The AAPS Journal

, 10:537 | Cite as

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

  • Emily O. DumasEmail author
  • Gary M. Pollack
Therapeutic Tolerance: Pharmacokinetic-Pharmacodynamic Mechanisms


The opioids are commonly used to treat acute and severe pain. Long-term opioid administration eventually reaches a dose ceiling that is attributable to the rapid onset of analgesic tolerance coupled with the slow development of tolerance to the untoward side effects of respiratory depression, nausea and decreased gastrointestinal motility. The need for effective-long term analgesia remains. In order to develop new therapeutics and novel strategies for use of current analgesics, the processes that mediate tolerance must be understood. This review highlights potential pharmacokinetic (changes in metabolite production, metabolizing enzyme expression, and transporter function) and pharmacodynamic (receptor type, location and functionality; alterations in signaling pathways and cross-tolerance) aspects of opioid tolerance development, and presents several pharmacodynamic modeling strategies that have been used to characterize time-dependent attenuation of opioid analgesia.

Key words

opioid pharmacodynamics pharmacokinetics tolerance 



adenylyl cyclase


blood brain barrier


cAMP-responsive element binding protein


cytochrome P450


δ-opioid receptor


γ-amino-butyric acid




G-protein coupled receptor


G-protein receptor kinase


human pregnane X receptor


κ-opioid receptor


brain-to-serum ratio












neuronal nitric oxide synthase


NMDA receptor


opioid receptors








protein kinase A


post-synaptic density complex


soluble guanylyl cyclase


single nucleotide polymorphism





This work was supported by National Institutes of Health Grant R01 GM61191. E.R.O. was supported by a predoctoral fellowship from GlaxoSmithKline.


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Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  1. 1.Division of Pharmacotherapy and Experimental Therapeutics, School of PharmacyThe University of North Carolina at Chapel HillChapel HillUSA

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