Evidence Based Use of NSAIDS—Less is More

When we want to do an evidence-based approach to the use of any drug, we have to consider three factors:

  1. What beneficial effects do we want the drug to have on our patients?
  2. What harm might the drug cause?  How can we maximize benefit while minimizing risk?
  3. How much does the drug cost?  Can we get a better risk/benefit profile from a less expensive drug?

A great place to start using these tools to evaluate appropriate drug use is with the Non-Steroidal Anti-Inflammatory Drugs (NSAIDS).  NSAIDS are commonly prescribed drugs, but, in general, we practitioners use them in inappropriate ways.  We overestimate the benefit they give.  We underestimate the risks they carry.  We completely ignore their costs; preferring, it seems, to prescribe expensive NSAIDS which offer no benefits over the cheap stuff.

In this article, I want to summarize the evidence about NSAIDS and suggest a protocol for their use based on that evidence.  I say summarize, because the body of research on NSAIDS is very large and I cannot include everything in this short paper.  NSAIDS are a very well understood class of medications.  Most of the information I include is not controversial.  It can be found in most textbooks and review articles.  I have included a couple of these at the end of the article.

Let’s start by going over the potential harm that NSAIDS can cause.  Most people know that NSAIDS can cause GI complications like ulcers and GI bleeding.  The question is—how big of a problem is this?  It turns out to be a very big problem, indeed:

  1. An estimated 16,500 patients die from GI bleeding caused by NSAIDS each year.  This is far more people than die of AIDS each year (13,500).  In fact, the CDC ranks deaths due to NSAID induced GI bleeding as the 14th leading cause of death in this country.
  2. Over 100,000 people are hospitalized each year with GI complications caused by NSAID use.  Total spending in theUSto treat NSAID complications is greater than 2 billion dollars annually.
  3. The iatrogenic cost factor of NSAID use is approximately 2.  In other words, for every dollar spent on NSAIDS, approximately one more dollar is spent treating NSAID induced complications.

NSAIDS have other potential complications too.  Patients risk renal failure.  TheCOX-2 inhibitors increase the risk of cardiovascular complications as exemplified by Vioxx being pulled from the market due to this problem.

So the question now arises:  How can we reduce the substantial risks of using these drugs?  The answer to this question is twofold.  First, we should know that NSAIDS are not equal in their propensity to cause complications.  For example, ketorolac (Toradol) is over 12 times more likely to cause complications than plain old ibuprofen.  Table One summarizes various NSAIDS with respect to their relative risk (RR) to cause complications:

NSAID Used

RR

None

1

Ibuprofen

2.1

Diclofenac

2.7

Ketoprofen

3.2

Naproxen

4.3

Indomethacin

5.5

Piroxicam

9.3

Ketorolac

24.7

The second way to reduce risk is to understand the relation between the risk of complications and the benefit NSAIDS give.  So we need to discuss NSAID benefits first.

NSAIDS have two basic uses:   we use them as general pain relievers, and we use them to reduce inflammation.  Let’s discuss their pain relieving properties first.

  1. NSAIDS are equivalent as far as their analgesic effects.  No one NSAID has ever been shown to be superior to another.  They differ in their tendency to cause complications, but not in their ability to reduce pain.
  2. The analgesic effects of NSAIDS “max out” at a much lower dose than the anti-inflammatory effects.  Using ibuprofen for an example, the pain relieving properties of ibuprofen max out at a dose of 200mg to 400mg, depending on the patient’s size.  You will get no increased analgesic effect with ibuprofen 800 over a 200-400mg dose.
  3. However, the anti-inflammatory effect and the potential for complications continue to increase with increasing dose and increasing length of NSAID exposure.

So let’s discuss the anti-inflammatory properties of NSAIDS.  We may tell ourselves that we need to use an increased dose because we are treating “inflammation.”  When we do this, we are for the most part, deluding ourselves.  Few acutely painful conditions that we treat with NSAIDS are truly inflammatory.  Even chronic painful conditions will most likely not be amenable to treatment with anti-inflammatory doses of NSAIDS.  To use one example, osteoarthritis is not an inflammatory condition.  The bottom lines are these: NSAIDS are no better than acetaminophen for musculoskeletal pain and osteoarthritis. NSAIDS are not effective for chronic musculoskeletal conditions.

The obvious take home message here is that when we use NSAIDS, we should be using smaller doses for the shortest length of time possible.

The next factor to consider when deciding what NSAID to use is cost.  Remembering that all NSAIDS are equivalent in their pain relieving ability, let’s compare the cost of one day’s therapy using various NSAIDS. The difference in cost among NSAIDS is amazing. It ranges from ibuprofen, which costs around $0.03 per pill, to theCOX-2 inhibitors Celebrex and Bextra, which cost just under $3.00 a pill.  Table two compares prices of several NSAIDS.

NSAID Cost of One Day’s Therapy
Ibuprofen $0.18
Salsalate $0.30
Naproxen $0.20
Naproxen Sodium $0.60
Ketoprofen (Orudis) $0.80
Etodolac (Lodine) $0.72
Piroxicam (Feldene) $0.20
Celecoxib (Celebrex) $2.74
Valdecoxib (Bextra) $2.90

Remember that all NSAIDS are equivalent in their pain relieving ability; compare the cost of the various NSAIDS with their relative risk of causing complications.  You will notice that there is a clear winner:  ibuprofen is both the cheapest NSAID and the NSAID least likely to cause complications.

There is one final issue to consider however, and that is the COX-2 inhibitors.  These have been some of the most heavily (and successfully) marketed drugs in history.  The marketing message has been that COX-2 inhibitors cause fewer GI side effects than non-selective NSAIDS and therefore are safer.  It turns out that this message is both misleading and outright false.  First, it is debatable whether the COX-2 inhibitors have any real benefit over other NSAIDS at all with regards to serious GI side effects, such as serious GI bleeding. If they do, the effect is small and evident only after months of continuous usage—not the case for the majority of patients for whom these medicines are prescribed.  What has not been fully reported to doctors is that if you look at all serious complications, including death, MIs, heart failure, kidney failure, etc., the COX-2 inhibitors have consistently been shown to have an increased risk compared to other NSAIDS.  In other words, no matter how you spin it,COX-2 inhibitors are more dangerous, not less, than other NSAIDS.

So which NSAID should we be using in our prisons and jails?  We want an NSAID with the lowest relative risk compared to other NSAIDS and also cheap.  Well, it turns out that there is a clear winner in this competition.  Good old ibuprofen has the lowest relative risk of complications of all of the nonselective NSAIDS and, by fortuitous coincidence, is also the least expensive.  Don’t you just love it when the evidence-based best therapy is also the cheapest?

Take home message:

  1. Ibuprofen is the safest and cheapest NSAID.  Other low risk, low cost NSAIDS are salsalate and naproxen.
  2. NSAIDS should almost always be prescribed in the pain relief dosage range.  For ibuprofen, this is 200mg to 400mg per dose.
  3. We should rarely prescribe anti-inflammatory doses, and only for truly inflammatory conditions, such as rheumatoid arthritis and gout.
  4. We should not be usingCOX-2 inhibitors for acute pain, period.

References:  Instead of giving a long list of primary sources, I have instead included two excellent review articles easily referenced on the internet.  Those interested may use these as a springboard to a thorough review of the literature.

  1. Drug Class Review on Cyclo-Oxygenase (COX)-2 Inhibitors and Nonsteroidal Antiinflammatory Drugs (NSAIDS), Helfand and Peterson.OregonEvidence-BasedPracticeCenter. http://www.oregon.gov/DAS/OHPPR/ORRX/HRC/docs/NSAIDUpdatedFinalReport2.pdf

Evidence-based Use of NSAIDs in the ED, Raney. Emedhome.com. http://www.emedhome.com/features_archive-detail.cfm?SFID=100103&SFTID=news

4 thoughts on “Evidence Based Use of NSAIDS—Less is More

  1. Garrick Olsen

    Thank you for this great synopsis of NSAIDs. I chose Toradol IM w/ oral ketorolac quite a bit during my clinical rotations because I saw it as a better option than opioids for musculoskeletal complaints (mainly low back pain). Had I seen this article beforehand I likely would have recommended a lot more Advil. I’ll definitely be checking out that literature review you posted at the end of the article.

    I suspect I over-treat using the anti-inflammatory dose; can you give some examples of common complaints where the anti-inflammatory dose WOULD be appropriate?

    Reply
    1. Jeffrey Keller MD Post author

      Thanks for the comments Garrick. There are only three basic conditions in which the anti-inflammatory dose of NSAIDS works:

      1. Colic. The two best examples are Renal colic (kidney stone pain) and biliary colic (gall bladder attack).
      2. Menstrual pain.
      3. True inflammatory arthritis. Examples include autoimmune arthritis, like Rheumatoid arthritis and psoriatic arthritis and acute gout. This category does not include osteoarthritis.

      Reply
      1. Garrick Olsen

        I finally have some time to sit down and look over the evidence you cited at the end of your article. Unfortunately, neither of the links are working (I don’t have an Emed subscription so that could play a role). If you want to update your source, I was able to find the latest Final Report from OHSU here: http://www.ncbi.nlm.nih.gov/books/NBK53955/.

        Thanks again — I look forward to reading this and am considering presenting it the next time my facility does a lunch and learn.

        Reply

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