Non-aspirin Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Safety and precautions

NSAIDs can have serious, even life-threatening side effects. Some NSAIDs have more frequent or more serious side effects than others. Use them only under medical supervision.

Cancer mortality or risk

Some use of NSAIDs is linked to a few instances of higher cancer mortalitydeath, or the death rate in a population; cancer studies often report all-cause mortality (death from any cause) and cancer-specific mortality (death due to the cancer under investigation) or risk of cancer.

• Higher cancer-specific mortality among people with a non-serous ovarian tumor with non-aspirin NSAID use after diagnosis in a large observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study¹Verdoodt F, Dehlendorff C, Friis S, Kjaer SK. Non-aspirin NSAID use and ovarian cancer mortality. Gynecologic Oncology. 2018 Aug;150(2):331-337.
• Higher risk of ER+/PR+, HER2−, and p53− breast cancers, as well as luminal A or B breast cancers, among people with recent use of ibuprofen compared to no use in a large observational study²Brasky TM, Bonner MR et al. Non-steroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk: differences by molecular subtype. Cancer Causes and Control. 2011 Jul;22(7):965-75.  

Modest evidencesignificant effects in at least three small but well-designed randomized controlled trials (RCTs), or one or more well-designed, mid-sized clinical studies of reasonably good quality (RCTs or observational studies), or several small studies aggregated into a meta-analysis (this is the CancerChoices definition; other researchers and studies may define this differently) of higher risk of recurrent advanced adenomas and/or 2 or more adenomas after colorectal adenoma surgery among people using NSAIDs 4 or more days/week and using vitamin D₃

• Higher risk of recurrent advanced adenomas and/or 2 or more adenomas after colorectal adenoma surgery among people using aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) 4 or more days/week and using 1000 IU/day vitamin D₃ compared to those with less frequent NSAID use in a large RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects³Calderwood AH, Baron JA, et al. No evidence for posttreatment effects of vitamin D and calcium supplementation on risk of colorectal adenomas in a randomized trial. Cancer Prevention Research. 2019 May;12(5):295-304.

Cancer-specific side effects and symptoms

A few side effects and symptoms of cancer are worsened by some uses of NSAIDs.

Cardiovascular side effects 

Celecoxib (Celebrex): strong evidenceconsistent, significant effects in several large (or at least one very large) well designed clinical studies or at least two meta-analyses of clinical studies of moderate or better quality (or one large meta-analysis) finding similar results (this is the CancerChoices definition; other researchers and studies may define this differently) of higher risk of hypertension of any grade during FOLFOX treatment and increased risk of a grade 2 or higher elevation in creatinine levels after completion of FOLFOX among people with stage III colon cancer using celecoxib

• Higher risk of hypertension of any grade during FOLFOX treatment and increased risk of a grade 2 or higher elevation in creatinine levels after completion of FOLFOX among people with stage III colon cancer using celecoxib in a very large RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects⁴Meyerhardt JA, Shi Q. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage III colon cancer: the CALGB/SWOG 80702 (Alliance) randomized clinical trial. JAMA. 2021 Apr 6;325(13):1277-1286.

Pain

Celcoxib: preliminary evidencesignificant effects in small or poorly designed clinical studies OR conflicting results in adequate studies but a preponderance of evidence of an effect (this is the CancerChoices definition; other researchers and studies may define this differently) of worse pain during chemotherapy among people with metastatic or postoperative recurrent stomach (gastric) cancer treated with celecoxib

• Worse pain scores among people with metastatic or postoperative recurrent stomach (gastric) cancer treated with chemotherapy with celecoxib compared to chemotherapy alone in a mid-sized RTC⁵Guo Q, Li Q et al. A comprehensive evaluation of clinical efficacy and safety of celecoxib in combination with chemotherapy in metastatic or postoperative recurrent gastric cancer patients: a preliminary, three-center, clinical trial study. Medicine (Baltimore). 2019 Jul;98(27):e16234.

Indomethacin: good evidencesignificant effects in one large or several mid-sized and well-designed clinical studies (randomized controlled trials (RCTs) with an appropriate placebo or other strong comparison control or observational studies that control for confounds) (this is the CancerChoices definition; other researchers and studies may define this differently) of worse persistent cancer pain among people treated with indomethacin

• Worse persistent (chronic) cancer pain among people treated with indomethacin compared to placebo in a large meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 18 RCTs⁶Huang R, Jiang L et al. Comparative efficacy of therapeutics for chronic cancer pain: a Bayesian network meta-analysis. Journal of Clinical Oncology. 2019 Jul 10;37(20):1742-1752.

Other side effects or adverse events

The US Food and Drug Administration warns that ibuprofen (Advil, Motrin and other brands), naproxen (Aleve and other brands), diclofenac, celecoxib (Celebrex) and other NSAIDs increase the risk of heart attack or stroke, even after just a few weeks of use. Medical supervision is strongly advised with all NSAIDs.⁷US Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. US Department of Health and Human Services. February 26, 2018. Viewed January 11, 2021.

Because of these risks, many researchers investigating use of NSAIDs other than aspirin for reducing cancer risk have concluded that risks of serious cardiovascular events outweigh the cancer-preventive benefits of long-term use;⁸Veettil SK, Lim KG et al. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMC Cancer. 2017 Nov 14;17(1):763; Wakeman C, Keenan J et al. Chemoprevention of colorectal neoplasia. ANZ Journal of Surgery. 2017 Dec;87(12):E228-E232; Arber N, Eagle CJ et al. Celecoxib for the prevention of colorectal adenomatous polyps. New England Journal of Medicine. 2006 Aug 31;355(9):885-95; Bertagnolli MM, Eagle CJ et al. Celecoxib for the prevention of sporadic colorectal adenomas. New England Journal of Medicine. 2006 Aug 31;355(9):873-84; Mohammed A, Yarla NS, Madka V, Rao CV. Clinically relevant anti-inflammatory agents for chemoprevention of colorectal cancer: new perspectives. International Journal of Molecular Sciences. 2018 Aug 8;19(8). pii: E2332; Kerr DJ, Dunn JA et al; VICTOR Trial Group. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. New England Journal of Medicine. 2007 Jul 26;357(4):360-9; Tomić T, Domínguez-López S, Barrios-Rodríguez R. Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: a systematic review and meta-analysis. Cancer Epidemiology. 2019;58:52–62; Fajardo AM, Piazza GA. Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2015 Jul 15;309(2):G59-70. several studies were halted before completion because of safety concerns.⁹Bertagnolli MM, Eagle CJ et al; Adenoma Prevention with Celecoxib Study Investigators. Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial. Cancer Prevention Research (Phila). 2009 Apr;2(4):310-21. 

All NSAIDs, including those available over-the-counter, can have these common side effects:¹⁰Ogbru A, Marks JW. COX-2 Inhibitor Medications. Rx List. Viewed February 8, 2021; Pantziarka P, Sukhatme V, Bouche G, Meheus L, Sukhatme VP. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent. Ecancermedicalscience. 2016;10:610.

Rare side effects:¹¹Ogbru A, Marks JW. COX-2 Inhibitor Medications. Rx List. Viewed February 8, 2021; Pantziarka P, Sukhatme V, Bouche G, Meheus L, Sukhatme VP. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent. Ecancermedicalscience. 2016;10:610.

Drug Interactions

Celecoxib (Celebrex) may interact with these drugs:¹²Ogbru A, Marks JW. COX-2 Inhibitor Medications. Rx List. Viewed February 8, 2021.

• Increases the concentration of lithium in the blood and may increase the blood-thinning effect of warfarin (Coumadin)
• Fluconazole (Diflucan) impairs metabolism of celecoxib (Celebrex), increasing its level in the body.

Further drug interactions are listed on these sites:

Do not use (contraindications)

If you’re receiving treatments—for cancer or other conditions—that cause low platelet counts or thin your blood, you should check with your doctor before use.

Caution is advised if you have hypertension or risk factors for gastrointestinal bleeding. Avoiding or discontinuing NSAID use in cancer patients is not advised in one review, but careful monitoring for side effects such as cardiovascular events (with COX-2 inhibitors) or gastrointestinal bleeding is recommended if used.¹³Solheim TS, Fearon KC, Blum D, Kaasa S. Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review. Acta Oncologica 2013 Jan;52(1):6-17.

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