Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain : systematic review and meta-analysis

Abstract: Objective To investigate the efficacy, acceptability, and safety of muscle relaxants for low back pain. Design: Systematic review and meta-analysis of randomised controlled trials. Data sources: Medline, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and WHO ICTRP from inception to 23 February 2021. Eligibility criteria for study selection: Randomised controlled trials of muscle relaxants compared with placebo, usual care, waiting list, or no treatment in adults (≥18 years) reporting non-specific low back pain. Data extraction and synthesis: Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty of the evidence using the Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development and Evaluations, respectively. Random effects meta-analytical models through restricted maximum likelihood estimation were used to estimate pooled effects and corresponding 95% confidence intervals. Outcomes included pain intensity (measured on a 0-100 point scale), disability (0-100 point scale), acceptability (discontinuation of the drug for any reason during treatment), and safety (adverse events, serious adverse events, and number of participants who withdrew from the trial because of an adverse event). Results: 49 trials were included in the review, of which 31, sampling 6505 participants, were quantitatively analysed. For acute low back pain, very low certainty evidence showed that at two weeks or less non-benzodiazepine antispasmodics were associated with a reduction in pain intensity compared with control (mean difference -7.7, 95% confidence interval-12.1 to-3.3) but not a reduction in disability (-3.3, -7.3 to 0.7). Low and very low certainty evidence showed that non-benzodiazepine antispasmodics might increase the risk of an adverse event (relative risk 1.6, 1.2 to 2.0) and might have little to no effect on acceptability (0.8, 0.6 to 1.1) compared with control for acute low back pain, respectively. The number of trials investigating other muscle relaxants and different durations of low back pain were small and the certainty of evidence was reduced because most trials were at high risk of bias. Conclusions: Considerable uncertainty exists about the clinical efficacy and safety of muscle relaxants. Very low and low certainty evidence shows that non-benzodiazepine antispasmodics might provide small but not clinically important reductions in pain intensity at or before two weeks and might increase the risk of an adverse event in acute low back pain, respectively. Large, high quality, placebo controlled trials are urgently needed to resolve uncertainty. Systematic review registration PROSPERO CRD42019126820 and Open Science Framework https://osf.io/mu2f5/

Trials we cannot trust: investigating their impact on systematic reviews and clinical guidelines in spinal pain

Data Sharing Statement: The full data underpinning the analysis of the impact of studies on published meta-analyses is available via Figshare: 10.17633/rd.brunel.21427995 .Supplementary material is available online at https://www.jpain.org/article/S1526-5900(23)00467-4/fulltext#supplementaryMaterial .Copyright © 2023 The Author(s). We previously conducted an exploration of the trustworthiness of a group of clinical trials of cognitive behavioural therapy (CBT) and exercise in spinal pain. We identified multiple concerns in eight trials, judging them untrustworthy. In this study, we systematically explored the impact of these trials (“index trials”) on results, conclusions and recommendations of systematic reviews and clinical practice guidelines (CPGs). We conducted forward citation tracking using Google Scholar and the citationchaser tool, searched the Guidelines International Network (GIN) library and National Institute of Health and Care Excellence (NICE) archive to June 2022 to identify systematic reviews and CPGs. We explored how index trials impacted their findings. Where reviews presented meta-analyses, we extracted or conducted sensitivity analyses for the outcomes pain and disability, to explore how exclusion of index trials affected effect estimates. We developed and applied an ’Impact Index’ to categorise the extent to which index studies impacted their results. We included 32 unique reviews and 10 CPGs. None directly raised concerns regarding the veracity of the trials. Across meta-analyses (55 comparisons), removal of index trials reduced effect sizes by a median 58% (IQR 40 to 74). 85% of comparisons were classified as highly, 3% as moderately, and 11% as minimally impacted. Nine out 10 reviews conducting narrative synthesis drew positive conclusions regarding the intervention tested. Nine out of 10 CPGs made positive recommendations for the intervention(s) evaluated. This cohort of trials, with concerns regarding trustworthiness, has substantially impacted the results of systematic reviews and guideline recommendations. Perspective: We found that a group of trials of CBT for spinal pain with concerns relating to their trustworthiness have had substantial impacts on the analyses and conclusions of systematic reviews and clinical practice guidelines. This highlights the need for a greater focus on the trustworthiness of studies in evidence appraisal. Pre-registration: Our protocol was pre-registered on the Open Science Framework: https://osf.io/m92ax/This study was not supported by any external funding

Effect of graded sensorimotor retraining on pain intensity in patients with chronic low back pain: a randomized clinical trial

Original Investigation. All JAMA articles reporting original research are made freely available 6 months after publication, subject to certain conditions. All research articles published after April 2017 will be deposited into PubMed Central (PMC) after publication and are publicly available 6 months after publication. A few weeks after publication, you may obtain your PMCID on the PMC site at: https://www.ncbi.nlm.nih.gov/pmc/pmctopmid/. Authors of research articles published before April 2017 may deposit copies of the published article into PMC provided that the article not be made public access until 6 months after publication. These options apply only to research articles. Non-research articles may not be deposited into PMC.National Health and Medical Research Council of Australia (ID1087045)

The smallest worthwhile effect on pain intensity of exercise therapy for people with chronic low back pain:a discrete choice experiment study

OBJECTIVE: To identify the smallest worthwhile effect (SWE) of exercise therapy for people with non-specific chronic low back pain (CLBP). DESIGN: Discrete choice experiment. METHODS: The SWE was estimated as the lowest reduction in pain that participants would consider exercising worthwhile, compared to not exercising i.e., effects due to natural history and other components (e.g., regression to the mean). We recruited English-speaking adults in Australia with non-specific CLBP to our online survey via email obtained from a registry of previous participants and advertisements on social media. We used discrete choice experiment to estimate the SWE of exercise compared to no exercise for pain intensity. We analysed the discrete choice experiment using a mixed logit model, and mitigated hypothetical bias through certainty calibration, with sensitivity analyses performed with different certainty calibration thresholds. RESULTS: Two-hundred and thirteen participants completed the survey. The mean age (±SD) was 50.7±16.5, median (IQR) pain duration 10 years (5-20), and mean pain intensity (±SD) was 5.8±2.3 on a 0-10 numerical rating scale. For people with CLBP the SWE of exercise was a between-group reduction in pain of 20%, compared to no exercise. In the sensitivity analyses, the SWE varied with different levels of certainty calibration; from 0% without certainty calibration to 60% with more extreme certainty calibration. CONCLUSION: This patient-informed threshold of clinical importance could guide the interpretation of findings from randomised trials and meta-analyses of exercise therapy compared to no exercise. </p

The smallest worthwhile effect on pain intensity of exercise therapy for people with chronic low back pain: a discrete choice experiment study.

OBJECTIVE: To identify the smallest worthwhile effect (SWE) of exercise therapy for people with non-specific chronic low back pain (CLBP). DESIGN: Discrete choice experiment. METHODS: The SWE was estimated as the lowest reduction in pain that participants would consider exercising worthwhile, compared to not exercising i.e., effects due to natural history and other components (e.g., regression to the mean). We recruited English-speaking adults in Australia with non-specific CLBP to our online survey via email obtained from a registry of previous participants and advertisements on social media. We used discrete choice experiment to estimate the SWE of exercise compared to no exercise for pain intensity. We analysed the discrete choice experiment using a mixed logit model, and mitigated hypothetical bias through certainty calibration, with sensitivity analyses performed with different certainty calibration thresholds. RESULTS: Two-hundred and thirteen participants completed the survey. The mean age (±SD) was 50.7±16.5, median (IQR) pain duration 10 years (5-20), and mean pain intensity (±SD) was 5.8±2.3 on a 0-10 numerical rating scale. For people with CLBP the SWE of exercise was a between-group reduction in pain of 20%, compared to no exercise. In the sensitivity analyses, the SWE varied with different levels of certainty calibration; from 0% without certainty calibration to 60% with more extreme certainty calibration. CONCLUSION: This patient-informed threshold of clinical importance could guide the interpretation of findings from randomised trials and meta-analyses of exercise therapy compared to no exercise

Comparative effectiveness and safety of analgesic medicines for adults with acute non-specific low back pain: Systematic review and network meta-analysis

Objective To evaluate the comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain. Design Systematic review and network meta-analysis. Data sources Medline, PubMed, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and World Health Organization’s International Clinical Trials Registry Platform from database inception to 20 February 2022. Eligibility criteria for study selection Randomised controlled trials of analgesic medicines (eg, non-steroidal anti-inflammatory drugs, paracetamol, opioids, anti-convulsant drugs, skeletal muscle relaxants, or corticosteroids) compared with another analgesic medicine, placebo, or no treatment. Adults (≥18 years) who reported acute non-specific low back pain (for less than six weeks). Data extraction and synthesis Primary outcomes were low back pain intensity (0-100 scale) at end of treatment and safety (number of participants who reported any adverse event during treatment). Secondary outcomes were low back specific function, serious adverse events, and discontinuation from treatment. Two reviewers independently identified studies, extracted data, and assessed risk of bias. A random effects network meta-analysis was done and confidence was evaluated by the Confidence in Network Meta-Analysis method. Results 98 randomised controlled trials (15 134 participants, 49% women) included 69 different medicines or combinations. Low or very low confidence was noted in evidence for reduced pain intensity after treatment with tolperisone (mean difference −26.1 (95% confidence intervals −34.0 to −18.2)), aceclofenac plus tizanidine (−26.1 (−38.5 to −13.6)), pregabalin (−24.7 (−34.6 to −14.7)), and 14 other medicines compared with placebo. Low or very low confidence was noted for no difference between the effects of several of these medicines. Increased adverse events had moderate to very low confidence with tramadol (risk ratio 2.6 (95% confidence interval 1.5 to 4.5)), paracetamol plus sustained release tramadol (2.4 (1.5 to 3.8)), baclofen (2.3 (1.5 to 3.4)), and paracetamol plus tramadol (2.1 (1.3 to 3.4)) compared with placebo. These medicines could increase the risk of adverse events compared with other medicines with moderate to low confidence. Moderate to low confidence was also noted for secondary outcomes and secondary analysis of medicine classes. Conclusions The comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain are uncertain. Until higher quality randomised controlled trials of head-to-head comparisons are published, clinicians and patients are recommended to take a cautious approach to manage acute non-specific low back pain with analgesic medicines. Systematic review registration PROSPERO CRD4201914525