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:

Winter et al. Oral Surg Oral Med Oral Pathol. 1978 Feb;45(2):159-66.
 
Laska et al. Clin Pharmacol Ther. 1986 Jul;40(1):1-7.

Staquet MJ J Clin Pharmacol. 1989 Nov;29(11):1031-6.