Oliceridine

Uses

Oliceridine is a biased opioid agonist indicated for the management of severe acute pain in adult patients. Through preferential activation of G-protein-coupled signalling pathways, oliceridine provides analgesic effect with a comparable or improved safety profile over conventional opioid agonists.

Oliceridine is indicated for the management of acute pain in adults severe enough to require intravenous opioid analgesics and for whom no acceptable alternative treatments exist.

Oliceridine is also used to associated treatment for these conditions: Severe Pain, Acute

How Oliceridine works

Pain perception follows a complex pathway initiated in primary sensory neurons, subsequently transmitted to the spinal cord dorsal horn and through ascending axons to multiple regions within the thalamus, brainstem, and midbrain, and finally relayed through descending signals that either inhibit or facilitate the nociceptive signalling. Opioid receptors are seven-transmembrane G-protein-coupled receptors (GPCRs) that can be divided into μ, κ, δ, and opioid-like-1 (ORL1) subtypes,. However, the μ-opioid receptor is predominantly targeted by and is responsible for the effects of traditional opioids. GPCRs in the inactive state are bound intracellularly by a complex consisting of a G_α, β, and γ subunit together with guanosine diphosphate (GDP). Activation of the GPCR through extracellular agonist binding catalyzes the replacement of GDP with guanosine triphosphate (GTP), dissociation of both G_α-GTP and a βγ heterodimer, and subsequent downstream effects.

In the case of the μ-opioid receptor, the G_α-GTP directly interacts with the potassium channel K_ir3 while the dissociated Gβγ subunit directly binds to and occludes the pore of P/Q-, N-, and L-type Ca^{2+ In addition to the G-protein pathway, μ-opioid receptor activation can also result in downstream signalling through β-arrestin, which results in receptor internalization and is associated with negative effects of opioid use including respiratory depression, gastrointestinal effects, and desensitization/tolerance.}

Oliceridine acts as a "biased agonist" at the μ-opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of β-arrestin. Competetive binding assays and structural modelling suggest that the binding site for oliceridine on the μ-opioid receptor is the same as for classical opioids. However, molecular modelling supports a model whereby oliceridine binding induces a different intracellular conformation of the μ-opioid receptor, specifically due to a lack of coupling with transmembrane helix six, which confers the specificity for G-protein over β-arrestin interaction. Numerous in vitro, in vivo, and clinical studies support the view that this biased agonism results in comparable analgesia compared with traditional opioids at a comparable or decreased risk of opioid-related adverse effects such as constipation and respiratory depression.

Toxicity

Symptoms of oliceridine overdose are variable but can include respiratory depression, airway obstruction, pulmonary edema, bradycardia, hypotension, muscle flaccidity, cold skin, and somnolence progressing to either stupor or coma. Miosis is commonly observed but in cases of severe hypoxia, mydriasis may be observed instead. Oliceridine overdose may be fatal. In case of overdose, the establishment of a protected airway followed by the institution of assisted or controlled ventilation is a high priority; in case of cardiac arrhythmias or arrest, additional supportive measures may be immediately required. Supportive treatment, including oxygen, vasopressors, and the administration of an opioid antagonist such as naloxone may be applied but should be tailored to the individual patient's condition.

Food Interaction

[Major] GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including oliceridine.

Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills.

In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentrations of oliceridine by inhibiting the CYP450 3A4-mediated metabolism of oliceridine, although the interaction has not been studied.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with oliceridine.

Any history of alcohol or illicit drug use should be considered when prescribing oliceridine, and therapy initiated at a lower dosage if necessary.

Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension.

Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with oliceridine should preferably avoid the consumption of grapefruit and grapefruit juice.

Oliceridine Disease Interaction

Major: impaired GI motility, acute alcohol intoxication, drug dependence, gastrointestinal obstruction, hypotension, intracranial pressure, respiratory depressionModerate: adrenal insufficiency, seizure disorders, urinary retention

Volume of Distribution

Oliceridine has a mean steady-state volume of distribution of 90-120 L.

Elimination Route

Oliceridine administered as a single intravenous injection of 1.5, 3, or 4.5 mg in healthy male volunteers had a corresponding C_max of 47, 76, and 119 ng/mL and a corresponding AUC_0-24 of 43, 82, and 122 ng*h/mL. Simulations of single doses of oliceridine between 1-3 mg suggest that the expected median C_max is between 43 and 130 ng/mL while the expected median AUC is between 22 and 70 ng*h/mL.

Half Life

Oliceridine has a half-life of 1.3-3 hours while its metabolites, none of which are known to be active, have a substantially longer half-life of 44 hours.

Clearance

Healthy volunteers given doses of oliceridine between 0.15 and 7 mg had mean clearance rates between 34 and 59.6 L/h.

Elimination Route

Approximately 70% of oliceridine is eliminated via the renal route, of which only 0.97-6.75% of an initial dose is recovered unchanged. The remaining 30% is eliminated in feces.

Innovators Monograph

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