Neurocognitive Effect of Biased mu-opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine

A comparison of the neurocognitive (sedation and body orientation) effects of oliceridine versus morphine including the more rapid onset and offset of neurocognitive effects for oliceridine and a smaller magnitude of neurocognitive effects over time.

Laurence Moss, M.D., Hemme Hijma, Ph.D., Mark Demitrack, M.D., Jessica Kim, M.Sc., Geert Jan Groeneveld, M.D., Ph.D., Monique van Velzen, Ph.D., Marieke Niesters, M.D., Ph.D., Erik Olofsen, Ph.D., Albert Dahan, M.D., Ph.D.

Oliceridine for the Management of Moderate to Severe Acute Postoperative Pain: A Narrative Review

Conventional opioid analgesics, such as morphine, fentanyl, and hydromorphone, are mainstays of acute pain management; however, their use is accompanied by well-known opioid related adverse events (ORAEs), nausea, vomiting, and central nervous system effects. Oliceridine demonstrated analgesic efficacy superior to placebo and comparable to morphine, with favorable results on reduction of ORAEs.

Neil Daksla, Ashley Wang, Zhaosheng Jin, Abhishek Gupta, Sergio Bergese

Respiratory Effects of Biased Ligand Oliceridine in Older Volunteers: A Pharmacokinetic– Pharmacodynamic Comparison with Morphine

A comparison of the respiratory effects of Oliceridine versus morphine including the more rapid onset and offset of respiratory depression for oliceridine and a smaller magnitude of respiratory depression over time.

Pieter Simons, M.D., Rutger van der Schrier, M.D., Maarten van Lemmen, B.Sc., Simone Jansen, M.D., Kiki W.K. Kuijpers, B.Sc., Monique van Velzen, Ph.D., Elise Sarton, M.D., Ph.D., Todd Nicklas, M.S.N., Cathy Michalsky, M.Sc., Mark A. Demitrack, M.D., Michael Fossler, Pharm.D., Ph.D., F.C.P., Erik Olofsen, Ph.D., Marieke Niesters, M.D., Ph.D., Albert Dahan, M.D. Ph.D.

Anesthesiology 2023; 138:249–63

Expert Review on the Clinical Profile of Oliceridine in Post-Operative Care

Review highlights the strength of the evidence base for the safety and efficacy of Oliceridine and also elucidates the practical clinical importance of the responder rate used as the primary outcome measure in the randomized controlled pivotal Phase 3 APOLLO trials

Viscusi ER. A critical review of oliceridine injection as an IV opioid analgesic for the management of severe acute pain. Expert Rev Neurother. 2022 May 17:1-8. doi: 10.1080/14737175.2022.2072731. Epub ahead of print.

Health Economic Models- Model in high-risk (elderly/obese) patients and Budget Impact model

Budget impact and pharmacy costs with targeted use of oliceridine for postsurgical pain in patients at high risk of opioid-related adverse events

Kit N Simpson, Michael J Fossler, Linda Wase, Mark A Demitrack, Todd L Wandstrat

Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Logistic regression analysis

Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials

Gregory B. Hammer, Ashish K. Khanna, Cathy Michalsky, Linda Wase, Mark A. Demitrack, Roderick Little, Michael J. Fossler & Sabry Ayad

Health economic model – base case

Cost–effectiveness and cost-benefit analysis of oliceridine in the treatment of acute pain

Kit N Simpson, Michael J Fossler, Linda Wase & Mark A Demitrack

Postoperative oliceridine use in patients with advanced age and/or increased BMI was not associated with increased risk of OIRD

Low Incidence of Opioid-Induced Respiratory Depression Observed with Oliceridine Regardless of Age or Body Mass Index: Exploratory Analysis from a Phase 3 Open-Label Trial in Postsurgical Pain

Marek Brzezinski, Gregory B. Hammer, Keith A. Candiotti, Sergio D. Bergese, Peter H. Pan, Michael H. Bourne, Cathy Michalsky, Linda Wase, Mark A. Demitrack, Ashraf S. Habib. Pain & Therapy 2021.

Review of the efficacy and safety of intravenous oliceridine in the treatment of moderate to severe acute pain

Oliceridine in the treatment of moderate to severe acute pain

Sarada S Eleswarpu & Ashraf S Habib. Future Medicine 2021.

DOI: 10.2217/pmt-2020-0087

Oliceridine significantly reduced risk of vomiting and rescue antiemetic use compared to IV morphine in a retrospective analysis

Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials

Timothy L. Beard,  Cathy Michalsky, Keith A. Candiotti, Paul Rider, Linda Wase, Ashraf S. Habib, Mark A. Demitrack, Michael J. Fossler, Eugene R. Viscusi

Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine.

Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine.

Albert Dahan, C. Jan van Dam, Marieke Niesters, Monique van Velzen, Michael J. Fossler, Mark A. Demitrack, Erik Olofsen. Anesthesiology 2020. doi:

Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain: Findings indicate improved safety with oliceridine.

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

Sabry Ayad, Mark A. Demitrack, David A. Burt, Cathy Michalsky, Linda Wase, Michael J. Fossler & Ashish K. Khanna. Clin Drug Investig (2020).

Oliceridine Monograph

Oliceridine, a G protein-selective ligand at the μ-opioid receptor, for the management of moderate to severe acute pain

Gan TJ & Wase L. Drugs Today (Barc). 2020 Apr;56(4):269-286. doi: 10.1358/dot.2020.56.4.3107707.

Phase 3 “Real World” Safety Study for Oliceridine

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The μ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy

Bergese SD, Brzezinski M, Hammer GB, Beard TL, Pan PH, Mace SE, Berkowitz RD, Cochrane K, Wase L, Minkowitz HS, Habib AS. J Pain Research. 2019, 12: 3113-3126.

DOI: 10.2147/JPR.S217563 [open access]

Pharmacokinetics of IV oliceridine in patients with renal impairment or patients with mild/moderate hepatic impairment- No dose adjustments required

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Oliceridine

Nafziger AN, Arscott KA, Cochrane K, Skobieranda F, Burt DA, Fossler MJ. Clin Pharmacol Drug Dev. 2019 Nov 7. doi:10.1002/cpdd.750.[open access]

Oliceridine (TRV130) Phase-3 Pivotal trial in soft-tissue (abdominoplasty) acute pain

APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the μ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty

Neil K. Singla, Franck Skobieranda, David G. Soergel, Monica Salamea, David A. Burt, Mark A. Demitrack, Eugene R. Viscusi Pain Pract. 2019 Sep;19(7):715-731

Oliceridine (TRV130) Phase-3 Pivotal trial in hard-tissue (bunionectomy) acute pain

APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the µ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy

Eugene R Viscusi, Franck Skobieranda, David G Soergel,Emily Cook, David A Burt, and Neil Singla. J Pain Res. 2019; 12: 927–943.

Oliceridine (TRV130) Phase 2b trial in soft-tissue (abdominoplasty) acute pain

A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (μ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty

Neil Singla, Harold S Minkowitz, David G Soergel, David A Burt, Ruth Ann Subach, Monica Y Salamea, Michael J Fossler, and Franck Skobieranda. J Pain Res. 2017; 10: 2413–2424

Oliceridine (TRV130) Phase 2 trial in hard-tissue (bunionectomy) acute pain

A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain.

Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F. Pain. 2016 Jan;157(1):264-72.

TRV130 – analgesia and ventilatory response to hypercapnia vs. morphine in healthy volunteers

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

Soergel DG, Subach RA, Burnham N, et al. Pain. 2014;155(9):1829-1835. doi:10.1016/j.pain.2014.06.011

TRV130- First clinical experience, pharmacokinetics and pharmacodynamics

First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers

Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan CL, Violin JD, Lark MW. J Clin Pharmacol. 2014 Mar;54(3):351-7.

TRV130-Concept of biased ligand

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

Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS. J Med Chem. 2013 Oct 24;56(20):8019-31.

TRV-130 preclinical safety results

A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine

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. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.

Postoperative Vomiting with IV Oliceridine in Postoperative Recovery: a Single-group Prospective Cohort Study

Authors: Mark A. Demitrack MD¹, Nataya Disher BS², Linda Wase MD¹, Karen Heart¹, Jessica Kim¹, Julio Garcia BS2¹,, Sydney Ward BS², Jaclyn Eberting BS², Sabry Ayad MD³, Ashish K Khanna MD, MS²

¹ Trevena, Inc., ²Wake Forest, ³Cleveland Clinic, Fairview

ARTEMIS, A Real-World Evidence Trial Examining the Use of Oliceridine, a Biased Agonist at the μ(Mu) Receptor, in Patients Requiring Post-Surgical Pain Control

Annie N. Simpson, PhD¹, Kit N. Simpson, DrPH¹, Todd L. Wandstrat, PharmD², Mark A. Demitrack, MD², Amit Saha, PhD³, Doug Jaffe, MD4, Nataya S Disher, BS⁴, Ashish K Khanna, MD⁴

¹ Medical University of South Carolina, ² Trevena Inc, Chesterbrook, PA, USA, ³ Wake Forest University, Baptist Medical Center, ⁴ Wake Forest University School of Medicine

Antinociception versus neurocognitive effect of biased mu-opioid receptor oliceridine versus morphine – utility function analyses

Albert Dahan¹, Erik Olofsen¹, Laurence Moss², Hemme Hijma², Jessica Kim³, Mark A. Demitrack³ 

¹ Anesthesiology, Leiden University Medical Center, Leiden, Netherlands, ² Centre for Human Drug Research, Leiden, Netherlands, ³ Trevena Inc, Chesterbrook, PA, USA

Gastrointestinal Adverse Effects Associated with the Use of Intravenous Oliceridine Compared to Intravenous

Hydromorphone or Fentanyl in Acute Pain Management Utilizing Indirect Treatment Comparison Methods

Joseph Biskupiak, PhD, MBA1, Gary Oderda, PharmD, MPH1, Diana Brixner, PhD, RPh1, Todd L. Wandstrat, PharmD, RPh2

ASHP Mid-Year Conference  December 2022

Oliceridine demonstrates a reduced effect on neurocognitive function in humans, compared to morphine: A Phase 1, randomized, placebo-controlled, dose-ranging, partial block, cross-over study

Mark A. Demitrack, Michael S. Kramer, Cathy Michalsky, Hemme Hijma, Laurence Moss, Geert Jan Groeneveld; Trevena, Inc., Chesterbrook, PA, Centre for Human Drug Research, Leiden, Netherlands

American College of Neuropsychopharmacology (ACNP) Annual Meeting  December 2022

Low Incidence of Events with Oliceridine in Patients Predicted at High Risk for Developing Opioid-Induced Respiratory Depression

Ashish K. Khanna, Cathy Michalsky, Kanaka Sridharan, Erik DeBoer, Sabry Ayad

ASRA  Pain Medicine, Spring Meeting, 2022

Potential for Reduced Postoperative Ileus with Use of Oliceridine, An IV Opioid Analgesic, In Colorectal Surgery

Timothy L. Beard, Cathy Michalsky, Kanaka Sridharan, Erik DeBoer, Suzanne Griffith, Paul Rider

ASCRS, 2022

Safety of Intravenous Oliceridine in Patients with Renal Impairment: Findings from a Phase 3 Open-label Study

Ashraf S. Habib, Timothy L. Beard, Cathy Michalsky, Kanaka Sridharan, Linda Wase, Mark Demitrack, Joseph F. Answine

ANESTHESIOLOGY® 2021

Elevated Body Mass Index Does Not Affect Adverse Events Associated with Oliceridine, An Intravenous Opioid Agonist

Joseph F. Answine, Timothy L. Beard, Cathy Michalsky, Kanaka Sridharan, Linda Wase, Mark Demitrack, Ashraf S. Habib

ANESTHESIOLOGY® 2021

Low Incidence of Opioid-Induced Respiratory Depression Observed with Oliceridine In High-Risk Elderly Obese Patients

Chen Joy, Kiana Nouri, Cathy Michalsky, Linda Wase, Jasleen Kukreja, Marek Brzezinski 

Regional Anesthesiology and Acute Pain Medicine (ASRA); 2021

Cost Effectiveness Analysis of Oliceridine Compared with Morphine in The Management of Postoperative Moderate to Severe Acute Pain in a High-Risk Population

Kit N Simpson, Linda Wase, Michael J Fossler, Mark A Demitrack

AMCP; 2021

Budget Impact Analysis for Oliceridine in the Management of Moderate to Severe Acute Postoperative Pain

Kit N Simpson, Linda Wase, Michael J Fossler, Mark A Demitrack

AMCP; 2021

Reduced Incidence of Postoperative Vomiting with Oliceridine than with Morphine at Equianalgesic Conditions

Timothy L Beard, Cathy Michalsky, Keith A Candiotti, Paul Rider, Linda Wase, Ashraf S Habib, Mark A Demitrack, Michael J Fossler, Eugene R Viscusi

Annual Meeting of the American Society of Anesthesiologists (ASA); 2020

Evaluating Predictive Value of Postoperative O2 Saturation Levels to Rate of Respiratory Safety Events In Oliceridine Trials

Sabry Ayad, Ashish K Khanna, Cathy Michalsky, Linda Wase, Mark A Demitrack, Michael J Fossler, Kit N Simpson

Annual Meeting of the American Society of Anesthesiologists (ASA); 2020

Improved Tolerability with Oliceridine Compared to Morphine at Equianalgesic Conditions

Gregory B Hammer, Cathy Michalsky, Linda Wase, Mark A Demitrack, Roderick Little, Sabry Ayad, Ashish K Khanna, Michael J Fossler

Annual Meeting of the American Society of Anesthesiologists (ASA); 2020

Improved Safety of Opioid Analgesic Oliceridine Compared to Morphine Assessed by Utility Function Analysis

Albert Dahan, Marieke Niesters, Michael J. Fossler, Mark A. Demitrack, Erik Olofsen.

Annual Meeting of the American Society of Anesthesiologists (ASA); 2019

TRV045, a novel, selective SIP receptor subtype-1 modulator that does not cause lymphopenia is efficacious in acute and chronic rodent epilepsy models

Michael S. Kramer, Ruihua Chen, Mark A. Demitrack 

American College of Neuropsychopharmacology (ACNP) Annual Meeting  December 2022

TRV045, a novel, selective S1PR1 modulator, is efficacious in reversing neuropathic pain without affecting lymphocyte trafficking

Michael S. Kramer, Stefania Risso, Michael J.Fossler, Mark A. Demitrack.

American College of Neuropsychopharmacology 59th Annual Meeting; 2020

TRV045, a novel, selective S1P1 receptor modulator that is not an immunosuppressant, is efficacious in rodent models of epilepsy

Stefania Risso, Michael S. Kramer, Michael J.Fossler, Mark A. Demitrack

American College of Neuropsychopharmacology 59^th Annual Meeting; 2020

Biased ligands at G-protein-coupled receptors: promise and progress

Violin JD, Crombie AL, Soergel DG, Lark MW. Trends Pharmacol Sci. 2014 Jul;35(7):308-16.

Signalling bias in new drug discovery: detection, quantification and therapeutic impact

Kenakin T, Christopoulos A. Nat Rev Drug Discov. 2013 Mar;12(3):205-16.

Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy

Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18488-93.

Structural features for functional selectivity at serotonin receptors

Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC. Science. 2013 May 3;340(6132):615-9.

Quantifying ligand bias at seven-transmembrane receptors

Rajagopal S, Ahn S, Rominger DH, Gowen-MacDonald W, Lam CM, Dewire SM, Violin JD, Lefkowitz RJ. Mol Pharmacol. 2011 Sep;80(3):367-77.

Beta-arrestin-biased ligands at seven-transmembrane receptors

Violin JD, Lefkowitz RJ. Trends Pharmacol Sci. 2007 Aug;28(8):416-22.

Beta-arrestins and cell signaling

DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Annu Rev Physiol. 2007;69:483-510.

Biased ligands: pathway validation for novel GPCR therapeutics

Rominger DH, Cowan CL, Gowen-MacDonald W, Violin JD. Curr Opin Pharmacol. 2014 Jun;16:108-15

A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the μ-Opioid Receptor

James IE, Skobieranda F, Soergel DG, Ramos KA, Ruff D, Fossler MJ. Clin Pharmacol Drug Dev. 2019 Jul 8.

Formulation and Food Effect Studies of TRV734, an Oral, G Protein-biased Ligand of the μ-opioid Receptor

Franck Skobieranda, Ian E. James, Michael J. Fossler, Gregory Alcorn, David G. Soergel.

An orally available µ-opioid receptor biased ligand is analgesic with reduced constipation in rodents

Jonathan D. Violin, Scott M. DeWire, Mike Koblish, Daniel Chen, Aimee L. Crombie, Dennis Yamashita, Ruth Ann Subach, David G. Soergel, Michael W. Lark.

TRV250 – Phase 1 Study in Healthy Volunteers

A Phase I, Randomized, Single Blind, Placebo Controlled, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous and Oral TRV250, a G Protein-Selective Delta Receptor Agonist, in Healthy Subjects.

Fossler MJ, Schmith V, Greene SA, et al. CNS Drugs. 2020;34(8):853-865. doi:10.1007/s40263-020-00738-0

A Phase 1 Healthy Volunteer Study of the Safety, Tolerability and Pharmacokinetics of TRV250, a G Protein-Selective Delta Receptor Agonist

Mark A. Demitrack, Michael S. Kramer, Kelly Arscott, Ian E. James, Michael J.Fossler.

β-Arrestin-Biased Angiotensin II Receptor Agonists for COVID-19

Manglik A, Wingler LM, Rockman HA, Lefkowitz RJ. Circulation. 15 May 2020.