Oliceridine (Olinvyk), a potent μ-opioid receptor agonist, received United States Food and Drug Administration (US-FDA) approval on 7 August 2020 for the management of moderate to severe acute pain in adults. [1]

Compared to conventional opioids such as morphine, oliceridine has a promising potential to offer comparable analgesia, and a wider therapeutic window at a comparable or decreased risk of opioid-related adverse effects (constipation and respiratory depression). [2,3]

Pharmacological Class:  μ-opioid receptor agonist

• Management of moderate to severe acute pain in adults, where the pain is severe enough to require an intravenous opioid analgesic and for whom no acceptable alternative treatments exist
• For short-term intravenous use in hospitals or other controlled clinical settings, such as during inpatient and outpatient procedures

Oliceridine is a G protein-selective agonist at the µ-opioid receptor. [3] It primarily activates the G-protein pathway with minimal receptor phosphorylation and recruitment of β-arrestin. [2] Its major therapeutic action is analgesia. However, the precise mechanism of its pain-relieving action is not clearly known.

Throughout the brain and spinal cord, specific central nervous system (CNS) opioid receptors for endogenous compounds with opioid-like activity have been detected that are thought to play a pivotal role in the analgesic effects of oliceridine.

Like other full opioid agonists, no ceiling effect to analgesia is seen for the opioid oliceridine. Clinically, the dosage is titrated to offer adequate pain relief and may be restricted by noxious reactions, including CNS and respiratory depression. [4]

Oliceridine should be used for intravenous administration only. [4] The maximum recommended daily dose limit of this μ-opioid receptor agonist is 27 milligrams. [1] Single doses higher than 3 mg should not be given as it has not been yet investigated. [4]

Absorption

The oral bioavailability of oliceridine is low (5.77%). The half-life of oliceridine is 1.3-3 hours while its metabolites have a substantially longer half-life (~44 hours). None of these metabolites have any significant activity at the µ-opioid receptor.

Distribution

The opioid oliceridine possesses an extensive tissue distribution since its mean steady-state volume of distribution ranges between 90-120 L. In humans, the plasma protein binding is found to be 77%.

Metabolism

In the liver, oliceridine is considerably metabolized by CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19 into inactive metabolites.

With increasing dose, the mean clearance of oliceridine declines slightly. Particularly at doses higher than 2 mg, a greater than- proportional exposure is developed.

Oliceridine possesses a low renal clearance (2.2 – 5.1% of total clearance) since the percent of unchanged drug eliminated via the urine is low (0.97-6.75% of the dose). Kidney impairment does not affect the clearance of oliceridine. Its pharmacokinetics does not alter significantly (except for peak concentrations) when given over different infusion times.

Excretion

Approximately 70% of oliceridine is eliminated in the urine. Elimination of the remaining 30 % occurs via the feces. In the urine, only a small amount of unchanged drug (0.97-6.75% of a dose) is found. 

Contraindicated in patients having the following conditions:

• Known hypersensitivity to oliceridine (e.g. anaphylaxis)
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Significant respiratory depression
• Known or suspected gastrointestinal obstruction, including paralytic ileus

• Benzodiazepines and Other Central Nervous System (CNS) Depressants  (Sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol):

Due to the additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants substantially raises the risk of hypotension, respiratory depression, profound sedation, coma, and death.

• Anticholinergic Drugs:

Concomitant usage of anticholinergics may enhance the risk of urinary retention and severe constipation. This may develop paralytic ileus in patients.

•  Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics (butorphanol, nalbuphine, pentazocine, buprenorphine)

Concomitant use may considerably minimize the analgesic effect of oliceridine and/or precipitate withdrawal symptoms.

• Diuretics

The opioid agonist can remarkably minimize the efficacy of diuretics by stimulating the release of antidiuretic hormone. 

•  Serotonergic Drugs (Selective serotonin reuptake inhibitors (SSRIs,) serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, and monoamine oxidase (MAO) inhibitors)

Concomitant usage of the opioid with other drugs that affect the serotonergic neurotransmitter system can substantially develop serotonin syndrome.

• Muscle Relaxants

The opioid may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an elevated degree of respiratory depression.

• Moderate to strong CYP3A4 inhibitors (Macrolide antibiotics [e.g., erythromycin], azole-antifungal agents [e.g. ketoconazole], protease inhibitors [e.g., ritonavir])

Concomitant administration of moderate to strong CYP3A4 inhibitors can raise the plasma concentration of oliceridine. This, in turn, leads to prolonged or elevated opioid adverse reactions.

• Moderate to strong CYP2D6 inhibitor (paroxetine, fluoxetine, quinidine, bupropion)

Concomitant administration of a moderate to strong CYP2D6 inhibitor can elevate the plasma concentration of oliceridine leading to increased or prolonged opioid effects.

• Strong and Moderate CYP3A4 Inhibitors and CYP2D6 Inhibitors

(Inhibitors of CYP3A4: Macrolide antibiotics [e.g., erythromycin], azole-antifungal agents [e.g., ketoconazole, itraconazole], antiretroviral agents, selective serotonin reuptake inhibitors [SSRIs], protease inhibitors [e.g., ritonavir], NS3/4A inhibitors, Inhibitors of CYP2D6: Paroxetine, fluoxetine, quinidine, bupropion).

Oliceridine is primarily metabolized by both CYP3A4 and CYP2D6. Suppression of both the pathways can potentially enhance the plasma concentrations of the opioid, and prolong its noxious reactions.

• Inducers of CYP3A4 (Rifampin, carbamazepine, phenytoin)

Concomitant use of oliceridine and CYP3A4 inducers can considerably reduce the plasma concentration of oliceridine. This reduces the efficacy or onset of a withdrawal syndrome in individuals who have developed physical dependence to the opioid agonist. 

The most common side effects are: [1, 4]

• Nausea
• Headache
• Vomiting
• Dizziness
• Hypoxia (low blood oxygen)
• Constipation
• Itching

Other adverse reactions that may occur: [4]

• Life-threatening respiratory depression
• Gastrointestinal adverse reactions
• Neonatal opioid withdrawal syndrome
• Severe hypotension
• Seizures
• Interactions with benzodiazepines or other CNS depressants
• Addiction, Abuse, and Misuse
• Withdrawal 
  

• Not for use in a take-home prescription
• Should not be given to patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Should be avoided in patients with known hypersensitivity to the drug
• Should not be given to patients with known or suspected gastrointestinal obstruction
• Should be used with caution in pregnant women as prolonged use of opioid analgesics during pregnancy can result in neonatal opioid withdrawal syndrome
  

Olinvyk (oliceridine) can treat moderate to severe acute pain in adults, where the pain is severe enough to require an intravenous opioid and for whom alternative treatments are not adequate.

Randomized, controlled and open-label trials were conducted to investigate the safety and efficacy of oliceridine in 1,535 patients who had undergone bunion surgery or abdominal surgery and had moderate to severe acute pain.  At the approved doses, patients managed with oliceridine therapy reported minimized pain in comparison to placebo. [1]

Intravenous oliceridine is safe and well-tolerated for the management of moderate to severe acute pain

A phase 3, open-label, multi-center study (ATHENA) was carried out to explore the safety and tolerability of intravenous oliceridine for managing moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions.

The findings reported a prompt reduction in NRS pain score was offered by oliceridine which was maintained till the end of treatment. No deaths or significant cardio respiratory events were witnessed. The incidence of adverse events leading to early discontinuation and serious adverse events were 2% and 3%, respectively. Nausea, constipation, and vomiting were the most common treatment-emergent adverse events (mild or moderate severity) and probably related to oliceridine in 33% of patients. [6]

1. https://www.fda.gov/news-events/press-announcements/fda-approves-new-opioid-intravenous-use-hospitals-other-controlled-clinical-settings [Last Accessed on: 27 August, 2020]
2. https://www.drugbank.ca/drugs/DB14881[Last Accessed on: 27 August, 2020]
3. Gan TJ, Wase L. Oliceridine, a G protein-selective ligand at the μ-opioid receptor, for the management of moderate to severe acute pain. Drugs of Today (Barcelona, Spain: 1998). 2020 Apr 1;56(4):269-86.
4. https://www.rxlist.com/olinvyk-drug.htm [Last Accessed on: 27 August, 2020]
5. https://www.fda.gov/media/121230/download [Last Accessed on: 27 August, 2020]
6. Bergese SD, Brzezinski M, Hammer GB, Beard TL, et al. 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. Journal of Pain Research. 2019;12:3113.