Since 2000, there have been over 500,000 opioid related overdose deaths in the US. (Burke 2016).  Despite the epidemic of opioid deaths, these drugs continue to be used as first line agents for treatment of moderate to severe pain in Emergency Departments (EDs). While demonstration that ED use of an opiate causes future abuse and morbidity/mortality does not exist, there have been associations drawn between prescription in the ED and increased future use.  Many clinicians consider opioid pain medications to be more efficacious than non-opioid formulations driving their utilization.  Previous studies have demonstrated that combination non-opioids are as effective codeine/acetaminophen combinations. (Sniezek 2011, Daniels 2011, Mitchell 2008, Mitchell 2012). The absence of better efficacy of opioid medications for pain control in comparison to non-opioid medications would likely change prescribing patterns.

Clinical Question

Is there any difference in pain reduction at 2 hours after ingestion of a single dose of 4 oral combination analgesics.


Patients presenting to a large teaching hospital and community hospital in the Bronx, New York aged 21-64 for management of acute extremity pain of less than 7 days duration. Acute extremity pain was defined as pain distal to and including the shoulder joint and distal to and including the hip joint. All patients were required to have been ordered for radiographic imaging during ED stay.


Patient were randomized to one of four oral pain medication regimens, acetaminophen 1000mg ibuprofen 400mg, 5mg oxycodone 325mg acetaminophen, 5 mg hydrocodone 300mg acetaminophen, or 30mg of codeine 300mg of acetaminophen


Primary: Change in pain score on 11 point scale 2 hours after being given dose of medications.
Secondary: Difference in mean pain score at 1 hour, proportion of patients receiving rescue analgesics, and total amount of analgesics given in morphine equivalent units.


Randomized double blinded clinical trial


Exclusion criteria included past use of methadone, chronic pain conditions including sickle cell, fibromyalgia, neuropathy, history of adverse reaction to study medication, had taken opioids in past 24 hours, had taken acetaminophen or ibuprofen in past 8 hours, +bHCG, breast feeding, peptic ulcer disease, reported history of narcotic use, medical condition that could affect any the metabolism of any study drugs (hepatitis, renal dysfunction, thyroid abnormalities, adrenal dysfunction), medications that may interact with study drugs

Primary Results

Primary Results

  • 416 patients underwent randomization
    • 104 patients were randomized to each of the four arms.
  • 3 patients in the acetaminophen ibuprofen arm, 1 patient each in the hydrocodone acetaminophen and 1 patient in the codeine acetaminophen arm were excluded from analysis for having taken analgesics prior to arrival. 
  • 1 patient in each of the 4 arms had missing data.

Critical Results

  • Change in pain score at 2 hours (primary outcome)
    • No statically significant or clinically important difference in reduction in pain score between the 4 groups at 2 hours after administration of pain medication.
  • Overall, 18% of patients required rescue analgesia
Ibuprofen + APAP (95% CI) Oxycodone + APAP

(95% CI)

Hydrocodone + APAP (95% CI) Codeine + APAP (95% CI)
Baseline Pain Score 8.9 (8.5 – 9.2) 8.7 (8.3 – 9.0) 8.6 (8.3 – 9.0) 8.6 (8.2 – 8.9)
Decline in Pain Score at 2 hours 4.3 (3.6 – 4.9) 4.4 (3.7 – 5.0) 3.5 (2.9 – 4.2) 3.9 (3.2 – 4.5)
Rescue Analgesia Number (percentage) 17.8% (18/101) 13.5% (14/104) 17.5% (18/103) 22.3% (23/103)


  • Randomized blinded trial with clinically meaningful endpoint
  • Randomization and blinding was appropriately performed to minimize selection bias and unblinding
  • Selected for patients with more severe pain by requiring those enrolled to have an imaging study ordered
  • Follow up was complete and only 4 out of 416 randomized patients had missing data


  • Short follow up time with only clinical endpoint of reduction in pain score at 2 hours
  • Does not address pain after discharge or throughout rest of ED stay
  • Long list of exclusion criteria including “had taken ibuprofen or acetaminophen within the past 8 hours,” which limits application
  • Possible under dosing of some of the combination opioid analgesics in comparison to maximal dosing in the “control” arm (ibuprofen + APAP)
  • No adverse effect information was collected
  • Demographics of study population was 60% Latino and 31% Black, potentially limiting generalizability due to cultural and genetic differences in perception and response to pain

Author's Conclusions

“For patients presented to the ED with acute extremity pain, there is 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. Further research to assess adverse events and other dosing may be warranted”

Our Conclusions

In patients presenting to the ED with acute extremity pain, this study found no difference in average reduction in pain score in patients given combination acetaminophen and ibuprofen and three acetaminophen opioid combination medications. There was also no difference in the proportion of patients in these groups requiring rescue medication and the type of rescue medication that patients in each of these groups received.

Potential Impact To Current Practice

These results suggest that clinicians should strongly consider the use of nonopioid analgesics in the treatment of moderate to severe extremity pain instead of defaulting to an opioid first strategy. While the critique remains for underdosing of opiate medications in this study, many pain management providers agree that for naive patients the doses are appropriate. A reduction in ED use of opioids may lead to a reduction in discharge prescriptions of opioid medications to this group of patients if they achieve adequate pain control with combination acetaminophen and ibuprofen.

Bottom Line

In patients presenting to the ED with acute extremity pain, it is reasonable to use the combination of ibuprofen and acetaminophen rather than combination oral opioid medications as the initial pain management regimen.

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