Analgesic effect of oral ibuprofen 400, 600, and 800 mg; paracetamol 500 and 1000 mg; and paracetamol 1000 mg plus 60 mg codeine in acute postoperative pain: a single-dose, randomized, placebo-controlled, and double-blind study

Eur J Clin Pharmacol. 2021 Dec;77(12):1843-1852. doi: 10.1007/s00228-021-03231-9. Epub 2021 Oct 16.


Purpose: Effect size estimates of analgesic drugs can be misleading. Ibuprofen (400 mg, 600 mg, 800 mg), paracetamol (1000 mg, 500 mg), paracetamol 1000 mg/codeine 60 mg, and placebo were investigated to establish the multidimensional pharmacodynamic profiles of each drug on acute pain with calculated effect size estimates.

Methods: A randomized, double-blind, single-dose, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 350 patients (mean age 25 year, range 18 to 30 years) of homogenous ethnicity after third molar surgery. Primary outcome was sum pain intensity over 6 h. Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference, maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat values, adverse effects, overall drug assessment as patient-reported outcome measure (PROM), and the effect size estimates NNT and NNTp.

Results: Ibuprofen doses above 400 mg do not significantly increase analgesic effect. Paracetamol has a very flat analgesic dose-response profile. Paracetamol 1000/codeine 60 mg gives similar analgesia as ibuprofen from 400 mg, but has a shorter time to analgesic onset. Active drugs show no significant difference in maximal analgesic effect. Other secondary outcomes support these findings. The frequencies of adverse effects were low, mild to moderate in all active groups. NNT and NTTp values did not coincide well with PROMs.

Conclusion: Ibuprofen doses above 400 mg for acute pain offer limited analgesic gain. Paracetamol 1000 mg/codeine 60 mg is comparable to ibuprofen doses from 400 mg. Calculated effect size estimates and PROM in our study seem not to relate well as clinical analgesic efficacy estimators.

Trial registration: NCT00699114.

Keywords: Codeine; Ibuprofen; Paracetamol; Postoperative pain; Third molar.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / adverse effects
  • Acetaminophen / therapeutic use*
  • Adolescent
  • Adult
  • Analgesics / administration & dosage
  • Analgesics / adverse effects
  • Analgesics / therapeutic use*
  • Codeine / administration & dosage
  • Codeine / adverse effects
  • Codeine / therapeutic use*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Combinations
  • Drug Therapy, Combination
  • Female
  • Humans
  • Ibuprofen / administration & dosage
  • Ibuprofen / adverse effects
  • Ibuprofen / therapeutic use*
  • Male
  • Pain Measurement
  • Pain, Postoperative / drug therapy*
  • Young Adult


  • Analgesics
  • Drug Combinations
  • acetaminophen, codeine drug combination
  • Acetaminophen
  • Codeine
  • Ibuprofen

Associated data