A Randomized Control Trial Comparing Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the ED

Written by Mark Ramzy, DO REBEL EM Medical Category: Toxicology

Background Information: Non-steroidal Inflammatory drugs (NSAIDs) such as Ibuprofen are of the one of the most commonly used oral analgesics in the emergency department. 1 These medications work by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These are two enzymes which lead to prostaglandin production and ultimately promote pain, fever and inflammation. Prostaglandins also serve to line the stomach epithelium and protect it from the digestive acids. The COX-1 enzyme also plays a role in platelet activation through the production of Thrombaxane-2. Understanding the physiology behind these important enzymes helps us better anticipate the expected adverse effects that may occur when prescribing NSAIDs, especially at higher doses or over an extended period of time. Due to its linear kinetic effects, higher doses of ibuprofen results in longer duration of analgesia and not necessarily more effective pain control. 3, 4 The authors of this study sought to identify the analgesic effects of three different doses of ibuprofen. Furthermore, they hypothesized that a lower dose had comparable analgesic effects when compared to higher doses.

Clinical Question:

What is the analgesic efficacy of oral ibuprofen at three different doses for adult ED patients with acute pain?

What They Did:

Randomized double-blind equivalency trial, conducted at a single large urban hospital, assessing and comparing the analgesic efficacy of 400, 600 and 800 mg of oral ibuprofen for the treatment of acute pain

Screening and enrollment of patients only occurred Monday through Friday between 8am and 8pm, when an ED pharmacist was available for blinded medication preparation.

All patients were triaged and had pain scores documented by a triage nurse who determined study eligibility

All three groups received a single dose of oral ibuprofen with group breakdown as follows: Group 1: 400 mg Group 2: 600 mg Group 3: 800 mg

Medications were crushed and diluted using suspension medium into a 20cc syringe for administration.

Researchers collected data including Pain scores on a standard 11-point numeric rating scale from 0 to 10 (10 being the worst pain) Rates of rescue medication administration Rates of adverse effects at baseline and 60 minutes



Inclusion Criteria:

Adult ED patients over the age of 18 with acute pain and warranted oral ibuprofen as determined by the treating attending physician.

Exclusion Criteria:

Patients with the following: Peptic ulcer disease Gastrointestinal hemorrhage Renal or hepatic insufficiency Altered mental status Pregnant / Breast-feeding

Patients with allergies to NSAIDs

Patients who used opioids or NSAIDs within four hours of ED arrival

Outcomes:

Primary: Difference in mean pain scores between three groups at 60 minutes

Secondary: Comparison of mean pain score differences in each group from baseline to 60 minutes Rates of adverse events Need for rescue analgesia at 60 minutes



Results:

225 patients were enrolled, with 75 patients in each group. One patient each from the 600mg and 800mg group were lost to data collection due to discharge, resulting in 223 patients analyzed.

All three groups were relatively similar in age, sex and initial pain score

All three groups had similar chief complaints and final diagnoses (ie. musculoskeletal sprains, strains, fractures and cutaneous rashes, lacerations and abscesses)

Three patients in group 1, two patients in group 2 and four patients in group 3 received non-opioid analgesia (tablet, topical preparation, or both) prior to study enrollment

There were no clinically concerning adverse effects related to the study medications



Critical Results:

The differences in mean pain scores at 60 minutes between the groups were as follows: Between 400mg and 600mg was -0.14 (95% CI -0.67 to 0.39) Between 400mg and 800mg was also -0.14 (95% CI -0.67 to 0.37) Between 600mg and 800mg was 0.00 (95% CI -0.47 to 0.47)



Strengths:

First double-blind randomized control study comparing different doses of ibuprofen in the ED

Identified and compared the three most common doses of ibuprofen using a well-organized system of randomization

Blinding via medication suspension eliminates bias of pill volume.

To give an unbiased estimate of the effect of treatment, the authors of the study used an intention to treat analysis. This method of statistical analysis helps limit important prognostic differences between the two groups by analyzing every subject who is randomized.

Looked beyond analgesic efficacy and at the rates of adverse effects as a secondary outcome

Limitations:

Since patients were enrolled as a convenience according to the availability of members of the research and pharmacy teams this may have resulted in a selection bias and ultimately an underrepresentation of patients who present to the ED late at night.

Small sample size of patients and short duration of 60 minutes may not be enough to assess the variance of safety among the three different ibuprofen doses

A short 60 minute duration may not be enough time to assess the adverse effect profile of the three varying doses, especially since this study did not have any follow-up after discharge

With a limited and set duration of 60-minutes, this study was unable to assess whether higher doses may have resulted in prolonged pain relief beyond that set time.

No data provided on patient weight, height, or surface area, which may significantly alter medication efficacy.

Discussion:

It is important to note that by using that minimally effective dose, providers can decrease the incidence of gastrointestinal complications such as hemorrhage and ulcer development. 5

Even when using the most minimally effective dose, it is also important to consider some of the cardiovascular adverse effects of NSAIDS. Their use has not been recommended in patients with pre-existing cardiovascular disease due to the production of more Thromboxane A2 and Leukotriene B4. This metabolic shift results in abnormal platelet aggregation and arterial lining destruction. Unfortunately, there are no placebo controlled RCTs addressing the cardiovascular safety of NSAIDs, only observational studies. 5

While a higher dose of these medicationsmay have a similar onset of, their duration of action is different, and it is important to consider their analgesic ceiling. This is defined as the threshold at which any further increase in dosing will not offer any further analgesic benefit and may increase the adverse effects mentioned above. The current literature supports Ibuprofen’s analgesic ceiling dose at 400 mg per dose with a maximum of 1200 mg/day. 1

Furthermore, while the duration of effect may also be related to a higher dose, an important limitation of this study to touch upon is that the duration of the different Ibuprofen doses was not actually measured. A future study specifically looking at duration of effect among the different doses of ibuprofen among emergency department patients with acute pain would help tell us more.

The authors make a valid point regarding the current dosing of ibuprofen: we are over-prescribing this medication at supra-analgesic dosing regimens and may be contributing to the development of potentially serious adverse long term effects (though, notably, no significant short-term adverse effects were identified in the study).

Utilization of a pain scale is a subjective means of quantifying one’s pain and there has been much debate about its continued use given the current opioid epidemic

Lastly, this study helps add to the knowledge we currently have about NSAIDs, specifically in emergency department patients. Additional studies are warranted to better help us understandthe analgesic effect of NSAIDs when co-administered with other non-opioid analgesics such as acetaminophen, lidocaine patches, etc. A comparison study on how the different NSAIDs compare in their analgesic effect and duration of action would also provide us valuable information when treating these patients in the emergency department.

Author’s Conclusions:

Ibuprofen has similar analgesic efficacy profiles at single oral dosing regimens of 400 mg, 600 mg and 800 mg for short-term treatment of moderate to severe acute pain in the ED.

Our Conclusion:

This study opens the discussion and adds to our current knowledge on how the different doses of Ibuprofen may affect patients in acute pain. Prior to definitively recommending one set dose of an NSAID, future studies are needed to better evaluate duration of effect and their efficacy when used in conjunction with other non-opioid analgesics.

Clinical Bottom Line:

Varying doses of Ibuprofen appear to have similar efficacy in the short-term treatment of moderate to severe pain. Until further studies evaluating how dose affects the duration of effect of these medications, emergency physicians should utilize the most minimally effective dose of 400 mg to treat a patient’s pain.

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REFERENCES:

Motov S et al. Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Trating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med 2019. [Link is HERE] Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology. 2009. PMID: 19949916 Mazaleuskaya LL, et al. PharmGKB summary: ibuprofen pathways. Pharmacogenet Genomics. 2015 PMID: 25502615 Schwartz NA, et Patients’ perceptions of route of nonsteroidal anti-inflammatory drug administration and its effect on analgesia. Acad Emerg Med. Aug 2000. PMID: 10958124 Ong CK, et An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. March 2007 PMID: 17456832

Post Peer Reviewed By: Rick Pescatore, DO (Twitter: @Rick_Pescatore), Anand Swaminathan, MD (Twitter: @EMSwami), & Salim R. Rezaie, MD (Twitter: @srrezaie)