Journal of Marine Medical Society

: 2022  |  Volume : 24  |  Issue : 3  |  Page : 90--96

Journey of Oliceridine: A Novel Opioid

A Tejus1, Sharmila Sinha2, Prafull Mohan3, AG Mathur2,  
1 Department of Pharmacology, HQ IMTRAT, C/O 99 APO, Pune, Maharashtra, India
2 Department of Pharmacology, AFMC, Pune, Maharashtra, India
3 Commandant, 174 MH C/O 56 APO, Pune, Maharashtra, India

Correspondence Address:
Col (Dr) Sharmila Sinha
Department of Pharmacology, AFMC, Pune, Maharashtra


Opioid analgesics play a crucial role in the management of acute pain, but its use is often limited by various adverse effects, especially nausea, vomiting, and respiratory depression. There has always been an attempt to develop analgesics that are equi-efficacious to opioids but carry less risk of respiratory depression. Oliceridine has been the first among such biased/selective molecules approved by the United States Food and Drug Administration. Oliceridine is proposed to act selectively on mu-opioid receptors producing analgesia but does not propagate β-arrestin mediated mechanism postulated to be responsible for respiratory depression of other opioids, especially morphine. Oliceridine has favorable pharmacokinetics for intravenous administration and no significant drug interactions have been proposed.

How to cite this article:
Tejus A, Sinha S, Mohan P, Mathur A G. Journey of Oliceridine: A Novel Opioid.J Mar Med Soc 2022;24:90-96

How to cite this URL:
Tejus A, Sinha S, Mohan P, Mathur A G. Journey of Oliceridine: A Novel Opioid. J Mar Med Soc [serial online] 2022 [cited 2022 Dec 1 ];24:90-96
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 Introduction: Problem of Pain

Pain is defined by the International Association for Study of Pain as a sensory experience that is unpleasant, is associated with actual tissue damage or has the potential to cause the same, or is described in terms of the damage caused.[1] Pain can be of different types based on pathophysiology (nociceptive, neuropathic, or mixed), duration (acute, chronic, and breakthrough pain), etiology (cancer pain/chronic noncancer pain), and location (low back pain, headaches, referred pain, and neck and shoulder pain).[1],[2],[3]

Acute pain is a common feature in tissue injury associated with surgery, trauma, and postoperative patients. It also serves a protective function by restricting the movement of the injured part. Any pain lasting for >3 months is considered as chronic pain. The acute pain reappearing in a treated individual spontaneously or due to weaning off of the drug effect is considered as breakthrough pain (e.g.: cancer pain).[1] However, being noxious stimuli, it needs to be treated and there are a number of treatment modalities, both pharmacological and nonpharmacological, to treat pain. Opioid analgesics constitute the oldest and most efficacious pharmacological modality to treat pain, especially intractable pain.

 Problem with Opioids

Pain has the dual distinction of being one of the most common presenting symptoms and of being the most undermanaged as well. Frequently, multimodal pain management strategy is required to foster early recovery while minimizing adverse effects.[4],[5],[6]

Opioid analgesics in pain management are often seen as a double-edged sword, as although they improve pain but are associated with various dose-limiting adverse effects such as respiratory depression, nausea, vomiting, ileus, and on long-term use produce other disabling adverse effects such as constipation, neurotoxicity, and dependence.[6]

Studies suggest that almost 68% of the overdose-related deaths due to drugs in the United States involve an opioid medication.[7] The on-going epidemic of opioid abuse and ready availability of nonopioid options has given rise to a rethink on step ladder analgesic guidelines. This has resulted in opioids no longer being the first line of management for chronic pain but is still often utilized for managing acute pain.[6] Intravenous (IV) opioids (morphine and fentanyl) play a vital role in the management of postoperative pain and in the emergency department but are limited by their dose-limited adverse effects.[7] A new opioid “ Oliceridine” is a novel opioid which is first to be approved in the past 10 years by the US FDA which is likely to address some of the concerns associated with opioids as a class.[8]

Opioid receptors and oliceridine

Opioid receptors are classified by the International Union of Pharmacology as OP1/delta receptor (named after the tissue from which it was isolated vas deferens), OP2/kappa receptor (named after ketocyclazocine - its first ligand), OP3/mu receptor (named after morphine recognized as an exogenous ligand), and the latest of all the nociceptin receptor. All are G-protein-coupled receptors (GPCR) which produce a wide range of actions on their activation [Figure 1]. The exogenous ligands for these receptors include naturally occurring opioids (morphine, codeine, and thebaine), semisynthetic compounds (diamorphine/heroin, dihydromorphine, oxycodone, and buprenorphine), and synthetic compounds (fentanyl, remifentanil, alfentanil, methadone, and tapentadol).[9],[10]{Figure 1}

Opioid analgesics are known to cause analgesia using abovementioned GPCR mechanism, but the adverse effects associated with opioids, especially respiratory depression is mediated through β-arrestin signaling mechanism [Figure 2]. To tap into analgesic response avoiding adverse effects, biased/selective ligands acting through GPCR with minimal or no activation of β-arrestin signaling have been investigated. Normally β arrestin anchors to Transmembrane 6 (TM6) loop (intracellular loop 3 or cytosolic portion) of mu opioid receptors (MOR), but oliceridine, an agonist at MOR, acts by binding to Transmembrane™ loop 2 and 3 of MORs leading to reposition of TM6, thereby hindering binding of β arrestin to phosphorylated MORs.[9],[10],[11] Coupled with existing knowledge regarding the importance of β-arrestin pathway, oliceridine was an intuitively exciting idea.{Figure 2}

 Development of Oliceridine

There was always a search for a safer and better opioid analgesic for pain management. Studies using β-arrestin 2 gene knockout mice demonstrated that in these animals analgesic effect of morphine (using tail flick and hot plate test) was potentiated, prolonged, associated with no tolerance, reversed with naloxone, and no changes in naloxone binding in the brain.[12],[13] Studies also suggested that β-arrestin 2 gene knockout mice had less risk of constipation and respiratory depression demonstrated with whole-body plethysmography. However, the mouse models with deleted GPCR kinase-3, 4 5, and 6 did not demonstrate enhanced antinociceptin activity [Table 1]. This became the basis for identifying biased/selective opioids that act on MORs without activating β-arrestin pathway to enhance the analgesic activity but limiting its other adverse effects.[12],[13],[14]{Table 1}

TRV130 (Oliceridine) chemically N-[(3-methoxythiophen-2-yl) methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl] ethanamine), though structurally unrelated to morphine, but in cell-based assay acted as a strong MOR agonist with selective binding on MOR, weak recruitment of β-arrestin-2, reduced internalization of MORs, and less phosphorylation of MOR in comparison to morphine. The other ligands 7-hydroxy mitragynine and PZM21 although at lower dose acts as biased/selective agonist at MOR but at higher doses failed to produce similar effects.[15]

 Preclinical Development of Oliceridine

Oliceridine in rodent models (β-arrestin2 gene knockout mice) produced equivalent analgesia to morphine but less development of tolerance and respiratory depression.[15] Altarifi et al.[16] in their study compared the acute and repeated dose effects of oliceridine (10 mg/kg) subcutaneous (SC) injections on antinociception (tail withdrawal test using warm water), functioning of gastrointestinal (GI) tract (invivo using fecal output, in vitro using the propulsion of the colon, contraction of circular muscles of the colon and ileum) in mice, and abuse-related effects (intracranial self-stimulation procedure) in rats compared to vehicle and morphine (50 mg/kg SC injections). Oliceridine produced antinociception which was robust and in line with earlier performed studies.[16],[17],[18] GI function was completely inhibited and had a weak abuse-related effect in comparison to morphine. Repeated administration of oliceridine failed to produce tolerance to GI function/antinociception but showed enhanced abuse-related effects in comparison to morphine.[16]

Liang et al.[19] in their study observed a 4 fold more potent analgesic activity of oliceridine during tail-flick assay in comparison to morphine in mice. The administration of ascending dose of oliceridine over 4 days produced less tolerance compared to morphine. At analgesic doses reward behavior observed with morphine using conditioned place preference assay was not seen with oliceridine, but this difference was lost at higher doses highlighting the fact that physical dependence is not dependent on β-arrestin pathway. On administration for 7 days postfracture of the tibia and pinning in mice, oliceridine reduced impairment of gait and sensitization of nociception in comparison to morphine, thereby leading to the conclusion that oliceridine could reduce opioid maladaptations and enhance the quality of surgery recovery. Morphine induced enhanced expression of toll-like receptor 4 in tissues of lumbar spinal cord 3 weeks postfracture tibia in mice postulated to play a vital role in pain was not seen with oliceridine.[19] Other preclinical studies performed did not demonstrate significant cardiac adverse effects (QTc prolongation, arrhythmias) and definitive mutagenicity.[20]

 Clinical Development

Oliceridine clinical development started with human studies in 2014.[21] The summary of phase I to III studies conducted has been summarized [Table 2].[22],[23],[24],[25],[26],[27],[28],[29],[30] Following successful trials, a new drug application (NDA) was filed with US-FDA in November 2017 but was not granted by the US-FDA, requesting developers to furnish additional cardiac safety data (QTc data). A fresh NDA was filed in February 2020 with requisite data, leading to its approval by the US-FDA on August 10, 2020.[20]{Table 2}


Oliceridine has a very low oral bioavailability of 5.77%, hence it is administered IV to achieve good bioavailability. On IV administration onset of action is seen in 1–2 min with maximum concentration (Cmax) and area under the curve reached in plasma increasing proportionately to the dose and a half-life of 1.5–3 h with almost 77% bound to plasma proteins. It is metabolized in the liver by oxidation using cytochrome (CYP) 3A4 and CYP2D6 (equally) followed by glucuronide conjugation producing inactive metabolites TRV0109662 and M22. Metabolites are excreted predominantly in urine (70%) with rest excreted in feces. Hepatic impairment tends to increase the volume of distribution and half-life necessitating lower initial dose and fewer doses, but no dose adjustment is needed in renal and mild-moderate hepatic impairment.[20],[21]

 Adverse Effects

The most common adverse events noted across phase III trials include nausea, vomiting (most common), headache, dizziness, constipation, pruritis, hypoxia, somnolence, sedation, hot flushes, back pain, anxiety, hyperhidrosis, dry mouth, and reduced oxygen saturation (least common).[20]

 Drug Interaction

No clinically significant drug interactions have been demonstrated for oliceridine or its metabolites. Oliceridine does not inhibit its own metabolism but metabolic enzyme inhibitors, especially, can reduce its clearance by up to 44%. Hence, coadministration with inhibitors of CYP2D6 (fluoxetine, paroxetine, quinidine, etc.) and CYP3A4 (clarithromycin, itraconazole, indinavir) warrants precaution, but no dose adjustments are required.[20]

 Current Status

Oliceridine has been currently approved for the management of acute pain in adults needing management with IV opioids with inadequate alternative treatment [Figure 3]. Being an opioid with dependence-producing liability, oliceridine will be covered under the schedule of controlled substances. As the development of oliceridine is based on the reduction of adverse effects seen with conventional opioids, a robust periodic safety update report and pharmacovigilance are the need of the hour as the new drug enters the market. Further phase 4 trials would bring out the real difference between oliceridine and conventional opioids with respect to adverse effects. The commercial production of the same expected to begin at the earliest and currently no data on the cost of the product is available to compare with others.[20],[21],[22],[23],[24]{Figure 3}

Although the clinical trials have not thrown up any major drug interactions, there is likelihood of CYP2D6 mediated interactions. Hence, the evidence regarding its use in real-world settings may change this aspect.


The goal of any pain management protocol must be to provide optimal analgesia, thereby providing comfort to suffering individual and also facilitate the patient's functional recovery. As patients of acute pain (especially postoperative) need an IV opioid, providing optimal pain management is challenging in them as there has been no significant advance in the field of opioids over decades. Oliceridine being a biased ligand promises to provide analgesic efficacy similar to morphine but with additional safety profile. Although it promises safety, its success clinically will depend on its cost-effectiveness and it must be never be forgotten that its abuse potential is similar to morphine. Oliceridine and similar molecules must herald a new chapter in pain management lessening the suffering of patients of acute pain.


Declaration of AFMRC Project: This paper is not based on Armed Forces Medical Research Committee Project.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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