title: Effect of a high-dose target-controlled naloxone infusion on pain and hyperalgesia in patients following groin hernia repair: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Central sensitization is modulated by the endogenous opioid system and plays a major role in the development and maintenance of pain. Recent animal studies performed following resolution of inflammatory pain showed reinstatement of tactile hypersensitivity induced by administration of a mu-opioid-antagonist, suggesting latent sensitization is mediated by endogenous opioids. In a recent crossover study in healthy volunteers, following resolution of a first-degree burn, 4 out of 12 volunteers developed large secondary areas of hyperalgesia areas after a naloxone infusion, while no volunteer developed significant secondary hyperalgesia after the placebo infusion. In order to consistently demonstrate latent sensitization in humans, a pain model inducing deep tissue inflammation, as used in animal studies, might be necessary. The aim of the present study is to examine whether a high-dose target-controlled naloxone infusion can reinstate pain and hyperalgesia following recovery from open groin hernia repair and thus consistently demonstrate opioid-mediated latent sensitization in humans.
  
  
  METHODS
  Patients submitted to unilateral, primary, open groin hernia repair will be included in this randomized, placebo-controlled, double-blind, crossover study. The experimental days take place 6-8 weeks after surgery, time-points at which patients are expected to be almost pain- free. Prior to administration of naloxone or placebo, the primary outcome (a summated measure of pain: at rest, during transition from supine to standing position, and evoked by pressure algometry) and the secondary outcomes (secondary hyperalgesia/allodynia, pressure pain thresholds, assessed at the surgical site and at the mirror-site in the contralateral groin, and, opioid withdrawal symptoms) will be assessed. These assessments will be repeated at each step of the target-controlled infusion of placebo or naloxone at estimated median (95 % CI) plasma concentrations of 344 ng/ml (130;567), 1059 ng/ml (400;1752) and 3196 ng/ml (1205;5276).
  
  
  CONCLUSIONS
  We aim to demonstrate opioid-mediated latent sensitization in a post-surgical setting, using pain as a clinical relevant variable. Impairment of the protective endogenous opioid system may play an important role in the transition from acute to chronic pain. In order to sufficiently block the endogenous opioid system, a high-dose target-controlled naloxone-infusion is used, in accordance with recent findings in animal studies.
  
  
  BACKGROUND
  
  2015-000793-36 (Registration date: 16 February 2015) Clinicaltrials.gov: NCT01992146 (Registration date: 12 December 2014).
authors.affiliation: Department of Anaesthesiology, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. mpereira@anit.uni-muenster.de.
authors.forename: M P
authors.initials: MP
authors.lastname: Pereira
authors.affiliation: Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. mads.u.werner@gmail.com.
authors.forename: M U
authors.initials: MU
authors.lastname: Werner
authors.affiliation: Department of Anaesthesiology, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. Joergen.Berg.Dahl@regionh.dk.
authors.forename: J B
authors.initials: JB
authors.lastname: Dahl
authors.affiliation: Department of Anaesthesiology, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. mpereira@anit.uni-muenster.de.|Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. mpereira@anit.uni-muenster.de.
authors.forename: Manuel Pedro
authors.initials: MP
authors.lastname: Pereira
authors.affiliation: Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. mads.u.werner@gmail.com.
authors.forename: Mads
authors.initials: M
authors.lastname: Utke Werner
authors.affiliation: Department of Anaesthesiology, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. Joergen.Berg.Dahl@regionh.dk.
authors.forename: Joergen
authors.initials: J
authors.lastname: Berg Dahl
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use*; D059333:Central Nervous System Sensitization / Q000187:drug effects; D002985:Clinical Protocols; D018592:Cross-Over Studies; D003718:Denmark; D004311:Double-Blind Method; D016903:Drug Monitoring; D006552:Hernia, Inguinal / Q000175:diagnosis / Q000601:surgery*; D059685:Herniorrhaphy / Q000009:adverse effects*; D006801:Humans; D006930:Hyperalgesia / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007263:Infusions, Parenteral; D009270:Naloxone / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010149:Postoperative Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone