title: Objective markers of the analgesic response to morphine in experimental pain research.
abstract: BACKGROUND
  In experimental pain research the effect of opioids is normally assessed by verbal subjective response to analgesia. However, as many confounders in pain assessment exist, objective bed-side assessment of the effect is highly warranted. Therefore, we aimed to assess the effect of morphine on three objective pharmacodynamic markers (pupil diameter, prolactin concentration and resting electroencephalography (EEG)) and compare the changes from placebo with subjective analgesia on experimental muscle pain for convergent validation.
  
  
  METHODS
  Fifteen healthy male participants received placebo or 30 mg rectal morphine at two separate sessions. At baseline and several time points after drug administration, the central effects of morphine were assessed by experimental muscle pain, pupil diameter, prolactin concentration and resting EEG.
  
  
  RESULTS
  Morphine increased tolerance to muscle pain, together with significant reductions in pupil diameter and increase in prolactin concentration (all P < 0.001). Miosis was induced simultaneously with the onset of analgesic effect 30 min after dosing, while a significant increase in prolactin concentration was seen after 45 min. The change in pupil diameter was negatively correlated to change in tolerated muscle pressure (r = -0.40, P < 0.001), whereas the increase in prolactin concentration was positively correlated (r = 0.32, P = 0.001). The effect of morphine on EEG was seen as a decrease in the relative theta (4-7.5 Hz) activity (P = 0.03), but was not significant until 120 min after dosing and did not correlate to the increase in tolerated muscle pressure (r = -0.1, P=0.43).
  
  
  CONCLUSIONS
  Prolactin concentration and pupil diameter showed similar temporal development, had good dynamic ranges and were sensitive to morphine. Thus, both measures proved to be sensitive measures of morphine effects. EEG may give additive information on the brain's response to pain, however more advanced analysis may be necessary. We therefore recommend using pupil diameter in studies where a simple and reliable objective measure of the morphine-induced central activation is needed.
authors: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark. Electronic address: anne.brokjaer@rn.dk.
authors: Anne
authors: A
authors: Brokjær
authors: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: aneso@rn.dk.
authors: Anne Estrup
authors: AE
authors: Olesen
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: mads.kreilgaard@sund.ku.dk.
authors: Mads
authors: M
authors: Kreilgaard
authors: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark. Electronic address: carina.graversen@gmail.com.
authors: Carina
authors: C
authors: Graversen
authors: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark. Electronic address: mikkelgram@gmail.com.
authors: Mikkel
authors: M
authors: Gram
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: llc@sund.ku.dk.
authors: Lona Louring
authors: LL
authors: Christrup
authors: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: A.Dahan@lumc.nl.
authors: Albert
authors: A
authors: Dahan
authors: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. Electronic address: amd@rn.dk.
authors: Asbjørn Mohr
authors: AM
authors: Drewes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use*; D010146:Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: Electroencephalography; Methods; Morphine; Prolactin; Pupillometry; Quantitative sensory testing