Non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people taking methotrexate for inflammatory arthritis

This summary of a Cochrane review describes what we know from research about any safety issues from using non-steroidal anti-inflammatory drugs, or NSAIDs, including aspirin, or paracetamol (acetaminophen), or both, along with methotrexate in people with inflammatory arthritis.

The review shows that in people with inflammatory arthritis:

- NSAIDs, including aspirin, plus methotrexate may not increase lung problems in people with rheumatoid arthritis.

- High dose aspirin plus methotrexate may increase liver problems in people with rheumatoid arthritis.

- High dose aspirin plus methotrexate may increase kidney problems in people with rheumatoid arthritis.

- NSAIDs plus methotrexate may cause a brief and mild increase in blood problems (low platelet count) in people with rheumatoid arthritis, particularly if NSAIDs are taken on the same day as methotrexate.

- NSAIDs, including aspirin, plus methotrexate seems not to increase the chance of people with rheumatoid arthritis stopping taking their methotrexate due to side effects.

- No studies were found that looked at paracetamol plus methotrexate.

- No studies were found in people with conditions other than rheumatoid arthritis.

Often we do not have precise information about side effects and complications, particularly for rare but serious side effects. Possible side effects associated with high dose paracetamol includes liver problems. NSAIDs, including aspirin, may cause stomach, kidney or heart problems, and methotrexate may cause stomach problems, liver problems, anaemia or infection.

What is inflammatory arthritis, and what drugs are used to treat pain?

Inflammatory arthritis is a group of diseases that includes rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and other types of spondyloarthritis. When you have inflammatory arthritis, your immune system, which normally fights infection, attacks your joints. This makes your joints swollen, stiff and painful. In rheumatoid arthritis, the small joints of your hands and feet are usually affected first. In contrast, in ankylosing spondylitis the joints of the spine are the most affected. There is no cure for inflammatory arthritis at present, so the treatments aim to relieve pain and stiffness and improve your ability to move.

People with inflammatory arthritis therefore often need to use painkillers, like paracetamol, and NSAIDs such as aspirin or ibuprofen to help ease their pain. Paracetamol, also called acetaminophen, is used to relieve pain but does not affect swelling; non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, diclofenac and cyclo-oxygenase-2 inhibitors or COX-2s (for example celecoxib), are used to decrease pain and swelling.

Methotrexate is one of the medications most commonly used to treat people with inflammatory arthritis. Methotrexate is a disease-modifying anti-rheumatic drug.  Methotrexate can treat rheumatoid arthritis by decreasing the activity of the immune system. Methotrexate is a common treatment for rheumatoid arthritis and may be prescribed in combination with other drugs, especially for people who are not improving on methotrexate alone. Disease-modifying anti-rheumatic drugs like methotrexate come as tablets, capsules and, in some cases, injections. Unfortunately, there have been some concerns in the past that it may not be safe to use methotrexate at the same time as the painkillers that patients with inflammatory arthritis often need to use.

Authors' conclusions: 

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.

Read the full abstract...

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.

Search strategy: 

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.

Selection criteria: 

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.

Data collection and analysis: 

Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies.

Main results: 

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.