A number of years ago, it became popular to advocate a combination of acetaminophen and ibuprofen (or other non-steroidal anti-inflammatory medication) at the usual higher doses — e.g., 1,000 mg acetaminophen plus 400 mg ibuprofen [0] — because studies had shown increased efficacy over either medication alone in pain relief. In fact, I believe in Europe there are over-the-counter products that combine the two.

  1. Does the combination of the two medications taken together have increased risks above the combined risks of the individual medications?

  2. If so, is the mechanism of the untoward synergistic effect known?

[0] Dosage based on studies showing that higher doses of ibuprofen were no better at pain relief than 1200 mg/day.

  • 2
    this is an excellent question, and not well answered below (see my comment). I may give it a go myself, but I'd want to do an updated literature search first.
    – De Novo
    Commented Feb 25, 2019 at 19:28

1 Answer 1


Reference 1 refers to studies that trail various combinations of analgesics. Of note is the study concerning paracetamol (acetaminophen) and ibuprofen.

The study compared the adverse effects of 4 groups:

  1. paracetamol
  2. ibuprofen
  3. paracetamol and ibuprofen, and;
  4. placebo.

They found "adverse events (significant difference)" consisted of:

  • Vomiting: 24%–32%
  • Drowsiness: 5%
  • Abdominal pain: 3%–10%

And stated that the "paracetamol group was drowsier than other groups."

Reference 1 states: "Combining [the two] analgesics may increase the incidence of adverse effects."

A similar clinical trial was described in Reference 2. The paper found that adverse events were "numerically higher in the groups receiving combination tablets."

From this it can concluded that the likelihood of experiencing adverse effects is increased by combination of the two analgesics.

I could not find anything solid in regards to your last question. The increased likelihood of experiencing adverse effects may be due to the two agent's similar mechanism of action. Reference 3 states: "Due to their mechanisms of action, using paracetamol and ibuprofen together theoretically increases the risk of renal and hepatic toxicity." It is possible that this extends to other adverse effects.


  1. Combining Paracetamol (Acetaminophen) with Nonsteroidal Antiinflammatory Drugs: A Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain, http://www.endoexperience.com/documents/APAPOngetal.pdf
  2. Paracetamol, ibuprofen, or a combination of both drugs against knee pain: an excellent new randomised clinical trial answers old questions and suggests new therapeutic recommendations, http://ard.bmj.com/content/70/9/1521.full
  3. Evidence that alternate dosing of paracetamol and ibuprofen in children with fever may reduce temperature: other benefits uncertain http://www.bpac.org.nz/BPJ/2014/July/docs/BPJ62-news.pdf
  • This misinterprets the references. Ref 1 (a systematic review) concludes "there was no evidence of an increased incidence of side effects with combinations compared with individual drugs alone", and that "the risks are a function of the dose and duration of use. Hence, the case for combining ibuprofen with paracetamol to obtain increased analgesia without increasing the dose of the NSAID is strong." Reference 2 is an editorial, and discusses a trial with no significant difference in adverse effects, even with combining high doses (vs. using combination therapy to avoid higher doses).
    – De Novo
    Commented Feb 25, 2019 at 19:23
  • Ref 3 is a news article, and doesn't directly address the question. It discusses a cochrane review that concludes combination therapy is effective, with no adverse events reported, noting that "adverse effects were not a primary focus"
    – De Novo
    Commented Feb 25, 2019 at 19:31

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