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lüll Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective Dumas EO; Pollack GMAAPS J 2008[Dec]; 10 (4): 537-51The 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.|*Drug Tolerance/physiology[MESH]|Analgesics, Opioid/adverse effects/pharmacokinetics/*therapeutic use[MESH]|Dose-Response Relationship, Drug[MESH]|Drug Administration Schedule[MESH]|Humans[MESH]|Kinetics[MESH]|Models, Theoretical[MESH]|Morphine/adverse effects/therapeutic use[MESH]|Oxycodone/adverse effects/therapeutic use[MESH]|Pain/*drug therapy[MESH]|Phosphorylation[MESH]|Polymorphism, Genetic[MESH]|Receptors, N-Methyl-D-Aspartate/drug effects/physiology[MESH]|Receptors, Opioid, mu/drug effects/genetics/*physiology[MESH]|Time Factors[MESH] |