The sky isn’t the limit for NSAIDs analgesia

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Using the one-dose/one-size approach is detrimental to patient health.

As an ED clinician, I take enormous pride in taking care of patients presenting to my ED in pain. I take even bigger pride in the progress that Emergency Medicine has made over the past 15 years to perfect pain management.

Armed with a solid knowledge base, great evidential support, and a broad array of analgesics, ED doctors across the country are providing effective and safe relief of pain.


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However, from time to time I am still reminded that so-called “traditional” teaching is pushing for the “one-dose,” “one-size” fits all approach (0.1 mg/kg of IV morphine, 30 mg of ketorolac IV or 60 mg IM, 800 mg of ibuprofen, etc). This “traditional” approach to ED pain management is frequently based on outdated information (in textbooks) or debunked research (10– to 20-year-old studies).

Furthermore, the “one-dose/one-size fits all” approach is detrimental to safe and effective ED analgesia as it fails to provide a balance between the effective dose of therapeutics and occurrences of side effects.

Does the dose of an analgesic in the ED matter? Even if given as a single dose? Sure it does. Even more so when we talk about NSAIDs. This class of analgesic, antipyretic and anti-inflammatory agents possess a unique pharmacologic phenomenon known as an “analgesic ceiling.”


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This phenomenon implies that after reaching a certain dosing threshold, any further increase in dosing will not result in additional analgesia (Catapano 1996).

Based on this concept, the analgesic ceiling dose for Ibuprofen is 400 mg per dose, for ketorolac is 10 mg, Diclofenac is 50 mg, and for Naproxen it’s 220-250 mg (Catapano 1996, Ong 2007). The analgesic ceiling of NSAIDs is not a new discovery — it has been around since the 1970s (Bloomfield 1974, Winter 1978).

Unfortunately, it has not made its way into the traditional teaching of ED analgesia (textbooks) and, consequently, has not resulted in a practice change of ED doctors, or to the FDA-approved package insert of NSAIDs with resultant administration of these analgesics in supra-analgesic dosing regiments in the ED and at discharge.

I have fully embraced NSAID’s analgesic ceiling, incorporated it into my clinical work, and even studied it in ED patients presenting with acute painful conditions (Motov 2019, Motov 2017). However, the EM skeptics remain unconvinced citing the following arguments: ED studies were looking at short–term pain relief (one to two  hours), NSAIDSs follow a linear kinetic pattern (larger the dose, longer the duration of action), and that a single, supra-analgesic dose of ibuprofen or ketorolac would not harm patients.


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Let’s address these arguments by looking at the evidence.

Argument #1 –The duration of ED-based studies was too short to find a difference.

The ED study that compared analgesic efficacy of three doses of oral ibuprofen (400, 600 and 800 mg) in adult ED patients with acute painful conditions demonstrated similar analgesic efficacy of all three dosing regimens at 60 minutes post-medication administration (Motov 2019).

As the lead author, I decided that keeping study subjects in the ED for up to eight hours to collect pain scores after a single dose of ibuprofen was unfeasible and impractical as in reality such patients are routinely discharged from the ED within one to two hours after receiving oral NSAIDs. While I might be wrong in my assessment of the practical execution of ED studies of longer duration, numerous clinical trials compared different dosing of ibuprofen for acute pain in various clinical settings.

In a double-blind, placebo-controlled trial comparing analgesic efficacy of a single dose of Ibuprofen (400 mg and 800 mg) in volunteers with laser–induced pain demonstrated a lack of difference in pain relief between two doses up to eight hours (Nielsen 1980).  Both dosing regimens were superior to placebo up to five hours for 400 mg and up to four hours for 800 mg dose. Maximum analgesia was noted at three hours for both dosing regimens. However, the total analgesic effect (area under the time-efficacy curve (AUEC)) of 400 mg exceeded that of ibuprofen 800 mg after four and eight hours.

Another study comparing single oral doses of ibuprofen (300mg and 900 mg) with aspirin (900 mg) and placebo in adult patients with pain due to episiotomy demonstrated that summed pain intensity scores (SPID) were similar in magnitude between all three groups up to six hours and higher than the placebo (Bloomfield 1974).

A clinical trial that compared a single oral dose of ibuprofen (400 mg, 600 mg and 800 mg) with aluminum ibuprofen (400 mg), and placebo in patients with moderate or severe pain due to third molar extraction demonstrated similar analgesic efficacy of the three doses during the entire six hours of the study (Laska 1986).

The effectiveness of 400 mg and 800 mg of oral ibuprofen was evaluated in patients undergoing oral surgery and was found to be similar in both groups up to three hours (study duration) (Winter 1978).

Furthermore, a clinical trial that assessed the comparative efficacy of three single doses (200mg, 400 mg and 600 mg) of soluble ibuprofen and ibuprofen tablets after third molar surgery showed no significant difference in pain scores or time to taking additional analgesics between the respective doses of soluble and tablet formulations of ibuprofen over the 6 hours of the study period (Seymour 1996).

Finally, a multicenter, randomized, double-blind, placebo-controlled trial assessing the analgesic effects of IV ibuprofen 400 mg and 800 mg given every six hours for postoperative pain management of patients undergoing orthopedic or abdominal surgery revealed significant and similar reductions in pain in both dosing regimens at rest and with movement during the six- to 24-hour and 12- to 24-hour time periods compared with placebo (Southworth 2009).

So, it looks like the analgesic ceiling of ibuprofen of 400 mg has been validated in various clinical settings at the one-hour mark in the ED, three to six hours in dentistry, eight hours in laser-induced pain and up to 24 hours in the acute post-operative period.

But it gets more interesting.

Argument #2: NSAIDS’s follow a linear kinetic pattern (larger the dose, longer the duration of action).

In the study by Nielsen et al, the concentrations of the pharmacologically active S-enantiomer of ibuprofen in this study peaked at 90 minutes following the 400 mg dose, and at 80 minutes following the 800 mg dose. Concentrations after the higher dose (800 mg) were greater than those after the lower dose (400 mg) at all times. But, the 800 mg dose did not provide superior analgesia, and, contrary, had less of the total analgesic effect than 400 mg over the eight hour period.

A study by Laska et al showed revealed significant differences in the mean serum levels produced by the three ibuprofen doses beginning at one-hour post-administration with mean levels for the group receiving the 800 mg and 600 mg ibuprofen doses being greater than those of the group receiving the 400 mg dose. However, the three doses of ibuprofen did not differ significantly in mean pain intensity during the entire six hours.

The concentration goes up higher for dosages given above 400 mg of ibuprofen, but does not translate into greater or longer analgesia. How it could be? What happened to the linear kinetic pattern? Sure, it exists, but maybe not for the analgesic property of NSAIDs.

This ceiling effect of NSAIDs could be explained by a development of a rapid tolerance to the analgesic effect produced by the higher circulating drug concentrations (600 mg and 800 mg dose) as well as rapid saturation of the enzymatic sites.

Argument #3: No adverse effect after a single, supra-analgesic dose of NSAIDs in the ED.

I agree with the skeptics that a single, above analgesic ceiling dose of ibuprofen in the ED rarely (if ever) would cause a serious adverse effect. But the absence of evidence does not mean that the risk does not exist.

Several case reports describe the adverse effects related to the administration of a single dose of parenteral ketorolac (30 mg IV or 60 mg IM) and the development of acute post-operative bleeding in children undergoing tonsillectomy, of acute renal failure in a patient with sickle cell disease, and nearly 60% increase in bleeding time in healthy volunteers.

The actual risk of not honoring the analgesic ceiling dose of NSAIDs in the ED translates into potentially dangerous prescribing practices at discharge. I think it is fair to assume that if clinicians administer 800 mg of ibuprofen in the ED, the same dose will be written for the patient upon discharge.

The outpatient use of NSAIDs in supra-analgesic doses could lead to the development of potentially serious adverse effects since the anti-inflammatory properties of NSAIDs are dose-and time-dependent. Thus, changing a prescribing practice of NSAIDs in the ED by utilizing the lowest effective dose (aka the analgesic ceiling dose) has the potential to reduce harm associated with NSAID use post-discharge.

In Summary

I embrace the skepticism in medicine. Even more so, I embrace it in the ED. However, if this skepticism is based on “traditional teaching,” personal experience or the debunked myth (existence of oligoanalgesia in the ED), I will push against it by providing evidential support, by conducting research and by openly inviting anyone for a debate. I am encouraging ED clinicians to honor the analgesic ceiling of commonly used NSAIDs in the ED and at discharge.

References:

  1. Catapano MS. The analgesic efficacy of ketorolac for acute pain. J Emerg Med. 1996 Jan-Feb;14(1):67-75. doi: 10.1016/0736-4679(95)02052-7. PMID: 8655940.
  2. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007 Mar;5(1):19-34. doi: 10.3121/cmr.2007.698. PMID: 17456832; PMCID: PMC1855338.
  3. Bloomfield SS, Barden TP, Mitchell J. Comparative efficacy of ibuprofen and aspirin in episiotomy pain. Clin Pharmacol Ther. 1974 Jun;15(6):565-70. doi: 10.1002/cpt1974156565. PMID: 4601742.
  4. Winter L Jr, Bass E, Recant B, Cahaly JF. Analgesic activity of ibuprofen (Motrin) in postoperative oral surgical pain. Oral Surg Oral Med Oral Pathol. 1978 Feb;45(2):159-66. doi: 10.1016/0030-4220(78)90079-8. PMID: 343032.
  5. Motov S, Masoudi A, Drapkin J, Sotomayor C, Kim S, Butt M, Likourezos A, Fassassi C, Hossain R, Brady J, Rothberger N, Flom P, Marshall J. Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2019 Oct;74(4):530-537. doi: 10.1016/j.annemergmed.2019.05.037. Epub 2019 Aug 2. PMID: 31383385.
  6. Motov S, Yasavolian M, Likourezos A, Pushkar I, Hossain R, Drapkin J, Cohen V, Filk N, Smith A, Huang F, Rockoff B, Homel P, Fromm C. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2017 Aug;70(2):177-184. doi: 10.1016/j.annemergmed.2016.10.014. Epub 2016 Dec 16. PMID: 27993418.
  7. Nielsen JC, Bjerring P, Arendt-Nielsen L, Petterson KJ. A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain. Br J Clin Pharmacol. 1990 Nov;30(5):711-5. doi: 10.1111/j.1365-2125.1990.tb03840.x. PMID: 2271369; PMCID: PMC1368171.
  8. Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharmacol Ther. 1986 Jul;40(1):1-7. doi: 10.1038/clpt.1986.129. PMID: 3522030.
  9. Seymour RA, Ward-Booth P, Kelly PJ. Evaluation of different doses of soluble ibuprofen and ibuprofen tablets in postoperative dental pain. Br J Oral Maxillofac Surg. 1996 Feb;34(1):110-4. doi: 10.1016/s0266-4356(96)90147-3. PMID: 8645662.
  10. Southworth S, Peters J, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Clin Ther. 2009 Sep;31(9):1922-35. doi: 10.1016/j.clinthera.2009.08.026. PMID: 19843482.

ABOUT THE AUTHOR

Dr. Motov is an Attending Physician and Research Director in the Department of Emergency Medicine at Maimonides Medical Center with particular interest in safe and effective analgesia in the ED.

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