Nabumetone

What it is

Nabumetone is a non-steroidal anti-inflammatory drug (NSAID) taken as a tablet. It is a prodrug: the molecule swallowed has little anti-inflammatory activity itself and is converted in the liver to 6-methoxy-2-naphthylacetic acid (6MNA), which is the active substance. It is a non-selective NSAID of the naphthylalkanone class, approved in the United States for osteoarthritis and rheumatoid arthritis.

What the research says

It relieves the pain and inflammation of osteoarthritis and rheumatoid arthritis apparently by inhibiting prostaglandin production, as other NSAIDs do (the label states that its exact mode of action is not known). The distinctive claim made for it is gastrointestinal tolerability: an industry-era meta-analysis of 13 studies and 49,501 patients reported far fewer perforations, ulcers and bleeds than with comparator NSAIDs. That claim sits directly against the class boxed warning, which states that NSAIDs increase the risk of serious gastrointestinal bleeding, ulceration and perforation and of cardiovascular thrombotic events, and nabumetone was not separately quantified in the large independent meta-analyses of individual NSAIDs. Head-to-head trial evidence against other NSAIDs is of modest size and mostly short.

Evidence grade: Limited evidence.

How it works

Drug class: Non-selective non-steroidal anti-inflammatory drug (NSAID), naphthylalkanone; prodrug of 6-methoxy-2-naphthylacetic acid (6MNA)

Nabumetone is a prodrug: the liver converts it to 6-methoxy-2-naphthylacetic acid (6MNA), which the label describes as a potent inhibitor of prostaglandin synthesis. The label also states that, as with other NSAIDs, its mode of action is not known, but that inhibiting prostaglandin synthesis may be involved in the anti-inflammatory effect. Prostaglandins are the signalling molecules that drive pain, swelling and fever at a site of inflammation, and the same pathway is generally thought to explain why NSAIDs can injure the stomach lining and affect the kidneys and blood vessels. (Source 1)

Boxed warning

Cardiovascular Risk Nonsteroidal anti-inflammatory drugs (NSAIDs¹) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see WARNINGS and PRECAUTIONS ]. Nabumetone is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see CONTRAINDICATIONS and WARNINGS ]. ¹ Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug. Gastrointestinal Risk NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see WARNINGS ].

(Source 1)

What it is used for

• Approved for relief of the signs and symptoms of osteoarthritis. The randomised evidence we could read is modest: a 423-patient placebo-controlled trial in knee osteoarthritis in which drop-outs were far more frequent on placebo (33.9%) than on nabumetone (8.5%), which is consistent with symptomatic benefit but is not a pain-score effect size. No large placebo-controlled pain-outcome trial of nabumetone was located. Evidence: limited. (Source 2)
• Approved for relief of the signs and symptoms of rheumatoid arthritis. We found no placebo-controlled or head-to-head outcome trial in rheumatoid arthritis within this search; the GI-safety meta-analysis pooled arthritis trials without separating rheumatoid arthritis efficacy outcomes. Evidence: unknown. (Source 3)
• Nabumetone is prescribed for general musculoskeletal pain beyond the two approved arthritis indications. We found no trial evidence for these uses in this search; the label's indications are confined to osteoarthritis and rheumatoid arthritis. Evidence: unknown. (Source 3)

Interactions

• Alcohol (label): Drinking alcohol is listed in the Medication Guide among the factors that raise the chance of an NSAID-related stomach or intestinal ulcer or bleed, alongside past ulcers, corticosteroids, anticoagulants, SSRIs and SNRIs, higher doses, older age, longer use, poor health, smoking, advanced liver disease and bleeding problems. (Source 4)
• Alcohol (quantified in a prospective cohort) (cohort study): In a prospective cohort of men, the excess risk of major gastrointestinal bleeding associated with NSAID or aspirin use rose as alcohol intake rose, reaching a statistically significant 1.75-fold risk at 15 g or more of alcohol per day compared with non-drinkers. This is observational: it shows the risks compound, not that alcohol causes the bleed. (Source 5)
• Ginkgo biloba (case reports): A structured review of 15 published case reports found a possible causal link between ginkgo and bleeding events, with bleeding times elevated in the three reports that measured them. However, 13 of the 15 cases identified other risk factors for bleeding, and only six clearly described that ginkgo was stopped and bleeding did not recur. Combining ginkgo with an NSAID is therefore a plausible additive bleeding risk, but the evidence is case reports rather than trials. (Source 6)

Stopping it

• Nothing in the literature read describes physical dependence, a withdrawal syndrome or rebound on stopping nabumetone. The stopping guidance that exists is about limiting exposure in the first place: the label directs use of the lowest effective dose for the shortest duration consistent with the patient's treatment goals, because the boxed cardiovascular risk may increase with duration of use. (Source 7)
• Where a skin reaction such as pseudoporphyria occurs, the reported management in the case literature is withdrawal of the drug; the case report read describes the reaction arising on treatment rather than on stopping. (Source 8)

What goes wrong

In the same osteoarthritis trial, discontinuation for gastrointestinal intolerance was more than twice as frequent on nabumetone as on placebo. (Source 2)

• Randomized trial, Low certainty.
• Size: 423 patients.
• Who: Adults aged 40-64 with knee osteoarthritis.
• How long: up to four weeks.
• Result: Discontinuation for GI intolerance: placebo 2.1%, nabumetone 5%, aceclofenac 7.8%.
• Funding: not stated.

Limit of this finding: The paper's own figures do not fully agree. About 141 people were in each of the three groups (423 in total), so the 108 aceclofenac completers (76.6%) and 118 nabumetone completers (83.7%) imply that roughly 23% and 16% did not finish, yet the same abstract gives drop-out rates of 12.1% and 8.5%. The abstract does not explain the difference, and it says the treatment code was broken at the end of two weeks. Read the pattern (most drop-outs on placebo, fewer on the active drugs) rather than the exact percentages, and do not conclude how well nabumetone controls pain from drop-out rates alone.

Discontinuation due to G.I. intolerance was least in the placebo group (2.1%) followed by the nabumetone group (5%) and aceclofenac group (7.8%).

Dyspeptic symptoms - flatulence, constipation and diarrhoea - accounted for almost all gastrointestinal adverse events recorded in nabumetone trials. (Source 9)

• Meta-analysis, Low certainty.
• Size: 13 studies, 49,501 patients.
• Who: Arthritis patients in comparative NSAID trials.
• How long: varied.
• Result: 98.6% of all GI adverse events were dyspeptic symptoms; GI-related drop-outs and hospitalisations were 1.3-fold and 3.7-fold higher on comparator NSAIDs.
• Funding: not stated; journal supplement.

Overall, the dyspeptic symptoms flatulence, constipation, and diarrhea were the most commonly reported adverse events accounting for 98.6% of the total GI adverse events.

Nabumetone can cause pseudoporphyria - blistering skin lesions on sun-exposed areas - reported as a drug-induced photosensitivity reaction. (Source 8)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: An adult treated with nabumetone.
• How long: not stated in the abstract read.
• Result: Bullous (blistering) lesions over photoexposed areas; no incidence rate can be derived from a case report.
• Funding: not stated.

Nabumetone is a nonsteroidal anti-inflammatory drug, which has only rarely been associated with photosensitivity. We report a case of bullous lesions arising over photoexposed areas in a patient treated with nabumetone.

Across NSAIDs as a class, observational meta-analysis found an increased risk of acute myocardial infarction at high doses or in people with established coronary heart disease, with naproxen the exception; for diclofenac and rofecoxib the risk was raised at both low and high doses. (Source 10)

• Meta-analysis, Low certainty.
• Size: 18 independent study populations.
• Who: General populations and patients with coronary heart disease using NSAIDs.
• How long: observational follow-up, varied.
• Result: Pooled relative risks of acute myocardial infarction versus non-use, random effects: naproxen 1.06 (0.94-1.20), celecoxib 1.12 (1.00-1.24), ibuprofen 1.14 (0.98-1.31), meloxicam 1.25 (1.04-1.49), rofecoxib 1.34 (1.22-1.48), diclofenac 1.38 (1.26-1.52), indometacin 1.40 (1.21-1.62), etodolac 1.55 (1.16-2.06), etoricoxib 1.97 (1.35-2.89); nabumetone is not among the drugs estimated (it is not mentioned in the abstract or the open-access full text)
• Funding: not stated; SOS project.

Most frequently NSAIDs used in clinical practice, except naproxen, are associated with an increased risk of AMI at high doses or in persons with diagnosed coronary heart disease. For diclofenac and rofecoxib, the risk was increased at low and high doses.

The US prescribing information for nabumetone (Relafen DS) carries a boxed warning that NSAIDs increase the risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal, and that this risk may occur early in treatment and increase with duration of use. (Source 1)

• Official position, Low certainty.
• Size: not applicable (regulatory labelling)
• Who: Patients prescribed nabumetone, with the greatest concern for people with cardiovascular disease or risk factors.
• How long: risk may occur early and may increase with duration of use.
• Result: No incidence rate is given in the boxed warning; nabumetone is contraindicated in the setting of coronary artery bypass graft surgery.
• Funding: not applicable (regulatory position)

cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see WARNINGS and PRECAUTIONS ]. Nabumetone is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see CONTRAINDICATIONS and WARNINGS ].

The same boxed warning states that NSAIDs, a class that includes nabumetone, increase the risk of serious gastrointestinal bleeding, ulceration and perforation, which can occur at any time and without warning symptoms, with elderly patients at greater risk. (Source 1)

• Official position, Low certainty.
• Size: not applicable (regulatory labelling)
• Who: Patients prescribed nabumetone, with older adults at greater risk.
• How long: can occur at any time during use.
• Result: No incidence rate is given in the boxed warning.
• Funding: not applicable (regulatory position)

NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see WARNINGS ].

What the evidence supports

In a placebo-controlled randomised trial in knee osteoarthritis, patients on nabumetone were much less likely to drop out than patients on placebo. (Source 2)

• Randomized trial, Low certainty.
• Size: 423 patients.
• Who: Men and women aged 40-64 with uncomplicated osteoarthritis of the knee.
• How long: assessed at two weeks and four weeks.
• Result: Drop-outs 33.9% on placebo, 12.1% on aceclofenac, 8.5% on nabumetone; the abstract reports no pain-score difference or p-value between active arms.
• Funding: not stated.

Limit of this finding: The paper's own figures do not fully agree. About 141 people were in each of the three groups (423 in total), so the 108 aceclofenac completers (76.6%) and 118 nabumetone completers (83.7%) imply that roughly 23% and 16% did not finish, yet the same abstract gives drop-out rates of 12.1% and 8.5%. The abstract does not explain the difference, and it says the treatment code was broken at the end of two weeks. Read the pattern (most drop-outs on placebo, fewer on the active drugs) rather than the exact percentages, and do not conclude how well nabumetone controls pain from drop-out rates alone.

Drop outs were highest in the placebo group (33.9%) followed by the aceclofenac group (12.1%) and nabumetone group (8.5%).

A meta-analysis of comparative trials and postmarketing studies reported fewer gastrointestinal adverse events, and far fewer perforations, ulcers and bleeds, with nabumetone than with comparator NSAIDs. (Source 9)

• Meta-analysis, Low certainty.
• Size: 13 studies, 29 treatment arms, 49,501 patients; plus 39,389 patients over 17,502 treatment years in open-label data.
• Who: Patients with arthritis in comparative NSAID trials and postmarketing/open-label cohorts.
• How long: varied; postmarketing data covered 17,502 treatment years.
• Result: Significantly more GI adverse events on comparator NSAID (P = 0.007); after adjustment for patient-exposure years, perforations/ulcers/bleeds 10 to 36 times more likely on a comparator NSAID; one such event per 500 patient-exposure years in the open-label data.
• Funding: not stated; published in a sponsored-format American Journal of Medicine supplement (Vol 107, Suppl 1), and the comparison is against other NSAIDs rather than placebo.

After adjustment for patient-exposure years, PUBs were 10 to 36 times more likely to develop in patients treated with a comparator NSAID than with nabumetone.

Nabumetone is approved in the US for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis; this records the regulator's position, not trial evidence of benefit. (Source 3)

• Official position, Low certainty.
• Size: not applicable (regulatory labelling)
• Who: Adults with osteoarthritis or rheumatoid arthritis.
• How long: not applicable.
• Result: No effect size is given in the indication statement.
• Funding: not applicable (regulatory position)

Nabumetone tablets are indicated for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis

What the evidence does not support

The large independent meta-analysis of upper gastrointestinal complications with individual NSAIDs did not produce a pooled risk estimate for nabumetone, so its position in the class ranking is not established by that evidence. (Source 11)

• Meta-analysis, Moderate certainty.
• Size: 28 studies met inclusion criteria out of 2,984 articles screened.
• Who: General-practice and hospital populations using NSAIDs.
• How long: observational follow-up, varied.
• Result: Pooled relative risks for the NSAIDs that could be estimated ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone; nabumetone is not among the estimates in the abstract, and the open-access full text (PMC3714137) mentions nabumetone only in a cited reference title.
• Funding: not stated; conducted within the EU-funded Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) project.

Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone.

Where the research disagrees

Whether nabumetone is gentler on the stomach than other NSAIDs

• Huang, Sridhar and Hunt 1999 meta-analysis, meta-analysis of 13 comparative and open-label studies, 49,501 patients, published in a journal supplement, comparator NSAIDs rather than placebo: Significantly fewer treatment-related GI adverse events, especially PUBs, are seen in patients treated with nabumetone than with a comparator NSAID. Nabumetone is very safe for the GI tract. (Source 9)
• US prescribing information boxed warning for nabumetone, regulatory position carried as a class boxed warning: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. (Source 1)
• Castellsague et al 2012 (SOS project), meta-analysis of 28 observational studies; nabumetone not among the drugs for which a pooled estimate is reported: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. (Source 11)

How much

• Reference intake: Dosing is set by the prescriber, not by the reader. As a position, the US prescribing information states a recommended starting dose of 1,000 mg as a single daily dose, with some patients obtaining more relief from 1,500 mg to 2,000 mg per day, and instructs use of the lowest effective dose for the shortest duration. (Source 7)
• Upper limit: The label's stated ceiling is 2,000 mg per day; the labelling states that doses above 2,000 mg per day have not been studied. There is no reference intake or tolerable upper intake level, because nabumetone is a drug and not a nutrient. (Source 7)
• Studied: The 423-patient knee osteoarthritis trial compared nabumetone with aceclofenac and placebo over four weeks; the abstract read does not state the mg doses used in each arm. (Source 2)
• Studied: The gastrointestinal-safety meta-analysis pooled 29 treatment arms across 13 studies and 49,501 patients of nabumetone versus conventional NSAIDs, plus open-label nabumetone data covering 17,502 treatment years; doses are not stated in the abstract. (Source 9)

A common belief, and what the research shows

The belief: Nabumetone is the safe NSAID - it does not cause ulcers the way other anti-inflammatories do.

What the research shows: The claim traces to one 1999 meta-analysis that compared nabumetone with other NSAIDs rather than with placebo, was published in a journal supplement, and concluded 'Nabumetone is very safe for the GI tract.' Against that: the drug carries the full NSAID class boxed warning for fatal gastrointestinal bleeding, ulceration and perforation and for cardiovascular thrombotic events; in a placebo-controlled trial, discontinuation for gastrointestinal intolerance was 5% on nabumetone versus 2.1% on placebo; and the large independent meta-analysis that ranked individual NSAIDs by upper-gastrointestinal risk did not report an estimate for nabumetone at all, so its rank in the class is not actually established.

Questions and answers

What is it?

Nabumetone is a prescription anti-inflammatory tablet in the NSAID family, sold as Relafen among other names. What you swallow is a prodrug with little activity of its own: the liver converts it into 6-methoxy-2-naphthylacetic acid, which does the work. In the United States it is approved for osteoarthritis and rheumatoid arthritis. (Source 1)

What does it do in the body?

Like other NSAIDs, nabumetone is thought to work by reducing the body's production of prostaglandins, the local signals that drive pain and swelling in an inflamed joint, although the label states that its exact mode of action is not known. The same prostaglandin pathway is involved in protecting the stomach lining and in kidney and circulatory function, which is the usual explanation for why NSAIDs can harm those tissues. (Source 1)

Is it good or bad for you?

It is a drug with a benefit and a boxed harm, not a good or bad substance. Trial evidence supports symptom relief in knee osteoarthritis, and one meta-analysis argued it causes fewer ulcers and bleeds than other NSAIDs. The label nevertheless carries the class boxed warning that NSAIDs increase the risk of fatal gastrointestinal bleeding and of heart attack and stroke, with the cardiovascular risk rising with longer use. (Source 1)

How do you get more of it?

Does not apply: nabumetone is a prescription drug, not a nutrient, and no food or behaviour supplies it. The amount a person takes is set by their prescriber, and the label records a starting dose of 1,000 mg once daily, with instruction to use the lowest effective dose for the shortest duration. That is the label's position, recorded here, not a recommendation to the reader. (Source 7)

If it is harmful, what reduces it?

Where it is causing harm, what the literature describes is stopping the drug rather than removing it from the body: the case report of nabumetone-induced blistering photosensitivity concerns a reaction during treatment, and the label's own instruction is to minimise exposure in dose and duration. There is no antidote or clearance regimen in the sources read. (Source 7)

Why might someone be low in it or missing it?

Does not apply: there is no such thing as being low in nabumetone. A person has none unless it is prescribed. The reasons someone would not be taking it are clinical ones - it is contraindicated in the setting of coronary artery bypass graft surgery, and the label flags greater risk in people with cardiovascular disease or risk factors and in the elderly. (Source 1)

Which whole foods contain it or feed it?

No food contains nabumetone. The only food-related statement in the label read is that the starting dose can be taken with or without food, so meals are not required for it to work. The relevant dietary issue is the opposite direction: alcohol is listed among the things that raise the risk of an NSAID-related stomach bleed. (Source 7)

What happens if you do not have it?

Nothing is lost physiologically from not taking it - there is no deficiency. What the trial evidence describes is what is forgone in symptom control: in a placebo-controlled osteoarthritis trial, a third of placebo patients dropped out (33.9%) compared with 8.5% on nabumetone, which is read as untreated symptoms driving people off the study. (Source 2)

How can you test for it?

No test tells you whether you need nabumetone, and routine blood levels of the drug are not used in practice. What the literature frames as monitoring is harm surveillance rather than a test for the drug itself: the boxed warning notes that serious gastrointestinal events can occur at any time and without warning symptoms, which is precisely why no test reliably predicts them. (Source 1)

We searched: Searched for nabumetone therapeutic drug monitoring, 6MNA plasma assays and validated monitoring tests alongside the nabumetone prescribing information and the pooled GI-safety and NSAID-risk meta-analyses; none described a validated test of nabumetone status or need.

References

1. DailyMed (US National Library of Medicine), SPL set ID a9a0af85-6c43-4a2d-ba75-0be4ca64c931; label revision 12/2020, DailyMed version January 2024. RELAFEN DS (nabumetone) tablets - US prescribing information: boxed warning, Description and the opening of Clinical Pharmacology (labeler: Carwin Pharmaceutical Associates, LLC). 2020. Read the source
2. Journal of the Nepal Medical Association. The Effects of Aceclofenac and Nabumetone in Osteoarthritis. 2009. PMID 20387351, DOI 10.31729/jnma.226. Read the source
3. DailyMed (US National Library of Medicine), SPL set ID a9a0af85-6c43-4a2d-ba75-0be4ca64c931; label revision 12/2020, DailyMed version January 2024. RELAFEN DS (nabumetone) tablets - US prescribing information: Indications and Usage (labeler: Carwin Pharmaceutical Associates, LLC). 2020. Read the source
4. DailyMed (US National Library of Medicine), SPL set ID a9a0af85-6c43-4a2d-ba75-0be4ca64c931; label revision 12/2020, DailyMed version January 2024. RELAFEN DS (nabumetone) tablets - Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (labeler: Carwin Pharmaceutical Associates, LLC). 2020. Read the source
5. PLoS ONE. A Prospective Study of Alcohol Consumption and Smoking and the Risk of Major Gastrointestinal Bleeding in Men. 2016. PMID 27824864, DOI 10.1371/journal.pone.0165278. Read the source
6. Journal of General Internal Medicine. Spontaneous bleeding associated with ginkgo biloba: a case report and systematic review of the literature. 2005. PMID 16050865, DOI 10.1007/s11606-005-0114-4. Read the source
7. DailyMed (US National Library of Medicine), SPL set ID a9a0af85-6c43-4a2d-ba75-0be4ca64c931; label revision 12/2020, DailyMed version January 2024. RELAFEN DS (nabumetone) tablets - US prescribing information: Dosage and Administration (labeler: Carwin Pharmaceutical Associates, LLC). 2020. Read the source
8. Journal of the American Academy of Dermatology. Pseudoporphyria induced by nabumetone. 1999. PMID 10071328, DOI 10.1016/S0190-9622(99)70507-4. Read the source
9. The American Journal of Medicine (Vol 107, Suppl 1). Gastrointestinal safety profile of nabumetone: A meta-analysis. 1999. PMID 10628594, DOI 10.1016/s0002-9343(99)00368-x. Read the source
10. Pharmacoepidemiology and Drug Safety. Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies. 2013. PMID 23616423, DOI 10.1002/pds.3437. Read the source
11. Drug Safety. Individual NSAIDs and Upper Gastrointestinal Complications: A Systematic Review and Meta-Analysis of Observational Studies (the SOS Project). 2012. PMID 23137151, DOI 10.1007/BF03261999. Read the source