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Science in the News

A Randomized, Controlled Trial of Single-Dose Nonopioid versus Opioid Combination Analgesia for Moderate-to-Severe Acute Extremity Pain in Emergency Departments Showed No Difference Among the Agents in Terms of Pain Relief

November 09, 2017 A recent randomized, controlled trial1 compared the analgesic efficacy of single doses of 4 oral drug combinations for acute pain relief in the setting of 2 urban emergency departments (ED) in New York.  Adults (ages 21 to 64 years) eligible for enrollment (from July 2015 to August 2016) were those with acute, moderate-to-severe pain in an extremity; this was defined as pain originating distal to and including the shoulder joint in the upper extremities and distal to and including the hip joint in the lower extremities and could include sprains or fractures. Eligible patients were required to have a clinical indication for radiological imaging based on judgment of the attending physician; this was intended to provide a short delay during which most patients would be able to provide 1- and 2-hour pain scores. The need for imaging also was considered to be a proxy for more severe injury, increasing the likelihood that an oral opioid analgesic might be considered an appropriate choice for pain relief in the judgment of the ED attending physician.

Following randomization, patients (n=416) remained in the ED and provided pain ratings immediately before taking the single dose of study analgesic and then again at 1 and 2 hours after taking the drug combinations. For blinding purposes, all patients received 3 identical-looking capsules containing one of 4 drug combinations: 1) 400 mg of ibuprofen and 1000 mg of acetaminophen (n=104); 5 mg of oxycodone and 325 mg of acetaminophen (n=104); 5 mg of hydrocodone and 300 mg of acetaminophen (n=104); or 30 mg of codeine and 300 mg of acetaminophen (n=104). The primary outcome was the between-group difference in decline in pain 2 hours following medication ingestion. Pain intensity was assessed using an 11-point rating scale ranging from 0, indicating no pain, to 10, indicating the worst possible pain; the predefined minimal clinically important difference for the rating scale was 1.3 points.

Of the 416 patients randomized, data on 411 were available for analysis; analysis was by intention to treat. The baseline mean pain score was 8.7 (standard deviation [SD], 1.3). At 2 hours, the mean pain score decreased by 4.3 (95% confidence interval [CI], 3.6 to 4.9) in the ibuprofen/acetaminophen group; by 4.4 (95% CI, 3.7 to 5.0) in the oxycodone/acetaminophen group; by 3.5 (95% CI, 2.9 to 4.2) in the hydrocodone/acetaminophen group; and by 3.9 (95% CI, 3.2 to 4.5) in the codeine/acetaminophen group (p=0.053). The largest between-group difference in pain score decline from baseline to 2 hours was between the oxycodone/acetaminophen group and the hydrocodone/acetaminophen group (0.9; 99.2% CI, -0.1 to 1.8), which was less than the minimum clinically important difference of 1.3. Adverse events were not assessed, which was considered one of the limitations of the study.

The authors concluded that, “For patients presenting to the ED with acute extremity pain, there were no statistically significant or clinically important differences in pain reduction at 2 hours among single-dose treatment with ibuprofen and acetaminophen or with 3 different opioid and acetaminophen combination analgesics,” and that “Further research to assess adverse events and other dosing may be warranted.”

The accompanying editorial by Kyriacou2 notes that, “The combination of ibuprofen and acetaminophen with different mechanisms of action apparently provides additive analgesic effects while reducing the short-term risk for adverse effects” and also points out that “Except for the treatment of dental pain, this combination has not been extensively studied in the United States but has been used in New Zealand, Australia, and Europe.”


  1. Chang AK, Bijur PE, Esses D, Barnaby DP, Baer J. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: A randomized clinical trial. JAMA 2017;318(17):1661-67.
  2. Kyriacou DN. Opioid vs nonopioid acute pain management in the emergency department. JAMA 2017;318(17):1655-56.
Prepared by: Center for Scientific Information, ADA Science Institute

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