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      Paracetamol: not as safe as we thought? A systematic literature review of observational studies

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          We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol.


          We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome.


          Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43).


          Given the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

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          Most cited references 16

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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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            A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States.

            Acetaminophen is a commonly-used analgesic in the US and, at doses of more than 4 g/day, can lead to serious hepatotoxicity. Recent FDA and CMS decisions serve to limit and monitor exposure to high-dose acetaminophen. This literature review aims to describe the exposure to and consequences of high-dose acetaminophen among chronic pain patients in the US. Each year in the US, approximately 6% of adults are prescribed acetaminophen doses of more than 4 g/day and 30,000 patients are hospitalized for acetaminophen toxicity. Up to half of acetaminophen overdoses are unintentional, largely related to opioid-acetaminophen combinations and attempts to achieve better symptom relief. Liver injury occurs in 17% of adults with unintentional acetaminophen overdose.
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              A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain.

              To compare the efficacy and safety of single versus combination non-prescription oral analgesics in community-derived people aged 40 years and older with chronic knee pain. A randomised, double-blind, four-arm, parallel-group, active controlled trial investigating short-term (day 10) and long-term (week 13) benefits and side-effects of four regimens, each taken three times a day: ibuprofen (400 mg); paracetamol (1000 mg); one fixed-dose combination tablet (ibuprofen 200 mg/paracetamol 500 mg); two fixed-dose combination tablets (ibuprofen 400 mg/paracetamol 1000 mg). There were 892 participants (mean age 60.6, range 40-84 years); 63% had radiographic knee osteoarthritis and 85% fulfilled American College of Rheumatology criteria for osteoarthritis. At day 10, two combination tablets were superior to paracetamol (p<0.01) for pain relief (determined by mean change from baseline in WOMAC pain; n=786). At 13 weeks, significantly more participants taking one or two combination tablets rated their treatment as excellent/good compared with paracetamol (p=0.015, p=0.0002, respectively; n=615). The frequency of adverse events was comparable between groups. However, by 13 weeks, decreases in haemoglobin (≥1 g/dl) were observed in some participants in all groups. Twice as many participants taking two combination tablets had this decrease compared with those on monotherapy (p<0.001; paracetamol, 20.3%; ibuprofen, 19.6%; one or two combination tablets, 24.1%, 38.4%, respectively). Ibuprofen/paracetamol combination analgesia, at non-prescription doses, confers modest short-term benefits for knee pain/osteoarthritis. However, in this population, paracetamol 3 g/day may cause similar degrees of blood loss as ibuprofen 1200 mg/day, and the combination of the two appears to be additive. Study no ISRCTN77199439.

                Author and article information

                Ann Rheum Dis
                Ann. Rheum. Dis
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                March 2016
                2 March 2015
                : 75
                : 3
                : 552-559
                [1 ]South London and the Maudsley Mental Health Trust, Maudsley Hospital , London, UK
                [2 ]National Clinical Guideline Centre , London, UK
                [3 ]Division of Rheumatology, Orthopaedics and Dermatology, Clinical Sciences Building, City Hospital , Nottingham, UK
                [4 ]Northumbria Healthcare NHS Foundation Trust, Newcastle University , Ashington, UK
                [5 ]Research Institute for Primary Care and Health Sciences, Keele University , Keele, UK
                [6 ]Arthritis Research UK Primary Care Centre, Research Institute for Primary Care & Health Sciences, Keele University , Keele, UK
                [7 ]Ealing Hospital NHS Trust Community Musculoskeletal Service, Clayponds Hospital , London, UK
                [8 ]Gordon House Surgery , London, UK
                [9 ]Encompass Healthcare , Washington, Tyne and Wear, UK
                [10 ]Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit , LeedsUK
                Author notes

                Handling editor Tore K Kvien

                [Correspondence to ] Professor Philip G Conaghan Leeds Institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, Leeds LS7 4SA, UK; p.conaghan@ 123456leeds.ac.uk
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                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/

                Clinical and Epidemiological Research
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                epidemiology, outcomes research, osteoarthritis


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