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      Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials

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          Abstract

          Objective To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.

          Design Systematic review and meta-analysis.

          Data sources Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.

          Eligibility criteria for selecting studies Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.

          Data extraction Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.

          Results 12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.

          Conclusions Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.

          Systematic review registration PROSPERO registration number CRD42013006367.

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          Most cited references29

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          EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

          To develop evidence based recommendations for the management of hip osteoarthritis (OA). The multidisciplinary guideline development group comprised 18 rheumatologists, 4 orthopaedic surgeons, and 1 epidemiologist, representing 14 European countries. Each participant contributed up to 10 propositions describing key clinical aspects of hip OA management. Ten final recommendations were agreed using a Delphi consensus approach. Medline, Embase, CINAHL, Cochrane Library, and HTA reports were searched systematically to obtain research evidence for each proposition. Where possible, outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. Effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation was assessed using the traditional A-D grading scale and a visual analogue scale. Ten key treatment propositions were generated through three Delphi rounds. They included 21 interventions, such as paracetamol, NSAIDs, symptomatic slow acting disease modifying drugs, opioids, intra-articular steroids, non-pharmacological treatment, total hip replacement, osteotomy, and two general propositions. 461 studies were identified from the literature search for the proposed interventions of efficacy, side effects, and cost effectiveness. Research evidence supported 15 interventions in the treatment of hip OA. Evidence specific for the hip was strikingly lacking. Strength of recommendation varied according to category of research evidence and expert opinion. Ten key recommendations for the treatment of hip OA were developed based on research evidence and expert consensus. The effectiveness and cost effectiveness of these recommendations were evaluated and the strength of recommendation was scored.
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            Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.

            During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed. To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo. A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units. Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter. None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.
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              Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial.

              Regular paracetamol is the recommended first-line analgesic for acute low-back pain; however, no high-quality evidence supports this recommendation. We aimed to assess the efficacy of paracetamol taken regularly or as-needed to improve time to recovery from pain, compared with placebo, in patients with low-back pain.
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                Author and article information

                Contributors
                Role: PhD student
                Role: director
                Role: senior lecturer
                Role: PhD student
                Role: associate professor
                Role: professor
                Role: professor
                Role: associate professor
                Journal
                BMJ
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2015
                31 March 2015
                : 350
                : h1225
                Affiliations
                [1 ]The George Institute for Global Health, Sydney Medical School, University of Sydney, Sydney, NSW 2000, Australia
                [2 ]Faculty of Health Sciences, University of Sydney, Sydney, NSW 2141, Australia
                [3 ]Department of Clinical Pharmacology, St Vincent’s Hospital and University of New South Wales, Sydney, NSW 2010, Australia
                [4 ]School of Medical Sciences, Department of Medicine, University of New South Wales, Sydney, NSW 2033, Australia
                [5 ]Faculty of Pharmacy, University of Sydney, Sydney, NSW 2050, Australia
                [6 ]Centre for Education and Research on Ageing, Concord Hospital, Sydney, NSW 2139, Australia
                [7 ]Institute of Bone and Joint Research, The Kolling Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2065, Australia
                Author notes
                Correspondence to: G C Machado gmachado@ 123456georgeinstitute.org.au
                Article
                macg022316
                10.1136/bmj.h1225
                4381278
                25828856
                cd93fdab-650e-4b94-9843-6a10e1ddc94c
                © Machado et al 2015

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 04 February 2015
                Categories
                Research

                Medicine
                Medicine

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