial incorporated more than one week of active treatment and,

overall, no trial was longer than two weeks; the shortest duration

trials were three cross-over studies of single doses of drug given

for three consecutive nights (Bayley 1976; Hobkirk 1977; Sharma

1978). The other two cross-over studies included two one week

periods of treatment (Vince 1973; Walsh 1996).

Three studies evaluated inpatients (Bayley 1976; Hobkirk 1977;

Sharma 1978) and three studies (Drewes 1998; Vince 1973;

Walsh 1996) included outpatients. Most participants were women

(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

impairment (Walsh 1996). Only 17% (22/127) of patients were

receiving corticosteroids and 30% (38/127) were receiving disease

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

type of pain participants were suffering from or whether patients

suffered from depression.

Excluded studies

Three studies were excluded from this review (see ’Characteris-

tics of excluded studies’ table) because they included mixed pop-

ulations and it was not possible to extract data regarding the RA

patients alone for analysis (Durrigl 1969; Hardo 1991; Tarpley

1965).

Risk of bias in included studies

See Figure 2.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



All studies were rated at high risk of bias (Bayley 1976; Drewes

1998; Hobkirk 1977; Sharma 1978; Vince 1973; Walsh 1996).

The most common methodological shortcomings in the studies

involved the following, in order of frequency.

• Inadequate method of randomisation (6, 100% trials scored

’unclear’).

• Inadequate concealment of the drug allocation procedures

(6, 100% trials scored ’unclear’).

• Failing to apply intention-to-treat analysis (5, 87% trials

scored ’negative’ or ’unclear’).

• Non-equivalent co-interventions (4, 67% scored ’unclear’).

• Dissimilarity of the baseline characteristics (4, 67% trials


• Failure to blind study personnel (3, 50% trials scored

’unclear’).

• Failing to evaluate compliance (3, 50% trials scored

’negative’ or ’unclear’).

• Inadequate dropouts (2, 33% trials scored ’negative’ or

’unclear’).

• Failure to address incomplete outcome data (1, 17% trials


• Failure to blind participants (1, 17% trials scored ’negative’

or ’unclear’).

• Only reporting selective outcomes (no trials scored

’negative’ or ’unclear’).

Allocation

No study adequately described how participants were randomised

and all were deemed ’unclear’. No study provided any information

about whether allocation of treatment was adequately concealed

and all were deemed to be ’unclear’.

Blinding

All studies described the use of a placebo but did not provide spe-

cific information about the characteristics of the placebo and in

particular whether the placebo was identical to the active treat-

ment. No studies audited participants or study personnel on

whether they believed the participants were receiving the active

treatment.

None of the included studies provided specific information about

whether or not study personnel (including outcome assessors) were

blinded. This is important and raises the possibility that positive

results might be an artefact of physician expectations rather than

a true effect. This was illustrated in the Vince 1973 trial where pa-

tient global assessment outcomes were the same in both treatment

groups however the physician global assessment was higher in the

diazepam group than the placebo group.

Incomplete outcome data

Only one study failed to describe how incomplete outcome data

were addressed. In Vince 1973, 7/24 (29.2%) patients dropped

out without clear reasons or the group allocation being specified.

Selective reporting

All studies reported all prespecified outcomes as defined in their

methods sections.

Other potential sources of bias

In the five cross-over trials, no information was provided regarding

the randomisation of the order of treatments and no assessment

was made of a period effect. Three single dose studies of simi-

lar design each conducted the trial over three consecutive nights,

without any washout period (Bayley 1976; Hobkirk 1977; Sharma

1978). This may have exposed the trials to the possibility of a

carry-over effect. Another common source of bias was failure to

report co-interventions (Bayley 1976; Drewes 1998; Vince 1973;

Walsh 1996).

Effects of interventions

See: Summary of findings for the main comparison Muscle

relaxant versus control for pain management in rheumatoid

arthritis

Overall we were able to pool some of the data for three studies of

less than one week duration (Bayley 1976; Hobkirk 1977; Sharma

1978) and for three studies of one to six weeks duration (Drewes

1998; Vince 1973; Walsh 1996).

Primary outcomes

1) Effectiveness of muscle relaxants - pain intensity

No study reported the primary outcome measure of patient re-

ported pain relief of 30% or greater. Available pain data were con-

fined to mean pain VAS or means of ordinal outcomes in all trials.

Any muscle relaxant versus placebo

When pooled, the short term single dose studies assessing di-

azepam (52 participants) (Bayley 1976; Hobkirk 1977; Sharma

1978) showed no benefit in mean night pain VAS (0 to 10 cm)

scores over the control arm (SMD -0.22, 95% CI -1.02 to 0.58)

(Analysis 1.1, Figure 3). The other three studies of between one

and two weeks duration (Drewes 1998; Vince 1973; Walsh 1996)

also showed no significant improvement in mean pain over control

(SMD -0.20, 95% CI -0.59 to 0.18) (Analysis 1.2, Figure 4).



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

Three studies assessed the efficacy and safety of a benzodiazepine

versus placebo on pain intensity (Bayley 1976; Vince 1973; Walsh

1996) (Analysis 2.1). Two small cross-over trials (Bayley 1976;

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

placebo in relieving night pain (mean improvement of 0.9 cm,

95% CI -1.77 to -0.03) on a 10 cm VAS, while Vince 1973 re-

ported no difference in mean pain scores between diazepam and

placebo after one week.

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

scores between diazepam and placebo. Walsh 1996 compared tri-

azolam with placebo in patients with RA and sleep disturbance

and also found no significant difference in pain outcomes after

two weeks. Pooling these two one week studies using a random-

effects model yielded the same result (SMD -0.19, 95% CI -0.68

to 0.30) (Analysis 2.1).

Non-benzodiazepines versus placebo

One small study (1 trial, 41 patients) found no benefit of zopiclone

over placebo over two weeks on either present pain intensity (MD

-0.20, 95% CI -0.77 to 0.37) or total pain rating index (MD -

6.60, 95% CI -16.25 to 3.05) (Drewes 1998) (Analysis 4.1).

Benzodiazepine versus NSAID

One short term, single dose cross-over study (18 people) reported

no benefit of diazepam over indomethacin in pain outcomes in

inpatients with RA (Bayley 1976). However, insufficient data were

provided to extract any data regarding this result.

Benzodiazepine + NSAID versus NSAID

Two small cross-over trials (2 trials, 35 people) evaluated whether

or not there was any benefit in the addition of diazepam to an

NSAID over taking an NSAID alone (Hobkirk 1977; Sharma

1978). Both trials were small and were three consecutive night

trials of inpatients with active disease. Neither trial found an ad-

ditional benefit of the combination in terms of pain reduction



compared with NSAID alone. Standard deviations were estimated

from a conservative estimate of the P values in each of the trials

and when data were pooled the results were the same (SMD -0.14,

95% CI -1.65 to 1.36) (Analysis 3.1).

2) Safety of muscle relaxants

Number of withdrawals due to adverse events

There was a paucity of data available (n = 70) from the three studies

that compared a benzodiazepine with placebo. Overall there was

a trend towards more withdrawals in patients receiving a muscle

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,

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

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

1977; Sharma 1978). In the Hobkirk 1977 trial the patient “felt

generally unwell” after one dose of diazepam and indomethacin

and in the Sharma 1978 trial one patient withdrew after two nights

having “developed a plethora of minor symptoms”. It was not

specified as to which two treatments this patient had received

however as two arms of the study included diazepam and different

NSAIDs this was included as an experimental event. In the one

study of the non-benzodiazepine agent zopiclone versus placebo

there were no withdrawals due to adverse events at the end of the

two week trial (Drewes 1998).

Secondary outcomes

Total number of adverse events and serious adverse events

(SAEs)

Five trials reported adverse event data (Bayley 1976; Drewes 1998;

Hobkirk 1977; Sharma 1978; Vince 1973). When pooled there

was a trend towards a significant increase in total adverse events

only (RR 1.40, 95% CI 0.58 to 3.41) (Analysis 5.2, Figure 6). This

was explained by the heterogeneity in the results of the single dose

versus longer duration studies. In the single cross-over studies (3

trials, 106 people) evaluating short term (24 hr) outcomes of di-

azepam versus placebo there was no significant increase in the total

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

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).



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.



Figure 8. Forest plot of comparison: 5 Muscle relaxant versus control - safety, outcome: 5.5 Subgroups

adverse events.



When added to an NSAID in two small single dose trials (2 trials,

34 participants), there was no significant difference in adverse

events (RR 0.77, 95% CI 0.27 to 2.21) (Hobkirk 1977; Sharma

1978) (Analysis 5.5.3). Neither trial had a washout period so they

may have been biased by a carry-over effect.

In the one small trial of zopiclone versus placebo, 36% (8/22)

of patients were reported to have an adverse event however 5/8

of these were described as “bitter taste”. There was a trend to-

wards significance only over two weeks (RR 9.09, 95% CI 0.54

to 154.07) (Drewes 1998) (Analysis 5.5), which did not change

when the patients with bitter taste were removed from the analysis

(RR 14.04, 95% CI 0.87 to 227.89). The other adverse events

reported included sleepiness and dizziness (3/5).

Effectiveness of muscle relaxants versus placebo: functional

status

No trials including benzodiazepines reported a functional status

outcome. The one trial of zopiclone showed no difference in HAQ

scores at the end of the two week trial (RR 0.08, 95% CI -0.54 to

0.70) (Drewes 1998) (Analysis 4.2).

Effectiveness of muscle relaxants: quality of life

Only one trial measured a quality of life outcome, using the Arthri-

tis Impact Measure Scale (AIMS), and found no significant dif-

ference in any components (insufficient data available to confirm

this result) (Walsh 1996).

Effectiveness of muscle relaxants: participant withdrawals

due to inadequate analgesia

No trials recorded withdrawals due to inadequate analgesia.

Effectiveness of muscle relaxants: sleep

Five trials included a measure of sleep. Three studies evaluating

diazepam used the Wolfe sleep score (Wolff 1974) and reported

no significant short term benefit (at 24 hrs) over placebo (Bayley

1976); or in combination with an NSAID over an NSAID alone

(Hobkirk 1977, Sharma 1978). No standard deviations were pro-

vided in these trials. Data from the Sharma 1978 trial were used

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,

and subjective patient sleep outcomes using the VAS (Walsh 1996).

The MSLT is used to measure the time elapsed from the start of

a daytime nap period to the first signs of sleep. This test is based

on the idea that the sleepier people are, the faster they will fall

asleep. After one week, mean MSLT latencies were significantly

longer, that is participants less sleepy (11.0 min versus 7.9 min)

(MD 3.10, 95% CI 1.20 to 5.00) (Analysis 2.3), objective mean

total sleep time using polysomnography was significantly longer

in the triazolam group (408.2 min versus 389.1 min) (MD 19.10,

95% CI 5.34 to 32.86) with patients having fewer awakenings

(28.9 versus 21.7) (MD 7.20, 95% CI 0.90 to 13.50) (Analysis

2.4). Total sleep latency was not significantly different (MD -

8.40, 95% CI -33.05 to 16.25). In addition, the subjective sleep

outcome measures showed that patients receiving triazolam had

significantly increased total sleep time (434.4 min versus 397 min)

(MD 37.40, 95% CI 10.85 to 63.95), shorter sleep latency (time

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,

95% CI -2.05 to -0.35) (Analysis 2.5), however their daytime

sleepiness score was no different than for those receiving placebo.

One non-benzodiazepine trial evaluated sleep outcomes in pa-

tients receiving zopiclone using polysomnography (Analysis 4.3),

the Spiegel Sleep Questionnaire (Analysis 4.4), and the Leeds Sleep

Evaluation Questionnaire (Analysis 4.5) (Drewes 1998). There

were conflicting results between the objective and subjective sleep

outcomes. Patient reported outcomes tended to be in favour of

zopiclone while objective outcomes did not show a significant dif-

ference between the two treatments. Using the Spiegel Sleep Ques-

tionnaire, the authors reported a mean increase of 1.70 units (95%

CI 1.03 to 2.37) (0 to 5 scale) in the overall quality of sleep after

two weeks. The frequency of awakenings was reduced by a mean

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

to 1.27) (0 to 5 scale) (Analysis 4.4). With the Leeds Sleep Eval-

uation, there was a significant improvement in mean sleep onset

latency of 12 minutes (95% CI 4.73 to 19.27) and mean overall

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

compared with placebo. With objective polysomnography mea-

sures, total duration of sleep and number of awakenings were not

significantly different (Analysis 4.3). Overall there was a positive

effect on the subjective assessments of sleep while parameters from

conventional sleep staging were not significantly different. Despite

the improvements in subjective sleep ratings, clinical parameters

such as pain, morning stiffness, and sleepiness were unaltered dur-

ing treatment with zopiclone.

Effectiveness of muscle relaxants versus placebo: depression

Only one trial recorded a measure of depression (Walsh 1996). In

this trial there were no significant differences on any of the Profile

of Mood States (POMS) scales or on the depression scales of the

AIMS questionnaire in patients receiving triazolam compared with

placebo (Analysis 2.6).



Preplanned subgroup analyses

There were insufficient data available to carry out the preplanned

sensitivity analyses for age, gender, and duration of RA.

Other analyses

None of the planned subgroup analyses were performed due to

insufficient data and high risk of bias in all trials.

D I S C U S S I O N

Summary of main results

This systematic review identified six small double-blind ran-

domised trials (including five cross-over trials) investigating the

effects of muscle relaxants on pain management in patients with

RA. Five trials assessed a benzodiazepine (four trials diazepam, 71

participants; one trial triazolam, 15 participants) and one trial used

the non-benzodiazepine agent zopiclone (40 participants). Four

trials were placebo controlled and two were the benzodiazepine in

combination with an NSAID against an active NSAID compara-

tor. All of the trials were deemed to have a high risk of bias. No

trial was longer than two weeks duration with 50% of the included

trials being single dose studies. No benzodiazepine trial was longer

than one week in duration.

No study reported the primary outcome measure of patient re-

ported pain relief of 30% or greater. When pooled, the short term

single dose studies assessing diazepam showed no benefit over any

of the control arms. When compared with placebo, studies assess-

ing pain outcomes at 24 hours had conflicting results. One small,

single dose study of inpatients reported a significant benefit of

a single dose of diazepam over placebo in improving night pain

(Bayley 1976). Patients had a modest mean improvement of only

0.9 cm on a 10 cm VAS (95% CI 0.03 to 1.77), which is of ques-

tionable clinical significance. In this study there was no benefit

of a single dose of diazepam over indomethacin in reducing pain

levels in inpatients with RA (Bayley 1976). Similarly, there was

weak evidence from two small single dose cross-over studies that

there was no additional benefit on pain reduction from adding a

benzodiazepine to regular NSAID treatment versus NSAID treat-

ment alone (Hobkirk 1977; Sharma 1978) in inpatients with ac-

tive RA. Three studies evaluated muscle relaxants over one to two

weeks and found no benefit over placebo (Drewes 1998; Vince

1973; Walsh 1996). Pooling of these trials showed no significant

improvement in mean pain levels.

Reliable conclusions about comparative withdrawals due to ad-

verse events and the total adverse event rates could not be drawn

from these short trials. Abuse and addiction were not evaluated

and no serious adverse events or deaths were reported. Only one

of the three trials comparing a benzodiazepine with placebo re-

ported withdrawals due to adverse events and the event rate in this

single dose trial was zero (Bayley 1976). In the other two single

dose combination studies, there was one event only in each trial

(Hobkirk 1977; Sharma 1978). There were no withdrawals due

to adverse events after two weeks of treatment in the single study

of zopiclone.

Overall, 34% of patients receiving an intervention and 22% of

patients in the control groups suffered an adverse event. When

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

trials (11% to 28%) and the two week study (71%). When data

from the trials of more than 24 hours duration were pooled there

were significantly more adverse events (NNTH 3, 95% CI 2 to

8). Consistent with the literature, these were predominantly cen-

tral nervous system side effects, including dizziness and drowsiness

(NNTH 3, 95% CI 2 to 11). In the one small trial of zopiclone,

32% suffered an adverse event with 14% of events related to dizzi-

ness and drowsiness. Given the small sample size there was only a

trend towards significance (RR 14.04, 95% CI 0.87 to 227.89).

No trials with benzodiazepines reported functional status as an

outcome. One benzodiazepine trial measured quality of life and

depression and reported no significant difference for either of

these after one week (Walsh 1996). The non-benzodiazepine trial

showed no difference in HAQ scores after two weeks but it did

not measure quality of life or depression (Drewes 1998). There

was weak evidence of no short term improvement in any sub-

jective sleep outcomes in the small, single dose trials of patients

taking benzodiazepines when compared with placebo, NSAID, or

in combination with an NSAID (Bayley 1976; Hobkirk 1977;

Sharma 1978). Objective and subjective improvements in sleep la-

tency, total sleep time and the number of awakenings were seen af-

ter two weeks of treatment in one trial evaluating triazolam (Walsh

1996). Daytime sleepiness was, however, no different than for

those receiving placebo.

In the one non-benzodiazepine trial, there was a positive effect on

the subjective assessments of some sleep parameters (sleep latency,

frequency of awakenings) however objective sleep outcomes were

not significantly different (Drewes 1998). In this trial, despite the

improvements in subjective sleep ratings, clinical parameters such

as pain, morning stiffness and sleepiness remained unaltered.

Overall completeness and applicability ofevidence

There were many limitations of this review. There were no large

trials, limited head-to-head trials and no studies of longer than two

weeks duration. There was also a lack of data on many commonly

used benzodiazepine agents (alprazolam, clonazepam, lorazepam,

oxazepam etc.) as well as no available data on any of the skeletal

muscle relaxants. Physicians are also often concerned about the

potential problem of addiction and withdrawal associated with



these agents, however no study addressed these outcomes so no

conclusions can be made in regards to this in this patient popula-

tion.

The populations included in this review are not reflective of cur-

rent day patients with RA. More than half the included trial par-

ticipants were inpatients who were hospitalised with poorly con-

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

women and had various degrees of RA disease severity. It was un-

clear what other analgesics they were taking at the time of the

studies and whether the patients had any co-morbidities. It also

remains unclear as to what type of pain these agents were being

used for. The nature and duration of the pain and whether any

other analgesics were being used (or were no longer needed) were

not described in any of the studies. No trial reported the primary

efficacy outcome measure of patient reported pain relief of 30%

or greater. The mean changes reported were often small and even

though statistically significant they may not have been clinically

significant. Functional status, subjective and objective sleep out-

comes, depression and quality of life data are known to be im-

portant outcomes in this patient population, and any information

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-

azepine included in this review (zopiclone). Reliable conclusions

about withdrawal due to adverse events and total adverse event

rates can not, therefore, be drawn from these short trials. Although

not identified in our review, chlorzoxazone has been implicated in

the development of serious (including fatal) hepatocellular toxic-

ity. Chlormezanone has also been implicated in causing Stevens-

Johnson syndrome and toxic epidermal necrolysis.

Quality of the evidence

All trials were deemed to have a high risk of bias with the major

flaws being that they were too small and of too short duration to

be able to detect a clinically significant difference. The most com-

mon methodological flaws included failure to describe randomi-

sation, allocation concealment, and blinding of study participants

and personnel. In many studies, authors merely stated that the

trial was randomised, raising concerns about whether or not the

randomisation procedure was adequate. There was no evaluation

of a carry-over or period effect in any of the cross-over trials, and

with three trials failing to have a washout period this may have

also led to a more conservative estimate of any benefit seen.

No study recorded the use of any analgesic co-interventions. Com-

pliance gives an indication of the tolerability and acceptability of

the drugs to patients and was also not measured in any of the trials.

While not relevant to the controlled inpatient single dose studies,

three longer outpatient trials did not address this (Drewes 1998;

Vince 1973; Walsh 1996).

Reporting of adverse events was also poor. Adverse events were

not consistently reported in these trials and doses of medications

and titration methods differed markedly between studies. In the

cross-over studies only one of the five trials included a washout

period. This was not likely to have affected the single dose studies

however it may have introduced bias into the Vince 1973 trial.

Potential biases in the review process

We believe that all relevant studies were identified. A thorough

search strategy was devised and all major databases were searched

for relevant studies, with no language restrictions applied. Two

review authors assessed the trials for inclusion in the review and

the risk of bias, with a third review author adjudicating if there

was any discrepancy. The biggest limitation of the review process

was that many trials did not provide enough published data, or

data in a form that could be extracted for meta-analysis. Although

several authors were contacted, no further data were obtained. We

did not include the results of unpublished studies. Trials with both

positive and negative results were identified, making the possibility

of publication bias less likely.

Agreements and disagreements with otherstudies or reviews

No systematic review or meta-analysis has assessed the use of mus-

cle relaxants in patients with RA or in mixed populations of pa-

tients with arthritis that included RA patients.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There is currently weak evidence that benzodiazepines (diazepam

and triazolam) do not improve pain as measured by any clinically

significant difference over 24 hours or one week in patents with

RA. There is also weak evidence that there is no short term benefit

of diazepam over indomethacin and no change in pain score with

the addition of diazepam to an NSAID over an NSAID alone.

Weak evidence exists that diazepam does not improve quality of

life after one week of treatment. There was also no significant short

term benefit over placebo, or in combination with an NSAID over

an NSAID alone, in sleep. We are unable to make any conclu-

sions in regard to optimal dosing, whether any muscle relaxant is

superior to another, withdrawals due to inadequate analgesia and

functional status.

In addition, no reliable conclusions can be made from this data

regarding withdrawals due to adverse events. There was no sig-

nificant increase in the total number of adverse events over 24



hours, however adverse evenets were significantly increased when

the trials were of one or two weeks duration. The predominant

side effects were dizziness and drowsiness with, on average, one

adverse event occurring in every three people. The one small non-

benzodiazepine trial that was identified found no benefit of zopi-

clone over placebo in outpatients over a two week period.

Based on the currently available evidence, we are unable to recom-

mend the routine use of muscle relaxants for pain management

in patients with RA. Although conclusions cannot be made about

the risk of dependency on the drugs from the trials included in this

review, there is sufficient indirect evidence from other sources that

a substantial risk of dependency can develop when using muscle

relaxants. Until better evidence is available regarding their differ-

ential efficacy and safety, these agents should be used with caution

particularly in patients who are prone to addiction.

Implications for research

To better assess the efficacy and safety of muscle relaxants in pa-

tients with RA, large double-blind placebo controlled and head-to-

head RCTs with homogenous RA populations who have pain de-

spite optimal DMARD or bDMARD therapy are required. They

should be methodologically sound and involve longer term follow

up (six months). Safety data including deaths, withdrawals due to

adverse events, serious adverse events and total numbers and types

of adverse events should be evaluated. Compliance data, which

give an indication of tolerability and acceptability, should also be

routinely collected. Pain outcomes should be uniformly studied

and we recommend that the proportion of patients with reduc-

tions in pain intensity of ≥ 30% and ≥ 50%, which reflect mod-

erate and substantial clinically important differences, be reported.

The routine collection of functional and health-related quality

of life outcomes as well as sleep is also important. Descriptive

measures of the type of pain should be included to help readers

decide if the data are applicable to their particular patients’ pain.

Assessing a variety of muscle relaxants in doses commonly used in

current practice is also required to add to the field of knowledge

in this area.

A C K N O W L E D G E M E N T S

Louise Falzon for assistance with the search strategy.

R E F E R E N C E S

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C H A R A C T E R I S T I C S O F S T U D I E S

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 hos-

pital 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

bias)

Unclear risk No detailed information provided

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

Blinding (performance bias and detection

bias)

Participants

Low risk Quote: “double blind nature of the exper-

iment was ensured by using appropriate

dummies and individual packaged doses”

Comment: patients likely to have remained

blinded



Bayley 1976 (Continued)


bias)

Personnel

Low risk No detailed information provided

Comment: personnel likely to have re-

mained blinded

Incomplete outcome data (attrition bias)

All outcomes

Low risk All patients completed the short trial

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-

ment?

Unclear risk Quote: “the treatment order being ran-

domised”

Comment: cross-over trial. No specific in-

formation 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”


Interventions Zopiclone 7.5 mg versus placebo



Drewes 1998 (Continued)

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)

Unclear risk Quote: “Pts were randomised”

Comment: information not specified

Allocation concealment (selection bias) Unclear risk Information not specified


bias)

Participants

Low risk Quote: “similar placebo tablet” given

Comment: information not specified but

likely to have remained blind


bias)

Personnel

Unclear risk Information not specified


All outcomes

Low risk Only 1 drop out at time of first sleep study.

Patient was excluded from the analysis


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 med-

ication”

Comment: information not specified


ment?

Low risk Baseline characteristics were similar

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



Drewes 1998 (Continued)

Drop Outs? Low risk 1/41 patients dropped out due to technical

difficulties with sleep study


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


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

Outcomes Primary



3) EMS (mins)

4) Adverse events

Secondary

Patient preference


Conclusion: indomethacin plus diazepam was superior to placebo but not indomethacin

alone. Patient preference was for the combination treatment

Risk of bias



bias)




bias)

Participants

Low risk quote: “double blind nature of the exper-




blinded



Hobkirk 1977 (Continued)


bias)

Personnel

Low risk Information not specified


mained blinded


All outcomes

Low risk 1 patient excluded from the analysis who

suffered adverse event


Compliance? Low risk Quote: “The trial drugs replaced any anal-

gesic or hypnotic given at the 10 p.m.

medicine round”

Comment: likely to have been taken

Co-interventions? Low risk Information not specified



tra analgesics


ment?

Unclear risk quote: “the treatment order being ran-

domised”

Comment: cross-over trial. No specific in-


a period effect


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


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


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

+ 10mg diazepam



Sharma 1978 (Continued)

Outcomes Primary



3) EMS (mins)

4) Adverse events

Secondary

Patient preference


Conclusion: there was no significant difference in pain or sleep between the different

groups

Risk of bias



bias)




bias)

Participants

Low risk Quote: “double blind nature of the exper-




blinded, no specific details


bias)

Personnel

Low risk Information not specified


mained blinded


All outcomes

Low risk 1 patient dropped out after two nights and

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



tra analgesics



Sharma 1978 (Continued)


ment?

Unclear risk Quote: “the treatment order being ran-

domised”

Comment: Cross-over trial. No specific in-


a period effect


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, al-

though it was not clear which treatments

they had received


Underpowered

Vince 1973

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


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


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)


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



Vince 1973 (Continued)



bias)

Unclear risk Quote: “Treatment with diazepam and

placebo was allocated randomly.”

Information not specified



bias)

Participants

Unclear risk Authors refer to “placebo”, no details pro-

vided

Comment: it is likely patients were blinded


bias)

Personnel



All outcomes

High risk 7 patients dropped out and it was not spec-

ified how they were dealt with



Co-interventions? Unclear risk Information not specified


ment?

High risk Cross-over trial. No washout and no infor-

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 with-

out clear reasons specified


Walsh 1996

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

1-3 week washout period


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



Walsh 1996 (Continued)

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


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)




bias)

Participants

Low risk quote: “double blind”, “placebo”

Comment: no detailed information pro-

vided, participants likely to have remained

blind


bias)

Personnel



All outcomes

Low risk 1 patient withdrew in the first week “for

personal reasons unrelated to study proce-

dures or drug”

Comment: it is unlikely this patient suf-

fered an event that was related to the study



Walsh 1996 (Continued)



Co-interventions? Unclear risk Information not specified


ment?

Low risk Cross-over study with 1-3 week washout

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



D A T A A N D A N A L Y S E S

Comparison 1. Muscle relaxant versus control

Outcome or subgroup titleNo. of

studies

No. of

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


studies

No. of


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

(>15sec)

1 30 Mean Difference (IV, Fixed, 95% CI) 7.20 [0.90, 13.50]

5 Sleep (Patient reported outcome

measures)

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

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


studies

No. of


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]



Comparison 4. Non-benzodiazepine versus placebo


studies

No. of


1 Pain 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

1.1 Present Pain Intensity (2

weeks)

1 40 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.77, 0.37]

1.2 Total Pain Rating Index (2

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

(>2min)


4 Sleep (Patient reported

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

outcomes) Leeds Sleep

Evaluation

1 120 Mean Difference (IV, Fixed, 95% CI) -7.53 [-12.20, -2.86]

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


studies

No. of


1 Withdrawal due to adverse

events

5 180 Risk Ratio (M-H, Random, 95% CI) 2.84 [0.31, 26.08]

2 Total Adverse Events 5 180 Risk Ratio (M-H, Random, 95% CI) 1.40 [0.58, 3.41]

3 Total Adverse events - trials

greater than 24hrs duration


4 Total adverse events - trials 24hr

duration only

3 106 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.41, 1.48]

5 Subgroups Adverse Events 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

5.1 Benzodiazepine vs Placebo

24hrs


5.2 Benzodiazepine vs Placebo

1-2 weeks




5.3 Benzodiazepine + NSAID

vs NSAID


5.4 Non Benzodiazepine vs

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

Study or subgroup Muscle relaxant ControlMean

Difference WeightMean

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



Analysis 1.2. Comparison 1 Muscle relaxant versus control, Outcome 2 Pain 1-2 weeks.


Comparison: 1 Muscle relaxant versus control

Outcome: 2 Pain 1-2 weeks

Study or subgroup Muscle relaxant Control

Std.Mean

Difference Weight

Std.Mean

Difference


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%



-100 -50 0 50 100

Favours muscle relaxant Favours control

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


Comparison: 2 Benzodiazepine versus placebo


Study or subgroup Benzodiazepine PlaceboMean


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


-100 -50 0 50 100

Favours Benzodiazepine Favours Placebo



Analysis 2.2. Comparison 2 Benzodiazepine versus placebo, Outcome 2 Pain 1 week.



Outcome: 2 Pain 1 week

Study or subgroup Benzodiazepine Placebo

Std.Mean

Difference Weight

Std.Mean

Difference


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 ]




-100 -50 0 50 100

Favours Benzodiazepine Favours control

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



Outcome: 3 Sleep (MSLT)



Difference


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 ]




-100 -50 0 50 100

Favours Triazolam Favours Placebo



Analysis 2.4. Comparison 2 Benzodiazepine versus placebo, Outcome 4 Sleep (Polysomnography).



Outcome: 4 Sleep (Polysomnography)



Difference


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 ]



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 ]



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 ]



-100 -50 0 50 100

Favours experimental Favours control



Analysis 2.5. Comparison 2 Benzodiazepine versus placebo, Outcome 5 Sleep (Patient reported outcome

measures).



Outcome: 5 Sleep (Patient reported outcome measures)



Difference


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 ]



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 ]



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 ]



-100 -50 0 50 100

Favours Triazolam Favours Placebo



Analysis 2.6. Comparison 2 Benzodiazepine versus placebo, Outcome 6 Depression.



Outcome: 6 Depression

Study or subgroup Benzodiazepine Placebo

Std.Mean

Difference Weight

Std.Mean

Difference


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 ]




-100 -50 0 50 100


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


Comparison: 3 Benzodiazepine + NSAID versus NSAID - pain


Study or subgroup Experimental Control

Std.Mean

Difference Weight

Std.Mean

Difference


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 ]




-100 -50 0 50 100




Analysis 3.2. Comparison 3 Benzodiazepine + NSAID versus NSAID - pain, Outcome 2 Sleep (Wolff Sleep

Score).


Comparison: 3 Benzodiazepine + NSAID versus NSAID - pain

Outcome: 2 Sleep (Wolff Sleep Score)

Study or subgroupBenzodiazepine

+ NSAID NSAID

Std.Mean

Difference Weight

Std.Mean

Difference


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 ]




-100 -50 0 50 100


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


Comparison: 4 Non-benzodiazepine versus placebo

Outcome: 1 Pain

Study or subgroup Zopiclone PlaceboMean


Difference


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 ]



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 ]



Test for subgroup differences: Chi2 = 1.68, df = 1 (P = 0.19), I2 =41%

-100 -50 0 50 100

Favours Zopiclone Favours Placebo



Analysis 4.2. Comparison 4 Non-benzodiazepine versus placebo, Outcome 2 Functional Status.



Outcome: 2 Functional Status

Study or subgroup Zopiclone Placebo

Std.Mean

Difference Weight

Std.Mean

Difference


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 ]




-100 -50 0 50 100




Analysis 4.3. Comparison 4 Non-benzodiazepine versus placebo, Outcome 3 Sleep (Polysomnography).



Outcome: 3 Sleep (Polysomnography)



Difference


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 ]



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 ]



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 subgroup differences: Chi2 = 0.66, df = 1 (P = 0.42), I2 =0.0%

-100 -50 0 50 100




Analysis 4.4. Comparison 4 Non-benzodiazepine versus placebo, Outcome 4 Sleep (Patient reported

outcomes) Spiegel Sleep Questionnaire.



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



Difference


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 ]



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 ]



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 ]



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 ]


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%



-100 -50 0 50 100




Analysis 4.5. Comparison 4 Non-benzodiazepine versus placebo, Outcome 5 Sleep (Patient reported

outcomes) Leeds Sleep Evaluation.



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



Difference


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 ]



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 ]



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 ]



Total (95% CI) 66 54 100.0 % -7.53 [ -12.20, -2.86 ]

Heterogeneity: Chi2 = 5.16, df = 2 (P = 0.08); I2 =61%



-100 -50 0 50 100




Analysis 5.1. Comparison 5 Muscle relaxant versus control - safety, Outcome 1 Withdrawal due to adverse

events.


Comparison: 5 Muscle relaxant versus control - safety

Outcome: 1 Withdrawal due to adverse events

Study or subgroup Muscle Relaxant Control Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

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)




0.01 0.1 1 10 100

Favours Muscle Relaxant Favours control



Analysis 5.2. Comparison 5 Muscle relaxant versus control - safety, Outcome 2 Total Adverse Events.



Outcome: 2 Total Adverse Events

Study or subgroup Muscle Relaxant Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

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 ]





0.01 0.1 1 10 100




Analysis 5.3. Comparison 5 Muscle relaxant versus control - safety, Outcome 3 Total Adverse events - trials

greater than 24hrs duration.



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


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

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 ]





0.01 0.1 1 10 100


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

24hr duration only.



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


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 ]


Heterogeneity: Chi2 = 0.80, df = 2 (P = 0.67); I2 =0.0%



0.01 0.1 1 10 100




Analysis 5.5. Comparison 5 Muscle relaxant versus control - safety, Outcome 5 Subgroups Adverse Events.



Outcome: 5 Subgroups Adverse Events

Study or subgroup Muscle Relaxant Placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

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)



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 ]




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 ]




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 ]




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


(Continued . . . )



(. . . Continued)Study or subgroup Muscle Relaxant Placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 39 35 5.96 [ 1.77, 20.08 ]




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 ]




0.01 0.1 1 10 100


A P P E N D I C E S

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.



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.



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

W H A T ’ S N E W

Last assessed as up-to-date: 6 September 2011.

Date Event Description

28 September 2010 Amended CMSG ID A058-P

H I S T O R Y

Protocol first published: Issue 1, 2011

Review first published: Issue 1, 2012



C O N T R I B U T I O N S O F A U T H O R S

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.

D E C L A R A T I O N S O F I N T E R E S T

None known

S O U R C E S O F S U P P O R T

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



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