Opioid Analgesics and P-Glycoprotein Efflux Transporters: A Potential Systems-Level Contribution to Analgesic Tolerance

Mercer, Susan L.; Coop, Andrew

doi:10.2174/156802611795371288

Cited by 95 publications

(70 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly, many opioids are substrates for P-glycoprotein [31]. Although earlier data suggested that oxycodone was not a P-glycoprotein substrate, more recent data suggest that it is [32][33][34]. Oxycodone may in fact induce P-glycoprotein expression; this has been proposed as a mechanism of analgesic tolerance.…”

Section: Discussionmentioning

confidence: 99%

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

Hardy

Norris

Anderson

et al. 2011

Support Care Cancer

View full text Add to dashboard Cite

Purpose Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to nonessential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple noninvasive test to investigate opioid PKs. Methods Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection. Results One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day).Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9-269.4 μg/L, respectively. Salivary concentrations of oxycodone (range 0.93-3,620, mean 336 μg/L) were much higher than plasma concentrations (mean 38.2 μg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r 2 =0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method. Conclusion High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.

show abstract

Section: Discussionmentioning

confidence: 99%

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

Hardy

Norris

Anderson

et al. 2011

Support Care Cancer

View full text Add to dashboard Cite

show abstract

“…In vitro and in vivo studies have shown that morphine, fentanyl, and oxycodone are substrates for the ABCB1 transporter (28 ). Although for the ABCB1 gene over 8000 SNPs are reported, only 4% of those in fact have a MAF above 5%.…”

Section: Abcb1mentioning

confidence: 99%

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

et al. 2017

View full text Add to dashboard Cite

BACKGROUND The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

show abstract

“…In the context of the study by Mogadam and colleagues, this effect may involve the critical BBB efflux transporter P-gp. Specifically, gabapentin is a known P-gp inhibitor (7) while in vitro studies have suggested that meperidine is a P-gp transport substrate (8). Although in vivo studies in mdr1a knockout mice showed no difference in meperidine antinociception (9), a direct analysis of P-gp-mediated transport of meperidine in intact laboratory animals has not been undertaken.…”

Section: Dear Editormentioning

confidence: 99%

Gabapentin and Diclofenac Reduce Opioid Consumption in Patients Undergoing Tonsillectomy: A Result of Altered CNS Drug Delivery?

Ronaldson

Davis

2013

Arch Trauma Res

View full text Add to dashboard Cite

Implication for health policy/practice/research/medical education: Our letter highlights the role of CNS drug delivery mechanisms on the efficacy of opioid pharmacotherapy. Information presented in this letter emphasizes the importance of translational studies aimed at understanding specific mechanisms involved in CNS opioid delivery, opioid efficacy, and/or drug-opioid interactions.Copyright © 2013, Kashan University of Medical Sciences; License Kowsar Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dear Editor,We have read with great interest the article by Mogadam and colleagues on utilization of gabapentin and diclofenac for management of post-operative pain in patients undergoing tonsillectomy (1). Perhaps the most intriguing aspect of this study was the observation that pre-operative administration of gabapentin or diclofenac resulted in reduced post-operative utilization of meperidine, an opioid analgesic. Optimal therapeutic efficacy of opioids requires that they cross the bloodbrain barrier (BBB) and attain effective concentrations in the CNS (2). CNS delivery of opioids is determined by putative membrane transporters localized to the BBB endothelium (3, 4). Both pathophysiological factors (i.e., inflammatory signaling in pain) and pharmacological factors (i.e., use of ancillary pain medications) can modulate mechanisms involved in BBB opioid transport, an effect that can cause profound changes in CNS delivery of traditional opioids (i.e., morphine, meperidine). In fact, our research group has demonstrated that painful and/ or inflammatory stimuli in the periphery can significantly change transport mechanisms for opioids at the BBB such as the drug efflux transporter P-glycoprotein (P-gp) (5) and the drug influx transporter organic anion transporting polypeptide 1a4 (6). Of particular note, we have also shown that diclofenac itself can attenuate paininduced changes in BBB transporter activity (6). Our data suggest that a modulation in post-operative meperidine efficacy may, in part, be the result of altered CNS opioid delivery induced by diclofenac. An additional factor to consider is that some ancillary pain medications may act as chemical inhibitors of the same BBB transporters. In the context of the study by Mogadam and colleagues, this effect may involve the critical BBB efflux transporter P-gp. Specifically, gabapentin is a known P-gp inhibitor (7) while in vitro studies have suggested that meperidine is a P-gp transport substrate (8). Although in vivo studies in mdr1a knockout mice showed no difference in meperidine antinociception (9), a direct analysis of P-gp-mediated transport of meperidine in intact laboratory animals has not been undertaken. Furthermore, this study measured analgesic efficacy using only tail-pinch, a technique that may not have been sensitive enough...

show abstract

Opioid Analgesics and P-Glycoprotein Efflux Transporters: A Potential Systems-Level Contribution to Analgesic Tolerance

Cited by 95 publications

References 78 publications

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

Gabapentin and Diclofenac Reduce Opioid Consumption in Patients Undergoing Tonsillectomy: A Result of Altered CNS Drug Delivery?

Contact Info

Product

Resources

About