We often view the results of a trial from the perspective of our own preconceived notions. We extrapolate the results far beyond the limits of the data based on our own system of beliefs, using p-values and confidence intervals as statistical armor to substantiate our positions. It is with this in mind that we turn to a recently published article in JAMA examining the efficacy of various therapeutic strategies for the treatment of acute extremity pain in the Emergency Department (1).
Chang et al enrolled patients, 21 through 64 years of age, who presented to the Emergency Department for management of acute extremity pain (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). The patients were determined by the treating Emergency Physician to need emergent imaging, which the authors thought 1) was an appropriate surrogate for the severity of their injury, and 2) would provide adequate time in the department to ensure their 2-hour follow up assessment could be completed.
The patient’s pain was assessed immediately following randomization, after which they received one of four blinded treatment strategies, 400mg of ibuprofen/1000mg of acetaminophen, 5 mg of oxycodone/325 mg of acetaminophen, 5 mg of hydrocodone/300 mg of acetaminophen, or 30mg of codeine/300mg of acetaminophen. Patients were then observed for at least 2 hours and pain scores were assessed again at the one and two hour mark to assess the efficacy of the respective treatment strategies.
In short, the authors found no difference in the mean pain score at one or two hours between the groups. At 2 hours, the mean NRS pain score decreased by 4.3 in the ibuprofen/acetaminophen group, by 4.4 in the oxycodone/acetaminophen group, by 3.5 in the hydrocodone/acetaminophen group, and by 3.9 in the codeine/acetaminophen group. Nor did they note a statistical difference in the number of patients requiring rescue analgesia, 17.8%, 13.5%, 17.5%, and 22.3% in the 4 respective groups.
And while this was a very well done, methodologically robust study, it would be unwise to extrapolate our conclusions beyond the limits of the data. These results essentially demonstrated that in patients presenting to the Emergency Department with mild to moderate painful extremity injuries, an appropriate dose of non-opiate analgesia is equivalent to a generally ineffective dose of an opiate pain medication in combination with an inappropriate dose of a non-opiate analgesic. For simplicity sake we will use the oxycodone/acetaminophen combination with the understanding that the same comments apply to the hydrocodone/acetaminophen combination therapy.
In the past we have discussed the follies of single dose strategies when using opiate pain medication. These comments apply broadly and certainly to the interpretation of the study in question. There is a large body of literature demonstrating that in the majority of patients a 5 mg dose of oxycodone is not sufficient to gain adequate pain relief (2). In their Cochrane analysis, Derry et al found that 400 mg of ibuprofen provided similar pain relief to 400 mg of ibuprofen in combination with 5 mg of oxycodone (at least 50% reduction in pain in 50% and 60% respectively), indicating the 5 mg dose of oxycodone added little to the analgesic effects of ibuprofen. In fact, when 5 mg of oxycodone was examined as a solitary agent, only 23% achieved a 50% reduction in pain, which was very similar to the 17% reduction observed with placebo (2). These results should not come as a surprise, as a 5 mg dose of oxycodone is equivalent to 2-2.5 mg of IV morphine, which is an ineffective dose in the majority of patients. In fact, it was not until doses of 15 mg were used, that greater than 50% of patients achieved a 50% reduction in pain (3).
Viewed from this perspective it is not surprising these trivial doses of oxycodone and hydrocodone performed similarly to an effectively dosed ibuprofen/acetaminophen combination. What was surprising was how well the codeine group performed, when time and time again studies have demonstrated codeine provides little analgesic benefit to adequate doses of ibuprofen or acetaminophen (4). It makes one wonder how well a placebo group would have performed in this cohort.
It is clear from a large body of published literature that single dose opiates, especially at small doses provide ineffective analgesia. This study validates the inadequacies of such strategies. In addition, it demonstrates that in a population of patients with mild to moderate pain, ibuprofen and acetaminophen will provide adequate analgesia in the majority of patients, but their effectiveness is not universal, a large portion of this cohort required rescue opiate analgesics (approximately 17%). What this study is unable to determine is the efficacy of these analgesic strategies in patients with severe pain, the vast majority of these patients were diagnosed with strain, sprain, contusion or muscle pain. Nor does this trial reveal the effectiveness of opiate medications when they are administered at appropriate doses and titrated to effect. And of course these results are not capable assessing the risks associated with the use of opiate pain medication in the Emergency Department or if an alternative strategy would have any meaningful effect on curtailing the current opioid crisis.
Sources Cited:
- 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.
- Derry S, Derry CJ, Moore RA. Single dose oral ibuprofen plus oxycodone for acute postoperative pain in adults. Cochrane Database Syst Rev. 2013;(6):CD010289.
- Gaskell H, Derry S, Moore RA, Mcquay HJ. Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009;(3):CD002763.
- Moore RA, Derry S, Aldington D, Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults – an overview of Cochrane reviews. Cochrane Database Syst Rev. 2015;(9):CD008659.
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Resuscitation and Critical Care Fellowship Graduate
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rory
it is very disheartening that in the year 2017 JAMA would print such malarkey.
i suspect it is because of the current crisis, and national focus, and that this “study” seems to provides fuel for the argument that” those silly ER docs are pumping the nation with narcs”.
As you say, we need good studies to help steer us toward appropriate care (like the work that Sergey Motov is doing at Maimonides, and the folk at st joe’s in patterson,nj). what we dont need is fluff.
thank you
tom
A better study would be to have EMS give either 1g of IV acetaminophen, or 0.1mg/kg of IV morphine, or 1mcg/kg of IV fentanyl, and make it a double-blinded study.
As an emergency physician, the #1 pain control for extremity pain is splinting / casting / supporting. I would argue that no analgesia would have had the same effect if splinting / casting / supporting was done. Useless conclude anything else from this. My 2 cents.
The study isn’t equitable. Should have started with a baseline of 1g of acetaminophen/ paracetamol in all Pt’s and then compared the addition of 400mg of Brufen or a small dose of opiate. 300mg of acetaminophen is a sub therapeutic dose so the two arms aren’t comparable?
Thanks Rory.
The other thing to point out here is that in the real world we don’t blind our patients when giving the analgesia. When we hand them the two white paracetamols, or the two pink ibuprofens, most patients will quite reasonably ask, “what are you giving me?”. When they hear ‘paracetamol’ or ‘ibuprofen’ I would suggest that that triggers a cognitive bias in them (a kind of reverse placebo effect) if their pain is significant. Conversely, when we hand them the liquid morphine and they ask what’s in the cup, it may have the opposite effect