Acetaminophen-Plus-Ibuprofen Combo for Acute Pain

Saturday, January 2, 2010

Acetaminophen-Plus-Ibuprofen Combo for Acute Pain

Newly-reported research suggests that, for acute pain following minor surgery, combining acetaminophen-plus-ibuprofen may be superior to each of the ingredients alone. However, there is a question as to whether this is the best treatment for such pain.

Acetaminophen (APAP) is often used along with a nonsteroidal antiinflammatory drug (NSAID), such as ibuprofen, for acute pain. Currently, these drugs must be given individually and sometimes at different time intervals, which can be a complex and difficult-to-follow regimen. Researchers in New Zealand examined a new APAP-ibuprofen combination product — Maxigesic® (not yet approved in the U.S.) — in a randomized controlled trial to assess its efficacy compared with each ingredient administered as monotherapy [Merry et al. 2010].

Adults (more than 16 years of age) having one or more wisdom teeth removed under general or local anesthesia were randomly assigned to either (a) APAP 500 mg plus ibuprofen 150 mg per tablet (combination product, n=44); (b) APAP 500 mg per tablet alone (n=47); or (c) ibuprofen 150 mg per tablet alone (n=44). Subjects were instructed to take 2 tablets of their assigned medication before the operation, then 2 tablets every 6 hours for up to two days. The report, appearing in the January 2010 edition of the British Journal of Anaesthesia, concludes that the combination product was significantly superior (p < .01) in relieving pain than either APAP or ibuprofen alone (which were equivalent to each other). Adverse reactions were minimal and more evident in the APAP group (vomiting and other GI symptoms, headache, drowsiness), with the ibuprofen group reporting no medication-related side effects at all.

Caveats: On closer inspection, there are several aspects of this research — which was sponsored and overseen by the manufacturer of Maxigesic — that are of concern:

    1. The researchers used a somewhat novel primary outcome measure consisting of the area under the curve of visual analogue scale (VAS – 100 mm) pain measurements taken for up to 48 hours after surgery, divided by time, at rest and during activity. In essence, this produces a measure of average pain intensity throughout the study period, but it is unhelpful for gauging if there were times, particularly during the early postsurgical period, when either one of the agents or the combo was better than the other.


    1. Average VAS measures (100 mm scale) during activity over two days were APAP 40, ibuprofen 40, combo 28. Since there is no other control group for comparison — either placebo or alternate analgesia — it is difficult to gauge if this is a clinically significant improvement even at the lowest mean pain score.


    1. In a global pain-rating measure, more subjects reported “nil” or “mild” pain with the combo (68%), but this was a statistically significant improvement only over APAP (38%) rather than ibuprofen (54%) alone.


    1. Importantly, a majority of all patients required “rescue analgesia,” either fentanyl in the hospital or codeine during the first or second day at home (group, % of patients): APAP, 63%; ibuprofen, 58%; combo, 57%. Differences between groups were not statistically significant.


    1. Doses of APAP — 5000 mg on day 1, 4000 mg day 2 — were at or exceeded the recommended safe maximum of 4 grams. Liver function tests were not performed, and many practitioners may justifiably feel uncomfortable routinely prescribing such doses even for a short duration.


  1. Subjects were carefully selected, excluding those who weighed less than 50 kg, were taking any blood-thinning medication, or had a history of gastric, hepatic, or renal disease, among other criteria. Therefore, the external validity of this approach for many clinical populations may be questionable.

An earlier report comparing ibuprofen (2400 mg/d) vs APAP (3000 mg/d) vs a combination of the two following minor orthopedic surgery found that ibuprofen reduced pain to a greater extent than APAP, and combining the two agents provided no advantage [Dahl et al. 2004]. Of interest, doses of ibuprofen in this study were considerably greater (2400 vs 1500 mg/day 1) and APAP much lower (well within the safety range) than in the study by Merry et al. above. Taken together, the data from both studies suggest that ibuprofen alone, at reasonably higher doses, may be the most advantageous nonopioid analgesic.

Still, is this treatment optimal for acute pain following minor surgery? Since both studies noted that administration of opioid medication was required on a “rescue” basis, it raises the question of whether simply prescribing oral opioid analgesia at the outset, perhaps followed during day 2 or 3 by ibuprofen and/or APAP if needed, might be a superior approach. Any comments readers?

> Dahl V, Dybvik T, Steen T, et al. Ibuprofen vs. acetaminophen vs ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction. Eur J Anaesth. 2004;21(6):471-475 [abstract].
> Merry AF, Gibbs RD, Edwards J, et al. Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. Br J Anaesth. 2010 104(1):80-88 [PDF available here].