By Chris Faubel, M.D. – Nonsteroidal anti-inflammatory drugs (NSAIDs) are amongst the most widely used pain relievers used in the United States:  70+ million prescriptions are written each year, and if you include over-the-counter NSAIDs, 30+ billion doses are consumed annually. [1] As pain specialist, we should be aware of how NSAIDs work, what adverse effects they can cause, and how to minimize ……………. I will refer to those NSAIDs that preferentially inhibit COX-1 (but also inhibit COX-2) as “nonspecific” or “nonselective”.  Those that mostly inhibit COX-2, will be referred to as “COX-2 inhibitors” or “coxibs”. Mechanism of Action of NSAIDs

Source: Medscape

Baseline levels of prostaglandins are created for normal physiologic function.  The cyclooxygenase-1 enzyme (COX-1), converts arachidonic acid to prostaglandins (gastric mucosa protective by decreasing acid production), prostacyclins (inhibit platelet aggregation), and thromboxane A2 (aids in platelet aggregation).

  • Low-dose aspirin inhibits the ability of COX-1 to make thromboxane, without having much inhibitory effect on the production of prostacyclins.  This collectively inhibits platelet aggregation, and is the reason why long-term use of low-dose aspirin aids in decreasing the incidence of heart attacks.

In this same cascade (seen in the pic to the right) is COX-2.  While COX-1 is always working, COX-2 is essentially only induced to work when there is inflammation (pain). All NSAIDs block COX-1 and COX-2 to varying degrees.

Source: Medscape
  • Certain NSAIDs preferentially block COX-1, while others were designed to mostly block COX-2.
  • Predominantly COX-1 inhibitors:  ibuprofen, naproxen, aspirin, ketorolac (Toradol), indomethacin
  • Predominantly COX-2 inhibitors: etodolac (Lodine), diclofenac (Voltaren), celecoxib (Celebrex), meloxicam (Mobic), valdecoxib (Bextra – discontinued), rofecoxib (Vioxx – discontinued)
When we consider prescribing NSAIDs, we need to keep in mind three general adverse effects
  1. Gastrointestinal
  2. Cardiovascular (MI and stroke)
  3. Renal
Gastrointestinal Adverse Effects of NSAIDs
Nonspecific NSAIDs (those with mostly COX-1 inhibition) block the production of GI-protective prostaglandins.  Because of this, patients can develop upper and lower GI ulceration, as well as GI bleeds and perforations.
Endoscopic findings in patients taking chronic NSAIDs:  40-60% erosions; 15-30% ulcers
  • This is if you took asymptomatic patients off the street and performed an endoscopic exam; so they aren’t necessarily symptomatic.
Major GI effects (bleeding, perforations, symptomatic ulcers): 2.5-4.5% of patients
  • These are the patients that would seek medical attention.  A relatively small percentage of patients, but still a very large number considering the tens of millions of patients taking NSAIDs chronically.
  • Note the above image that depicts ketorolac (Toradol) as being the most COX-1 specific.  It is of no coincidence that ketorolac is not advised to be used for more than 5 consecutive days, because of the high GI bleed risk.
Risk factors for developing the above major GI adverse effects:
  1. Prior upper GI events
  2. Older age (>65)
  3. Concurrent anticoagulation use (warfarin)
  4. Corticosteroid use
  5. High-dose or multiple NSAIDs (NSAID + low dose aspirin)
  • High risk patients should take COX-2 selective NSAIDs + PPI (or not get NSAIDs at all)
Taking a COX-2 inhibitor with low-dose aspirin
  • Low-dose aspirin taken concurrently with a COX-2 inhibitor nearly negates the GI-protective effects of the COX-2 inhibitor.
  • As many of our older patients are taking low-dose aspirin for the cardiovascular benefits, this is important to know.
PPI with nonselective NSAID
  • Some physicians use the strategy of combining a proton-pump inhibitor with a nonselective NSAID (for example: omeprazole with diclofenac)
  • This has NOT been shown to decrease the number of patients developing dyspepsia.
Proven ways to decrease the incidence of upper GI events
  • PPIs, misoprostol, COX-2 selective – keep in mind, these do NOT eliminate GI risks
Dyspepsia is NOT a reliable predictor for the presence or absence of GI complications
  • Most bleeds have no antecedent symptoms
  • Also keep in mind that the presence of dyspepsia in a patient does NOT mean they will develop serious GI adverse effects
Cardiovascular Adverse Effects of NSAIDs

Striking a balance between prostacyclin production and thromboxane production

Source: Medscape
  • As noted above, prostacyclins help to prevent platelet aggregation (cardioprotective), while thromboxane A2 causes platelets to clump (and thus cause cardio issues).  Since both of these are produced via COX-1, the balance between prostacyclin and thromboxane presence is key.
  • It is important to note that not all NSAIDs that block COX-1, will affect prostacyclin and thromboxane production the same.  See the image to the right.
  • Note that a pure COX-2 inhibitor will have no effect on thromboxane production, and therefore no effect on inhibiting platelet aggregation like aspirin does.  Because of this, it is safe to use COX-2 inhibitors after surgery because it won’t have a bleeding risk.
  • High dose naproxen (500mg BID) significantly inhibits thromboxane production all day, while ibuprofen 800mg would inhibit platelet aggregation for 2-4 hours after each dose.
Can concurrent NSAID use block the beneficial effects of ASA?
  • The cardioprotective, inhibition of platelet aggregation effects of low-dose aspirin are well known.
  • But when ibuprofen or naproxen are given before the ASA, they preferentially block the COX-1 and don’t allow ASA to exert its effects.
  • In contrast, COX-2 selectives (specifically Vioxx) and diclofenac did NOT interfere with the binding and protective effects of ASA.
Uniqueness of Naproxen
  • High-dose naproxen (500mg BID) has a strong anti-platelet effect and has NOT been shown to increase the risk of CV events more than placebo.
  • Interestingly, low-dose naproxen (220mg BID) DID show an increased risk of CV events over placebo.
Bottomline: All NSAIDs (except high-dose naproxen) have shown an increased risk of cardiovascular events compared to placebo
Why is there an increased risk of CV events with NSAIDs?
  • This isn’t clearly understood, but it is thought that inhibiting COX-2 (either with nonselective NSAIDs or with COX-2 selectives) causes an imbalance in prostaglandins that leads to sodium retention, decrease glomerular filtration rate (GFR), and increased blood pressure.
  • Interestingly, high-dose naproxen has been shown to decrease the GFR and raise systolic BP just as much as COX-2 inhibitors.
It is still not known whether concurrent use of low-dose ASA would negate the increased CV events risk with NSAIDs.

References: 1) Wiegand, Timothy. Toxicity, Nonsteroidal Anti-inflammatory Agents.  Medscape. Updated: May 20, 2010


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