Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis

Br J Anaesth. 2019 Jun;122(6):e114-e126. doi: 10.1016/j.bja.2018.09.019. Epub 2018 Oct 25.


Background: Opioid-induced hyperalgesia (OIH) is well documented in preclinical studies, but findings of clinical studies are less consistent. The objective was to undertake a systematic review and meta-analysis of studies examining evidence for OIH in humans after opioid exposure.

Methods: Systematic electronic searches utilised six research databases (Embase, Medline, PubMed, CINAHL Plus, Web of Science, and OpenGrey). Manual 'grey' literature searches were also undertaken. The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was used to develop search strategies, and findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Data synthesis and subgroup analyses were undertaken using a random effects model (DerSimonian-Laird method).

Results: A total of 6167 articles were identified. After abstract and full-text reviews, 26 articles (involving 2706 participants) were included in the review. There was evidence of OIH, assessed by pain tolerance, in response to noxious thermal (hot and cold) stimuli, but not electrical stimuli. There was no evidence of OIH when assessing pain detection thresholds. OIH was more evident in patients with opioid use disorder than in patients with pain, and in patient groups treated with N-methyl-d-aspartate receptor antagonists (primarily evidenced in methadone-maintained populations).

Conclusions: OIH was evident in patients after chronic opioid exposure, but findings were dependent upon pain modality and assessment measures. Further studies should consider evaluating both pain threshold and pain tolerance across a range of modalities to ensure assessment validity. Significant subgroup findings suggest that potential confounders of pain judgements, such as illicit substance use, affective characteristics, or coping styles, should be rigorously controlled in future studies.

Keywords: analgesics, opioid; hyperalgesia; opioid-related disorders; pain; pain threshold.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects*
  • Chronic Pain / drug therapy
  • Drug Administration Schedule
  • Humans
  • Hyperalgesia / chemically induced*
  • Pain Measurement / methods
  • Pain Threshold / drug effects


  • Analgesics, Opioid