Pain management and sedation/original research
Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial

https://doi.org/10.1016/j.annemergmed.2019.05.037Get rights and content

Study objective

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively for the management of acute pain, with ibuprofen being one of the most frequently used oral analgesics in the emergency department (ED). We compare the analgesic efficacy of oral ibuprofen at 3 different doses for adult ED patients with acute pain.

Methods

This was a randomized, double-blind trial comparing analgesic efficacy of 3 doses of oral ibuprofen (400, 600, and 800 mg) in adult ED patients with acute painful conditions. Primary outcome included difference in pain scores between the 3 groups at 60 minutes.

Results

We enrolled 225 subjects (75 per group). The difference in mean pain scores at 60 minutes between the 400- and 600-mg groups was –0.14 (95% confidence interval [CI] –0.67 to 0.39); between the 400- and 800-mg groups, 0.14 (95% CI –0.65 to 0.37); and between the 600- and 800-mg groups, 0.00 (95% CI –0.47 to 0.47). Reductions in pain scores from baseline to 60 minutes were similar for all subjects in each of the 3 groups. No adverse events occurred in any group.

Conclusion

Oral ibuprofen administered at doses of 400, 600, and 800 mg has similar analgesic efficacy for short-term pain relief in adult patients presenting to the ED with acute pain.

Introduction

Ibuprofen (eg, Advil, Motrin) is one of the most commonly used oral analgesics in the emergency department (ED) for the treatment of mild to moderate pain as a single analgesic or in combination with acetaminophen, or severe pain in combination with opioid analgesics.1 It is a nonselective, nonsteroidal anti-inflammatory drug (NSAID) that primarily inhibits (reversibly) the activity of both cyclooxygenase-1 (constitutive) and cyclooxygenase-2 (inducible) enzymes and blocks the synthesis of prostaglandins and thromboxanes.2 Ibuprofen possesses analgesic, antipyretic, and anti-inflammatory properties and is available in oral, rectal, intravenous, and topical forms. It has been widely used in the ED for treatment of a variety of acute painful conditions such as musculoskeletal pain, dental pain, tension headache, and dysmenorrhea.1 Ibuprofen has a half-life of 2 to 2.5 hours and is extensively metabolized in the liver and eliminated through the kidneys.2 It has multiple drug-drug interactions, many of which arise from the reduction in glomerular filtration induced by blockade of cyclooxygenase or by competitive displacement of the second drug from protein-binding sites.3 Coadministration of ibuprofen with aspirin results in antagonism of the irreversible platelet inhibition induced by aspirin and loss of cardioprotective function; combination of ibuprofen with warfarin leads to worsening of gastrointestinal hemorrhage; with steroids, it leads to peptic ulcer disease; with diuretics and angiotensin-converting enzyme inhibitors, it elevates systolic blood pressure and worsens renal functions; and it increases toxicity of lithium.3, 4, 5

Editor’s Capsule Summary

What is already known on this topic

Many advocate ibuprofen doses greater than 400 mg orally, assuming a greater effect.

What question this study addressed

Do ibuprofen doses of 600 or 800 mg improve analgesia relative to 400 mg in emergency department patients with a variety of pain syndromes?

What this study adds to our knowledge

In this adequately powered, randomized, double-blind trial of 225 adults, there were similar decreases in pain scores at 60 minutes with all 3 dosages.

How this is relevant to clinical practice

Ibuprofen doses greater than 400 mg orally do not appear to provide more effective analgesia.

NSAIDs are commonly prescribed at doses above their analgesic ceiling, which is a dosing threshold beyond which any further increase in a dose will not offer an incremental analgesic advantage and potentially increases the risk of harm.2, 6, 7 The data from dental and oral surgery literature support an analgesic ceiling dose of ibuprofen of 400 mg per dose with 1,200 mg/day.8, 9, 10, 11, 12, 13, 14, 15

The analgesic ceiling dose of ibuprofen based on these studies is lower than both the dosing regimen recommended in emergency medicine textbooks and the Food and Drug Administration–approved doses: 400 to 800 mg orally every 4 to 6 hours, with a maximum daily dose of 2,400 mg.15, 16 Furthermore, the rates of the adverse effects of ibuprofen as a single analgesic and NSAIDs as a class are dose and duration dependent.17, 18 A meta-analysis evaluating gastrointestinal complications of nonselective NSAIDs found that ibuprofen had the lowest odds ratio, 1.9, for development of gastrointestinal bleeding at doses of less than or equal to 1,200 mg/day. However, the odds ratios doubled to 3.9 when ibuprofen was given at doses of greater than or equal to 1,800 mg/day.18, 19 Similarly, the relative risk of cardiovascular adverse effects nearly doubles (from 1.05 to 1.78) when ibuprofen is used in doses greater than 1,200 mg/day.18 Last, according to the Oxford League Table, the number needed to treat to achieve at least 50% pain reduction from baseline to 6 hours in patients with a variety of painful conditions is similar between ibuprofen dosages of 400 and 600 mg.7

A single dose of ibuprofen of 400, 600, and even 800 mg lacks severe toxicity and does not result in serious adverse effects. Because of linear kinetic pattern, the higher dosing of ibuprofen results in a longer duration of analgesia.20, 21 The anti-inflammatory ceiling dose of ibuprofen is much higher than its analgesic ceiling dose, with a dosing range of 2,400 to 3,200 mg/day.22, 23

We hypothesized that 400 mg of oral ibuprofen would provide analgesia comparable to that of a dose of either 600 or 800 mg for patients presenting to the ED with acute pain.

Section snippets

Study Design and Setting

We performed a randomized, double-blind, equivalency trial assessing and comparing the analgesic efficacy of 400, 600, and 800 mg of oral ibuprofen for the treatment of acute pain in the ED.

We conducted this study at a 711-bed urban community teaching hospital with an annual ED census of greater than 120,000 visits. Patient screening, enrollment, and data collection were performed by study investigators. The Maimonides Medical Center institutional review board approved the trial. We report

Results

We enrolled 225 subjects (75 in each group) in our study, with 223 patients available at 60 minutes for data analysis. The patient flow diagram is illustrated in Figure 1. Baseline characteristics with respect to age, sex, and initial pain score were similar between all 3 groups (Table 1). In addition, all 3 groups were relatively similar with respect to chief complaints and final diagnoses, primarily musculoskeletal (sprain, strain, and fractures) and cutaneous pain (rashes, lacerations, and

Limitations

This was a single-center study in which study participants were enrolled as a convenience sample according to the availability of members of both the research and pharmacy teams, which may have led to selection bias caused by underrepresentation of patients who may have presented to the ED late at night. A small sample size of 225 subjects and the short duration (60 minutes) of the study were inadequate to assess the variance in safety of the 3 different study medication doses. The study

Discussion

Ibuprofen is widely administered for pain management in a variety of inpatient and outpatient settings worldwide. Because of its analgesic and anti-inflammatory properties and availability in parenteral, enteral, and topical forms, it is frequently used as a first-line analgesic (either alone or in combination with acetaminophen) for alleviating a variety of acute traumatic and nontraumatic and chronic painful conditions in the ED.27, 28 In the ED setting, ibuprofen is often prescribed in doses

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    Please see page 531 for the Editor’s Capsule Summary of this article.

    Supervising editor: Steven M. Green, MD. Specific detailed information about possible conflict of interest for individual editors is available at https://www.annemergmed.com/editors.

    Author contributions: SM was responsible for study concept and design. All authors were responsible for acquisition, analysis, and interpretation of data. AL and PF were responsible for statistical analysis. SM and JD drafted the article. SM and JM were responsible for critical revision of the article for important intellectual content. SM, AL, and JM were responsible for study supervision. SM takes responsibility for the paper as a whole.

    All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. This research was supported by a grant from the Maimonides Research and Development Foundation.

    Trial registration number: NCT03441269

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