Hyperalgesia in Patients With a History of Opioid Use Disorder: A Systematic Review and Meta-Analysis.

IMPORTANCE: Short-term and long-term opioid treatment have been associated with increased pain sensitivity (ie, opioid-induced hyperalgesia). Treatment of opioid use disorder (OUD) mainly involves maintenance with methadone and buprenorphine, and observations of heightened cold pain sensitivity among patients are often considered evidence of opioid-induced hyperalgesia.

OBJECTIVE: To critically examine the evidence that hyperalgesia in patients with OUD is related to opioid use.

DATA SOURCES: Web of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, were searched.

STUDY SELECTION: Studies assessing cold pressor test (CPT) pain responses during treatment seeking, pharmacological treatment, or abstinence in patients with OUD history were included.

DATA EXTRACTION AND SYNTHESIS: Multilevel random-effects models with robust variance estimation were used for all analyses. Study quality was rated with the JBI checklist. Funnel plots and Egger regression tests were used to assess reporting bias.

MAIN OUTCOMES AND MEASURES: Main outcomes were pain threshold, tolerance, and intensity in patients and healthy controls, and unstandardized, standardized (Hedges g), and percentage differences (%Δ) in these measures between patients and controls. The association between pain sensitivity and opioid tolerance, withdrawal, and abstinence indices was tested with meta-regression.

RESULTS: Thirty-nine studies (1385 patients, 741 controls) met the inclusion criteria. Most studies reported CPT data on patients undergoing opioid agonist treatment. These patients had a mean 2- to 3-seconds lower pain threshold (95% CI, -4 to -1; t test P = .01; %Δ, -22%; g = -0.5) and 29-seconds lower pain tolerance (95% CI, -39 to -18; t test P < .001; %Δ, -52%; g = -0.9) than controls. Egger tests suggested that these differences may be overestimated. There were some concerns of bias due to inadequate sample matching and participant dropout. Meta-regressions yielded no clear support for hyperalgesia being opioid related.

CONCLUSION AND RELEVANCE: Patients receiving opioid agonist treatment for OUD are hypersensitive to cold pain. It remains unclear whether hyperalgesia develops prior to, independent of, or as a result of long-term opioid treatment. Regardless, future studies should investigate the impact of hyperalgesia on patients' well-being and treatment outcomes.