The Acetaminophen/Ibuprofen Ascendancy

The new hotness of the day is the piece out of JAMA comparing our various oral analgesic treatment options for acute pain the Emergency Department. This relatively mundane line of research has been relatively fertile over the last few years, so, what do we have in store here?

This was a double-blind, placebo-controlled trial of four different analgesic combinations for acute extremity pain. To enter the trial, one of the criteria was receipt of an imaging study, which served twofold: an assumed proxy for more serious injuries and pain, and because it increased ED length-of-stay enough to reduce patients lost to follow-up for their primary outcome. The primary outcome, then, was reduction in pain on a 0 to 10 numerical rating scale at the 2-hour mark, with an interim 1-hour mark recorded as well.

The study drugs were as follows: 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen. Approximately 100 patients per arm were targeted from their sample size calculations, and they ultimately randomized 416 into generally similar groups with respect to final diagnoses.

The outcomes are essentially a wash – raising a question of whether there is any advantage to opiate therapy for this indication.  In our beautiful public health tapestry of increasing opiate misuse and addiction, any opportunity to reduce opiate prescribing is important.  There are some reasonable takeaways with respect to the relative efficacy of ibuprofen/acetaminophen, oxycodone/acetaminophen,  hydrocodone/acetaminophen and codeine/acetaminophen combinations, but their clinical relevance is highly questionable considering the doses tested in this study.  This is, unfortunately, essentially a straw-man comparison between an adequate dose of non-opiate analgesia compared with the least-adequate preparation of each of the commonly used combination opiate products.  A proper comparison in patients with severe pain ought to use a more typical maximal dose, which would probably be twice as much of each of the combination opiate products.

There are a few other small oddities relating to this study, of course. As an unavoidable consequence of the study setting, 60% of their study cohort identified as Latino and another 31% identified as black. There are potential genetic differences in pharmacokinetics relating to ethnicity, as well as cultural factors relating to the cohort enrolled at the study site, so the generalization of these data requires some caution. The study protocol states patients were to be asked whether they were satisfied with their pain control and side effects were to be recorded (nausea, vomiting, itchiness, etc.), but these are not reported in the final manuscript or supplement. Finally, these data are also limited, essentially, to sprains, fractures, and contusions. This represents an important slice of outpatients seeking analgesia, but may not be applicable to other types of pain.

Overall, however, this is reasonable evidence to support strategies of combination non-opiate therapy in patients without contraindications to both acetaminophen and ibuprofen.  It should not, however, be offered as evidence of the disutility of commonly used combination opiate preparations.

“Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department”