BMJ
Confidential: For Review Only Efficacy, acceptability and harms of muscle relaxant medicines for adults with non-specific low back pain: systematic review and meta-analysis
Journal: BMJ
Manuscript ID BMJ-2020-063248
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the 19-Nov-2020 Author:
Complete List of Authors: Cashin, Aidan; University of New South Wales Faculty of Medicine, Prince of Wales Clinical School; Neuroscience Research Australia, Centre for PAIN IMPACT Folly, Thiago; Neuroscience Research Australia, Centre for Pain IMPACT Bagg, Matthew; Neuroscience Research Australia, Centre for Pain IMPACT; University of New South Wales, Prince of Wales Clinical School Wewege, Michael; Neuroscience Research Australia, Centre for Pain IMPACT; University of New South Wales, School of Medical Sciences Jones, Matthew; University of New South Wales Faculty of Medicine, School of Medical Sciences; Neuroscience Research Australia, Centre for Pain IMPACT Ferraro, Michael; Neuroscience Research Australia, Centre for Pain IMPACT; University of New South Wales Faculty of Medicine, School of Medical Sciences Leake, Hayley; University of South Australia, IIMPACT in Health Rizzo, Rodrigo; Neuroscience Research Australia, Centre for Pain IMPACT; University of New South Wales Faculty of Medicine, School of Medical Sciences Schabrun, Siobhan; Neuroscience Research Australia, Centre for Pain IMPACT Gustin, Sylvia; University of New South Wales, School of Psychology, Faculty of Science; Neuroscience Research Australia, Centre for Pain IMPACT Day, Richard; St Vincents Hospital Sydney and UNSW, Clinical Pharmacology & Toxicology; University of New South Wales, St. Vincent’s Clinical School, Faculty of Medicine Williams, Christopher; Hunter New England Population Health; The University of Newcastle, School of Medicine and Public Health McAuley, James; Neuroscience Research Australia, Centre for Pain IMPACT; University of New South Wales Faculty of Medicine, School of Medical Sciences
back pain, analgesics, muscle relaxant medicines, systematic review, Keywords: meta-analysis
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1 2 3 Efficacy, acceptability and harms of muscle relaxant medicines for adults 4 5 with non-specific low back pain: systematic review and meta-analysis 6 7 Aidan G Cashin (BSc)1,2, Thiago Folly (BSc)1, Matthew K Bagg (BSc(Hons)1,2,3, Michael A Wewege 8 1,4 1,4 1,4 9 (MSc) , Matthew D Jones (PhD) , Michael C Ferraro (BSc(Hons)) , Hayley B Leake 10 (BSc(Hons))5, Rodrigo R N Rizzo (MSc)1,4, Siobhan M Schabrun (PhD)1, Sylvia M Gustin (PhD)1,6, 11 12 Richard DayConfidential: (MD)7,8, Christopher M Williams For (PhD) 9,10Review, James H McAuley Only (PhD)1,4* 13 14 15 Affiliations: 16 17 1. Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, Australia 18 2. Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia 19 20 3. New College Village, University of New South Wales, Sydney, NSW, Australia 21 4. School of Medical Sciences, Faculty of Medicine UNSW, Sydney, NSW, Australia 22 23 5. IIMPACT in Health, University of South Australia, Adelaide, Australia 24 25 6. School of Psychology, Faculty of Science, Sydney, NSW, Australia 26 7. Clinical Pharmacology & Toxicology, St. Vincent’s Hospital, Sydney, NSW, Australia 27 28 8. St. Vincent’s Clinical School, Faculty of Medicine, UNSW, Sydney, Australia 29 9. School of Medicine and Public Health, University of Newcastle, Callaghan, Australia 30 31 10. Hunter New England Population Health, Hunter New England Local Health District, Newcastle 32 Australia 33 34 35 36 37 38 *Correspondence to: 39 A/Prof James H McAuley 40 Neuroscience Research Australia 41 PO Box 1165, Randwick, NSW 2031, Australia 42 43 Tel: +61 2 9399 1266 44 Email: [email protected] 45 46 47 Word Count: 4310 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 What is already known on this topic 4 5 6 Analgesic medicines are the most commonly prescribed treatment for low back pain. 7 The most recent systematic review provides evidence that muscle relaxant medicines produce 8 9 a clinically meaningful reduction in pain intensity for adults with acute low back pain. 10 A meta-epidemiology review highlighted that excluding evidence published in clinical trial 11 12 registriesConfidential: may have led to an overestimation For of Review the effect of muscle Only relaxant medicines. 13 14 What this study adds 15 16 17 This systematic review provides an update on the efficacy, acceptability and harms of muscle 18 relaxant medicines for adults with low back pain. 19 20 Muscle relaxant medicines are associated with small, non-clinically important improvements 21 in pain and function in the immediate term in adults with acute low back pain. 22 23 Muscle relaxant medicines are associated with increased odds of experiencing an adverse 24 25 event. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 ABSTRACT 4 5 6 Objective 7 8 To investigate the efficacy, acceptability and harms of muscle relaxant medicines for low back pain 9 10 (LBP). 11 12 Confidential: For Review Only 13 Design 14 Systematic review and meta-analysis of randomised controlled trials. 15 16 17 Data sources 18 19 MEDLINE, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and WHO 20 th 21 ICTRP from inception through to 4 June 2020. 22 23 24 Eligibility criteria for selecting studies 25 Randomised controlled trials of muscle relaxant medicines versus placebo, usual care, a waiting list, 26 27 or no treatment in adults reporting non-specific LBP. 28 29 30 Data extraction and synthesis 31 32 Two reviewers independently identified studies, extracted data, and assessed the risk of bias and 33 confidence in the evidence using the Cochrane risk-of-bias tool and GRADE, respectively. Random- 34 35 effects meta-analytic models through restricted maximum likelihood estimation were used to estimate 36 pooled effects and 95% confidence intervals. Outcomes included pain intensity (measured on a 0-100 37 38 point scale), function (measured on a 0-100 point scale), acceptability (discontinuation of the 39 40 medicine for any reason during treatment), and harms (the number of participants that reported 41 adverse events during treatment). 42 43 44 Results 45 46 We included 49 trials in the review, of which 31, sampling 6505 participants, were quantitatively 47 analysed. For acute LBP, there is very low and low confidence, respectively, that muscle relaxant 48 49 medicines provide a small, non-clinically important effect on pain intensity (mean difference [MD], - 50 51 7.52 points [95% CI -11.98 to -3.05]) and function (MD, -3.53 points [95% CI -6.61 to -0.45]) at 52 immediate term, and no effect at intermediate term. For acute LBP, there is low confidence that 53 54 muscle relaxant medicines are associated with twice the odds of experiencing an adverse event (odds 55 ratio [OR], 2.03 [95% CI 1.63 to 2.53]) and low confidence that muscle relaxant medicines are more 56 57 acceptable compared to placebo (OR, 0.76 [95% CI 0.61 to 0.95]). 58 59 60 Conclusions
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1 2 3 Treatment with muscle relaxant medicines provides small, non-clinically important improvements in 4 5 pain and function in the immediate term in adults with acute LBP, but are associated with increased 6 odds of experiencing an adverse event. As the certainty in evidence is low, the true effect of muscle 7 8 relaxant medicines remains unclear. 9 10 11 Registration 12 Confidential: For Review Only 13 PROSPERO (CRD42019126820); Open Science Framework (https://osf.io/mu2f5/) 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Introduction 4 5 Low back pain (LBP) is a major global public health problem. It has been the leading cause of 6 disability worldwide for the past 30 years,[1] placing a considerable burden on individuals, healthcare 7 8 and society. In the US, LBP is responsible for the highest total health care spending, estimated to be 9 10 $134.5 billion (95% Confidence Interval [CI], $122.4 to $146.9 billion) in 2016.[2] 11 12 Confidential: For Review Only 13 LBP is a common symptom related-reason to visit a GP,[3,4] with patients most commonly prescribed 14 analgesic medicines to manage their LBP.[5–7] Muscle relaxant medicines are the third most 15 16 frequently prescribed medicine for LBP.[5,7–9] Clinical guidelines provide conflicting 17 recommendations for prescribing muscle relaxant medicines to people with LBP.[10] 18 19 20 21 A systematic review that included five randomized controlled trials (RCTs) (n = 497 participants) 22 published up to October 2015 provides the most recent evidence that muscle relaxant medicines 23 24 produce a clinically meaningful reduction in pain intensity for people with acute LBP (Mean 25 Difference [MD], -21.3, [95% CI -29.0 to -13.5]).[11] However, in a recent meta-epidemiological 26 27 review Bagg et al., showed that excluding evidence published in clinical trial registries may have led 28 to an overestimation of the effect.[12] The true effect of muscle relaxant medicines for LBP is 29 30 therefore uncertain. 31 32 33 This systematic review and meta-analysis aimed to estimate the efficacy, acceptability and harms of 34 35 muscle relaxant medicines for the management of adults with LBP. 36 37 38 39 40 Methods 41 We prospectively registered the protocol on PROSPERO (CRD42019126820) and the Open Science 42 43 Framework (https://osf.io/mu2f5/) on 29 March 2019. We followed the Preferred Reporting Items for 44 Systematic reviews and Meta-Analyses (PRISMA) reporting guideline[13] (eTable 1 in the 45 46 Supplement). 47 48 49 Primary Outcomes 50 51 The primary outcomes were pain intensity, measured at the time point closest to the end of treatment, 52 and acceptability, which reflects satisfaction with the treatment strategy, operationalized as 53 54 discontinuation of the medicine for any reason during treatment. 55 56 57 Secondary Outcomes 58 59 The secondary outcomes were low back specific function, harms, serious harms and tolerability. Low 60 back specific function was measured as perceived disability at the time point closest to the end of
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1 2 3 treatment. Harms and serious harms were, respectively, operationalized as the number of participants 4 5 that reported adverse and serious adverse events during treatment. Tolerability was operationalized as 6 the number of participants that discontinued treatment specifically due to an adverse event. 7 8 9 10 Data Sources and Searches 11 We searched MEDLINE, Embase, CINAHL, the Cochrane Central Register of Controlled Trials 12 Confidential: For Review Only 13 (CENTRAL), the Cochrane Back and Neck Group’s trial register (through CENTRAL), 14 ClinicalTrials.gov, the EU Clinical Trials Register, and the World Health Organization’s (WHO) 15 16 International Clinical Trial Registry Platform from inception to 4 June 2020. We developed and 17 piloted the search strategies for bibliographic databases and clinical trial registries using medical 18 19 subject headings/Emtree and text words for 'LBP', 'RCTs' and 'spasmolytic muscle relaxant medicines' 20 21 (see Supplement for the MEDLINE search strategy & eTable 2 for trial registries search strategy). We 22 searched the reference lists from retrieved full-text articles and previous systematic reviews. We 23 24 searched PROSPERO for any ongoing or recently completed systematic reviews. 25 26 27 Study Selection 28 We included records of RCTs that allocated adult participants with non-specific LBP[14] to receive 29 30 (i) a systemically administered dose of a spasmolytic muscle relaxant medicine[15] or (ii) a sham 31 32 (placebo) medicine, (iii) continuation of usual care, (iv) placement on a waiting list or (v) no 33 treatment. We also included the combination of two medicines compared to one medicine alone (e.g., 34 35 tizanidine and ibuprofen vs ibuprofen alone). We included medicines that were classified 36 pharmacologically as muscle relaxant medicines, including benzodiazepines,[15] listed on the WHO 37 38 Anatomical Therapeutic Chemical (ATC) classification system[16] and licensed in either the US 39 40 (U.S. Food & Drug Administration[17]), Europe (European Medicines Agency[18]) or Australia 41 (Australian Register of Therapeutic Goods[19]) as at 29 March 2019 (eTable 3 in the Supplement). 42 43 We included trials reported in English, Italian, Portuguese, Spanish, German and Dutch. We excluded 44 trials reported in other languages or trials that sampled participants with specific spinal pathology 45 46 (e.g. infection, neoplasm, inflammatory disease or fracture)[14] or sciatica.[20] We excluded trials 47 that sampled multiple health conditions unless separate data were available for the participants with 48 49 LBP. We made no restriction on outcomes, duration of LBP or publication status. 50 51 52 The review team independently screened the titles and abstracts of all identified records in duplicate. 53 54 We retrieved full-length records of those deemed eligible and screened these again to confirm 55 inclusion. The full-length record of a trial registration was defined as the primary web-page and all 56 57 subsidiary pages and files located on the trial registry. We resolved disagreements through discussion 58 59 (AGC, MAW, MDJ, MCF, HBL, RRNR) or, when necessary, consultation of a third independent 60
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1 2 3 reviewer (MKB or JHM). We contacted authors up to three times within a six-week period when 4 5 further information was required to confirm eligibility. 6 7 8 In instances where a trial was linked to multiple record sources, we used an established hierarchy 9 10 preferencing the main published trial report, followed by other published records of the trial (e.g. 11 conference abstracts) and lastly, the trial registry record. We classified the trial registry record as the 12 Confidential: For Review Only 13 primary record if there was no evidence of publication. 14 15 16 Data Extraction and Quality Assessment 17 Using a standardized, piloted form, two reviewers independently extracted data and appraised study- 18 19 level risk of bias using the Cochrane ‘Risk of bias’ tool[21] and recommendations of Furlan et al. 20 21 2015.[22] We resolved disagreements through discussion, or with arbitration by a third reviewer if 22 necessary. We extracted the trial characteristics, participants, interventions, comparisons and 23 24 outcomes from each trial. In the absence of data, we estimated measures of variance using the 25 recommendations in the Cochrane Handbook for Systematic Reviews of Interventions.[23] We 26 27 assessed the risk of bias domains of selection, performance, attrition, detection, reporting and other 28 sources of bias, and determined overall risk of bias ratings for each trial using an adaptation of the 29 30 criteria in Furukawa et al. 2016.[24] We contacted authors up to three times to request additional 31 32 information. 33 34 35 Two reviewers independently formed judgements of confidence in the effects for each analysis using 36 the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.[25] 37 38 Disagreements were resolved through discussion or when required, with arbitration by a third 39 40 reviewer. The confidence in the evidence was initially classified as ‘high’ and was downgraded 41 according to the following recommended criteria: risk of bias, inconsistency, imprecision and 42 43 publication bias. The confidence in the evidence was defined as ‘high’, ‘moderate’, ‘low’ or ‘very 44 low’ confidence. 45 46 47 Data Synthesis and Analysis 48 49 We conducted meta-analyses of trials for each outcome using the available data for immediate term 50 51 (point closest to end of treatment) and intermediate term follow-up (>3 months post treatment). We 52 stratified these analyses by the duration of LBP observed in the included trials; acute (0-6 weeks), 53 54 sub-acute (6-12 weeks), chronic (>12 weeks), mixed (participants with multiple symptom durations) 55 and unclear (symptom duration not reported). We followed guidance[23] to incorporate trials with 56 57 multiple comparisons; dividing the control group sample size by the number of trial arms. We 58 59 converted aggregate outcome data (measure of central tendency and dispersion), for pain and low 60 back specific function, to a common 0 (no pain/complete function) to 100 (worst pain/no function)
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1 2 3 scale. We considered a difference in favour of muscle relaxant medicines of at least 10 points for pain 4 5 and function to be the minimal clinically important effect.[26,27] There are no published thresholds 6 for clinical meaningfulness for acceptability or harms outcomes for LBP. 7 8 9 10 We fit random-effects meta-analytic models through Restricted Maximum Likelihood Estimation, 11 using metafor in R (version 3.6.1).[28] We expressed effects for continuous outcomes with the mean 12 Confidential: For Review Only 13 between-group difference and accompanying 95% confidence intervals and effects for binary 14 outcomes using the odds ratio and accompanying 95% confidence intervals. We estimated the Q 15 16 statistic and the between-study variance (τ2) from each analysis and used these values to calculate 17 95% prediction intervals for the pooled effect and I² values. We used these measures to form 18 19 judgements about heterogeneity in conjunction with visual inspection of the distribution of effect 20 21 sizes in the forest plots. We formed judgements about publication bias for each meta-analysis by 22 visually assessing funnel plots and considering the proportion of trials we retrieved for that outcome 23 24 that were trial registry records. 25 26 27 Planned Investigation of Heterogeneity 28 We conducted planned subgroup analyses to explore whether heterogeneity varied by class of muscle 29 30 relaxant medicine and by prescribed dose. Class had three levels: antispasmodic, antispastic or 31 32 mixed/unclear.[15] Dose had three levels: standard dose, above standard dose or below standard dose, 33 according to the Prescribers Digital Reference,[29] Monthly Index of Medical Specialities[30] or 34 35 Australian Medicines Handbook.[31] 36 37 38 Sensitivity Analyses 39 40 We conducted planned sensitivity analyses to assess the influence on effect estimates of trials with 41 unclear definitions of non-specific LBP, and trials where measures of variance were imputed by 42 43 repeating the main analyses with and without the relevant trials included. 44 45 46 Secondary Analyses 47 We constructed an extended funnel plot to assess the impact of a hypothetical future trial on the 48 49 pooled effect for pain intensity in the intermediate term for acute LBP.[32–34] 50 51 52 We conducted additional post-hoc investigations excluding trials at high risk of bias, trials primarily 53 54 reported as trial registry records, and by subgrouping trials by type of muscle relaxant medicine. 55 56 57 58 59 Results 60
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1 2 3 We identified 3131 records, removed 194 duplicates and screened 2937 records during title and 4 5 abstract screening. We included 62 records, comprising 49 unique trials (Table 1 and Figure 1). Of 6 these unique trials, 34 were peer-reviewed journal articles,[35–70] 2 were conference abstracts[46,62] 7 8 and 13 were trial registry records. Thirty-one trials, including a total 6505 participants, contributed 9 10 data to the meta-analyses. Trials that did not provide eligible data for the meta-analyses were not 11 further synthesised. 12 Confidential: For Review Only 13 14 Study Characteristics 15 16 The included trials investigated 18 different muscle relaxant medicines, most commonly botulinum 17 toxin A (n = 8), tizanidine (n = 7), thiocolchicoside (n = 6) and carisoprodol (n = 5). The muscle 18 19 relaxant medicines investigated were administered orally in 36 trials, by intramuscular injections in 10 20 21 trials, and by intravenous injection in one trial. Two trials used mixed administration of a starting 22 intramuscular injection and subsequent oral doses. Most trials (n = 32) compared a muscle relaxant 23 24 medicine to placebo. 25 26 27 Thirty-five trials sampled participants with acute LBP, two with sub-acute LBP, and eight with 28 chronic LBP. Two trials investigated participants with both acute and sub-acute LBP (mixed duration 29 30 sample) and two trials did not report duration of LBP. 31 32 33 Risk of Bias and Confidence in the Evidence 34 35 We assessed completed trials (n = 38) for overall risk of bias; eight trials were assessed at low risk of 36 bias, three at moderate risk of bias, and 27 at high risk of bias. All trials reported equivalent timing of 37 38 outcome assessments between groups. Methodological shortcomings included failure to report 39 40 intention to treat effects (n = 8) and inadequate blinding of; participants (n = 4), care providers (n = 5) 41 and outcome assessors (n = 4). There was also unclear reporting of allocation concealment (n = 32), 42 43 treatment compliance (n = 25) and random sequence generation (n = 24) (eTable 4 in the 44 Supplement). The GRADE assessments for confidence in the evidence for each analysis are presented 45 46 in eTable 5 in the Supplement and referred to below. 47 48 49 Main Analyses 50 51 Primary outcome: pain intensity at end of treatment 52 Twenty-two trials (n = 5538 participants) reported data for pain immediately post treatment (Figure 53 54 2). Seventeen trials, including two trial registry records sampled 4761 participants with acute LBP. 55 We downgraded confidence in the evidence by three levels due to trial limitations and inconsistency. 56 57 There is very low confidence that the pooled effect of muscle relaxant medicines compared to placebo
58 2 59 is -7.52 [95% CI -11.98 to -3.05; Tau = 91.57] on a 0-100 scale. 60
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1 2 3 One trial sampled 28 participants with subacute LBP. We downgraded confidence in the 4 5 evidence by three levels due to trial limitations and imprecision. There is very low confidence that the 6 effect of muscle relaxant medicines compared to placebo is -19.00 points [95% CI -33.74 to -4.26] on 7 8 a 0-100 scale. 9 10 Two trials sampled 132 participants with chronic LBP. We downgraded confidence in the 11 evidence by three levels due to trial limitations and inconsistency. There is very low confidence that 12 Confidential: For Review Only 13 the pooled effect of muscle relaxant medicines compared to placebo is -10.10 points [95% CI -20.11 14 to -0.09; Tau2 = 41.25] on a 0-100 scale. 15 16 Two trials sampled 617 participants with mixed acute and subacute LBP. We downgraded 17 confidence in the evidence by two levels due to trial limitations. There is low confidence that the 18 19 pooled effect of muscle relaxant medicines compared to placebo is -4.39 points [95% CI -6.92 to - 20 2 21 1.86; Tau = 0.00] on a 0-100 scale. 22 23 24 Primary outcome: pain intensity at three months post treatment 25 Five trials (n = 922 participants) reported data for pain at three months post treatment (eFigure 1 in 26 27 the Supplement). Four trials sampled 814 participants with acute LBP. We downgraded confidence in 28 the evidence by one level due to imprecision. There is moderate confidence that the pooled effect of 29 30 muscle relaxant medicines compared to placebo is 0.71 points [95% CI -3.50 to 4.92; Tau2 = 0.00] on 31 32 a 0-100 scale. 33 One trial sampled 28 participants with subacute LBP. We downgraded confidence in the 34 35 evidence by three levels due to trial limitations and imprecision. There is very low confidence that the 36 effect of muscle relaxant medicines compared to placebo is -21.00 points [95% CI -34.36 to -7.54] on 37 38 a 0-100 scale. 39 40 One trial with four treatment arms sampled 80 participants with chronic LBP. We 41 downgraded confidence in the evidence by three levels due to trial limitations and imprecision. There 42 43 is very low confidence that the pooled effect of muscle relaxant medicines compared to placebo is - 44 2.04 points [95% CI -10.91 to 6.83; Tau2 = 0.00] on a 0-100 scale. 45 46 47 Primary outcome: acceptability 48 49 Sixteen trials (n = 3019 participants) reported data for acceptability (all-cause discontinuation) (Figure 50 51 3). Thirteen trials sampled 2834 participants with acute LBP. We downgraded the confidence in the 52 evidence by two levels due to trial limitations. There is low confidence that the odds of all-cause 53 54 discontinuation are lower for muscle relaxant medicines compared to placebo; odds ratio 0.76 [95% 55 CI 0.61 to 0.95; Tau2 = 0.00]. 56 57 Three trials sampled 185 participants with chronic LBP. We downgraded the confidence in 58 59 the evidence by two levels due to trial limitations and imprecision. There is low confidence that the 60
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1 2 3 odds of all-cause discontinuation are lower for muscle relaxant medicines compared to placebo; odds 4 5 ratio 0.64 [95% CI 0.23 to 1.80; Tau2 = 0.13]. 6 7 8 Secondary outcome: function at end of treatment 9 10 Eleven trials (n = 3114 participants) reported data for function immediately post treatment (eFigure 2 11 in the Supplement). All trials assessed function on the Roland Morris Disability Questionnaire.[71] 12 Confidential: For Review Only 13 Eight trials, including one trial registry record sampled 2653 participants with acute LBP. We 14 downgraded the confidence in the evidence by two levels due to trial limitations. There is low 15 16 confidence that the pooled effect of muscle relaxant medicines compared to placebo is -3.53 points 17 [95% CI -6.61 to -0.45; Tau2 = 8.76] on a 0-100 scale. 18 19 Two trials sampled 132 participants with chronic LBP. We downgraded confidence in the 20 21 evidence by three levels due to trial limitations and imprecision. There is very low confidence that the 22 pooled effect of muscle relaxant medicines compared to placebo is -3.49 points [95% CI -8.28 to 23 24 1.31; Tau2 = 0.00] on a 0-100 scale. 25 One trial sampled 329 participants with mixed acute and subacute LBP. We downgraded 26 27 confidence in the evidence by three levels due to trial limitations and imprecision. There is very low 28 confidence that the pooled effect of muscle relaxant medicines compared to placebo is -19.17 points 29 30 [95% CI -27.70 to -10.64] on a 0-100 scale. 31 32 33 Secondary outcome: function at three months post treatment 34 35 Five trials (n = 605 participants) reported data for function at three months post treatment (eFigure 3 36 in the Supplement). All trials assessed function on the Roland Morris Disability Questionnaire.[71] 37 38 Four trials sampled 525 participants with acute LBP. We downgraded confidence in the evidence by 39 40 two levels due to inconsistency and imprecision. There is low confidence that the pooled effect of 41 muscle relaxant medicines compared to placebo is 0.66 points [95% CI -6.35 to 7.67; Tau2 = 30.00] 42 43 on a 0-100 scale. 44 One trial with four treatment arms sampled 80 participants with chronic LBP. We 45 46 downgraded confidence in the evidence by three levels due to trial limitations and imprecision. There 47 is very low confidence that the pooled effect of muscle relaxant medicines compared to placebo is - 48 49 3.14 points [95% CI -12.10 to 5.91; Tau2 = 0.00] on a 0-100 scale. 50 51 52 Secondary outcome: harms 53 54 Twenty-two trials (n = 4277 participants) reported data for harms (adverse events) (eFigure 4 in the 55 Supplement). Nineteen trials, including two trial registry records sampled 3853 participants with acute 56 57 LBP. We downgraded confidence in the evidence by two levels due to trial limitations. There is low 58 59 confidence that the odds of experiencing an adverse event are higher for muscle relaxant medicines 60 compared to placebo; odds ratio 2.03 [95% CI 1.63 to 2.53; Tau2 = 0.07].
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1 2 3 Two trials sampled 95 participants with chronic LBP. We downgraded confidence in the 4 5 evidence by one level due to imprecision. There is moderate confidence that the odds of experiencing 6 an adverse event are higher for muscle relaxant medicines compared to placebo; odds ratio 1.50 [95% 7 8 CI 0.33 to 6.78; Tau2 = 0.00]. 9 10 One trial sampled 329 participants with mixed acute and subacute LBP. We downgraded 11 confidence in the evidence by three levels due to trial limitations and imprecision. There is very low 12 Confidential: For Review Only 13 confidence that the odds of experiencing an adverse event are higher for muscle relaxant medicines 14 compared to placebo; odds ratio 1.68 [95% CI 0.60 to 4.64]. 15 16 17 Secondary outcome: serious harms 18 19 Two trials, both trial registry records, including 830 participants with acute LBP reported data for 20 21 serious harms (serious adverse events) (eFigure 5 in the Supplement). We downgraded confidence in 22 the evidence by three levels due to trial limitations and imprecision. There is very low confidence that 23 24 the odds of experiencing a serious adverse event is higher for muscle relaxant medicines compared to 25 placebo; odds ratio 2.36 [95% CI 0.27 to 20.86; Tau2 = 0.00]. 26 27 28 Secondary outcome: tolerability 29 30 Six trials including 1836 participants with acute LBP reported data for tolerability (discontinuation 31 32 due to adverse events) (eFigure 6 in the Supplement). We downgraded confidence in the evidence by 33 three levels due to trial limitations and imprecision. There is very low confidence that the odds of 34 35 discontinuing treatment due to an adverse event are higher for muscle relaxant medicines compared to 36 placebo; odds ratio 2.03 [95% CI 0.75 to 5.49; Tau2 = 0.91]. 37 38 39 40 Other Analyses 41 Subgroup analyses 42 43 We conducted planned subgroup analyses to investigate heterogeneity in the primary outcome pain 44 intensity at immediate term follow-up in participants with acute LBP. The results of the subgroup 45 46 analyses are presented in eFigures 7 and 8 in the Supplement. Subgrouping by muscle relaxant 47 medicine class or dose failed to explain the identified heterogeneity. 48 49 50 51 The planned sensitivity analyses and influence of further research on results are presented in eResults 52 and eFigure 9, respectively, in the Supplement. 53 54 55 Post-hoc subgroup analyses 56 57 The post-hoc subgroup analyses excluding trials primarily reported as trial registry records and trials 58 59 subgrouped by medicine type are presented in eFigures 10-14 in the Supplement. The results of the 60 subgroup analysis investigating the effect of removing trials at high risk of bias in the primary
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1 2 3 outcome pain intensity at immediate term follow-up for acute LBP are presented in eFigure 15 in the 4 5 Supplement. Subgrouping by overall study level risk of bias reduced heterogeneity in the 'low’ and 6 ‘moderate’ risk of bias subgroup but did not reduce heterogeneity in the ‘high’ risk of bias subgroup. 7 8 Further, the pooled effect estimate included the null when ‘high’ risk of bias studies were removed 9 10 (MD, 0.23, [95% CI -4.20 to 4.73]). 11 12 Confidential: For Review Only 13 Discussion 14 There is very low confidence that immediately following treatment, muscle relaxant medicines reduce 15 16 pain intensity for people with acute LBP. This effect is small, <8 points on a 0–100 point scale, and 17 18 does not meet our pre-specified threshold to be clinically meaningful. There is very low confidence 19 that muscle relaxant medicines provide a clinically meaningful reduction in pain intensity 20 21 immediately following treatment for people with chronic LBP. There is no effect of muscle relaxant 22 medicines compared with placebo on pain intensity in people with acute or chronic LBP in the 23 24 intermediate term. No trials evaluated the effect of muscle relaxant medicines on long term outcomes. 25 There were small effects on function for people with acute and chronic LBP. Muscle relaxant 26 27 medicines compared to placebo are associated with more adverse events but are more acceptable. The 28 29 certainty in these findings is reduced by the large number of studies at high risk of bias. However, our 30 post hoc analysis showed that removing studies at high risk of bias reduced the effect to zero. 31 32 33 Strengths and weaknesses of the study 34 35 This systematic review was prospectively registered and reported in line with PRISMA.[13] We 36 37 included only licensed muscle relaxant medicines evaluated in randomized controlled trials as they 38 provide the best evidence on the efficacy of currently used muscle relaxant medicines. We included 39 40 findings from 49 published or trial registration reports. We used the Cochrane ‘Risk of bias’ tool and 41 published recommendations from the Cochrane Back and Neck Group[22] to assess study level risk of 42 43 bias and evaluated the confidence in the evidence using the GRADE system.[25] Finally, this is the 44 first review to evaluate the acceptability and tolerability – both important aspects of clinical decision 45 46 making – of receiving a muscle relaxant medicine compared to placebo in people with LBP. 47 48 49 Inadequate reporting and a failure to respond to data requests meant some relevant trials were not 50 51 included in each meta-analysis. From the 20 trialists contacted, only one author, responsible for four 52 trials, provided relevant data. Further, most of the included trials were at high risk of bias mainly due 53 54 to a lack of blinding (participant, therapist and assessor) and failure to report whether analysis was 55 conducted by intention to treat. The increased prevalence of high risk trials downgraded the certainty 56 57 of the evidence reported in this review. We restricted the inclusion of studies based on publication 58 59 language. Although we included trials published in English, Italian, Portuguese, Spanish, German and 60 Dutch, we acknowledge that we may have missed some relevant trials. Finally, we included trials in
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1 2 3 which participants received co-administration of additional analgesic medicines. Although most 4 5 included trials were compared to placebo, the inclusion of other analgesic medicines may influence 6 the interpretation of findings. 7 8 9 10 Strengths and weaknesses in relation to other studies 11 Findings from previous systematic reviews suggest that muscle relaxant medicines provide significant 12 Confidential: For Review Only 13 and clinically meaningful reductions in pain in the immediate term for people with acute LBP.[11,72] 14 Compared to the most recent review,[11] our meta-analysis included an additional 12 trials (n = 15 16 4265), and demonstrated a smaller and more precise pooled estimate below the proposed threshold of 17 clinical importance for pain.[26] We included 12 additional trials through an extensive and up to date 18 19 search including data from trial registry reports, and by including trials reporting pain intensity on 20 21 verbal rating scales[73] and trials comparing the combination of a muscle relaxant medicine and 22 analgesic medicine compared to an analgesic medicine alone. In addition, our review contributes 23 24 evidence for the efficacy of muscle relaxant medicines compared to placebo at immediate term 25 follow-up in people with chronic LBP. Although the effect is clinically meaningful, caution is 26 27 required in interpretation considering the width of the confidence interval (spanning -20.1 to -0.1 28 points on a 0-100 pain scale) and the very low confidence on which this result is based. Future trials 29 30 are needed to improve the precision of this effect. 31 32 33 We focused on spasmolytic muscle relaxant medicines which encompass a range of chemically 34 35 unrelated medicines that typically act on the central nervous system, or in some cases, the skeletal 36 muscle cell.[15] We grouped muscle relaxant medicines according to their shared pharmacology. The 37 38 choice of muscle relaxant medicine and frequency of prescription by a physician varies between 39 40 countries,[8,74] with considerable clinical uncertainty in preferencing one muscle relaxant medicine 41 over another. Considering this uncertainty, we combined all included muscle relaxant medicines to 42 43 produce a single pooled effect size for each outcome. To explore heterogeneity in the pain outcome, 44 we conducted pre-planned subgroup analyses based on muscle relaxant medicine class and dose. 45 46 Subgroup analyses did not help explain the heterogeneity observed in the pooled effect for pain. 47 48 49 Implications for clinicians and policymakers 50 51 Analgesic medicines are the most common treatment for LBP.[5–7] Our findings indicate that muscle 52 relaxant medicines are an acceptable treatment strategy for people with acute LBP, producing small, 53 54 but likely clinically unimportant effects on immediate term pain and function. Acceptability is a 55 complex construct, reflecting the influence of multiple factors on an individual’s decision to follow a 56 57 treatment strategy. As well, prescription of muscle relaxant medicines should be considered alongside 58 59 the harms and tolerability. Compared to placebo, muscle relaxant medicines are associated with twice 60 the odds of experiencing an adverse event (commonly dizziness, drowsiness, headache and
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1 2 3 nausea[75]) and twice the odds of dropping out of treatment following an adverse event. Although 4 5 this review did not assess the risk of dependency and abuse associated with muscle relaxant 6 medicines, indirect evidence suggests misuse or abuse should be considered.[72,75] 7 8 9 10 Conclusions 11 This systematic review found that muscle relaxant medicines for the treatment of acute LBP do not 12 Confidential: For Review Only 13 provide clinically meaningful improvements in pain intensity immediately, or up to three months after 14 treatment, and are associated with twice the odds of adverse and serious adverse events. For the 15 16 treatment of chronic LBP, muscle relaxant medicines compared to placebo provide clinically 17 meaningful improvements in pain intensity at immediate term which are not sustained at intermediate 18 19 term follow-up. Although muscle relaxant medicines are considered acceptable, with less all-cause 20 21 treatment discontinuations compared to placebo, clinicians and patients must carefully weigh the 22 benefits against the harms when discussing the possibility of muscle relaxant medicines for treatment 23 24 of LBP. 25 26 27 28 29 Funding/ Support 30 No external funding was obtained for this review. AGC is supported by the University of New South 31 32 Wales Prince of Wales Clinical School Postgraduate Research Scholarship and a NeuRA PhD 33 Candidature Supplementary Scholarship. MKB is supported by a NeuRA PhD Candidature 34 35 Scholarship and Supplementary Scholarship and was additionally funded during this work by an 36 37 Australian Government Research Training Program Scholarship and a UNSW Research Excellence 38 Award. MAW is supported by a University Postgraduate Award and School of Medical Sciences Top- 39 40 Up Scholarship from the University of New South Wales, and a Postgraduate Scholarship from the 41 National Health and Medical Research Council of Australia. MCF is supported by an Australian 42 43 Medical Research Future Fund Grant GNTID1170205. HBL is supported by Australian Government 44 45 post-graduate award. RRNR is supported by the University of New South Wales School of Medical 46 Sciences Postgraduate Research Scholarship and a NeuRA PhD Candidature Supplementary 47 48 Scholarship. SMS receives salary support from the National Health and Medical Research Council of 49 Australia (#1105040). SMG is supported by the Rebecca L. Cooper Medical Research Foundation. 50 51 52 53 Conflict of Interest Disclosures 54 All authors declare no conflicts of interest relevant to this study. 55 56 57 Reproducible Research Statement 58 59 Study protocol: PROSPERO (CRD42019126820); Open Science Framework (https://osf.io/mu2f5/) 60
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1 2 3 4 5 Data set and statistical code: The dataset used and analysed during this study, and the accompanying 6 7 code is available from the corresponding author upon reasonable request. 8 9 10 Transparency statement 11 The manuscript is an honest, accurate, and transparent account of the study being reported; no 12 Confidential: For Review Only 13 important aspects of the study have been omitted; and any discrepancies from the study as originally 14 planned (and, if relevant, registered) have been explained. 15 16 17 18 Patient and public involvement 19 Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination 20 21 plans of this study. 22 23 24 Patient consent for publication 25 Not required. 26 27 28 29 Ethical Approval 30 This study did not require ethical approval. It is a re-analysis of published trials, using data publicly 31 32 available online. 33 34 35 Author Contributions 36 37 TF, MKB and JHM conceived the idea for the project. TF, MKB, MAW, MCF, SMS, SMG, RD and 38 JHM contributed to the project design and protocol development. TF conducted the search. AGC, TF, 39 40 MKB, MDJ, MAW, MCF, RRNR, HBL conducted the study selection, data extraction and quality 41 appraisal. AGC and MAW analysed the data. AGC, MAW and JHM had full access to all the data in 42 43 the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. 44 AGC wrote the first draft of the manuscript. All authors provided substantive feedback on the 45 46 manuscript and have read and approved the final version. The corresponding author attests that all 47 48 listed authors meet authorship criteria and that no others meeting the criteria have been omitted. 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Table 1. Characteristics of included studies 4 5 Study, Year Study sample Setting Number of Test intervention, n Comparison intervention, Duration of Overall 6 (Reference) relevant n treatment risk of trial arms Bias 7 Mean age (SD) and percentage female (%) 8 Akhter 2017[35] 288 participantsConfidential: with mixed acute and India 2 ForOral thiocolchicoside Review Oral diclofenac sodium, Only7 days High 9 subacute LBP 150mg/day + diclofenac 144 10 sodium, 144 11 Age and sex not reported 12 Aksoy 2002[36] 329 participants with mixed acute and Turkey 2 Oral thiocolchicoside Standard treatment (oral 5-7 days High 13 subacute LBP 16mg/day + standard NSAID or another 14 treatment (NSAID or an analgesic), 155 thiocolchicoside group 39.7 (11) yrs, 67% analgesic), 174 15 female; standard treatment group 40.2 16 (11.3) yrs, 61% female 17 18 Aparna 2016[47] 200 participants with acute LBP India 2 Oral thiocolchicoside Oral aceclofenac, 100 7 days High 19 8mg/day + aceclofenac, 20 Age and sex not reported 100 21 Baratta 1982[58] 120 participants with acute LBP USA 2 Oral cyclobenzaprine Oral placebo, 60 10 days High 22 30mg/day, 60 23 cyclobenzaprine group 35 yrs a, 41% 24 female; placebo group 38 yrs a, 41% female 25 26 Berry (a) 105 participants with acute LBP UK 2 Oral tizanidine Oral placebo + ibuprofen, 7 days High 27 1988[65] 12mg/day + ibuprofen, 54 28 tizanidine group 43 (12.4) yrs, 47% 51 female; placebo group 42 (12.4) years, 29 43% female 30 31 Berry (b) 112 participants with acute LBP UK 2 Oral tizanidine Oral placebo, 53 7 days High 32 1988[66] 12mg/day, 59 tizanidine group 44 (13) yrs, 49% female; 33 placebo group 38 (13) yrs, 49% female 34 35 Borenstein 40 participants with acute LBP USA 2 Oral cyclobenzaprine Oral naproxen, 20 14 days High 36 1990[67] 30mg/day + naproxen, cyclobenzaprine group 37 yrs a, 35% 20 37 female; comparator group 37 yrs a, 25% 38 female 39 40 41 42 Cashin et al. 2020 Page 22 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 24 of 57
1 2 3 Casale 1988[68] 20 participants with acute LBP Italy 2 Oral dantrolene Oral placebo, 10 4 days Moderate 4 25mg/day, 10 5 dantrolene group 46.7 yrs a, 30% female; placebo group 47.1 yrs a, 20% female 6 7 Cogné 2017[69] 19 participants with chronic LBP France 2 IM botulinum toxin A IM placebo, 10 Single dose High 8 Confidential: For200 units, 9 Review Only 9 (crossover) botulinum toxin A group 38.1 (5.94) yrs, 67% female; placebo group 38.2 (10.27) 10 yrs, 100% female 11 12 Dapas 1985[70] 200 participants with acute LBP USA 2 Oral baclofen range 30- Oral placebo, 100 14 days High 13 80mg/day, 100 baclofen group 42.7 yrs a, 48% female; 14 placebo group 41.8 yrs a, 56% female 15 16 Emrich 2015[37] 202 participants with acute LBP Germany 2 Oral methocarbamol Oral placebo, 104 8 days High 17 4500mg/day, 98 methocarbamol group 45.3 (11) yrs, 63% 18 female; placebo group 43.8 (11.6) yrs, 19 71% female 20 21 Fathie 1964[38] 200 participants with acute LBP USA 2 Oral metaxalone Oral placebo, 99 7 days High 3200mg/day, 101 22 Age and sex not reported 23 24 Foster 2001[39] 31 participants with chronic LBP USA 2 IM botulinum toxin A IM placebo Single dose Low 25 200 units botulinum toxin A group 46.4 yrs a, 53% 26 female; placebo group 47 yrs a, 50% 27 female 28 29 Friedman 323 participants with acute LBP USA 2 Oral cyclobenzaprine Oral placebo +naproxen, 10 days Low 2015[40] range 5-30mg/day + 107 30 cyclobenzaprine group 38 (11) yrs, 42% naproxen, 108 31 female; oxycodone group 39 (11) yrs, 56% 32 female [not synthesized]; placebo 39 (11) 33 yrs, 50% female 34 Friedman 114 participants with acute LBP USA 2 Oral diazepam range 5- Oral placebo + naproxen 7 days Low 35 2017[41] 20mg/day + naproxen, 36 diazepam group 34 (12) yrs, 47% female; 57 37 placebo group 38 (12) yrs, 42% female 38 39 40 41 42 Cashin et al. 2020 Page 23 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 25 of 57 BMJ
1 2 3 Friedman 240 participants with acute LBP USA 3 Oral orphenadrine Oral placebo + naproxen, 7 days Low 4 2018[42] 200mg/day + naproxen, 79 5 orphenadrine group 40 (12) yrs, 43% 80 female; methocarbamol group 38 (12) yrs, 6 51% female; placebo group 39 (12) yrs, Oral methocarbamol 7 43% female range 2250-4500mg/day 8 Confidential: For+ naproxen, 81 Review Only 9 Friedman 320 participants with acute LBP USA 4 Oral tizanidine range 2- Oral placebo + ibuprofen, 7 days Low 10 2019[43] 16mg/day + ibuprofen, 80 11 tizanidine group 40 (11) yrs, 48% female; 80 12 metaxalone group 37 (10) yrs, 45% female; baclofen group 39 (12) yrs, 29% Oral metaxalone range 13 female; placebo group 39 (11) yrs, 45% 400-3200mg/day+ 14 female ibuprofen, 80 15 16 Oral baclofen range 10- 80mg/day + ibuprofen, 17 80 18 19 Goforth 2014[44] 58 participants with chronic LBP USA 2 Oral eszopiclone Oral placebo + naproxen, 28 days Low 20 3mg/day + naproxen, 33 25 eszopiclone group 45.7 (11) yrs, 61% 21 female; placebo group 40.1 (12.8) yrs, 22 72% female 23 Gold 1978[45] 60 participants with acute LBP USA 2 Oral orphenadrine Oral placebo, 20 7 days High 24 200mg/day, 20 25 Age and sex not reported 26 27 Herskowitz 28 participants with subacute LBP USA 2 IM botulinum toxin A IM placebo, 15 Single dose High 28 2004[46] 400 units, 13 Age and sex not reported 29 30 Hindle 1972[48] 48 participants with acute LBP USA 2 Oral carisoprodol Oral placebo, 16 4 days High 31 1400mg/day, 16 32 carisoprodol group 37 yrs a; butabarbital group 34.6 yrs a; placebo group 43.5 yrs a 33 34 Entire sample 44% female 35 36 Hingorani 50 participants with acute LBP UK 2 IM diazepam 40mg + IM placebo + oral placebo, 6 days High 1966[49] oral diazepam 8mg/day, 25 37 Age not reported 25 38 39 Entire sample 20% female 40 41 42 Cashin et al. 2020 Page 24 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 26 of 57
1 2 3 Jazayeri 2011[50] 50 participants with chronic LBP Iran 2 IM botulinum toxin A IM placebo 25 Single dose High 4 200 units, 25 5 botulinum toxin A group 41.7 yrs a, 52% female; placebo group 42.3 yrs a, 56% 6 female 7 8 Ketenci 2005[51] 97 participantsConfidential: with acute LBP Turkey 3 ForOral thiocolchicoside Review Oral placebo, 27 Only7 days High 9 16mg/day, 38 thiocolchicoside group 37 yrs a, 42% 10 female; tizanidine group 37 yrs a, 63% Oral tizanidine 6mg/day, 11 female; placebo group 40 yrs a, 52% 32 12 female 13 Klinger 1988[52] 80 participants with acute LBP USA 2 IV orphenadrine 60mg, IV placebo, 40 Single dose Low 14 40 15 orphenadrine group 35.7 (12.4) yrs, 1% 16 female; placebo group 31.9 (11.7) yrs, 30% female 17 18 Lepisto 1979[53] 30 participants with acute LBP Finland 2 Oral tizanidine 6mg/day, Oral placebo, 15 7 days Moderate 19 15 20 tizanidine group 42.5 yrs a, 47% female; placebo group 40.8 yrs a, 53% female 21 22 Machado 43 participants with chronic LBP USA 2 IM botulinum toxin A IM placebo, 22 Single Moderate 23 2016[54] range 500-1000 units, 21 injection 24 botulinum toxin A group 51.3 yrs a, 67% female; placebo group 48.6 yrs a, 45% 25 female 26 27 Pareek 2009[55] 197 participants with acute LBP India 2 Oral tizanidine 4mg/day Oral aceclofenac, 96 7 days High 28 + aceclofenac, 101 tizanidine group 43.3 (12.7) yrs, 39% 29 female; comparator group 43.5 (10.9) yrs, 30 40% female 31 32 Ralph 2008[56] 562 participants with acute LBP USA 2 Oral carisoprodol Oral placebo, 285 7 days High 1000mg/day, 277 33 carisoprodol group 39.3 (11.8) yrs, 47% 34 female; comparator group 41.5 (11.7) yrs, 35 54% female 36 Salvini 1986[57] 30 participants with LBP Italy 2 Oral dantrolene Oral ibuprofen, 15 8 days High 37 1200mg/day + 38 Age and sex not reported ibuprofen, 15 39 40 41 42 Cashin et al. 2020 Page 25 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 27 of 57 BMJ
1 2 3 Schliessbach 98 participants with chronic LBP Switzerland 2 Oral clobazam 20mg, 49 Oral placebo, 49 2 hours Low 4 2017[59] 5 Age and sex not reported (crossover) 6 7 Serfer 2010[60] 828 participants with acute LBP USA 3 Oral carisoprodol Oral placebo, 276 7 days High 8 Confidential: For(350mg) 1400mg/day, Review Only 9 carisoprodol (350mg) group 40.5 (12.4) 281 yrs, 54% female; carisoprodol (250mg) 10 group 40.9 (11.7) yrs, 51% female; Oral carisoprodol 11 placebo group 40.7 (13.1) yrs, 59% female (250mg) 1000mg/day, 12 271 13 Tervo 1976[61] 50 participants with acute LBP Finland 2 IM orphenadrine 60mg + IM placebo + oral 7-10 days High 14 oral orphenadrine paracetamol, 25 15 Age not reported 210mg/day & 16 paracetamol, 25 17 Entire sample 66% female 18 Thompson 76 participants with acute LBP UK 2 Oral tizanidine 6mg/day Oral placebo 10 days High 19 1983[62] 20 Age and sex not reported 21 Tüzün 2003[63] 149 participants with acute LBP Turkey 2 IM thiocolchicoside IM placebo, 72 5 days High 22 8mg/day, 77 23 thiocolchicoside group 40.7 (10.3) yrs, 24 48% female; placebo group 41 (11) yrs, 25 56% female 26 Zaringhalam 84 participants with chronic LBP Iran 4 Oral baclofen 30mg/day, No treatment, 21 35 days High 27 2010[64] 21 28 baclofen group 55.1 (3.3) yrs; no treatment 29 group 54.3 (4.2) yrs; acupuncture group Oral baclofen 30mg/day 54.2 (5.4) yrs; baclofen + acupuncture + acupuncture, 21 Acupuncture, 21 30 group 54.2 (5.6) yrs 31 32 Entire sample 0% female 33 ACTRN12616000 Participants with acute LBP Australia 2 Oral zoplicone Oral placebo 14 days NA 34 017426 7.5mg/day 35 36 (status: terminated) 37 38 EUCTR2017- 134 participants with acute LBP Greece 2 IM thiocolchicoside 4mg IM diclofenac Single NA 39 004530-29 + diclofenac injection 40 41 42 Cashin et al. 2020 Page 26 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 28 of 57
1 2 3 Age and sex not reported 4 5 EUCTR2019- Participants with acute LBP and/or sciatica Hungry 2 Oral tolperisone Oral placebo 14 days NA 001885-14 6 (status: ongoing) 7 IRCT2011110900 46 participants with LBP Iran 2 Oral zolpidem 5mg/day Oral placebo 28 days NA 8 8035N4 Confidential: For Review Only 9 Age and sex not reported 10 NCT00671879 840 participants with acute LBP USA 3 Oral carisoprodol Oral placebo, 280 14 days High 11 (500mg) 1000mg/day, 12 carisoprodol (500mg) group 41.6 (11.8) 279 13 yrs, 52% female; carisoprodol (700mg) group 41.5 (12.4) yrs, 53% female; Oral carisoprodol 14 placebo group 41.4 (11.9) yrs, 51% female (700mg) 1400mg/day, 15 281 16 17 NCT00671502 840 participants with acute LBP USA 3 Oral carisoprodol Oral placebo, 279 14 days High (500mg) 1000mg/day, 18 carisoprodol (500mg) group 41.4 (12.6) 280 19 yrs, 51% female; carisoprodol (700mg) 20 group 40.3 (13.1) yrs, 47% female; Oral carisoprodol placebo group 40.9 (12.7) yrs, 49% female (700mg) 1400mg/day, 21 281 22 23 NCT00817986 161 participants with acute LBP USA 4 Oral arbaclofen placarbil Oral placebo 14 days NA 24 (20mg) 40mg/day Age and sex not reported 25 Oral arbaclofen placarbil 26 (30mg) 60mg/day 27 28 Oral arbaclofen placarbil (40mg) 80mg/day 29 30 NCT03802565 415 participants with acute LBP USA 5 Oral tolperisone (50mg) Oral placebo 14 days NA 31 150mg/day 32 Age and sex not reported Oral tolperisone (100mg) 33 300mg/day 34 35 Oral tolperisone (150mg) 36 450mg/day 37 Oral tolperisone (200mg) 38 600mg/day 39 40 41 42 Cashin et al. 2020 Page 27 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 29 of 57 BMJ
1 2 3 NCT00404417 Participants with chronic LBP USA 4 IM botulinum toxin A IM placebo Single dose NA 4 5 (crossover, status: active not 6 recruiting) 7 8 NCT00384579 ParticipantsConfidential: with acute LBP USA 2 ForIM botulinum toxinReview B IM placebo OnlySingle dose NA 9 (status: 10 terminated) 11 12 NCT00384371 Participants with subacute LBP USA 2 IM botulinum toxin A IM placebo Single dose NA 13 (status: 14 terminated) 15 16 NCT02887534 Participants with acute LBP Not 5 Oral tizanidine Oral placebo Not reported NA 17 reported (status: Oral SPARC1401-low 18 withdrawn) dose 19 20 Oral SPARC1401-mid 21 dose 22 Oral SPARC1401-high 23 dose 24 25 NCT01587508 Participants with acute LBP Brazil 3 Oral cyclobenzaprine Oral meloxicam & 7 days NA 20mg/day cyclobenzaprine 26 (status: 27 withdrawn) Oral meloxicam 28 a 29 Standard deviation not reported. Abbreviations: LBP, Low Back Pain; SD, Standard Deviation; IM, Intramuscular; IV, Intravenous; NA, Not Applicable 30 31 32 33 34 35 36 37 38 39 40 41 42 Cashin et al. 2020 Page 28 of 29 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 30 of 57
1 2 3 Figure captions 4 5 6 Figure 1. PRISMA flow diagram of the record selection process. 7 8 9 10 11 Figure 2. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) at 12 immediateConfidential: term follow-up for adults with LBP For. Negative Review values for the mean Only difference indicate that 13 14 the effect favors muscle relaxant medicines compared to placebo. Whereas, negative values for the 15 trial observations indicate change from baseline. a Standard deviation imputed. b Standard deviation 16 17 transformed. 18 19 20 21 Figure 3. All-cause discontinuation (acceptability) of muscle relaxant medicines compared to placebo 22 for adults with LBP. An odds ratio of less than 1 indicates greater odds of discontinuation in the 23 24 placebo group (i.e. the effect favors muscle relaxant medicines). 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4
5 Records identified through Records identified through Additional records identified 6 database searching trial registry searching through other sources 7 (n = 2683) (n = 445) (n = 3) 8
9 Identification 10 11 12 Confidential:Records Forafter duplicates Review removed Only 13 (n =2937) 14 15 16 17 18 Screening Records screened Records excluded 19 (n = 2937) (n = 2750) 20 21 22 23 Records linked Full-text articles assessed for Full-text articles excluded, 24 (n = 42) eligibility with reasons 25 (n =186) (n = 95)
26 35 ineligible publication type Eligibility 27 28 17 ineligible patient 29 Studies included in this population or data not 30 review available (n = 49) 31 29 ineligible medicine or 32 route of administration
33 13 ineligible language 34 35 Studies included in meta- 1 full text not available
Included 36 analyses (n = 31) 37 38 39 40 41 42 43 44 45 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta- 46 Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097
47 For more information, visit www.prisma-statement.org. 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3
4 a a 5 a a 6 b b 7 8 Confidential: For Review Only 9 10 b b
11 b b 12 b b a a 13 a a 14 b b 15 b b 16 a a 17 18 19 20 21 22 23 b b 24 25 26 27 28 29 30 31
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1 2 3 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 https://mc.manuscriptcentral.com/bmj 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 34 of 57
1 2 3 Supplementary Online Content 4 5 6 7 Search Strategy. Ovid MEDLINE 8 9 eTable 2. Search strategies for Trial Registries 10 11 eTable 3. Interventions of interest 12 Confidential: For Review Only 13 eTable 4. Risk of Bias Assessments 14
15 16 eTable 5. Strength of Evidence (GRADE) 17 18 eResults. Planned sensitivity analyses 19 20 eFigure 1. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) at 21 intermediate term follow-up for adults with low back pain 22 23 eFigure 2. Effect of muscle relaxant medicines compared to placebo on function (0-100 scale) at 24 immediate term follow-up for adults with low back pain 25
26 27 eFigure 3. Effect of muscle relaxant medicines compared to placebo on function (0-100 scale) at 28 intermediate term follow-up for adults with low back pain 29 30 eFigure 4. Adverse events (harms) of muscle relaxant medicines compared to placebo for adults with 31 low back pain 32 33 eFigure 5. Serious adverse events (serious harms) of muscle relaxant medicines compared to 34 placebo for adults with low back pain 35
36 37 eFigure 6. Discontinuation due to adverse events (tolerability) of muscle relaxant medicines 38 compared to placebo for adults with low back pain 39 40 eFigure 7. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) at 41 intermediate term follow-up for adults with acute low back pain subgrouped by muscle relaxant 42 medicine class 43 44 eFigure 8. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) at 45 intermediate term follow-up for adults with acute low back pain subgrouped by prescribed medicine 46 dose 47 48 49 eFigure 9. Extended funnel plot. Significance contours for comparison of muscle relaxant medicines 50 and placebo for adults with acute low back pain on pain intensity (0-100 scale) at immediate term 51 follow-up 52 53 eFigure 10. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) 54 at immediate term follow-up for adults with acute low back pain subgrouped by medicine type 55 56 eFigure 11. Acceptability (all cause discontinuation of treatment) of muscle relaxant medicines 57 compared to placebo for adults with acute low back pain subgrouped by medicine type 58 59 60
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1 2 3 eFigure 12. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) 4 immediate term follow-up for people with acute low back pain subgrouped by primary trial record 5 6 eFigure 13. Effect of muscle relaxant medicines compared to placebo on function (0-100 scale) 7 8 immediate term follow-up for people with acute low back pain subgrouped by primary trial record 9 10 eFigure 14. Harms (incidence of any adverse event) of muscle relaxant medicines compared to 11 placebo for people with acute LBP subgrouped by primary trial record 12 Confidential: For Review Only 13 eFigure 15. Effect of muscle relaxant medicines compared to placebo on pain intensity (0-100 scale) 14 at immediate term follow-up for people with acute low back pain subgrouped by overall risk of bias 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 Search Strategy 5 6 7 Search Strategy for Ovid MEDLINE: 8 9 Part A: Generic search for randomized controlled trials 10 1. randomized controlled trial.pt. 11 2. controlled clinical trial.pt. 12 Confidential: For Review Only 3. comparative study.pt. 13 14 4. clinical trial.pt. 15 5. random*.ab,ti. 16 6. placebo.ab,ti. 17 7. drug therapy.fs. 18 8. trial.ab,ti. 19 9. groups.ab,ti. 20 10. or/1-9 21 11. (animals not (humans and animals)).sh. 22 12. (adolescent* or teen* or youth? or puberty or childhood or children* or p?ediatri* or preschool or 23 24 pre-school or nursery or kindergarten or infant? or newborn? or neonat* or prematurity or fetal or 25 foetal).mp. 26 13. 11 or 12 27 14. 10 not 13 28 29 Part B: Specific search for low back, sacrum and coccyx problems 30 15. dorsalgia.ti,ab. 31 16. exp Back Pain/ 32 17. backache.ti,ab. 33 18. (lumbar adj pain).ti,ab. 34 35 19. coccydynia.ti,ab. 36 20. sciatica.ti,ab. 37 21. spondylosis.ti,ab. 38 22. lumbago.ti,ab. 39 23. back disorder$.ti,ab 40 24. or/15-23 41 42 Part C: Specific search for other spinal disorders 43 25. Coccyx.sh 44 26. Lumbar Vertebrae.sh 45 46 27. Intervertebral disc.sh 47 28. Sacrum.sh 48 29. Intervertebral disc degeneration.sh 49 30. (disc adj degeneration).ti,ab. 50 31. (disc adj prolapse).ti,ab. 51 32. (disc adj herniation).ti,ab. 52 33. spinal fusion.sh. 53 34. (facet adj joints).ti,ab. 54 35. Intervertebral Disc Displacement.sh. 55 36. or/25-35 56 57 58 Part D: Specific search for interventions of interest 59 37. suxamethonium.mp. or Succinylcholine/ 60 38. exp Botulinum Toxins/
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1 2 3 39. pancuronium/ 4 40. Vecuronium Bromide/ 5 41. Atracurium/ 6 42. Rocuronium/ 7 8 43. mivacurium bromide.mp. 9 44. cisatracurium.mp. 10 45. Carisoprodol/ 11 46. Methocarbamol/ 12 47. Chlorzoxazone/Confidential: For Review Only 13 48. Orphenadrine/ 14 49. Baclofen/ 15 50. tizanidine.mp. 16 51. Tolperisone/ 17 52. thiocolchicoside.mp. 18 19 53. cyclobenzaprine.mp. 20 54. Dantrolene/ 21 55. Clonazepam/ 22 56. exp Diazepam/ 23 57. Chlordiazepoxide/ 24 58. Oxazepam/ 25 59. Lorazepam/ 26 60. Bromazepam/ 27 61. Clobazam/ 28 62. Alprazolam/ 29 30 63. clotiazepam.mp. 31 64. Flurazepam/ 32 65. Nitrazepam/ 33 66. Flunitrazepam/ 34 67. Estazolam/ 35 68. Triazolam/ 36 69. lormetazepam.mp. 37 70. Temazepam/ 38 71. Midazolam/ 39 72. quazepam.mp. 40 41 73. Zolpidem/ 42 74. zaleplon.mp. 43 75. Eszopiclone/ 44 76. metaxalone.mp. 45 77. or/37-76 (all interventions of interest) 46 47 Results 48 78. 24 or 36 (all back pain) 49 79. 77 and 78 (all back pain and all interventions of interest) 50 80. 14 and 79 (all RCTs of interventions of interest in back pain) 51
52 53 54 55 56 57 58 59 60
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1 2 3 eTable 2. Search strategies for Trial Registries 4 5 Muscle Relaxant Medicines 6 7 WHO ICTRP: Advanced 8 search 9 10 Title: – 11 12 Condition:Confidential: ‘backFor pain’ Review Only 13 14 Intervention: 1-40 15 16 Recruitment status: ALL 17 18 Phases are: ALL 19 20 ClinicalTrials.gov: 21 Advanced search 22 23 Study Type: Interventional Studies 24 25 Study Results: All studies 26 27 Recruitment: All studies 28 29 Age: Adult and Senior 30 31 Gender: All studies 32 33 Conditions: ‘back pain’ 34 35 Interventions: 1-40 36 37 Titles: – 38 39 Outcome Measures: – 40 41 Sponsor/Collaborators: – 42 43 Sponsor (Lead): – 44 45 Study IDs: – 46 47 Locations: – 48 49 Phase: – 50 51 Funder Type: – 52 53 First Received: – 54 55 Last Updated: – 56 57 58 59 60
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1 2 3 EU ClinicalTrials Register: Muscle Relaxant Medicines 4 Advanced search 5 6 Search Term: back pain AND ‘intervention’ 7 (1-40) 8 9 Country: – 10 11 Age Range: Adult and Elderly 12 Confidential: For Review Only 13 Trial Status: – 14 15 Trial Phase: – 16 17 Gender: Both 18 19 Date Range: – 20 21 Results Status: – 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 eTable 3. Interventions of interest 4 5 6 Drug name ATC code Licenses 7 Number 8 ARTG FDA EMA 9 1 suxamethonium M03AB01 yes - yes 10 2 M03AX01 11 botulinum toxin yes yes yes 12 3 Confidential:pancuronium M03AC01 For Reviewyes yesOnly - 13 4 vecuronium M03AC03 yes yes yes 14 5 M03AC04 15 atracurium - yes - 16 6 rocuronium bromide M03AC09 - - yes 17 7 mivacurium bromide M03AC10 yes - yes 18 8 M03AC11 19 cisatracurium yes yes yes 20 9 carisoprodol M03BA02 - yes yes 21 10 methocarbamol M03BA03 - yes - 22 11 23 chlorzoxazone M03BB03 - yes - 24 12 orphenadrine citrate M03BC01 yes yes - 25 13 baclofen M03BX01 yes yes yes 26 14 27 tizanidine M03BX02 - yes yes 28 15 tolperisone M03BX04 - - yes 29 16 thiocolchicoside M03BX05 - - yes 30 17 31 cyclobenzaprine M03BX08 - yes - 32 18 dantrolene M03CA01 yes yes yes 33 19 N03AE01 34 clonazepam yes yes yes 35 20 diazepam N05BA01 yes yes - 36 21 chlordiazepoxide N05BA02 - yes - 37 22 N05BA04 38 oxazepam yes yes - 39 23 lorazepam N05BA06 yes yes yes 40 24 bromazepam N05BA08 yes - yes 41 25 N05BA09 42 clobazam yes yes - 43 26 alprazolam N05BA12 yes yes yes 44 27 clotiazepam N05BA21 - - yes 45 28 46 flurazepam N05CD01 - yes - 47 29 nitrazepam N05CD02 yes - yes 48 30 flunitrazepam N05CD03 yes - yes 49 31 50 estazolam N05CD04 - yes - 51 32 triazolam N05CD05 yes yes yes 52 33 lormetazepam N05CD06 - - yes 53 34 54 temazepam N05CD07 yes yes - 55 35 midazolam N05CD08 yes yes yes 56 36 N05CD10 57 quazepam - yes - 58 37 zolpidem N05CF02 yes yes - 59 38 zaleplon N05CF03 yes yes - 60
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1 2 3 Licenses Drug name ATC code 4 5 Number ARTG FDA EMA 6 39 7 eszopiclone N05CF04 yes yes - 8 40 metaxalone - - yes - 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 eTable 4. Risk of Bias Assessments 4
5
6
7
treat treat 8 Confidential: For Review- Only to
9 -
10 providers) - Blinding reporting analysis? 11 interventions Allocation Drop Outs Other bias generation assessors) - Compliance 12 concealment (Care Co Intention Selective outcome Blinding (Patients) Random sequence Blinding (Outcome
13 Overall Risk of Bias Similarity at baseline
Study Year Timing of assessment 14 Low Low Low Low Low High Low Low 15 Unclear Unclear Unclear Unclear Unclear High Fathie 1964 risk risk risk risk risk risk risk risk 16 Low Low Low Low Low High Low 17 Unclear Unclear Unclear Unclear Unclear Unclear High Hingorani 1966 risk risk risk risk risk risk risk 18 Low Low Low Low Low High Low Low Low Unclear Unclear Unclear Unclear High 19 Hindle 1972 risk risk risk risk risk risk risk risk risk 20 Low Low Low Low High Low Low Unclear Unclear Unclear Unclear Unclear Unclear High 21 Tervo 1976 risk risk risk risk risk risk risk 22 Low Low Low Low Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear High 23 Gold 1978 risk risk risk risk 24 Low Low Low Low Low Low Low Low Low Unclear Unclear Unclear Unclear Moderate 25 Lepisto 1979 risk risk risk risk risk risk risk risk risk 26 Low Low Low Low Low High Low Low Low Low Unclear Unclear Unclear High 27 Baratta 1982 risk risk risk risk risk risk risk risk risk risk 28 Low Low Low Low Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear High 29 Thompson 1983 risk risk risk risk 30 Low Low Low High High High Low Low Unclear Unclear Unclear Unclear Unclear High 31 Dapas 1985 risk risk risk risk risk risk risk risk 32 High High High Low Low Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear High 33 Salvini 1986 risk risk risk risk risk 34 Low Low Low Low High Low Low Low Unclear Unclear Unclear Unclear Unclear High 35 Berry (a) 1988 risk risk risk risk risk risk risk risk 36 Low Low Low Low Low Low Low Low Unclear Unclear Unclear Unclear Unclear High 37 Berry (b) 1988 risk risk risk risk risk risk risk risk 38 Low Low Low Low Low Low Low Low Low Unclear Unclear Unclear Unclear Moderate 39 Casale 1988 risk risk risk risk risk risk risk risk risk 40 41 42 Cashin et al. 2020 Page 9 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 43 of 57 BMJ
1 2
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treat treat 6 - to
7 -
8 providers) Confidential:- For Review Only Blinding reporting analysis? interventions
9 Allocation Drop Outs Other bias generation assessors) - Compliance concealment 10 (Care Co Intention Selective outcome Blinding (Patients) Random sequence Blinding (Outcome
11 Overall Risk of Bias Similarity at baseline 12 Study Year Timing of assessment Low Low Low Low Low Low Low Low Low 13 Unclear Unclear Low risk Unclear Low 14 Klinger 1988 risk risk risk risk risk risk risk risk risk High High High Low Low Low Low Low Low 15 Unclear Unclear Unclear Unclear High 16 Borenstein 1990 risk risk risk risk risk risk risk risk risk Low Low Low Low Low Low Low Low Low Low Low 17 Low risk Unclear Low Foster 2001 risk risk risk risk risk risk risk risk risk risk risk 18 Low High High High Low Low Low Low Low 19 Unclear Unclear Unclear Unclear High Aksoy 2002 risk risk risk risk risk risk risk risk risk 20 Low Low Low Low Low Low Low Low 21 Unclear Unclear Unclear Unclear Unclear High Tuzun 2003 risk risk risk risk risk risk risk risk 22 Low Low Low Low Low 23 Unclear Unclear Unclear Unclear Unclear Unclear Low risk Unclear High Herskowitz 2004 risk risk risk risk risk 24 Low Low Low Low Low Low Low High Low Unclear Unclear Unclear Unclear High 25 Ketenci 2005 risk risk risk risk risk risk risk risk risk 26 Low Low Low Low Low Low Low Low Low High Unclear Unclear Low risk High 27 Ralph 2008 risk risk risk risk risk risk risk risk risk risk 28 Low Low Low Low High Low Low Low High Unclear Unclear Unclear Unclear High 29 Pareek 2009 risk risk risk risk risk risk risk risk risk 30 Low Low Low Low Low Low Low Low Low Low High Unclear High risk High 31 Serfer 2010 risk risk risk risk risk risk risk risk risk risk risk 32 Low High High High High Low High Low Low Low Low Low Unclear High 33 Zaringhalam 2010 risk risk risk risk risk risk risk risk risk risk risk risk 34 Low High Low Low Low Low Low Low Low Unclear Unclear Unclear Low risk High 35 Jazayeri 2011 risk risk risk risk risk risk risk risk risk 36 Low Low Low Low High Low Unclear Unclear Unclear Unclear Unclear Unclear Unclear High 37 NCT00671502 2011 risk risk risk risk risk risk 38 39 40 41 42 Cashin et al. 2020 Page 10 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 44 of 57
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8 providers) Confidential:- For Review Only Blinding reporting analysis? interventions
9 Allocation Drop Outs Other bias generation assessors) - Compliance concealment 10 (Care Co Intention Selective outcome Blinding (Patients) Random sequence Blinding (Outcome
11 Overall Risk of Bias Similarity at baseline 12 Study Year Timing of assessment Low Low Low Low Low Low 13 Unclear Unclear Unclear Unclear Unclear Unclear Unclear High 14 NCT00671879 2012 risk risk risk risk risk risk Low Low Low Low Low Low Low Low Low Low 15 Unclear Unclear Unclear Low 16 Goforth 2014 risk risk risk risk risk risk risk risk risk risk Low Low Low High Low Low Low Low 17 Unclear Unclear Unclear Low risk Unclear High Emrich 2015 risk risk risk risk risk risk risk risk 18 Low Low Low Low Low Low Low Low Low 19 Unclear Unclear Unclear Low risk Low Friedman 2015 risk risk risk risk risk risk risk risk risk 20 High Low Low 21 Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear High Aparna 2016 risk risk risk 22 Low Low Low Low Low Low Low Low Low 23 Unclear Unclear Unclear Unclear Moderate Machado 2016 risk risk risk risk risk risk risk risk risk 24 Low Low Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear High 25 Akhter 2017 risk risk 26 Low Low Low Low Low High Low Low Low Low Low Unclear Low risk High 27 Cogne 2017 risk risk risk risk risk risk risk risk risk risk risk 28 Low Low Low Low Low Low Low Low Low Unclear Unclear Unclear Low risk Low 29 Friedman 2017 risk risk risk risk risk risk risk risk risk 30 Low Low Low Low Low Low Low Low Low Low Unclear Unclear Low risk Low 31 Schliessbach 2017 risk risk risk risk risk risk risk risk risk risk 32 Low Low Low Low Low Low Low Low Low Low Unclear Unclear Low risk Low 33 Friedman 2018 risk risk risk risk risk risk risk risk risk risk 34 Low Low Low Low Low Low Low Low Low Unclear Unclear Unclear Low risk Low 35 Friedman 2019 risk risk risk risk risk risk risk risk risk 36 37 38 39 40 41 42 Cashin et al. 2020 Page 11 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 45 of 57 BMJ
1 2 3 eTable 5. Strength of Evidence (GRADE) 4 5 Outcome Studies and Pooled effect Risk of Bias Inconsistency Imprecision Publication Strength of 6 Participants Bias Evidence 7 (95% CI) 8 Confidential:(n) For Review Only 9 Pain, mean difference, 17 studies -7.52 >50% of trials Inconsistent Imprecise Absent 10 11 immediate, acute low (n=4761) at high overall (-11.98 to - Tau =71.2 (CI crosses Very Low 12 back pain risk 13 3.05) MCID) I2 =80.1% 14 (-2) (-1) 15 (-1) 16 17 Pain, mean difference, 1 study -19.00 >50% High risk Cannot Imprecise Cannot Very Low 18 immediate, subacute low determine (1 determine (1 19 back pain (n=28) (-33.74 to - (-2) study) (n<400) study) 20 4.26) 21 (-1) 22 23 Pain, mean difference, 2 studies -10.10 >50% High risk Inconsistent Imprecise Absent Very Low 24 immediate, chronic low 25 back pain (n=132) (-20.11 to - (-2) Tau =41.2 (n<400) 26 0.09) 27 I2 =52.7% (-1) 28 29 (-1) 30 31 Pain, mean difference, 2 studies -4.39 >50% High risk Consistent Precise Absent Low 32 immediate, mixed low 33 back pain (n=617) (-6.92 to -1.86) (-2) Tau =0 34 35 I2 =0 36 37 38 39 40 41 42 Cashin et al. 2020 Page 12 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 46 of 57
1 2 3 Outcome Studies and Pooled effect Risk of Bias Inconsistency Imprecision Publication Strength of 4 Participants Bias Evidence 5 (n) (95% CI) 6 7 Pain, mean difference, 4 studies 0.71 Low Consistent Imprecise Absent Moderate 8 intermediate, acuteConfidential: low For Review Only 9 (n=814) (-3.50 to 4.92) Tau =0 (CI crosses 10 back pain null) 11 I2 =0 12 (-1) 13 14 Pain, mean difference, 1 study -21.00 >50% High risk Cannot Imprecise Cannot Very Low 15 intermediate, subacute determine (1 determine (1 16 low back pain (n=28) (-34.46 to - (-2) study) (n<400) study) 17 7.54) 18 (-1) 19 20 Pain, mean difference, 1 study -2.04 >50% High risk Consistent Imprecise Absent Very Low 21 intermediate, chronic low 22 back pain (n=80) (-10.91 to 6.83) (-2) Tau =0 (n<400) 23 24 I2 =0 (-1) 25 26 Acceptability, odds ratio, 13 studies 0.76 >50% High risk Consistent Precise Absent Low 27 acute low back pain 28 (n=2834) (0.61 to 0.95) (-2) Tau =0 29 30 I2 =0 31 32 Acceptability, odds ratio, 3 studies 0.64 >25%<50% Consistent Imprecise Absent Low 33 chronic low back pain High risk 34 (n=185) (0.23 to 1.80) Tau =0.1 (n<400) 35 (-1) 2 36 I =10.4% (-1) 37 38 39 40 41 42 Cashin et al. 2020 Page 13 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 47 of 57 BMJ
1 2 3 Outcome Studies and Pooled effect Risk of Bias Inconsistency Imprecision Publication Strength of 4 Participants Bias Evidence 5 (n) (95% CI) 6 7 Function, mean 8 studies -3.53 >50% High risk Consistent Precise Absent Low 8 difference, immediate,Confidential: For Review Only 9 (n=2653) (-6.61 to -0.45) (-2) Tau =6.6 10 acute low back pain 11 I2 =27% 12 13 Function, mean 2 studies -3.49 >50% High risk Consistent Imprecise Absent Very Low 14 difference, immediate, 15 chronic low back pain (n=132) (-8.28 to 1.31) (-2) Tau =0 (n<400) 16 17 I2 =0 (-1) 18 19 Function, mean 1 study -19.17 >50% High risk Cannot Imprecise Cannot Very Low 20 difference, immediate, determine (1 determine (1 21 mixed low back pain (n=329) (-27.70 to - (-2) study) (n<400) study) 22 10.64) 23 (-1) 24 25 Function, mean 3 studies 0.66 Low Inconsistent Imprecise Absent Low 26 difference, intermediate, 27 acute low back pain (n=525) (-6.35 to 7.67) Tau =30.0 (CI crosses 28 null) 29 I2 =61.2% 30 (-1) 31 (-1) 32 33 Function, mean 1 studies -3.14 >50% High risk Consistent Imprecise Cannot Very Low 34 difference, intermediate, determine (1 35 chronic low back pain (n=80) (-12.19 to 5.91) (-2) Tau =0 (CI crosses study) null & MCID) 36 2 37 I =0 38 (-2) 39 40 41 42 Cashin et al. 2020 Page 14 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Page 48 of 57
1 2 3 Outcome Studies and Pooled effect Risk of Bias Inconsistency Imprecision Publication Strength of 4 Participants Bias Evidence 5 (n) (95% CI) 6 7 Harms, odds ratio, acute 19 studies 2.03 >50% High risk Consistent Precise Absent Low 8 low back pain Confidential: For Review Only 9 (n=3853) (1.63 to 2.53) (-2) Tau =0.1 10 11 I2 = 25% 12 13 Harms, odds ratio, 2 studies 1.50 Moderate Consistent Imprecise Absent Moderate 14 chronic low back pain 15 (n=95) (0.33 to 6.78) Tau =0 (n<400) 16 17 I2 =0 (-1) 18 19 Harms, odds ratio, mixed 1 study 1.68 >50% High risk Cannot Imprecise Cannot Very Low 20 low back pain determine (1 determine (1 21 (n=329) (0.60 to 4.64) (-2) study) (n<400) study) 22 23 (-1) 24 25 Serious harms, odds ratio, 2 studies 2.36 >50% High risk Consistent Imprecise Absent Very Low 26 acute low back pain 27 (n=830) (0.27 to 20.86) (-2) Tau =0 (CI crosses 28 null) 29 I2 =0 30 (-1) 31 32 Tolerability, odds ratio, 6 studies 2.03 >50% High risk Inconsistent Imprecise Absent Very Low 33 acute low back pain 34 (n=1836) (0.75 to 5.49) (-2) Tau =0.9 (CI crosses 35 null) 2 36 I =56.1% 37 (-1) 38 39 40 41 42 Cashin et al. 2020 Page 15 of 25 43 https://mc.manuscriptcentral.com/bmj 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 49 of 57 BMJ
1 2 3 eResults. Planned sensitivity analyses 4 5 6 Sensitivity analysis: studies where the definition of non-specific LBP is not clear (pain 7 intensity) 8 9 The exclusion of 1 trial with an unclear definition of non-specific LBP (Berry (b) 1988) increased the 10 effect size for pain by 5.1% to -7.90 [95% CI -12.55 to -3.24]. Tau2 increased to 96.01. 11 12 Confidential: For Review Only 13 14 Sensitivity analysis: studies where the definition of non-specific LBP is not clear 15 (acceptability) 16 17 The exclusion of 2 trials with an unclear definition of non-specific LBP (Berry (b) 1988, Emrich 2015) 18 reduced the odds of all-cause discontinuation (acceptability) by 1.3% to 0.75 [95% CI 0.58 to 0.95]. 19 Tau2 remained at 0. 20 21 22 23 Sensitivity analysis: studies where the measures of variance were imputed (pain intensity) 24 25 The exclusion of 4 trials where measures of variance were imputed (Hindle 1972, Lepisto 1979, 26 NCT00671502 2011, Aparna 2016) increased the effect size for pain by 1.3% to -7.62 [95% CI -12.44 27 to -2.80]. Tau2 reduced to 83.93. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 eFigure 1. Effect of muscle relaxant medicines compared to placebo on pain 4 intensity (0-100 scale) intermediate term follow-up for people with low back 5 6 pain 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19
20 a a 21 22 23 24 25 26 27 28 29 30 31 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 32 observations indicate change from baseline. a Standard deviation transformed. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 eFigure 2. Effect of muscle relaxant medicines compared to placebo on 4 function (0-100 scale) immediate term follow-up for people with low back pain. 5 6 Negative values for mean difference indicate effect favors drug compared to 7 placebo 8 9 10 a a b b 11 b b b b 12 Confidential:b For Review Only b 13 b b 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 30 observations indicate change from baseline. a Standard deviation imputed. b Standard deviation transformed. 31 32 33 34 eFigure 3. Effect of muscle relaxant medicines compared to placebo on 35 function (0-100 scale) intermediate term follow-up for people with low back 36 pain 37 38 39 40 41 42 43 a a
44 a a 45 46 47 48 49
50 a a 51 52 53 54 55 56 57
58 a 59 Negative values for mean difference indicate effect favors drug compared to placebo. Standard deviation transformed. 60
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1 2 3 eFigure 4. Harms (incidence of any adverse effect) of muscle relaxant 4 medicines compared to placebo for people with LBP 5 6 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Odds ratio greater than 1 indicates greater odds of an adverse event in the muscle relaxant group (i.e. effect favors placebo). 31 32 33 34 35 eFigure 5. Serious harms (incidence of any serious adverse effect) of muscle 36 relaxant medicines compared to placebo for people with LBP 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Odds ratio greater than 1 indicates greater odds of a serious adverse event in the muscle relaxant group (i.e. effect favors placebo). 55 56 57 58 59 60
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1 2 3 eFigure 6. Discontinuation due to adverse events (tolerability) of muscle 4 relaxant medicines compared to placebo for people with LBP 5 6 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23
24 25 Odds ratio greater than 1 indicates greater odds of discontinuation due to an adverse event in the muscle relaxant group (i.e. 26 effect favors placebo). 27 28 29 30 eFigure 7. Effect of muscle relaxant medicines compared to placebo on pain 31 intensity (0-100 scale) immediate term follow-up for people with acute low back 32 pain sub grouped by muscle relaxant medicine class 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 Unclear/Mixed describes medicines with either combined or no clear class. Negative values for mean difference indicate effect 56 favors drug compared to placebo. Whereas, negative values for the trial observations indicate change from baseline. 57 58 59 60
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1 2 3 eFigure 8. Effect of muscle relaxant medicines compared to placebo on pain 4 intensity (0-100 scale) immediate term follow-up for people with acute low back 5 6 pain sub grouped by prescribed medicine dose 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 32 observations indicate change from baseline. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 eFigure 9. Extended funnel plot. Significance contours for comparison of 4 5 muscle relaxant medicines and placebo for adults with acute low back pain on 6 pain intensity (0-100 scale) at immediate term follow-up 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 The black dots represent the point estimates for the included trials. A new trial would need to occupy the non-shaded portion of 30 the plot in order to change the statistical significance of the finding. The plot indicates that the meta-analysis finding is unlikely 31 to change statistical significance. 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 eFigure 10. Effect of muscle relaxant medicines compared to placebo on pain 4 intensity (0-100 scale) at immediate term follow-up for adults with acute low 5 6 back pain subgrouped by medicine type 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26
27 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 28 observations indicate change from baseline. 29 30 31
32 33 eFigure 11. Acceptability (all cause discontinuation of treatment) of muscle 34 relaxant medicines compared to placebo for adults with acute low back pain 35 36 subgrouped by medicine type 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Odds ratio greater than 1 indicates greater odds of all cause discontinuation of treatment in the muscle relaxant group (i.e. 60 effect favors placebo).
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1 2 3 eFigure 12. Effect of muscle relaxant medicines compared to placebo on pain 4 intensity (0-100 scale) immediate term follow-up for people with acute low back 5 6 pain subgrouped by primary trial record 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 29 observations indicate change from baseline. 30 31 32 33 eFigure 13. Effect of muscle relaxant medicines compared to placebo on 34 function (0-100 scale) immediate term follow-up for people with acute low back 35 pain subgrouped by primary trial record 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 59 observations indicate change from baseline. 60
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1 2 3 eFigure 14. Harms (incidence of any adverse effect) of muscle relaxant 4 medicines compared to placebo for people with acute LBP subgrouped by 5 6 primary trial record 7 8 9 10 11 12 Confidential: For Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Odds ratio greater than 1 indicates greater odds of an adverse event in the muscle relaxant group (i.e. effect favors placebo).
31 32 33 34 35 eFigure 15. Effect of muscle relaxant medicines compared to placebo on pain 36 intensity (0-100 scale) at immediate term follow-up for people with acute low 37 back pain subgrouped by overall risk of bias 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Negative values for mean difference indicate effect favors drug compared to placebo. Whereas, negative values for the trial 60 observations indicate change from baseline.
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