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Anti-inflammatory Medications
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)


NSAIDs can damage the stomach as well as the small and large intestines, causing ulceration, chronic bleeding, and eventually iron deficiency (Bertschinger et al. 1996; Bjarnason and Macpherson 1994; Davies 1995).

Significance of Depletion

Iron deficiency may be associated with oxidative DNA damage (Ames 2000). In children, iron deficiency leads to cognitive dysfunction. Other pathologies associated with depleted levels of iron include anemia and compromised immune function. Symptoms include dizziness, fatigue, shortness of breath, pallor, and tachycardia (Covington 1999).

Replacement Therapy

Therapeutic doses for replacement therapy for adults range from 100 to 200 mg/day (2 to 3 mg/kg/day) of elemental iron, usually in 3 divided doses (Covington 1999). Iron levels should be monitored carefully; excess levels could also be associated with oxidative DNA damage as well as increased risk of cancer and heart disease (Ames 2000). The oral lethal dose of elemental iron is estimated to be 200 to 250 mg/kg with symptoms presenting after ingestion of 30 to 60 mg/kg (Covington 1999). Iron supplements can cause GI irritation; administering the supplement with food will prevent GI upset and bleeding (Hines Burnham et al. 2000).


Plasma levels of melatonin were significantly reduced after administration of both ibuprofen (400 mg) and indomethacin (75 mg) compared to controls, perhaps through interference with prostaglandin synthesis (Surrall et al. 1987).

Significance of Depletion

Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).

Replacement Therapy

Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms.

Vitamin B9 (Folic Acid)

Non-steroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, have antifolate activity (Baggott et al. 1992). It is not known if chronic ibuprofen treatment will cause a folate deficiency.

Significance of Depletion

Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.

Replacement Therapy

The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen.


Administration of naproxen (250 mg tid) in ten healthy volunteers for either 7 or 14 days resulted in a 35% increase in urinary zinc excretion but serum zinc levels remained unchanged (Elling et al. 1980). However, another report indicates that serum zinc levels were altered by NSAID therapy and decreased to 10.47 mmol/L in patients treated with NSAIDs (Balogh et al. 1980).

Significance of Depletion

Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000).

Replacement Therapy

Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.

Editorial Note

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.


Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.

Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med. 1998;30:122-130.

Baggott JE, Morgan SL, Ha T, et al. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochem J. 1992;282(Pt 1):197-202.

Balogh Z, El-Ghobarey AF, Fell GS, et al. Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis. Ann Rheum Dis. 1980;39:329-332.

Bertschinger P, Zala GF, Fried M. [Effect of non-steroidal antirheumatic agents on the gastrointestinal tract: clinical aspects and pathophysiology]. Schweiz Med Wochenschr. 1996;126(37):1566-1568.

Bjarnason I, Macpherson AJ. Intestinal toxicity of non-steroidal anti-inflammatory drugs. Pharmacol Ther. 1994;62(1-2):145-157.

Covington T, ed. Nonprescription Drug Therapy Guiding Patient Self-Care. St Louis, MO: Facts and Comparisons; 1999: 467-545.

Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum. 1995;38(12):1311-1321.

Elling H, Kiilerich S, Sabro J, Elling P. Influence of a non-steroid anti-rheumatic drug on serum and urinary zinc in healthy volunteers. Scand J Rheumatol. 1980;9:161-163.

Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies Health Professional Division; 1998:490-491.

Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S Suppl):1344S-1349S.

Hines Burnham T, et al, eds. Drug Facts and Comparisons. St Louis, MO: Facts and Comparisons; 2000.

Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.

Surrall K, Smith JA, Bird H, Okala B, Othman H, Padwick DJ. Effect of ibuprofen and indomethacin on human plasma melatonin. J Pharm Pharmacol. 1987;39(10):840-843. 

Copyright © 2000 Integrative Medicine Communications

This publication contains information relating to general principles of medical care that should not in any event be construed as specific instructions for individual patients. The publisher does not accept any responsibility for the accuracy of the information or the consequences arising from the application, use, or misuse of any of the information contained herein, including any injury and/or damage to any person or property as a matter of product liability, negligence, or otherwise. No warranty, expressed or implied, is made in regard to the contents of this material. No claims or endorsements are made for any drugs or compounds currently marketed or in investigative use. The reader is advised to check product information (including package inserts) for changes and new information regarding dosage, precautions, warnings, interactions, and contraindications before administering any drug, herb, or supplement discussed herein.