Nonsteroidal anti-inflammatory drugs (NSAIDs) and drug reactions

DEFINITION: Drugs used to treat pain, fever, and inflammation.

• INTERACTIONS: Arginine, chondroitin, cyclosporine, dong quai, feverfew, folate, garlic, ginkgo, policosanol, potassium citrate, reishi, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), St. John’s wort, tricyclic antidepressants, vinpocetine, vitamin E (possible mixed interaction), white willow
• DRUGS IN THIS FAMILY: Aspirin, alternatively called acetylsalicylic acid or ASA (Acuprin, Ascriptin, Aspergum, Aspridox, Aspir-Mox, Aspirtab, Aspir-tin, Bayer, BC, Buffex, Easprin, Ecotrin, Empirin, Entaprin, Entercote, Fasprin, Genacote, Gennin-FC, Genprin, Goody's, Halfprin, Lortab, Magnaprin, Micrainin, Miniprin, Momentum, Norgesic, Orphengesic, Panasal, Percodan, Ridiprin, Robaxisal, Roxiprin, Saleto, Sloprin, Soma, Supac, Synalgos-DC, Talwin, Valomag, Vanquish, Zorprin), celecoxib (Celebrex), choline salicylate (Arthropan), choline magnesium trisalicylate (Trilisate), diclofenac potassium (Cataflam, Voltaren Rapide), diclofenac sodium (Arthrotec, Voltaren, Voltaren SR, Voltaren-XR), diclofenac sodium/misoprostol (Arthrotec), diflunisal (Dolobid), etodolac (Lodine, Lodine XL), fenoprofen calcium (Nalfon), flurbiprofen (Ansaid), ibuprofen (Advil, Arthritis Foundation Ibuprofen, Bayer Select Ibuprofen, Dynafed IB, Genpril, Haltran, IBU, Ibuprin, Ibuprohm, Menadol, Midol IB, Motrin, Nuprin, Saleto), indomethacin (Indochron E-R, Indocin, Indocin SR, Indomethacin, Indomethacin SR, Novo-Methacin), ketoprofen (Actron, Orudis, Orudis KT, Oruvail), ketorolac tromethamine (Toradol), magnesium salicylate (Doan’s, Magan, Mobidin, Bayer Back and Body, Bayer Select, Momentum Muscular Backache Formula, Nuprin Backache, Mobigesic, Magsal), meclofenamate sodium (Mecolfen, Meclomen), mefenamic acid (Ponstan, Ponstel), nabumetone (Relafen), naproxen (EC-Naprosyn, Napron X, Naprosyn), naproxen sodium (Aleve, Anaprox, Anaprox DS, Naprelan), oxaprozin (Daypro), piroxicam (Feldene), salsalate or salicylic acid (Amigesic, Argesic-SA, Arthra-G, Disalcid, Marthritic, Mono-Gesic, Salflex, Salgesic, Salsitab), sodium salicylate (Pabalate), sodium thiosalicylate (Rexolate), sulfasalazine (Azulfidine EN-tabs, Salazopyrin, SAS-500), sulindac (Clinoril), tolmetin sodium (Tolectin, Tolectin DS)

Arginine

Effect: Possible Harmful Interaction

Arginine is an amino acid found in many foods, including dairy products, meat, poultry, and fish. Supplemental arginine has been proposed as a treatment for various conditions, including heart problems.

Arginine has been found to stimulate the body’s production of gastrin, a hormone that increases stomach acid. Because excessive acid can irritate the stomach, there are concerns that arginine could be harmful for persons taking drugs that can negatively affect the stomach (such as NSAIDs). It may be best not to mix arginine with NSAIDs unless approved by a doctor.

Other studies indicate that ibuprofen combined with arginine may improve ibuprofen's impact and reduce side effects. Positive impacts were observed in post-operative swelling reduction, faster pain relief, and a reduced risk of gastric lesions.

Cyclosporine

Effect: Possible Harmful Interaction

Cyclosporine is a calcineurin inhibitor that is taken as an immunosuppressant, typically after an organ transplant. Concurrent use of NSAIDs and cyclosporine may result in an increased risk of nephrotoxicity, or kidney damage.

Feverfew

Effect: Possible Harmful Interaction

The herb feverfew (Tanacetum parthenium) is primarily used for the prevention and treatment of migraine headaches. NSAIDs are also used for migraines, so there is a chance that some persons might use both the herb and drug at once, a combination that may present risks.

The biggest concern with NSAIDs is that they can cause stomach ulcers, which may progress to bleeding or perforation without pain or other warning symptoms. This stomach damage is caused by drug interference with the body’s protective prostaglandins. Newer NSAIDs called COX-2 inhibitors may be less likely to produce this side effect. Feverfew also affects prostaglandins, so combining it with an NSAID might increase the risk of stomach problems. Concurrent use of feverfew and NSAIDs may also cause renal damage.

Garlic, Ginkgo

Effect: Possible Harmful Interaction

Among many other proposed uses, the herb garlic (Allium sativum) is taken to lower cholesterol. One of the possible side effects of garlic is a decreased ability of the blood to clot, leading to an increased bleeding tendency. Therefore, one should not combine garlic and aspirin or other NSAIDs except under medical supervision.

Among many other uses, the herb ginkgo is used to treat Alzheimer’s disease and ordinary age-related memory loss. Some evidence suggests that ginkgo might also decrease the ability of the blood to clot, probably through effects on platelets.

Policosanol (Sugarcane Source)

Effect: Possible Harmful Interaction

A sugarcane-derived form of the supplement policosanol is used to reduce cholesterol levels. It also interferes with platelet clumping, creating potential benefits and a risk of interactions with blood-thinning drugs.

A thirty-day, double-blind, placebo-controlled trial of twenty-seven people with high cholesterol levels found that policosanol at 10 milligrams (mg) a day markedly reduced the ability of blood platelets to clump together. Another double-blind, placebo-controlled study of thirty-seven healthy volunteers found evidence that the blood-thinning effect of policosanol increased as the dose was increased: the larger the policosanol dose, the greater the effect.

Another double-blind placebo-controlled study of forty-three healthy volunteers compared the effects of policosanol (20 mg daily), aspirin (100 mg daily), and policosanol and aspirin combined at these same doses. The results again showed that policosanol substantially reduced the ability of blood platelets to stick together and that the combined therapy exhibited additive effects.

Based on these findings, one should avoid combining aspirin or other NSAIDs with sugarcane policosanol except under medical supervision. Beeswax policosanol, discussed below, is substantially different from sugarcane policosanol.

Potassium Citrate

Effect: Possible Harmful Interaction

Potassium citrate and other forms of citrate (such as calcium citrate and magnesium citrate) may be used to prevent kidney stones. These agents work by making the urine less acidic. This effect on the urine may lead to decreased blood levels and therapeutic effects of several drugs, including aspirin and other salicylates (choline salicylate, magnesium salicylate, salsalate, sodium salicylate, and sodium thiosalicylate). One should avoid these citrate compounds during therapy with aspirin or salicylates, except under medical supervision.

Reishi

Effect: Possible Harmful Interaction

One study suggests that reishi impairs platelet clumping. This creates the potential for an interaction with any blood-thinning medication.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Effect: Possible Harmful Interaction

Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression, anxiety, and other psychiatric conditions. Taking NSAIDs and SSRIs concurrently is associated with an increased risk of gastrointestinal problems, including bleeding. Similar harmful interactions with NSAIDs have also been documented with other antidepressant medications, including serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants.

Dong Quai, St. John’s Wort

Effect: Possible Harmful Interaction

The herb dong quai (Angelica sinensis) is often recommended for menstrual disorders such as dysmenorrhea, premenstrual syndrome, and irregular menstruation. St. John’s wort (Hypericum perforatum) is primarily used to treat mild to moderate depression.

Certain NSAIDs, including most notably piroxicam, can cause increased sensitivity to the sun, amplifying the risk of sunburn or skin rash. Because St. John’s wort and dong quai may also cause this problem, taking these herbal supplements during NSAID therapy might add to this risk. One should use sunscreen or wear protective clothing during sun exposure if also taking one of these herbs while using an NSAID.

Vinpocetine

Effect: Possible Harmful Interaction

The substance vinpocetine is not approved by the US Food and Drug Administration (FDA) but can be sold as a dietary supplement and is sometimes taken for age-related memory loss and impaired mental function. Vinpocetine is thought to inhibit blood platelets from forming clots. For this reason, it should not be combined with medications or natural substances that impair the blood’s ability to clot normally, as this may lead to excessive bleeding. One study found only a minimal interaction between the blood-thinning drug warfarin and vinpocetine, but one should use caution anyway.

Vitamin E

Effect: Possible Mixed Interaction

Vitamin E appears to add to the blood-thinning effects of NSAIDs. One study suggests that the combination of aspirin and even relatively small amounts of vitamin E (50 mg daily) may lead to a significantly increased risk of bleeding. In another study of 28,519 men, vitamin E supplementation at a low dose of about 50 IU (international units) daily was associated with an increase in fatal hemorrhagic strokes, the kind of stroke caused by bleeding within the brain. However, there was a reduced risk of the more common ischemic stroke caused by obstruction of a blood vessel in the brain.

Weak evidence from one animal study hints that vitamin E might reduce stomach inflammation caused by NSAIDs. One should seek medical advice before combining vitamin E and aspirin.

White Willow

Effect: Possible Harmful Interaction

The herb white willow (Salix alba), also known as willow bark, is used to treat pain and fever. White willow contains a substance that the body converts into a salicylate similar to aspirin. It is therefore possible that taking NSAIDs and white willow could lead to an increased risk of side effects, just as would occur if one combined NSAIDs with aspirin.

Herbs and Supplements

Effect: Possible Harmful Interaction

Based on their known effects or constituents, the herbs dong quai, garlic, ginger (Zingiber officinale), horse chestnut (Aesculus hippocastanum), and red clover (Trifolium pratense), and the substances fish oil, omega-3 fatty acids, mesoglycan, and OPCs (oligomeric proanthocyanidins), might present an increased risk of bleeding if combined with aspirin.

Citrate

Effect: Possible Harmful Interaction

Potassium citrate, sodium citrate, and potassium-magnesium citrate are sometimes used to prevent kidney stones. These supplements reduce urinary acidity and can, therefore, lead to decreased blood levels and decreased effectiveness of NSAIDs.

Cayenne

Effect: Supplementation Possibly Helpful

Cayenne (Capsicum annuum or C. frutescens) and other hot peppers used in chili and various dishes contain as their “hot” ingredient capsaicin, a substance that is thought to be stomach-protective. For years, people have believed that spicy foods were a cause of stomach ulcers. However, preliminary evidence suggests that cayenne peppers might actually help protect the stomach against ulcers caused by aspirin and possibly other NSAIDs.

In a study involving eighteen healthy volunteers, one group received chili powder, water, and aspirin; the control group received only water and aspirin. Chili powder was found to significantly protect the stomach against damage from aspirin, a known stomach irritant. It was suggested that this protective effect might result from capsaicin-induced stimulation of blood flow in the lining of the stomach.

Further support for this theory comes from a study in rats, which found that capsaicin protected the stomach against damage caused by aspirin, ethanol (consumable alcohol), and acid. Increasing the dose of capsaicin brought even greater benefit, as did increasing the time between giving capsaicin and giving the other agents. An earlier study in rats found that capsaicin conferred similar protection against aspirin damage.

Some researchers have used these data to advocate chili or capsaicin as a treatment for peptic ulcer disease. However, one should consult with a doctor before trying to self-treat this serious condition.

Colostrum

Effect: Supplementation Possibly Helpful

Colostrum is the fluid in breast milk produced during the first day or two after giving birth. The fluid gives newborns a rich mixture of antibodies and growth factors that help them get a good start on nutrition. According to one study involving rats, taking colostrum from cows (bovine colostrum) as a supplement might help protect against the ulcers caused by NSAIDs.

Folate

Effect: Supplementation Possibly Helpful

Folate (also known as folic acid) is a B vitamin that plays an important role in many vital aspects of health, including preventing neural tube congenital abnormalities and possibly reducing the risk of heart disease. Because inadequate folate intake is widespread, persons taking any medication that depletes or impairs folate even slightly may need supplementation.

There is some evidence that NSAIDs might produce this effect. In test-tube studies, many NSAIDs have been found to interfere with folate activity. In addition, a study of twenty-five people with arthritis receiving the drug sulfasalazine found evidence of folate deficiency. In another report, a woman taking 650 mg of aspirin every four hours for three days experienced a significant fall in blood levels of folate. Based on this preliminary evidence, folate supplementation may be warranted for persons taking drugs in the NSAID family.

Licorice

Effect: Supplementation Possibly Helpful

Licorice root (Glycyrrhiza glabra or G. uralensis), a member of the pea family, has been used since ancient times as both food and medicine. Preliminary evidence suggests that a specific form of licorice called DGL (deglycyrrhizinated licorice) might help protect the stomach against damage caused by the use of aspirin and possibly other NSAIDs. (DGL is a modified version of licorice that is safer to use.)

In a double-blind study of nine healthy volunteers, participants were given aspirin alone (325 mg) or aspirin (325 mg) plus DGL (175 mg). Stomach damage (as measured by blood loss) was found to be about 20 percent less when DGL was given with aspirin. As part of the same study, DGL also was found to reduce stomach damage caused by aspirin in rats, though the benefit was small. It is possible that larger doses of DGL might provide greater protection.

Vitamin C

Effect: Supplementation Possibly Helpful

Test-tube studies suggest that aspirin promotes the loss of vitamin C through the urine, which could lead to tissue depletion of the vitamin. In addition, low vitamin C levels have been noted in persons with rheumatoid arthritis, and this has been attributed to aspirin therapy taken for this condition. Vitamin C supplementation may be advisable in persons who regularly take aspirin. Additionally, vitamin C increases naproxen levels in the blood, which may increase side effects.

Policosanol (Beeswax Form)

Effect: Possible Helpful Interaction

The supplement policosanol is a mixture of numerous related substances, and its exact composition varies with its source. Policosanol made from sugar cane appears to reduce cholesterol levels. Policosanol from beeswax may help protect the stomach from damage caused by NSAIDs. However, it is unclear if beeswax policosanol amplifies the blood-thinning effect of anti-inflammatory drugs in the same manner as sugarcane policosanol.

Chondroitin

Effect: Possible Harmful Interaction

Based on chondroitin’s chemical similarity to the anticoagulant drug heparin, it has been suggested that chondroitin also might have anticoagulant effects. There are no case reports of any related problems, and studies suggest that chondroitin has at most a mild anticoagulant effect. Nonetheless, chondroitin should not be combined with NSAIDs except under physician supervision.

Other Interactions

Other potential interactions include an increased risk of bleeding when taking NSAIDs with ginseng, cinnamon, bromelain, or turmeric. Taking fiber supplements with NSAIDS may decrease the body's ability to absorb the medication. The effects of choline magnesium trisalicylate (Trilisate) may decrease with the use of vitamin D or calcium supplements, and vitamin D₃ may increase the risk of side effects.

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