scholarly journals Contribution of CYP2D6 Functional Activity to Oxycodone Efficacy in Pain Management: Genetic Polymorphisms, Phenoconversion, and Tissue-Selective Metabolism

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1466
Author(s):  
Malavika Deodhar ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Drug Interaction ◽  
Opioid Receptor ◽  
Current Knowledge ◽  
Analgesic Efficacy ◽  
Local Formation ◽  
Pharmacogenetic Testing ◽  
Analgesic Effects ◽  
Interaction Studies ◽  
Gene Coding ◽  
Μ Opioid Receptor

Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor (OPRM1). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The CYP2D6 gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to OPRM1 variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for CYP2D6 with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy.

scholarly journals Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

Pain ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 2277-2284 ◽  
Author(s):  
Antonio Rodriguez-Gaztelumendi ◽  
Viola Spahn ◽  
Dominika Labuz ◽  
Halina Machelska ◽  
Christoph Stein
Keyword(s):  
Abdominal Pain ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Analgesic Effects ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor ◽  
Ph Dependent

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients

2010 ◽  
Vol 1 (1) ◽  
pp. 24-33 ◽  
Author(s):  
K.K. Lemberg ◽  
T.E. Heiskanen ◽  
M. Neuvonen ◽  
V.K. Kontinen ◽  
P.J. Neuvonen ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Adverse Effects ◽  
Opioid Receptor ◽  
Placebo Administration ◽  
Rescue Analgesia ◽  
Analgesic Effects ◽  
Patient Reported ◽  
Chronic Pain Patients ◽  
Μ Opioid Receptor ◽  
Pain Patients

AbstractOxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients.The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20 mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1.Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0–12h of oxycodone by 19% (−23 to 113%; P = 0.003), and that of noroxycodone by 100% (5–280%; P < 0.0001) but decreased the AUC0–12 h of oxymorphone by 67% (−100 to −22%; P < 0.0001) and that of noroxymorphone by 68% (−100 to −16%; P < 0.0001).Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P = 0.0471) indicating that these adverse effects were due to paroxetine.No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied.The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

scholarly journals Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

2020 ◽  
Vol 21 (13) ◽  
pp. 4699 ◽  
Author(s):  
Zhennan Zhao ◽  
Tingting Huang ◽  
Jiazhong Li
Keyword(s):  
Molecular Dynamics ◽  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Opioid Analgesics ◽  
Dynamics Simulation ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

Enhancement of Morphine Analgesic Effect with Induction of μ-Opioid Receptor Endocytosis in Rats

2006 ◽  
Vol 105 (3) ◽  
pp. 574-580 ◽  
Author(s):  
Tatsuya Hashimoto ◽  
Yoji Saito ◽  
Kazuo Yamada ◽  
Nobumasa Hara ◽  
Yumiko Kirihara ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Relative Activity ◽  
Receptor Internalization ◽  
Hot Plate Test ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Opiate Drug ◽  
Satisfactory Analgesia

Background Morphine can desensitize mu-opioid receptor (MOR), but it does not cause internalization of the receptor after binding. Acute desensitization of MOR impairs the efficiency of signaling, whereas the receptor internalization restores the cell responsiveness to the agonists. Thereby, the property of morphine may limit the analgesic effects of this opiate drug. It has been shown that [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), a potent MOR agonist inducing the internalization, facilitates morphine to internalize MOR, suggesting that MOR agonists with low relative activity versus endocytosis (RAVE) values such as DAMGO can potentiate analgesic effects of morphine through stimulating MOR internalization. The authors examined whether the acute analgesic effect of morphine can be potentiated by low relative activity versus endocytosis agonists DAMGO and fentanyl. Methods Rats injected intrathecally with opioids were subjected to a hot plate test for antinociceptive effect. Immunostained spinal dorsal horn was analyzed by confocal microscopy. Results Fentanyl induced MOR internalization to a lesser extent than DAMGO at equianalgesic doses. Coadministration of fentanyl promoted morphine-induced MOR internalization. The analgesic effect of morphine was greatly potentiated together with decrease in the relative activity versus endocytosis value when MOR internalization was induced by coadministration of a subanalgesic dose of DAMGO or fentanyl. In contrast, the combination of DAMGO and fentanyl increased neither the analgesic effect nor the internalization of MOR. Conclusions The results suggest that the coadministration of morphine with MOR-internalizing agonist is clinically applicable to develop successful pain-management regimens to achieve satisfactory analgesia using less morphine.

scholarly journals Synthesis and Evaluation of Novel Biased μ-Opioid-Receptor (μOR) Agonists

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 259 ◽  
Author(s):  
Mengjun Ma ◽  
Jialin Sun ◽  
Menghua Li ◽  
Zixing Yu ◽  
Jingchao Cheng ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
G Protein Coupled Receptors ◽  
Formalin Injection ◽  
Writhing Test ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
G Protein Coupled ◽  
Target Side

‘Biased’ ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent μ-opioid-receptor (μOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable β-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased μOR agonists for treating pain.

Drug interaction studies of esomeprazole with amoxicillin and clarithromycin

2001 ◽  
Vol 120 (5) ◽  
pp. A581-A581
Author(s):  
T ANDERSSON ◽  
L ASTRAZENECA ◽  
K ROHSS ◽  
M HASSANALIN
Keyword(s):  
Drug Interaction ◽  
Interaction Studies
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