Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)
Methotrexate is routinely used in the treatment of inflammatory arthritis. There have been concerns regarding the safety of using concurrent non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or paracetamol (acetaminophen), or both, in these people.
To systematically appraise and summarise the scientific evidence on the safety of using NSAIDs, including aspirin, or paracetamol, or both, with methotrexate in inflammatory arthritis; and to identify gaps in the current evidence, assess the implications of those gaps and to make recommendations for future research to address these deficiencies.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, second quarter 2010); MEDLINE (from 1950); EMBASE (from 1980); the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) (2008 to 2009) and checked the websites of regulatory agencies for reported adverse events, labels and warnings.
Randomised controlled trials and non-randomised studies comparing the safety of methotrexate alone to methotrexate with concurrent NSAIDs, including aspirin, or paracetamol, or both, in people with inflammatory arthritis.
Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies.
Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis using various NSAIDs, including aspirin. There were no identified studies for other forms of inflammatory arthritis.For NSAIDs, 13 studies were included that used concurrent NSAIDs, of which nine studies examined unspecified NSAIDs. The mean number of participants was 150.4 (range 19 to 315), mean duration 2182.9 (range 183 to 5490) days, although the study duration was not always clearly defined, and the studies were mainly of low to moderate quality. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; one study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; one study identified no adverse effect on liver function; three studies demonstrated no increase in methotrexate withdrawal; and one study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in one study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib), with a mean number of participants of 25.8 (range 14 to 50) and mean study duration of 16.8 (range 14 to 23) days. These studies were mainly of moderate quality. The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches.For aspirin, seven studies provided data on adverse events with the use of aspirin and methotrexate. These studies included a mean number of participants of 100 (range 11 to 232), had a mean duration of 1325 (range 8 to 2928) days and were mainly of low to moderate quality. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.For paracetamol, no studies were identified for inclusion.
In the management of rheumatoid arthritis, the concurrent use of NSAIDs with methotrexate appears to be safe provided appropriate monitoring is performed. The use of anti-inflammatory doses of aspirin should be avoided.
"DNA synthesis eventually halts and cells can no longer replicate . Polyglutamination of this drug prolongs its intracellular presence [6, 7]. Hence, cells with the capability of effective polyglutamination such as leukemic myeloblasts, synovial macrophages, lymphoblasts, and epithelia are more susceptible to this medication [6, 7]. "
[Show abstract][Hide abstract] ABSTRACT: The well-reported methotrexate (MTX) toxicities are based on the duration and cumulative dosing of drug. The typical toxicities can be predicted by the timing of drug administration, where mucositis occurs as an earlier effect, while myelosuppression and the sequelae of pancytopenia occur later after MTX administration. Despite these well-known toxicities, low dose MTX therapy can become problematic, in particular with the elderly, who are at a greater risk for significant myelosuppression. We present a case of a 73-year-old female with pancytopenia causing severe neutropenia, mucocutaneous bleeding, and bruising and requiring intravenous antibiotic therapy and limited transfusion dependence as a result of low dose daily MTX for rheumatoid arthritis.
"NSAIDs, which have serious side effects, such as gastric ulcers (Glaser, 1995). Etodolac, as a selective COX-2 inhibitor, is widely used for the treatment of inflammatory disorders and painful conditions such as rheumatoid arthritis (Tirunagari et al., 2009; Sancheti et al., 2010; Colebatch et al., 2011). A recent study shows that etodolac induced Ca 21 influx in TRPA1-expressing cells and sensory neurons and that this increase in intracellular calcium was blocked by a TRPA1-selective antagonist. "
[Show abstract][Hide abstract] ABSTRACT: To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA).
A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008-09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice.
A total of 49,242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice.
Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.
Gary J. Macfarlane, Maxwell S. Barnish, Elizabeth A. Jones, Lesley Kay, Andrew Keat, Karen T. Meldrum, Ejaz Pathan, Roger D. Sturrock, Claudia Zabke, Paul McNamee, Gareth T. Jones,
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