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NSAIDs: Friend or Foe

NSAIDs: Friend or Foe. Non-Steroidal Anti-Inflammatory Drugs. Acetylsalicylic acid first produced by Charles Frederic Gerhardt in 1853 Not until1897 that Bayer, a drug and dye firm, began investigating its use as a less irritating version of standard salicylate medicines.

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NSAIDs: Friend or Foe

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  1. NSAIDs: Friend or Foe

  2. Non-Steroidal Anti-Inflammatory Drugs • Acetylsalicylic acid first produced by Charles Frederic Gerhardt in 1853 • Not until1897 that Bayer, a drug and dye firm, began investigating its use as a less irritating version of standard salicylate medicines. • By 1899, Bayer was distributing their Aspirin around the world • Ibuprofen launched in 1969 • COX-2 enzyme discovered in 1988 • Celecoxib launched in 1999

  3. How do they work? • Cyclo-oxygenase (COX) enzyme used by cells in the synthesis of prostaglandins • Exists in 2 forms – COX-1 and COX-2 • Analgesic and anti-inflammatory effect mainly dependent on COX-2 • Unwanted GI side effects due to inhibition of COX-1

  4. GI Effects • Traditional NSAIDs (tNSAIDs) associated with 4-fold increase in incidence of severe upper GI ulcer complications (e.g. bleeding or perforation) • No clear consistent evidence that any non-aspirin tNSAID is any better than another • COX-2 selective NSAIDs (coxibs) result in significant decrease in upper GI complications

  5. Renal Effects • NSAIDs inhibit prostaglandin-induced vasodilation • Potentially causes reduced renal blood flow and can precipitate renal failure • Likelihood highest if existing renal impairment, CCF, liver cirrhosis and those on ACE inhibitors, ARBs or diuretics • No difference between tNSAIDs or coxibs

  6. What about CV effects? • Natural balance between: • Pro-thrombotic Thromboxane A (synthesised by platelets using COX-1) • Anti-thrombotic Prostacyclin (synthesised in vascular endothelium by COX-2)

  7. Prostanoid hypothesis • Aspirin is an irreversible non-selective inhibitor of COX-1 and COX-2. • Platelets have no nucleus so blockade from aspirin lasts for their entire lifespan • Prostacyclin can be synthesised de novo by endothelial cells so aspirin tips balance to anti-thrombotic side • Hence aspirins use in secondary prevention of CV disease

  8. Does this explain NSAID CV risk? • Other NSAIDs not irreversible blockers so may tip things into prothrombotic balance (especially coxibs) – or so the theory goes • Thought to be oversimplistic, however… • No alternative full and credible mechanism for CV s/e of NSAID’s yet been demonstrated

  9. Vioxx (Rofecoxib) • Large RCT by Bombardier et al (2000) found higher rate of MI in patients taking Vioxx compared to naproxen • Subsequent studies found Vioxx to be associated with significant increase in thrombotic events • Worldwide withdrawal of Vioxx in 2004 • Sparked numerous further trials looking into CV safety of coxibs and tNSAIDs (e.g. ADAPT, CLASS, MEDAL, TARGET)

  10. Meta-analysis McGettigan P, Henry D. JAMA 2006;296(13);1633-44

  11. So what does this mean for us? • BOTH tNSAIDs and coxibs are associated to varying degrees with increased CV risk • We must consider co-morbidities and concurrent medications that may sway risk • Older patients are at increased risk of CV, GI and renal side effects – weigh up risk/benefit • Both tNSAIDs and coxibs are viable and effective options to treat pain and have manageable side effect profiles

  12. Practical Advice • In terms of CV effects, naproxen is associated with lowest risk and diclofenac the highest • All NSAIDs contraindicated in active peptic ulceration but coxib may be used in those with a history of ulceration • Always consider prescribing gastric protection in form of PPI for those requiring long-term tNSAIDs OR coxibs • NICE judged that it is cost-effective to add generic PPI to tNSAIDs or coxibs used as treatment for rheumatoid or osteoarthritis • NICE advises against use of any NSAID in those taking low-dose aspirin • Avoid tNSAIDs and coxibs in those with history of heart failure • Avoid tNSAID or coxib in those with GFR <30, use with caution when GFR 30<60

  13. Practical Advice – Bottom Line • Prescribe lowest effective dose for the shortest period of time • In chronic pain consider as required dosing and review regularly • Advise patient regarding potential side effects and do what you can to minimise risks • Monitor BP, renal function and liver function in those on long term

  14. The Future • Await results of trials such as PRECISION (Prospective Randomised Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen)

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