Opioid Tolerance Development: a Pharmacokinetic/pharmacodynamic Perspective

Overview

Journal AAPS J

Specialty Pharmacology

Date 2008 Nov 8

PMID 18989788

Citations 95

Authors

Emily O Dumas

Gary M Pollack

Affiliations

Soon will be listed here.

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.

Citing Articles

Discordance between preclinical and clinical testing of Na V 1.7-selective inhibitors for pain.

Yang J, Xie Y, Smith R, Ratte S, Prescott S Pain. 2025; 166(3):481-501.

PMID: 39928833 PMC: 11808711. DOI: 10.1097/j.pain.0000000000003425.

Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine.

Galambos A, Essmat N, Lakatos P, Szucs E, Boldizsar Jr I, Abbood S Int J Mol Sci. 2024; 25(20).

PMID: 39456918 PMC: 11508341. DOI: 10.3390/ijms252011136.

The Health Costs of Cost Sharing.

Chandra A, Flack E, Obermeyer Z Q J Econ. 2024; 139(4):2037-2082.

PMID: 39391632 PMC: 11461808. DOI: 10.1093/qje/qjae015.

Inpatient Management of Pain Episodes in Children with Sickle Cell Disease: A Review.

Barnawi Z, Thomas R, Peddinti R, Abou Baker N Children (Basel). 2024; 11(9).

PMID: 39334638 PMC: 11430294. DOI: 10.3390/children11091106.

A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model.

Bober A, Piotrowska A, Pawlik K, Ciapala K, Maciuszek M, Makuch W Int J Mol Sci. 2024; 25(13).

PMID: 39000516 PMC: 11242565. DOI: 10.3390/ijms25137410.

References

Bernard S, Neville K, Nguyen A, Flockhart D . Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist. 2006; 11(2):126-35. DOI: 10.1634/theoncologist.11-2-126. View

Suzuki M, Narita M, Niikura K, Nakamura A, Miyatake M, Yajima Y . mu-Opioid receptor internalization-dependent and -independent mechanisms of the development of tolerance to mu-opioid receptor agonists: Comparison between etorphine and morphine. Neuroscience. 2006; 138(2):609-19. DOI: 10.1016/j.neuroscience.2005.11.046. View

Zhao M, Joo D . Subpopulation of dorsal horn neurons displays enhanced N-methyl-D-aspartate receptor function after chronic morphine exposure. Anesthesiology. 2006; 104(4):815-25. DOI: 10.1097/00000542-200604000-00028. View

Gupta A, Decaillot F, Devi L . Targeting opioid receptor heterodimers: strategies for screening and drug development. AAPS J. 2006; 8(1):E153-9. PMC: 2751434. DOI: 10.1208/aapsj080118. View

Wittwer E, Kern S . Role of morphine's metabolites in analgesia: concepts and controversies. AAPS J. 2006; 8(2):E348-52. PMC: 3231567. DOI: 10.1007/BF02854905. View

Chen H, Lipton S . The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006; 97(6):1611-26. DOI: 10.1111/j.1471-4159.2006.03991.x. View

Oertel B, Schmidt R, Schneider A, Geisslinger G, Lotsch J . The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genomics. 2006; 16(9):625-36. DOI: 10.1097/01.fpc.0000220566.90466.a2. View

Bauer B, Yang X, Hartz A, Olson E, Zhao R, Kalvass J . In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol. 2006; 70(4):1212-9. DOI: 10.1124/mol.106.023796. View

Cosman K, Boyle L, Porsteinsson A . Memantine in the treatment of mild-to-moderate Alzheimer's disease. Expert Opin Pharmacother. 2007; 8(2):203-14. DOI: 10.1517/14656566.8.2.203. View

10.

Fredheim O, Borchgrevink P, Klepstad P, Kaasa S, Dale O . Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects. Eur J Pain. 2006; 11(6):599-604. DOI: 10.1016/j.ejpain.2006.09.006. View

11.

Hassan H, Myers A, Lee I, Coop A, Eddington N . Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats. J Pharm Sci. 2007; 96(9):2494-506. PMC: 3401599. DOI: 10.1002/jps.20893. View

12.

Sim-Selley L, Scoggins K, Cassidy M, Smith L, Dewey W, Smith F . Region-dependent attenuation of mu opioid receptor-mediated G-protein activation in mouse CNS as a function of morphine tolerance. Br J Pharmacol. 2007; 151(8):1324-33. PMC: 2189837. DOI: 10.1038/sj.bjp.0707328. View

13.

Thompson D, Pusch M, Whistler J . Changes in G protein-coupled receptor sorting protein affinity regulate postendocytic targeting of G protein-coupled receptors. J Biol Chem. 2007; 282(40):29178-85. DOI: 10.1074/jbc.M704014200. View

14.

Li S, Zhu J, Chen C, Chen Y, DeRiel J, Ashby B . Molecular cloning and expression of a rat kappa opioid receptor. Biochem J. 1993; 295 ( Pt 3):629-33. PMC: 1134604. DOI: 10.1042/bj2950629. View

15.

Bohn L, Lefkowitz R, Gainetdinov R, Peppel K, Caron M, Lin F . Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 2000; 286(5449):2495-8. DOI: 10.1126/science.286.5449.2495. View

16.

Aquilante C, Letrent S, Pollack G, Brouwer K . Increased brain P-glycoprotein in morphine tolerant rats. Life Sci. 2000; 66(4):PL47-51. DOI: 10.1016/s0024-3205(99)00599-8. View

17.

Smith M . Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000; 27(7):524-8. DOI: 10.1046/j.1440-1681.2000.03290.x. View

18.

Allen R, Dykstra L . Attenuation of mu-opioid tolerance and cross-tolerance by the competitive N-methyl-D-aspartate receptor antagonist LY235959 is related to tolerance and cross-tolerance magnitude. J Pharmacol Exp Ther. 2000; 295(3):1012-21. View

19.

Bohn L, Gainetdinov R, Lin F, Lefkowitz R, Caron M . Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000; 408(6813):720-3. DOI: 10.1038/35047086. View

20.

LaForge K, Yuferov V, Kreek M . Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur J Pharmacol. 2001; 410(2-3):249-268. DOI: 10.1016/s0014-2999(00)00819-0. View