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Duke Orthopaedics
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Wheeless' Textbook of Orthopaedics

NSAIDS: Non-Steroidal Anti-Inflammatory Drugs


- Discussion:

    - non steroidals exert their actions by inhibiting isoforms of cyclo-oxygenase 1 and 2;
           - cox 1: expressed in the stomach and kidneys;
           - cox 2:
                 - cox 2 receptor is not normally expressed in synovial tissue;
                 - regulates inflammatory response and is responsible for disease symptoms;      

- Specific Agents:
         - Aspirin
    - Propionic Acids:
         - Naproxen
         - Oxaprozin
         - Ibuprofen
         - Ketoprofen / Oruvail
               - 100 mg, 150 mg, or 200 mg - extended release daily dosing;
    - Indoleacetic Acids:
         - Sulindac / Clinoril
         - Indomethacin
         - Etodolac / Lodine:
               - 200-400 mg q 6-8 hrs; (1200 mg/day divided doses)
               - Lodine XL 400 mg or 500 mg PO qd;
    - Oxicams:
         - Piroxicam / Feldene
    - Phenylacetic Acids:
         - Diclofenac / Volteren / Arthrotec
    - Misc:
         - Diflunisal / Dolobid
         - Fenoprofen / Nalfon
         - Meclofenamate / Meclomen
         - Phenylbutazone
         - Salicylate
         - Tolmentin
         - Relafen (Nabumetone):
                  - available in 500 mg and 750 mg tablets;
                  - usual dose is 1000 mg per day, but upto 2000 mg may be needed in some cases;
                  - metabolized in the liver and therefore no dose restrictions are need w/ renal insufficiency;

    - Cox 2 Inhibitors:
            - highly selective cyclooxygenase-2 (COX-2) inhibitors have no effect on platelet aggregation and bleeding time;

            - celecoxib / celebrex




                  - available in 100 mg and 200 mg tab;
                  - theoretically is safe for patients taking warfarin;
                  - patients w/ a sulfa allergy may show a hypersensitivity reaction;
                  - in the study by Dahlen B, et al (2001), the authors studied the effect of celebrex on patients with reactive airway disease.
                          - 17 women and 10 men had stable chronic asthma, with no exacerbations and with stable medication use during the prior three months;
                          - before each study visit, leukotriene antagonists and long-acting bronchodilators were withheld for at least two days, and short-acting bronchodilators for at least six hours;
                          - criterion for inclusion in trial was a 20 % drop in the forced expiratory volume  in one sec after the inhalation of lysine aspirin (3) on the first visit.
                          - patients did not have bronchoconstriction or extrapulmonary reactions after a graded oral challenge with increasing doses of celecoxib (suspensions of 10, 30, and 100 mg), given every second hour;
                          - on the final day of the study, each patient initially ingested 200 mg of celecoxib suspension, followed two hours later by the commercially available 200-mg capsule, without pulmonary or systemic reactions;
                  - authors concluded that celecoxib, a selective COX-2 NSAID, did not induce bronchospasm in patients w/ syndrome of asthma and aspirin intolerance;
                  - references:
                          - Celecoxib in patients with asthma and aspirin intolerance. The Celecoxib in Aspirin-Intolerant Asthma Study Group.  
                          - Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain


- Complications:
    - note that the two main complications of NSAID use are peptic ulcer formation and ATN;
          - in patients at risk, consider the use of alternative medications such as ultram, tylenol, or narcotics;
    - bleeding:
          - most often takes the form of a bleeding peptic ulcer, but if heparin or coumadin are used together other forms of life threatening hemorrhage may occur;
                - relative risk of GI bleeding from NSAIDS: Tolmentin (8.5), Piroxican (6.4), Fenoprofen (4.3), Naprosyn (4.3), Sulindac (4.2), Indomethacin (3.8), and Ibuprofen (2.3);
                - ref: Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.
          - NSAIDS should not be given to patients on heparin or coumadin (instead consider salicylate);
    - peptic ulcer disease:
          - misoprostol / cytotec:
                - is a prostaglandin E1 analog, and is used to prevent NSAID induced ulcers;
                - usual dose: 200 micrograms 4 times daily;
                - can cause miscarriage if taken during pregnancy;
          - references:
                - Controversies in the detection and management of nonsteroidal antiinflammatory drug-induced side effects of the upper gastrointestinal tract.
                - Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.
    - renal failure / insufficiency
          - renal insufficiency may be due to ATN or intersitial nephritis;
                - elderly patients w/ pre-existing renal insufficiency who are on diuretics are especially at risk;
          - patients with early NSAID related renal complications may note water retention (bloated face or feet), hematuria, or sudden increase in blood pressure;
          - special attention should be given to patients on ACE inhibitors and NSAIDS;
                - these patients may develop a fatal hyperkalemia;
                - other risk factors for this complication include pre-existing renal insufficiency, CHF, and/or diabetes;
          - in the report by Fored CM, et al, in a nationwide, population-based, case-control study of early-stage chronic renal failure in Sweden, face-to-face interviews 
                were conducted with 926 patients with newly diagnosed renal failure and 998 control subjects, of whom 918 and 980, respectively, had complete data;
                - results Aspirin and acetaminophen were used regularly by 37 % and 25 %, respectively, of patients with renal failure and by 19 percent and
                         12 percent, respectively, of the controls;
                - regular use of either drug in the absence of the other was associated with an increase by a factor of 2.5 in risk of chronic renal failure from any cause;
          - references:
                - Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs.
                - Original Article: Analgesic Use And Chronic Renal Disease.
                - Medical Progress: Renal Syndromes Associated with Nonsteroidal Antiinflammatory Drugs.
                - Acetaminophen, Aspirin, and Chronic Renal Failure   
    - pulmonary reactions:
          - in some patients with asthma, the administration of aspirin and other NSAIDS leads to bronchospasm
          - there is some evidence that Cox-2 medications are less likely to cause this complication.
          - ref: Celecoxib in patients with asthma and aspirin intolerance. The Celecoxib in Aspirin-Intolerant Asthma Study Group.  
    - stroke and MI:
          - Nonaspirin NSAIDs, Cyclooxygenase 2 Inhibitors, and the Risk for Stroke.
          - Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study.
          - Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study.  


Prevention of heterotopic ossification by nonsteroid antiinflammatory drugs after total hip arthroplasty.

Prophylaxis with indomethacin for heterotopic bone. After open reduction of fractures of the acetabulum.

The use of indomethacin to prevent the formation of heterotopic bone after total hip replacement. A randomized, double-blind clinical trial.

Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee.

The effect of piroxicam on the metabolism of isolated human chondrocytes.

Anti-inflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function.

Nonsteroidal anti-inflammatory drugs: effects on kidney function.  

Renal toxicity of the NSAID drugs. Murray MD and Brater DC. Ann Rev Pharmacol Toxicol. 1993;33:435-465.

Fatal outcome of interaction between warfarin and a non-steroidal anti-inflammatory drug.

Aspirin-induced asthma: advances in pathogenesis and management.  

Celecoxib versus Diclofenac and Omeprazole in Reducing the Risk of Recurrent Ulcer Bleeding in Patients with Arthritis

Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing

Effects of nonsteroidal anti-inflammatory drugs on post-operative renal function in normal adults.

Alternatives to Total Knee Replacement:
      Autologous Hamstring Resurfacing Arthroplasty



Original Text by Clifford R. Wheeless, III, MD.

Last updated by Data Trace Staff on Tuesday, July 3, 2012 11:44 am