Oliceridine: Difference between revisions

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<!-- Chemical and physical data -->| IUPAC_name = ''N''-[(3-Methoxythiophen-2-yl)methyl]-2-[(9''R'')-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine

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Oliceridine is a [[mu-opioid receptor|μ-opioid receptor]] [[biased agonist]] developed by [[Trevena Inc|Trevena]]. In cell-based (''in vitro'') research, oliceridine elicits robust [[G protein]] [[signal transduction|signaling]], with [[potency (pharmacology)|potency]] and [[intrinsic activity|efficacy]] similar to that of [[morphine]], but with less [[arrestin beta 2|β-arrestin 2]] recruitment and [[receptor internalization]].<ref name="pmid23300227">{{cite journal | vauthors = DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD | display-authors = 6 | title = A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 344 | issue = 3 | pages = 708–17708–717 | date = March 2013 | pmid = 23300227 | doi = 10.1124/jpet.112.201616 | s2cid = 8785003 }}</ref> However,It recenthas reportsbeen highlightsuggested that this might be due to its low intrinsic efficacy,<ref>{{cite journal | vauthors = Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzwanker S, Schmiedel F, Katte TA, Reekie T, Grimsey NL, Kassiou M, Kellam B, Krasel C, Halls ML, Connor M, Lane JR, Schulz S, Christie MJ, Canals M | display-authors = 6 | title = Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists | journal = Science Signaling | volume = 13 | issue = 625 | pages = eaaz3140 | date = March 2020 | pmid = 32234959 | doi = 10.1126/scisignal.aaz3140 | s2cid = 214771721 | url = https://nottingham-repository.worktribe.com/output/4193457 }}</ref> rather than functional selectivity or 'G protein bias', asalthough initiallythe reportedvalidity of that conclusion has also been questioned.<ref>{{cite journal | vauthors = Stahl EL, Bohn LM | title = Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists | journal = Biochemistry | volume = 61 | issue = 18 | pages = 1923–1935 | date = September 2022 | pmid = 34468132 | doi = 10.1021/acs.biochem.1c00466 | pmc = 8885792 }}</ref> ''In vivo'', it may have fewer [[adverse effect]]s (including respiratory depression and constipation) compared with [[morphine]].<ref name="pmid24063433">{{cite journal | vauthors = Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS | display-authors = 6 | title = Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain | journal = Journal of Medicinal Chemistry | volume = 56 | issue = 20 | pages = 8019–318019–8031 | date = October 2013 | pmid = 24063433 | doi = 10.1021/jm4010829 }}</ref><ref name="pmid24122908">{{cite journal | vauthors = Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan CL, Violin JD, Lark MW | display-authors = 6 | title = First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers | journal = Journal of Clinical Pharmacology | volume = 54 | issue = 3 | pages = 351–7351–357 | date = March 2014 | pmid = 24122908 | doi = 10.1002/jcph.207 | s2cid = 25049515 }}</ref><ref>{{Cite journal|last=Staff|date=1 October 2015|title=Acute Postoperative Pain|journal=[[Gen. Eng. Biotechnol. News|Genetic Engineering & Biotechnology News]]|type=Paper|volume=35|issue=17|page=40}}</ref> In general, ''in vitro'' potency does not guarantee any clinical relevance in humans.<ref name="Waldman">{{cite journal | vauthors = Waldman SA | title = Does potency predict clinical efficacy? Illustration through an antihistamine model | journal = Annals of Allergy, Asthma & Immunology | volume = 89 | issue = 1 | pages = 7–11; quiz 11-211–2, 77 | date = July 2002 | pmid = 12141724 | doi = 10.1016/S1081-1206(10)61904-7 }}</ref>

TrialsTrial 1 enrolled participants who underwent bunion surgery.<ref name="FDA snapshot" /> Participants with moderate to severe post-surgical pain were randomly assigned to receive oliceridine, placebo or an approved drug to treat pain (morphine) for 48 hours through the veinintravenously.<ref name="FDA snapshot" /> Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.<ref name="FDA snapshot" /> All participants were allowed to use a rescue pain medication, if the pain was not well controlled using the trial medications.<ref name="FDA snapshot" />

Trial 2 enrolled participants who underwent surgical removal of abdominal wall fat (abdominoplasty) and had moderate to severe pain.<ref name="FDA snapshot" /> Participants were randomly assigned to receive oliceridine, placebo or an approved drug to treat pain (morphine) for 24 hours through the veinintravenously.<ref name="FDA snapshot" /> Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.<ref name="FDA snapshot" /> All participants were allowed to use a rescue pain medication, if the pain was not well controlled using the trial medications.<ref name="FDA snapshot" />

An advisory committee of the U.S. [[Food and Drug Administration]] (FDA) voted against the approval of oliceridine in 2018, due to concerns that the benefit of the drug did not exceed the risk. The risks of oliceridine include prolongation of the [[QT interval]] on the [[ECG]], and [[hypoventilation|depression of the respiratory drive]] (which could cause a person to stop breathing).<ref name="FDA Vote Against 18">{{cite web |title=FDA Panel Votes Against Analgesic Oliceridine |url=https://www.medpagetoday.com/painmanagement/opioids/75668 |website=www.medpagetoday.com |publisher=MedPage Today, LLC |access-date=23 December 2018 |language=en |date=11 October 2018}}</ref> As a result of the committee's vote, the FDA declined to approve oliceridine, citing safety concerns.<ref name="FDA rejection 2018">{{cite web |title=FDA rejects Trevena's painkiller oliceridine {{!}} FierceBiotech |url=https://www.fiercebiotech.com/biotech/fda-rejects-trevena-s-painkiller-oliceridine |website=www.fiercebiotech.com |date=5 November 2018 |publisher=Questex LLC |access-date=23 December 2018 }}</ref><ref name="pmid31010646">{{cite journal | vauthors = Azzam AA, McDonald J, Lambert DG | title = Hot topics in opioid pharmacology: mixed and biased opioids | journal = British Journal of Anaesthesia | volume = 122 | issue = 6 | pages = e136–e145 | date = June 2019 | pmid = 31010646 | doi = 10.1016/j.bja.2019.03.006 | hdl-access = 2381/43829free | s2cid = 128360210 | hdl-access = free2381/43829 }}</ref>

The DEA issued an interim final rule on October 30, 2020, designating oliceridine as CSA Schedule II (DEA Code 9245).{{fcn|date=July 2022}}

== See also ==

[[Category:Pyridines2-Pyridyl compounds]]