Do opioids induce hyperalgesia in humans? An evidence-based structured review

David A. Fishbain, Brandly Cole, John E. Lewis, Jinrun Gao, R. Steele Rosomoff

Research output: Contribution to journalReview articlepeer-review

130 Scopus citations


Design/Objectives: Consistent rodent evidence indicates that opioid exposure will decrease the rodent's pain threshold (ptr). This is termed opioids-induced hyperalgesia (OIH). Currently, the consistency of the evidence for the occurrence of OIH in humans is unclear. This is a structured evidence-based review for all levels of evidence (all studies and case reports) on OIH in humans in order to determine the consistency of this evidence. Methods: Computer and manual literature searches yielded 504 OIH references (human and animal). Of these, 48 remained after application of inclusion/exclusion criteria. These references addressed 10 hypotheses that the OIH literature has utilized to test for the possibility of OIH in humans. These are the following: opioid addicts maintained on opioids will have decreased ptr and/or tolerance; detoxifying opioid addicts from opioids will increase their ptr and/or tolerance; stopping, decreasing, or rotating to a different opioid or detoxifying from an opioid will improve pain and/or allodynia; chronic pain patients(CPPs) placed on opioids will develop decreased ptr and/or tolerance; CPPs on opioids will have decreased ptr and/or tolerance vs CPPs not on opioids; opioid infusion in normal volunteers or CPPs will decrease ptr and/or tolerance; former opioid addicts exposed to opioids will demonstrate a decrease in ptr and/or tolerance; opioid infusion in normal volunteers will increase secondary hyperalgesia as measured by allodynia or hyperalgesia; perioperative opioids will increase postoperative pain and/or opioid requirements; and placement on opioids postsurgery leads to progressive increased intake (acute tolerance). Each report was characterized by the type of study it represented according to the Agency for Health Care Policy and Research (AHCPR) guidelines and independently rated by two raters according to 14 quality criteria with a quality score calculated. For studies under each hypothesis, an average quality score and the percentage of studies supporting the hypothesis was calculated. Finally, for studies under each hypothesis, utilizing AHCPR criteria, a consistency rating was derived based on the percentage score of studies supporting the hypothesis. Results: Two studies had quality scores below 65% and were not utilized. Overall, the strongest evidence (consistent, A) came from opioid infusion studies in normal volunteers as measured by secondary hyperalgesia. This evidence was supported by inconsistent evidence (C) from: studies addressing opioid infusions in normal volunteers or CPPs for decreasing ptr and/or tolerance; and studies addressing increases in postop opioid requirements or pain if peri-opioids were utilized. For the other seven hypotheses, there were too few studies to draw a conclusion or the evidence for the hypothesis were case reports or the results of the studies within the hypothesis were not interpretable. Conclusions: There is not sufficient evidence to support or refute the existence of OIH in humans except in the case of normal volunteers receiving opioid infusions. Prospective CPP clinical studies measuring ptrs and tolerances pre- and post-opioid placement with CPP non-opioid control groups are required.

Original languageEnglish (US)
Pages (from-to)829-839
Number of pages11
JournalPain Medicine
Issue number5
StatePublished - 2009
Externally publishedYes


  • Allodynia
  • Evidence-based structured review
  • Humans
  • Hyperalgesia
  • Opioid-induced hyperalgesia
  • Opioids
  • Pain

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine


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