Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance

Curr Top Med Chem. 2011;11(9):1157-64. doi: 10.2174/156802611795371288.


Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Analgesics, Opioid* / administration & dosage
  • Analgesics, Opioid* / adverse effects
  • Analgesics, Opioid* / chemical synthesis
  • Animals
  • Chronic Disease
  • Drug Tolerance
  • Gene Expression
  • Humans
  • Mice
  • Mice, Knockout
  • Narcotic Antagonists*
  • Opioid-Related Disorders / physiopathology
  • Pain / drug therapy*
  • Pain / physiopathology
  • Rats
  • Receptors, Opioid / metabolism
  • Structure-Activity Relationship
  • Up-Regulation


  • ATP Binding Cassette Transporter, Subfamily B
  • Analgesics, Opioid
  • Narcotic Antagonists
  • Receptors, Opioid