The synergistic analgesic interactions between hydrocodone and ibuprofen

Anesth Analg. 2003 Dec;97(6):1721-3. doi: 10.1213/01.ane.0000087801.20395.97.


The practice of combining opioids with nonsteroidal antiinflammatory drugs is widespread in the clinical management of acute and chronic pain. Using the mouse radiant heat tail-flick nociception model, we observed potent analgesia with hydrocodone. In contrast, ibuprofen as a single drug was inactive in this model of moderate to severe pain, perhaps reflecting its limited analgesic potential. Despite the inactivity of ibuprofen alone in this model, the inclusion of ibuprofen with hydrocodone markedly enhanced the analgesic response. Dose-response studies revealed an 50% effective dose for hydrocodone alone in mice of 11 mg/kg, SC. Inclusion of a fixed ibuprofen dose with the various hydrocodone doses shifted the 50% effective dose value almost seven-fold to the left to 1.6 mg/kg, SC, despite the lack of effect of ibuprofen alone in this model. Using a fixed hydrocodone:ibuprofen ratio (1:40) also revealed a marked four-fold shift to 2.6 mg/kg, SC. These findings suggest a synergistic interaction between ibuprofen and hydrocodone in a noninflammatory pain model.

Implications: Opioids are frequently used in combination with nonsteroidal antiinflammatory drugs clinically. These studies demonstrate strong interactions between ibuprofen and hydrocodone, implying synergy between the two drugs, which may help explain their utility when given together.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Hot Temperature
  • Hydrocodone / pharmacology*
  • Ibuprofen / pharmacology*
  • Male
  • Mice
  • Pain Measurement / drug effects
  • Reaction Time / drug effects


  • Analgesics, Opioid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Hydrocodone
  • Ibuprofen