Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, fever, and inflammation. Traditional NSAIDs block COX-1 and COX-2 enzymes that the body uses to manufacture substances called prostaglandins. Since COX-1 prostaglandins are stomach-protective, blocking this enzyme is associated with gastrointestinal toxicity, a known side effect of these drugs. Newer NSAIDs (called COX-2 inhibitors) block primarily COX-2 prostaglandins associated with pain, fever, and inflammation, and might be less risky to the stomach. However, this is not proven, and some COX-2s have been taken off the market due to excess risk of heart attacks attributable to their use. Drugs in this family include:

  • Aspirin, alternatively called acetylsalicylic acid or ASA (Adprin-B, Anacin, Arthritis Foundation Aspirin, Ascriptin, Aspergum, Asprimox, Bayer, BC, Bufferin, Buffex, Cama, Cope, Easprin, Ecotrin, Empirin, Equagesic, Fiorinal, Fiorital, Halfprin, Heartline, Genprin, Lanorinal, Magnaprin, Measurin, Micrainin, Momentum, Norwich, St. Joseph, Zorprin)
  • Celecoxib (Celebrex)
  • Choline salicylate (Arthropan)
  • Choline salicylate/magnesium salicylate (Tricosal, 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, Backache Maximum Strength Relief, Bayer Select Maximum Strength Backache, 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)
  • and others

Note : Besides reducing pain and inflammation, aspirin and, to a lesser extent, other NSAIDs interfere with cells in the blood called platelets, which facilitate clotting.

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.1 Because excessive acid can irritate the stomach, there are concerns that arginine could be harmful for individuals taking drugs that are also hard on the stomach (such as NSAIDs).

It may be best not to mix arginine with NSAIDs unless approved by your doctor.

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 individuals 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 due to 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.2,3,4 Thus, combining it with an NSAID might increase the risk of stomach problems.

Possible Harmful Interaction

The herb garlic (Allium sativum) is taken to lower cholesterol, among many other proposed uses.

One of the possible side effects of garlic is a decreased ability of the blood to clot, leading to an increased bleeding tendency.5,6 Therefore, you should not combine garlic and aspirin or other NSAIDs except under medical supervision.

The herb ginkgo is used to treat Alzheimer's disease and ordinary age-related memory loss, among many other uses. Some evidence suggests that ginkgo might also decrease the ability of the blood to clot, probably through effects on platelets.39-48 However, one double-blind study found that ginkgo does not increase the anticoagulant effects of aspirin;49 another found that while it did not interact with the antiplatelet drug clopidogrel. But, the herb did interact slightly with the related drug cilostazol.50 Taken together, this evidence still suggests that one should not take ginkgo while using aspirin or other NSAIDs except under medical supervision.

Policosanol (sugarcane source)
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 benefit as well as a risk of interactions with blood-thinning drugs.

For example, a 30-day, double-blind, placebo-controlled trial of 27 individuals with high cholesterol levels found that policosanol at 10 mg daily markedly reduced the ability of blood platelets to clump together.9 Another double-blind, placebo-controlled study of 37 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.10 Yet another double-blind placebo-controlled study of 43 healthy volunteers compared the effects of policosanol (20 mg daily), aspirin (100 mg daily), and policosanol and aspirin combined at these same doses.11 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, it would be advisable to avoid combining aspirin or other NSAIDs with sugarcane policosanol except under medical supervision. Note : Beeswax policosanol is substantially different from sugarcane policosanol, and is described separately below.

Possible Harmful Interaction

PC-SPES is an herbal combination that has shown promise for the treatment of prostate cancer. One case report suggests that PC-SPES might increase risk of bleeding complications if combined with blood-thinning medications.32 Subsequent evidence has indicated that PC-SPES contains the strong prescription blood thinner warfarin, making this interaction inevitable.36

Potassium Citrate
Possible Harmful Interaction

Potassium citrate and other forms of citrate (for example, calcium citrate, 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, sodium thiosalicylate).12

It may be advisable to avoid these citrate compounds during therapy with aspirin or salicylates except under medical supervision.

Possible Harmful Interaction

One study suggests that reishi impairs platelet clumping.33 This creates the potential for an interaction with any blood-thinning medication.

Possible Harmful Interaction

St. John's wort (Hypericum perforatum) is primarily used to treat mild to moderate depression.

The herb dong quai (Angelica sinensis) is often recommended for menstrual disorders such as dysmenorrhea, PMS, and irregular menstruation.

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.

It may be a good idea to wear a sunscreen or protective clothing during sun exposure if you take one of these herbs while using an NSAID.

Possible Harmful Interaction

The substance vinpocetine is sold as a dietary supplement for the treatment of age-related memory loss and impaired mental function.

Vinpocetine is thought to inhibit blood platelets from forming clots.34 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 (Coumadin) and vinpocetine, but prudence dictates caution anyway.35

Possible Mixed Interaction

Vitamin E appears to add to aspirin's blood-thinning effects. 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.13 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.14 However, there was a reduced risk of the more common ischemic stroke, caused by obstruction of a blood vessel in the brain, and the two effects were found essentially to cancel each other out.

Weak evidence from one animal study hints that vitamin E might reduce stomach inflammation caused by NSAIDs.50

The bottom line: Seek medical advice before combining vitamin E and aspirin.

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 is converted by the body into a salicylate similar to aspirin. It is therefore possible that taking NSAIDs and white willow could lead to increased risk of side effects, just as would occur if you combined NSAIDs with aspirin.

Herbs and Supplements
Possible Harmful Interaction

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

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 effectiveness of NSAIDs.38

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.15,16,17

In a study involving 18 healthy human volunteers, one group received chili powder, water, and aspirin; the control group received only water and aspirin.18 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 (drinking alcohol), and acid.19 Increasing the dose of capsaicin brought even greater benefit, as did increasing the time between giving capsaicin and the other agents. An earlier study in rats found that capsaicin exerted similar protection against aspirin damage.20

Some researchers have used this data to advocate chili or capsaicin as treatment for peptic ulcer disease,21 but check with your doctor before trying to self-treat this serious condition.

Supplementation Possibly Helpful

Colostrum is the fluid that new mothers' breasts produce during the first day or two after birth. It gives newborns a rich mixture of antibodies and growth factors that help them get a good start.

According to one study involving rats, taking colostrum from cows (bovine colostrum) as a supplement might help protect against the ulcers caused by NSAIDs.22

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 birth defects and possibly reducing the risk of heart disease. Because inadequate intake of folate is widespread, if you are taking any medication that depletes or impairs folate even slightly, you 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.23,24,25 In addition, a study of 25 people with arthritis receiving the drug sulfasalazine found evidence of folate deficiency.26 In another report, a woman taking 650 mg of aspirin every 4 hours for 3 days experienced a significant fall in blood levels of folate.27

Based on this preliminary evidence, folate supplementation may be warranted if you are taking drugs in the NSAID family.

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 9 healthy human volunteers, participants were given aspirin alone (325 mg) or aspirin (325 mg) plus DGL (175 mg).28 Stomach damage (as measured by blood loss) was found to be about 20% less when DGL was given with aspirin. As part of the same study, DGL was also 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.

Supplementation Possibly Helpful

Test tube studies suggest that aspirin promotes the loss of vitamin C through the urine,29,30 which could lead to tissue depletion of the vitamin. In addition, low vitamin C levels have been noted in individuals with rheumatoid arthritis, and this has been attributed to aspirin therapy taken for this condition.31

If you take aspirin regularly, vitamin C supplementation may be advisable.

Policosanol (beeswax form)
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 not clear whether beeswax policosanol might amplify the "blood thinning" effect of anti-inflammatory drugs in the same manner as sugarcane policosanol, as described above.

Possible Harmful Interaction

Based on chondroitin’s chemical similarity to the anticoagulant drug heparin, it has been suggested that chondroitin might have anticoagulant effects as well. There are no case reports of any problems relating to this, and studies suggest that chondroitin has at most a mild anticoagulant effect.37 Nonetheless, prudence suggests that chondroitin should not be combined with NSAIDs except under physician supervision.

References[ + ]

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3. Sumner H, Salan U, Knight DW, et al. Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. Biochem Pharmacol. 1992;43:2313-2320.

4. Williams CA, Hoult JR, Harborne JB, et al. A biologically active lipophilic flavonol from Tanacetum parthenium.Phytochemistry. 1995;38:267-270.

5. Gadkari JV, Joshi VD. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med. 1991;37:128-131.

6. Burnham BE. Garlic as a possible risk for postoperative bleeding. Plast Reconstr Surg. 1995;95:213.

7. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract [letter]. N Engl J Med. 1997;336:1108.

8. Arruzazabala ML, Mas R, Molina V, et al. Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients. Int J Tissue React. 1998;20:119-124.

9. Arruzazabala ML, Mas R, Molina V, et al. Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients. Int J Tissue React. 1998;20:119-124.

10. Arruzazabala ML, Valdes S, Mas R, et al. Effect of policosanol successive dose increases on platelet aggregation in healthy volunteers. Pharmacol Res. 1996;34:181-185.

11. Arruzazabala ML, Valdes S, Mas R, et al. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Pharmacol Res. 1997;36:293-297.

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13. Liede KE, Haukka JK, Saxen LM, et al. Increased tendency towards gingival bleeding caused by joint effect of alpha-tocopherol supplementation and acetylsalicylic acid. Ann Med. 1998;30:542-546.

14. Leppala JM, Virtamo J, Fogelholm R, et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000;20:230-235.

15. Abdel Salam OM, Moszik G, Szolcsanyi J. Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-induced cytoprotection in rats. Pharmacol Res. 1995;32:209-215.

16. Holzer P, Pabst MA, Lippe IT. Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa. Gastroenterology. 1989;96:1425-1433.

17. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci. 1995;40:580-583.

18. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci. 1995;40:580-583.

19. Abdel Salam OM, Moszik G, Szolcsanyi J. Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-induced cytoprotection in rats. Pharmacol Res. 1995;32:209-215.

20. Holzer P, Pabst MA, Lippe IT. Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa. Gastroenterology. 1989;96:1425-1433.

21. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci. 1995;40:580-583.

22. Playford RJ, Floyd DN, Macdonald CE, et al. Bovine colostrum is a health food supplement which prevents NSAID induced gut damage. Gut. 1999;44:653-658.

23. Baggott JE, Morgan SL, Ha T, et al. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochem J. 1992;282:197-202.

24. Baum CL, Selhub J, Rosenberg IH. Antifolate actions of sulfasalazine on intact lymphocytes. J Lab Clin Med. 1981;97:779-784.

25. Selhub J, Dhar GJ, Rosenberg IH. Inhibition of folate enzymes by sulfasalazine. J Clin Invest. 1979;61:221-224.

26. Krogh Jensen M, Ekelund S, Svendsen L. Folate and homocysteine status and haemolysis in patients treated with sulfasalazine for arthritis. Scand J Clin Lab Invest. 1996;56:421-429.

27. Lawrence VA, Loewenstein JE, Eichner ER. Aspirin and folate binding: in vivo and in vitro studies of serum binding and urinary excretion of endogenous folate. J Lab Clin Med. 1984;103:944-948.

28. Rees WD, Rhodes J, Wright JE, et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol. 1979;14:605-607.

29. Das N, Nebioglu S. Vitamin C aspirin interactions in laboratory animals. J Clin Pharm Ther. 1992;17:343-346.

30. Molloy TP, Wilson CW. Protein-binding of ascorbic acid 2. Interaction with acetylsalicylic acid. Int J Vitam Nutr Res. 1980;50:387-392.

31. Sahud MA, Cohen RJ. Effect of aspirin ingestion on ascorbic-acid levels in rheumatoid arthritis. Lancet. 1971;1:937-938.

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33. Su C, Shiao M, Wang C. Potentiation of ganodermic acid S on prostaglandin E(1)-induced cyclic AMP elevation in human platelets. Thromb Res. 2000;99:135-145.

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37. AbdelFattah W, Hammad T. Chondroitin sulfate and glucosamine: A review of their safety profile. JANA. 2001;3:16-23.

38. Tatro D, ed. Drug Interaction Facts. St. Louis, MO: Facts and Comparisons; 1999.

39. Kudolo GB, Wang W, Barrientos J, et al. The Ingestion of Gingko Biloba Extract (EGb 761) Inhibits Arachidonic Acid-Mediated Platelet Aggregation and Thromboxane B 2 Production in Healthy Volunteers. J Herb Pharmacother. 2005;4:13-26.

40. Chung KF, Dent G, McCusker M, et al. Effect of a ginkgolide mixture (BN 52063) in antagonising skin and platelet responses to platelet activating factor in man. Lancet. 1987;1:248-251.

41. Fong KC, Kinnear PE. Retrobulbar haemorrhage associated with chronic Gingko biloba ingestion. Postgrad Med J. 2003;79:531-532.

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44. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology. 1996;46:1775-1776.

45. Fessenden JM, Wittenborn W, Clarke L. Gingko biloba: a case report of herbal medicine and bleeding postoperatively from a laparoscopic cholecystectomy. Am Surg. 2001;67:33-35.

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47. Gilbert GJ. Ginkgo biloba.Neurology. 1997;48:1137.

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Last reviewed December 2015 by EBSCO CAM Review Board
Last Updated: 12/15/2015

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