NSAIDs Part 3: Gastrointestinal Side Effects and Toxicity

In part 1 of our discussion on NSAIDs, we discussed the equal efficacy of various NSAIDs, while in part 2, we looked at the concept of an analgesic ceiling effect when using NSAIDs.

Congrats to all of those who identified the ceiling in part 2 as the Chihuly work at the Bellagio in Las Vegas.  Damon Tedford (@DamonTedford) wins the sammich for being the first to get the correct answer.

Today we’ll look at the side effect profiles of different NSAIDs.  While all NSAIDs are created equal with regards to analgesia, this is not the case for their side effect profiles.  Some NSAIDs are definitely more toxic than others.

While NSAIDs are a great bunch of analgesics, they unfortunately have GI, renal, and cardiac side effects.   For young, healthy patients, the upper GI complications (UGICs) are the most common side effect, as their renal/cardio complications are better tolerated.  In the over 60 population, those with pre-existing cardiac/renal disease, and a few other groups, the renal and cardiac complications are also often seen.

So which NSAIDs are most dangerous?

Golden-poison-frog P. terribilis (No joke, it’s actual species name is terribilis)

If this frog were an NSAID, which one would it be?

If you guessed ketorolac, nice work.

This 2010 systematic review looks at the relative risk for upper GI bleeding/perforation for both traditional and non-traditional (ie: coxib) NSAIDs.  It should be noted that NSAIDs increase the risk of lower GI bleeding as well, despite UGICs being most commonly discussed in the literature.

 

NSAIDtoxicityhttp://link.springer.com/article/10.1007/s00296-011-2263-6/fulltext.html

 

As you can see, the traditional NSAIDs fall into 3 rough categories for UGIG: low-risk, intermediate risk and high-risk. (Pooled RRs in parentheses)

Low risk

Ibuprofen (2.23)

Intermediate risk

Diclofenac (3.61)

Naproxen (4.6)

Indomethacin (5.12)

High risk

Ketorolac (14.54)

 

In addition to being no better for pain, ketorolac is also way nastier than other NSAIDs.  Depending upon the paper you read, you’ll find slightly different numbers, but the relative risk of traditional NSAIDs will pretty much always fall into these 3 groups.

An important caveat to these numbers is that they are pooled RRs between low dose and high dose NSAIDs.  All NSAIDs have much greater toxicity at higher doses.

Here is an example from a paper looking at UGICs with traditional NSAIDs.

The odds ratios for UGICs with Ibuprofen at:

Dose (mg/day)                        OR:

<1200                                        1.1 (95% CI 0.6-2.0)

1200-1799                                 1.8 (0.8-3.7)

>1800                                        4.6 (0.9-22.3)

Thus, 400 mg QID and 600 mg QID of ibuprofen have the same analgesic effect, but a total daily dose of 2400 mg is associated with more side effects than 1600 mg.

With ketorolac, risk similarly increases, but the complication rate is already so high (RR 20 at <20 mg/day) in this 2001 study, why would you even want to prescribe it in the first place.  For those wondering about risk when given parenterally, the RR for IM ketorolac is even greater than PO (28.3 vs. 20) in the same study.

 

So who will get the bleed?  In this great 2012 review article from Conaghan, the risk factors for UGIC are:

*Elderly (Age >60)

*History of PUD (especially if complicated by bleed/perforation)

*Multiple NSAID use

Concomitant ASA, steroids, anticoagulants or SSRIs

Concurrent H. pylori infection

Smoking

*denotes major risk factor

 

But I want to prescribe my patient some NSAIDs for their pain.  Can I prevent these side effects?

Fortunately you can.  Both misoprostol and PPIs will significantly reduce side effects of traditional NSAIDs, while H2 blockers will not.  This has been studied in the ARAMIS cohort study, where it was found that the RR for UGICs when misoprostol or omeprazole was added was 0.6, while the RR was 1.4 with H2 blockers.

Bottom line:

Different NSAIDs all produce similar levels of analgesia, but some are much worse than others when it comes to side effects.  There is no need to prescribe NSAIDs above their dose ceiling, as it endangers the patient without providing any benefit.  Be aware of risk factors for UGICs (esp. age >60, previous ulcer and multiple NSAIDs) and always consider prescribing a PPI when giving out an NSAID.

Cheers,

Chris

@SocmobEM

 

Post written by Chris Bond and peer reviewed by Nadim Lalani (@ermentor) and Brent Thoma (@boringem).

 

References

ARAMIS Study: Singh G Am J Ther. 2000 Mar;7(2):115-21.

García Rodríguez LA, Hernández-Díaz S. Epidemiology. 2001 Sep;12(5):570-6.

Conaghan PG, Rheumatol Int. 2012 Jun;32(6):1491-502. doi: 10.1007/s00296-011-2263-6. Epub 2011 Dec 23. Review.

Lewis, S. C., Langman, M. J. S., Laporte, J.-R., Matthews, J. N. S., Rawlins, M. D. and Wiholm, B.-E. (2002), Dose–response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. British Journal of Clinical Pharmacology, 54: 320–326. doi: 10.1046/j.1365-2125.2002.01636.x

Massó González, E. L., Patrignani, P., Tacconelli, S. and Rodríguez, L. A. G. (2010), Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis & Rheumatism, 62: 1592–1601. doi: 10.1002/art.27412

 

 

 

NSAIDs part 2: The Ceiling Effect

Sorry readers.  I’ve been slacking off on vacation in NYC, eating too much and blogging about food more than medicine.  Tonight at dinner with Mr. EMCrit, Scott called me out a bit for insufficient content.  Also, one of my readers has some rounds coming up soon, and needs to talk NSAIDs.  With that in mind, here’s part 2 of the NSAID saga.

In part 1 on NSAIDs, we looked at NSAID equivalency for analgesia and the myth that is  ketorolac (Toradol).  

Hat tip to readers Moshe and Elisha (@ETtube on twitter) for pointing out the concept of the ceiling effect with NSAIDs.  I did not mention this in part 1, and will discuss it today.
There’s a great talk by Larry Raney on the Free Emergency Talks website that discusses NSAIDs and the ceiling effect.  You can find it here.  As an aside, the Free Emergency Talks website is run by Joe Lex, one of the great EM educators, and has a thousands of talks from any conference you can think of.

What is the ceiling effect?

* Free sammich to the first reader who tells me where this ceiling is. (Sammich will be good when it goes in the mail, but I can’t guarantee quality on arrival.  Might make it a cockroach and twinkie sammich to prevent spoilage.)

The ceiling effect is the concept that there is a maximum level of analgesia that can be reached with a dose of medication, and beyond that dose, you get no more analgesia.

In addition, you continue to get more side effects That double sucks!

Tylenol and NSAIDs classically fall into the category of analgesics with a ceiling, while opiates have no ceiling.  This is why we can bomb in loads of fentanyl or morphine, but you don’t see us pounding patients with ibuprofen.

If you look at the doses of NSAIDs listed in part 1, you’ll see some pretty whopping doses.
Aside from the ceiling of anti-inflammatory dosing, there is also the concept of a second ceiling for acute pain?

Two ceilings?  Yup, two ceilings.

The ceiling dose for acute pain with ibuprofen is 400 mg po.

The higher ibuprofen dose ceiling of 800 mg I mentioned in part 1 is the anti-inflammatory ceiling of the NSAID and comes from the rheumatology literature.   I apologize if I confused anyone with this.  One key to understanding the NSAID literature is that it generally comes from 3 patient groups: rheumatologic disease, post-operative pain and dental pain.  The latter two are probably both representative of pain we see in ED patients, ie: acute, non-inflammatory pain.

This is the reason why meta-analyses of NSAID efficacy are a challenge; the indications, duration of therapy, dose, etc. are completely different.   In some studies, you are looking at patients with chronic inflammatory conditions on long term therapy.  These patients may need higher dose NSAIDs for their anti-inflammatory effects.  In other studies, it is single dose or short-term NSAIDs where analgesic ceiling will be 400 mg.

You can see how lumping all of these studies together in a review would misconstrue pretty much any endpoint.

Let’s now look at the two main studies supporting the 400 mg ceiling dose of ibuprofen and 10 mg ceiling dose of ketorolac.

In contrast to the usual scenario in which old research = bad research (or a HSSP: High School Science Project), there are papers from 1978 and 1986 looking at the ibuprofen ceiling effect.

The first, by Winter et al. in 1978 looked at 510 post oral surgery patients who had 1 or more extractions, impactions and even a few with alveolectomies. That all sounds pretty painful!  They compared five treatments: ibuprofen 400 mg, ibuprofen 800 mg, ASA 650 mg, Darvon 65 mg and placebo.  Both ibuprofen groups had similar reduction in pain scores and were better than the other 3 treatment arms.  The study was done with pooled data from two separate dentists; in one group 400 mg ibuprofen seemed slightly more effective, while 800 mg seemed slightly more effective in the other.  However, there are no data to support any statistically significant difference between ibuprofen groups in the article.

The second article, by Laska et al. in 1986 was a double blind parallel group study with 200 patients post oral surgery compared doses of 400 mg , 600 mg and 800 mg of ibuprofen.  There was no evidence of a dose response efficacy difference between 400, 600 and 800 mg.

Considering that dental pain hurts like hell, I’m inclined to believe these studies are sufficiently representative of ED patients with most injuries.  *As an aside, learn to do dental blocks, they are invaluable to patients.

With regards to ketorolac, this double blind RCT from Staquet in 1989 compared 10 mg, 30 mg and 90 mg IM ketorolac with placebo in 128 patients with cancer pain.  Again, no difference was found between the 3 ketorolac dosing regimens, with all being much superior to placebo.

Other similar studies have been done and show 10 mg is probably the ceiling dose of ketorolac both orally and parenterally.  

In the next parts of the NSAID saga, we’ll discuss side effects profiles of various NSAIDs, and NSAID hodgepodge such as effect on fracture healing, use in renal colic and more.

Cheers,

SOCMOBEM

References:

NSAIDs Part 1: Which one is best?

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I love NSAIDs!  Yup, love ‘em!
NSAIDs (Non-steroidal anti-inflammatory drugs) are some of the best analgesics available, plus they’re generally over the counter.  Despite their daily use for decades, NSAIDs remain sorely misunderstood.  I know they’re not a panacea, and they have some serious side effects in certain populations.   But for healthy patients without co-morbidities, they are pretty awesome painkillers, with no addictive potential (that I’m aware of).
Before we start, perform a Gedanken experiment if you will.  Not a true Gedanken Schrodinger’s Cat type experiment, but answer the following questions in your mind.
1) What is the best NSAID for analgesia?
2) Do oral or parenteral NSAIDs provide better pain relief?
Got your answers? Good.
Based on the conversations among staff, residents and nurses in the ED, oral or parenteral ketorolac (AKA: IM Toradol) is the strongest/bestest/most fantastic/awesome NSAID out there. 
WRONG!
I know that regardless of what I say from here on, some of you will stand by IM Toradol like a dying loved one. That’s okay, I understand.  It’s not your fault that you’ve been brainwashed into thinking this way.  Or maybe it’s anecdotal experience from years of practice, and I’m just a young pup who doesn’t know anything.
Just hear me out. 
What is the best NSAID for analgesia?
There isn’t one.
They’re all the same when dosed appropriately. I cannot say it better than Grant Innes did in this 2005 review of ED pain medications.
“Although some agents have been advocated for specific indications (eg, indomethacin for gout), there is no compelling evidence that any one NSAID is superior to any other—for any indication. Consequently, NSAIDS should be selected based on convenience, cost, and availability rather than on theoretical efficacy advantages.”
Important to note are the dosing regimes for each NSAID, as they are more than often used in the ED:
Ibuprofen up to 800 mg QID
Naproxen up to 500 mg TID
Ketorolac up to 10 mg QID
Indomethacin up to 50 mg QID

*Edit: There is an important concept of ceiling effect with NSAIDs.  I left this out here, and it is very important so we’ll discuss it in part two of the NSAID saga.  Thanks to reader @ETtube for pointing this out.

Other NSAID regimes are also found in this paper, but these are the most common ones in North America.
But what about IM toradol?  It always works for my patients.
I don’t know but maybe these these guys know the answer.
That’s right, Sanjay Arora and Mel Herbert from EM:RAPactually wrote a paper on this.  6 years ago!
I highly suggest you take 10 minutes of your day to read this great article in CJEM in 2007. The full text version is free as well.
Alternatively, I’ll summarize it here.
1994 Wright et al.– Retrospective analysis of data that was collected by prior prospective survey.
800 mg ibuprofen po vs. 60 mg ketorolac IM – NO DIFFERENCEin pain as rated by visual analogue scale (VAS)
1995 Turturro et al. – Prospective DBRCT (Double blind randomized controlled trial).
800 mg ibuprofen vs. 60 mg ketorolac IM  – NO DIFFERENCE
1998 Neighbor and Puntillo – Prospective DBRCT. 800 mg ibuprofen vs. 60 mg ketorolac IM.  All patients had self-assessed pain between 5-8/10 on VAS.
NO DIFFERENCE
*Funny thing about this study is the author’s name is spelled as Neighbour with a “U” in the text, but not in the references.  Funny because the Canadian CJEM autocorrect probably added the “U”.  Maybe funny just to me.*
They also cite two more trials comparing post-op pain with the same ibuprofen vs. ketorolac dosing, but at this point, you get the picture.
Finally, all of these studies compared 60 mg of ketorolac IM to 800 mg of ibuprofen.  Who actually gives 60 mg?  I’ve never seen it where I work, where 30 mg is the standard dose.  So, maybe ibuprofen is actually better than the 30 mg of IM ketorolac that we give.
Some of you may say, “I use the toradol for the placebo effect of an injection.  You can’t argue with that.” 
Sorry, someone studied that too.
This study by Schwartz et al. was a prospective DBRCT in which patients “were unknowingly given 800 mg oral ibuprofen in a flavoured drink and then given either a placebo IM injection or a placebo pill.”  No patient really received any IM medication in either group, and there was similarly no difference in the VAS between the two groups.  So IM for placebo effect only also appears unwarranted.
Also, that study design is kick ass!
Treatment bottom line: 
There is no difference between NSAIDs when it comes to pain control.  Just use an adequate dose of whichever you choose.   
IM ketorolac still has a role in vomiting patients or those unable to take po meds, but don’t kid yourself that it’s a “stronger” medication.  It’s not.
Despite all of this, I agree that some NSAIDs work better for certain people?  Why is this?
Watch for parts 2 and 3 of the NSAID discussion, where we’ll talk about this and much more.
*Personal disclosure: I use ibuprofen almost exclusively, but also use Naproxen, as the BID (can go TID) dosing regimen generally means patients will be more compliant and hopefully have better pain control for a greater duration.  When we discuss side effect profiles in the coming weeks, you’ll see why I don’t use ketorolac.
Cheers,
SOCMOBEM
References:
Innes GD, Zed PJ, Emerg Med Clin North Am. 2005 May;23(2):433-65, ix-x. 
Arora S, Wagner JG, Herbert M. CJEM. 2007 Jan;9(1):30-2. 
Schwartz NA, et al. Acad Emerg Med. 2000 Aug;7(8):857-61.