Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.
Journal
Anesthesia and analgesia
ISSN: 1526-7598
Titre abrégé: Anesth Analg
Pays: United States
ID NLM: 1310650
Informations de publication
Date de publication:
01 05 2022
01 05 2022
Historique:
entrez:
15
4
2022
pubmed:
16
4
2022
medline:
20
4
2022
Statut:
ppublish
Résumé
Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and β-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. In cells stably expressing μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while β-arrestin-mediated pathways were analyzed with β-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the β-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.
Sections du résumé
BACKGROUND
Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and β-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine.
METHODS
In cells stably expressing μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while β-arrestin-mediated pathways were analyzed with β-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated.
RESULTS
In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the β-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects.
CONCLUSIONS
While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.
Identifiants
pubmed: 35427270
doi: 10.1213/ANE.0000000000005954
pii: 00000539-202205000-00026
pmc: PMC8986634
doi:
Substances chimiques
Analgesics, Opioid
0
Receptors, Opioid
0
Receptors, Opioid, mu
0
beta-Arrestins
0
Morphine
76I7G6D29C
GTP-Binding Proteins
EC 3.6.1.-
Fentanyl
UF599785JZ
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1082-1093Informations de copyright
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.
Déclaration de conflit d'intérêts
Conflicts of Interest: See Disclosures at the end of the article.
Références
Rodriguez C, Ji M, Wang HL, Padhya T, McMillan SC. Cancer pain and quality of life. J Hosp Palliat Nurs. 2019;21:116–123.
Blake A, Wan BA, Malek L, et al. A selective review of medical cannabis in cancer pain management. Ann Palliat Med. 2017;6:S215–S222.
Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain—an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;7:Cd012592.
Ahn JS, Lin J, Ogawa S, et al. Transdermal buprenorphine and fentanyl patches in cancer pain: a network systematic review. J Pain Res. 2017;10:1963–1972.
Vithlani RH, Baranidharan G. Transdermal opioids for cancer pain management. Rev Pain. 2010;4:8–13.
Lehmann KA, Zech D. Transdermal fentanyl: clinical pharmacology. J Pain Symptom Manage. 1992;7:S8–16.
WHO Guidelines Approved by the Guidelines Review Committee. WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. World Health Organization © World Health Organization 2018. 2018.
Marwah H, Garg T, Goyal AK, Rath G. Permeation enhancer strategies in transdermal drug delivery. Drug Deliv. 2016;23:564–578.
Kress HG, Von der Laage D, Hoerauf KH, et al. A randomized, open, parallel group, multicenter trial to investigate analgesic efficacy and safety of a new transdermal fentanyl patch compared to standard opioid treatment in cancer pain. J Pain Symptom Manage. 2008;36:268–279.
Aurilio C, Pace MC, Pota V, et al. Opioids switching with transdermal systems in chronic cancer pain. J Exp Clin Cancer Res. 2009;28:61.
Mercadante S, Villari P, Ferrera P, Casuccio A. Addition of a second opioid may improve opioid response in cancer pain: preliminary data. Support Care Cancer. 2004;12:762–766.
Hair PI, Keating GM, McKeage K. Transdermal matrix fentanyl membrane patch (matrifen): in severe cancer-related chronic pain. Drugs. 2008;68:2001–2009.
Clemens KE, Klaschik E. Clinical experience with transdermal and orally administered opioids in palliative care patients–a retrospective study. Jpn J Clin Oncol. 2007;37:302–309.
Schmid CL, Kennedy NM, Ross NC, et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell. 2017;171:1165–1175.e13.
Raehal KM, Schmid CL, Groer CE, Bohn LM. Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharmacol Rev. 2011;63:1001–1019.
Rovira X, Pin JP, Giraldo J. The asymmetric/symmetric activation of GPCR dimers as a possible mechanistic rationale for multiple signalling pathways. Trends Pharmacol Sci. 2010;31:15–21.
Manabe S, Miyano K, Fujii Y, et al. Possible biased analgesic of hydromorphone through the G protein-over β-arrestin-mediated pathway: cAMP, CellKey™, and receptor internalization analyses. J Pharmacol Sci. 2019;140:171–177.
Okude J, Ueda T, Kofuku Y, et al. Identification of a conformational equilibrium that determines the efficacy and functional selectivity of the μ-Opioid receptor. Angew Chem Int Ed Engl. 2015;54:15771–15776.
Raffa RB, Martinez RP, Connelly CD. G-protein antisense oligodeoxyribonucleotides and mu-opioid supraspinal antinociception. Eur J Pharmacol. 1994;258:R5–R7.
Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999;286:2495–2498.
Cordery SF, Husbands SM, Bailey CP, Guy RH, Delgado-Charro MB. Simultaneous transdermal delivery of buprenorphine hydrochloride and naltrexone hydrochloride by iontophoresis. Mol Pharm. 2019;16:2808–2816.
Majumdar S, Srirangam R. Solubility, stability, physicochemical characteristics and in vitro ocular tissue permeability of hesperidin: a natural bioflavonoid. Pharm Res. 2009;26:1217–1225.
Tamura G, Ichinose M, Fukuchi Y, Miyamoto T. Transdermal tulobuterol patch, a long-actingβ(2)-agonist. Allergol Int. 2012;61:219–229.
Miyano K, Sudo Y, Yokoyama A, et al. History of the G protein-coupled receptor (GPCR) assays from traditional to a state-of-the-art biosensor assay. J Pharmacol Sci. 2014;126:302–309.
Meguro Y, Miyano K, Hirayama S, et al. Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator. J Pharmacol Sci. 2018;137:67–75.
D’amour FE, Smith DL. A method for determining loss of pain sensation. J Pharmacol Exp Ther. 1941;72:74–79.
Cachia E, Ahmedzai SH. Transdermal opioids for cancer pain. Curr Opin Support Palliat Care. 2011;5:15–19.
Kornick CA, Santiago-Palma J, Moryl N, Payne R, Obbens EA. Benefit-risk assessment of transdermal fentanyl for the treatment of chronic pain. Drug Saf. 2003;26:951–973.
Franz TJ. Percutaneous absorption. On the relevance of in vitro data. J Invest Dermatol. 1975;64:190–195.
Azzam AAH, McDonald J, Lambert DG. Hot topics in opioid pharmacology: mixed and biased opioids. Br J Anaesth. 2019;122:e136–e145.
Raehal KM, Walker JKL, Bohn LM. Morphine side effects in β-Arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005;314:1195–1201.
Maguma HT, Dewey WL, Akbarali HI. Differences in the characteristics of tolerance to μ-opioid receptor agonists in the colon from wild type and β-arrestin2 knockout mice. Eur J Pharmacol. 2012;685:133–140.
Kang M, Maguma HT, Smith TH, Ross GR, Dewey WL, Akbarali HI. The role of β-arrestin2 in the mechanism of morphine tolerance in the mouse and guinea pig gastrointestinal tract. J Pharmacol Exp Ther. 2012;340:567–576.
Chu Sin Chung P, Kieffer BL. Delta opioid receptors in brain function and diseases. Pharmacol Ther. 2013;140:112–120.
Vanderah TW. Delta and kappa opioid receptors as suitable drug targets for pain. Clin J Pain. 2010;26(suppl 10):S10–S15.
Holdridge SV, Cahill CM. Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Eur J Pain. 2007;11:685–693.
Baamonde A, Lastra A, Juárez L, García V, Hidalgo A, Menéndez L. Effects of the local administration of selective mu-, delta-and kappa-opioid receptor agonists on osteosarcoma-induced hyperalgesia. Naunyn Schmiedebergs Arch Pharmacol. 2005;372:213–219.