What evidence supports the use of oliceridine for severe pain?

Background

Oliceridine (Olinvyk), a new opioid receptor agonist, was approved in the United States on August 7^th, 2020 for the treatment of uncontrolled severe pain that requires an intravenous opioid.¹ Due in part to the risk of addiction and misuse with opioids, oliceridine was approved with restrictions to be used when pain cannot be controlled with alternative treatments along with use within a hospital or a controlled setting. In the context of the opioid crisis, the unique mechanism of oliceridine was proposed to potentially have less risk for addiction and misuse.² However, this proposal remains controversial.³ The purpose of this review is to discuss this agent in detail and provide existing evidence for the use of this medication to help clinicians decide when and how to use this medication.

Pharmacodynamics and pharmacokinetics

The analgesic effect of opioids is mediated by the activation of the µ-opioid receptor (MOR). Binding of an agonist at the extracellular site of the receptor can result in activation of the G protein signaling pathway, as well as the β-arrestin signaling pathway.⁴ Traditional opioids non-selectively activate both the G protein and β-arrestin pathways. While the G-protein signaling pathway is responsible for most of the analgesic effect, the β-arrestin signaling pathway has been found to be associated with the adverse effects and tolerance of opioids. It is also proposed to be involved in the rewarding mechanism of opioids, which can lead to opioid abuse. Oliceridine is a G-protein-biased MOR agonist that activates the G-protein signaling pathway but has a significantly less effect on the β-arrestin signaling pathway. Therefore, oliceridine was presumed during clinical development to have less unfavorable adverse effects such as respiratory depression and less risk of abuse, while keeping its analgesic effect, compared to other opioids.

Oliceridine has extensive tissue distribution with a volume of distribution of 90 to 120 L.⁵ It undergoes extensive hepatic metabolism primarily by cytochrome P450 (CYP)3A4 and CYP2D6 into inactive metabolites. The metabolites are then excreted in the urine. Only 0.97% to 6.75% of a dose is excreted in the urine as unchanged drug. The onset of effect is around 2 to 5 minutes.

Dosage and administration

Oliceridine is administered intravenously with a single dose of up to 3 mg and a cumulative maximum daily dose of 27 mg.⁵ It has to be given in a controlled environment by a healthcare provider and is intended to be administered through a patient-controlled analgesia (PCA) pump. The recommended initial dose is 1.5 mg for a single use and 0.35 mg as the initial demand dose for PCA use. Oliceridine should be subsequently titrated based on each individual’s response. Since oliceridine is extensively metabolized by the liver, a lower initial dose should be considered in patients with severe hepatic impairment.^5,6 The clearance of oliceridine was not changed in patients with end-stage renal disease or mild to moderate hepatic impairment, therefore, no dosage adjustment is needed for patients with renal impairment or patients with mild to moderate hepatic impairment (though the latter population may require less frequent dosing). Since oliceridine is metabolized through CYP3A4 and CYP2D6, less frequent dosing may be warranted when used concomitantly with moderate and strong CYP3A4 and/or CYP2D6 inhibitors such as azole antifungal medications and some antidepressants, and dose increases may be needed when used with CYP3A4 and/or CYP2D6 inducers.⁵ Similar to other opioid medications, oliceridine carries the risk of profound sedation, respiratory depression, coma, and death when used with benzodiazepines or other central nervous system depressants.

Literature review

Two phase 3 double-blind randomized controlled trials have been completed comparing oliceridine to placebo and morphine in patients undergoing either first-metatarsal bunionectomy with osteotomy and internal fixation (APOLLO-1) or abdominoplasty procedure (APOLLO-2) with moderate to severe pain post-surgery.^7,8 Additionally, an open-label phase 3 safety trial (ATHENA) has been completed.⁹ Oliceridine was used for 48 hours in APOLLO-1 and 24 hours in APOLLO-2.^7,8 Other analgesic therapies were allowed immediately after the procedures but only etodolac 200 mg as rescue analgesia was allowed once study medications were started. Prophylactic antiemetics and supplemental oxygen were not allowed as they may mask adverse effects of oliceridine. The primary endpoint compared the percentage of responders to oliceridine versus placebo. Responders were defined as patients who had at least a 30% improvement in pain intensity difference from baseline, did not require rescue pain medication, did not discontinue the study medication early, and did not reach pre-specified dosing limits. For the analysis, a stepwise approach was used in evaluating endpoints (subsequent outcomes were not analyzed if a non-significant difference was found). Following analysis of the primary endpoint, the impact of oliceridine on respiratory safety burden (RSB), defined as the mathematical product of the incidence of a defined set of observed respiratory safety events multiplied by the mean expected cumulative duration of these events (in hours), was compared to morphine before proceeding to the rest of the efficacy analysis.

Both studies showed that patients receiving oliceridine regimens had a higher response rate compared to patients receiving placebo, with the oliceridine 0.35 mg and 0.5 mg regimens resulting in a higher response rate compared to the 0.1 mg regimen.^7,8 All regimens were significantly different than placebo with a p<0.05. Both studies failed to show a difference in RSB between oliceridine and morphine, therefore, no formal analyses were done to compare the efficacy endpoints between oliceridine and morphine based on their hierarchical statistical analysis plan. In APOLLO-1 and 2, exploratory analysis indicated that oliceridine 0.35 mg and 0.5 mg regimens were comparable to morphine. The effect of pain relief with oliceridine 0.35 mg and 0.5 mg was comparable with morphine as assessed by the proportion of patients that were treatment responders over the full treatment period, the number of patients who discontinued treatment owing to lack of efficacy, the number of patients who used rescue medications, and the median time to pain relief. The oliceridine 0.1 mg regimen showed less efficacy in both studies compared to higher doses. In APOLLO-2, more patients in the oliceridine 0.35 and 0.5 mg regimen groups had response within the first hour of treatment (p<0.05) versus morphine.⁸ Patients receiving oliceridine 0.35 mg regimen also had a significantly shorter time to a 1-point numerical rating scale (NRS) score improvement versus patients in the morphine group. Similar results were found in APOLLO-1 where oliceridine was associated with a faster onset in the first 30 minutes after the treatment and shorter time to reach 2-point or 3-point of NRS score improvement compared to morphine.⁷

As for safety outcomes, oliceridine failed to show a superior RSB as compared to morphine.^7,8 Generally, the impact of oliceridine on respiratory function was dose related. In APOLLO-1 and 2, the respiratory safety event number with the oliceridine 0.1 mg regimen was comparable to placebo and significantly less than morphine, while the higher oliceridine doses were not significantly different from morphine. Across all 3 trials, most patients receiving oliceridine had mild to moderate adverse events.^7-9 Severe adverse events were observed in 2% of patients in the open-label ATHENA trial, which specifically evaluated the safety profile of oliceridine.⁹ In that trial, the most frequent adverse events were nausea (31%), constipation (11%) and vomiting (10%). No patient specific factors, such as age and obesity, were shown to affect the incidence of adverse effects. Three percent of patients reported moderate withdrawal symptoms and less than 1% of patients reported severe withdrawal symptoms. Oxygen desaturation was associated with higher doses.

Discussion

Oliceridine, a biased G-protein MOR agonist, was designed with the intention to reduce the adverse effects as well as the abuse potential of opioids while keeping the analgesic effect.¹⁰ Animal experiments have shown that β-arrestin may be associated with the adverse effects as well as tolerance to morphine.⁴ With the discovery that G-protein biased agonism is separate from the β-arrestin signaling pathway and the effects of these 2 pathways are different, drugs were developed to selectively activate the G-protein pathway to minimize the unwanted effects caused by the activation of β-arrestin signaling pathway. Oliceridine was one of the agents that was found to have more effect on G-protein signaling pathway versus β-arrestin pathway. However, initial clinical trials with oliceridine have not demonstrated a greatly improved safety profile compared to traditional opioids.

Although oliceridine has a quick onset of action for pain relief and was shown to be more effective than placebo in clinical trials, there was no significant difference found with RSB compared to morphine.^7,8 The trials showed that oliceridine had comparable analgesic effects with morphine when used with a minimum loading dose of 1.5 mg followed by at least 0.35 mg as a demand dose via PCA (0.35 mg regimen). However, respiratory depression, the most concerning adverse effect with opioids was also similar to morphine at this effective dose. Other adverse effects, including gastrointestinal effects, were potentially lower with the 0.35 mg regimen but increased with the 0.5 mg regimen, displaying a dose-dependent effect.

Oliceridine showed a fast onset with an amplitude of pain relief similar to morphine at the end of the treatment period.^7,8 The presumed avoidance of tolerance was unable to be evaluated due to the short study period in these 2 studies (48 hours in APOLLO-1 and 24 hours in APOLLO-2). As oliceridine is only approved to be used for acute pain and for a short period of time, it may be less likely that patients will develop tolerance with oliceridine in real-world practice. Patients included in the APOLLO trials were all surgical patients with post-operative pain and in ATHENA, 94% were surgical patients, so it is unknown if these results can be extrapolated to patients suffering non-surgical acute pain.^7-9

In the setting of the opioid crisis, the introduction of a G-protein-biased MOR agonist was thought to lead to new opioids with a more favorable safety profile. However, current evidence from phase 3 trials have not shown that oliceridine has a superior safety profile compared to traditional opioids.^7,8 Animal studies also have shown that oliceridine has comparable abuse potential and potential of tolerance as compared with morphine and oxycodone.¹¹ The theory that β-arrestin signaling pathway is associated with tolerance and adverse events may need to be re-considered.

Conclusion

Oliceridine, when used at an effective dose, was comparable to morphine in phase 3 trials. It is approved to be used for a short period of time in patients with severe pain when alternative options are inadequate. However, the safety profile has not been shown to be superior to other opioids; therefore, all the precautions with other opioids remain with oliceridine.

References

1. FDA approves new opioid for intravenous use in hospitals, other controlled clinical settings. U.S. Food and Drug Administration. August 7, 2020. Accessed November 25, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-opioid-intravenous-use-hospitals-other-controlled-clinical-settings
2. Markham A. Oliceridine: first approval. Drugs. 2020;80(16):1739-1744. doi:10.1007/s40265-020-01414-9
3. Mullard A. FDA approves first GPCR biased agonist. Nature News. September 3, 2020. Accessed November 25, 2020. https://www.nature.com/articles/d41573-020-00159-0
4. Rankovic Z, Brust TF, Bohn LM. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett. 2016;26(2):241-250. doi:10.1016/j.bmcl.2015.12.024
5. Olinvyk. Package insert. Trevena, Inc; 2020.
6. Nafziger AN, Arscott KA, Cochrane K, Skobieranda F, Burt DA, Fossler MJ. The influence of renal or hepatic impairment on the pharmacokinetics, safety, and tolerability of oliceridine. Clin Pharmacol Drug Dev. 2020;9(5):639-650. doi:10.1002/cpdd.750
7. Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N. 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. J Pain Res. 2019;12:927-943. doi:10.2147/JPR.S171013
8. Singla NK, Skobieranda F, Soergel DG, et al. 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. Pain Pract. 2019;19(7):715-731. doi:10.1111/papr.12801
9. Bergese SD, Brzezinski M, Hammer GB, 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. J Pain Res. 2019;12:3113-3126. doi:10.2147/JPR.S217563
10. Volkow ND, Collins FS. The role of science in addressing the opioid crisis. N Engl J Med. 2017;377(4):391-394. doi:10.1056/NEJMsr1706626
11. Negus SS, Freeman KB. Abuse potential of biased mu opioid receptor agonists. Trends Pharmacol Sci. 2018;39(11):916-919. doi:10.1016/j.tips.2018.08.007

Prepared by:
Tracy (Xunjie) Zhang, PharmD
UIC PGY1 Pharmacy Practice Resident

December 2020

The information presented is current as 11/24/2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.