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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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non steroidal anti inflammatory drugs
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
how do they work
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
gi effects
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
renal effects
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
what about cv effects
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)
prostanoid hypothesis
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
does this explain nsaid cv risk
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
vioxx rofecoxib
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)
meta analysis
Meta-analysis

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

so what does this mean for us
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
practical advice
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
practical advice bottom line
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
the future
The Future
  • Await results of trials such as PRECISION (Prospective Randomised Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen)