title: In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile.
abstract: OBJECTIVE
  For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.
  
  
  METHODS
  Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine(2,5) ]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively.
  
  
  RESULTS
  These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose-response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.
  
  
  CONCLUSIONS
  For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of 'opioid rotation'.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia; Centre for Integrated Preclinical Drug Development, St Lucia Campus, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Kuo
authors.forename: B D
authors.initials: BD
authors.lastname: Wyse
authors.forename: W
authors.initials: W
authors.lastname: Meutermans
authors.forename: M T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000627:therapeutic use*; D000818:Animals; D044482:Benzeneacetamides / Q000009:adverse effects / Q000627:therapeutic use; D002047:Buprenorphine / Q000009:adverse effects / Q000627:therapeutic use; D002368:Castor Oil; D003248:Constipation / Q000139:chemically induced*; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000009:adverse effects / Q000627:therapeutic use; D005283:Fentanyl / Q000009:adverse effects / Q000627:therapeutic use; D006358:Hot Temperature; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000009:adverse effects / Q000627:therapeutic use; D010098:Oxycodone / Q000009:adverse effects / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D009022:Morphine Derivatives; D011759:Pyrrolidines; D002047:Buprenorphine; C035349:morphine-6-glucuronide; D009020:Morphine; D002368:Castor Oil; D020881:Enkephalin, D-Penicillamine (2,5)-; D010098:Oxycodone; C045444:U 69593; D005283:Fentanyl
keywords: antinociception; buprenorphine; constipation; fentanyl; intracerebroventricular; morphine; morphine-6-glucuronide (M6G); oxycodone; rat; respiratory depression