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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

Abstract

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 

Abbreviations

AC

adenylyl cyclase

BBB

blood brain barrier

CREB

cAMP-responsive element binding protein

CYP

cytochrome P450

DOR

δ-opioid receptor

GABA

γ-amino-butyric acid

Glu

glutamate

GPCR

G-protein coupled receptor

GRK

G-protein receptor kinase

hPXR

human pregnane X receptor

KOR

κ-opioid receptor

Kp,brain

brain-to-serum ratio

l-Arg

l-arginine

l-Cit

l-citrulline

M3G

morphine-3-glucuronide

M6G

morphine-6-glucuronide

NMDA

N-methyl-d-aspartate

nNOS

neuronal nitric oxide synthase

NR

NMDA receptor

OR

opioid receptors

PD

pharmacodynamic

P-gp

P-glycoprotein

PK

pharmacokinetic

PKA

protein kinase A

PSD-95

post-synaptic density complex

sGC

soluble guanylyl cyclase

SNP

single nucleotide polymorphism

UGT

uridine-5′-diphosphate-glucuronosyltranserase

Notes

Acknowledgements

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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