Opioid-induced hyperalgesia and tolerance

Am J Ther. 2010 Sep-Oct;17(5):498-510. doi: 10.1097/MJT.0b013e3181ed83a0.


We have all encountered the following postanesthesia care unit dilemma a myriad of times. As the attending covering the postanesthesia care unit, the anesthesiologist will be confronted not infrequently with the following clinical scenario: "He needed 500 μg fentanyl in the operating room for a toe amputation and has received 20 mg morphine, and he's still complaining of severe pain…. Do you think he may need more morphine?" Opiates do prevail as first-line therapy for moderate to severe surgical and chronic pain states. However, their use may actually confound the clinical picture postoperatively, because opiate exposure counterintuitively may actually trigger exaggerated pain sensation. When assessing a patient experiencing exaggerated postoperative or chronic pain, several questions should come to mind. First, is this patient experiencing tolerance or hyperalgesia induced by opiate therapy? Second, does the management differ for the two etiologies? Third, what underlying mechanisms, both at the neuroanatomic and molecular/chemical levels, underlie the two processes? Fourth, how does the recent literature on opiate-induced hyperalgesia influence previously accepted views of pre-emptive analgesia? Fifth, what treatment modalities exist for opiate-induced hyperalgesia? Most importantly, sixth, how can opiate-induced hyperalgesia be prevented? In this literature review, we aim to address these questions and to hopefully change the current perception and management of perioperative and chronic pain states with opiates.

MeSH terms

  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Animals
  • Cholecystokinin / metabolism
  • Clinical Trials as Topic
  • Drug Evaluation, Preclinical
  • Drug Tolerance*
  • Dynorphins / pharmacology
  • Fentanyl / adverse effects
  • Fentanyl / pharmacology
  • Fentanyl / therapeutic use
  • Humans
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / prevention & control
  • Ketamine / therapeutic use
  • Morphine / administration & dosage
  • Morphine / pharmacology
  • Morphine / therapeutic use
  • Neuroimmunomodulation / drug effects
  • Pain / drug therapy
  • Pain Measurement
  • Pain Threshold / drug effects
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Analgesics, Opioid
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Dynorphins
  • Morphine
  • Cholecystokinin
  • Fentanyl