title: Modulation of remifentanil-induced postinfusion hyperalgesia by the β-blocker propranolol in humans.
abstract: Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Larry F
authors.initials: LF
authors.lastname: Chu
authors.forename: Tony
authors.initials: T
authors.lastname: Cun
authors.forename: Lynn K
authors.initials: LK
authors.lastname: Ngai
authors.forename: Julie E
authors.initials: JE
authors.lastname: Kim
authors.forename: Abigail K
authors.initials: AK
authors.lastname: Zamora
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Young
authors.forename: Martin S
authors.initials: MS
authors.lastname: Angst
authors.forename: David J
authors.initials: DJ
authors.lastname: Clark
mesh_terms: D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology*; D011433:Propranolol / Q000627:therapeutic use*; D000077208:Remifentanil; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D010880:Piperidines; D011433:Propranolol; D000077208:Remifentanil