This article was updated November 23, 2020 to include all authors.

Opioid use in the United States has evolved significantly during a recognized opioid epidemic. Related morbidity and mortality, along with regulatory scrutiny, have led to fear of opioid prescribing among clinicians. Within this landscape, opioid stewardship programs in hospitals have become popular, particularly to reduce overall daily morphine equivalent doses, traditional opioid use, and total days of therapy.1 Moreover, pharmacists and physicians have favored the use of nonopioid adjuvants for preemptive analgesia, such as acetaminophen, nerve blocks, nonsteroidal anti-inflammatory drugs, and various sedative-hypnotics.2

The FDA approved oliceridine (Olinvyk), a novel centrally acting μ-opioid receptor agonist with reduced β-arrestin recruitment, on August 7, 2020, for managing moderate to severe acute pain in adults who require an intravenous (IV) opioid and for whom alternative treatment is inadequate.3 Oliceridine is a schedule II ethanamine opioid medication structurally different from natural (ie, morphine) and semisynthetic (ie, hydromorphone) opioids and other opioid classes. Conventional opioids activate the μ-opioid receptor, resulting in G protein–mediated analgesia. The receptor activation by established full agonist opioids also leads to recruitment of β-arrestin, which is associated with receptor downregulation and respiratory depression, constipation, and nausea, adverse effects (AEs) of opioids, though the latter 3 have been called into question.4

Compared with conventional opioids, oliceridine stimulates G protein signaling with profoundly less β-arrestin activation. The understood receptor activity of a G protein–biased μ-opioid receptor agonism with less β-arrestin recruitment allows this agent to provide analgesia while potentially mitigating the risks of respiratory depression and gastrointestinal (GI) AEs.5,6

Buprenorphine also stimulates the μ-opioid receptor with less β-arrestin recruitment compared with traditional opioids. However, it is more difficult to overcome receptor occupation by buprenorphine with naloxone reversal because the latter has a lower binding affinity compared with buprenorphine. Conversely, oliceridine has been shown be reversed handily by naloxone.5,7

Onset of action for oliceridine is 1 to 3 minutes, making it optimal for managing acute pain. Oliceridine has the same boxed warnings as other opioids, including risks of abuse, addiction, life-threatening respiratory depression, misuse, neonatal opioid withdrawal syndrome if abruptly discontinued, and profound sedation with concomitant use of central nervous system depressants. There is also a risk of QT interval prolongation in doses greater than 27 mg, though studies did not find significant QT interval changes at FDA-approved doses.8

Oliceridine is metabolized by cytochrome P450 (CYP) 2D6 and 3A4 to inactive metabolites, and renal dose adjustment is not required. Concomitant use of oliceridine and strong to moderate CYP2D6 (ie, fluoxetine) and CYP3A4 (ie, clarithromycin) inhibitors, along with discontinuation of CYP3A4 inducers, can result in increased plasma concentration of oliceridine, raising the risk of opioid-related AEs and exacerbated respiratory depression. Similarly, there is a greater risk of toxicity in patients expressing CYP2D6 poor metabolizer phenotypes.5,8 Of note, the effects of enzyme induction are delayed about 3 weeks; enzyme inhibition, about 48 hours.9 Additionally, this medication is intended for acute use in controlled settings, where patients are closely monitored, mitigating some of the risk.

Findings of pivotal trials indicated the efficacy and safety of oliceridine, ultimately leading to its FDA approval. The study results showed improved analgesia with oliceridine compared with the placebo and similar efficacy to morphine. Additionally, less potential for nausea and lower rates of respiratory risk were reported in the oliceridine group than with those receiving morphine. Notably, the trials also showed that AEs of oliceridine, though of less risk than morphine, are dose dependent. Doses greater than 27 mg/day were not evaluated. Oliceridine was not evaluated in several patient populations, including those who have sleep apnea, are obese, or were already receiving chronic opioid therapy; therefore, clinical judgment is required when considering use in these populations.10,11

The novel approach of limiting β-arrestin recruitment has been shown to limit GI and respiratory AEs.6 Oliceridine may be used in emergency department settings or after surgery in patients who require acute pain management. Overall, oliceridine offers an alternative for patients in hospitals or other controlled settings, with moderate to severe acute pain when nonpharmacological and nonopioid options are inappropriate.8 Pharmacists can help ensure the safe use of oliceridine by identifying and appropriately managing drug-drug interactions, particularly CYP medication issues and concomitant use of corrected QT interval–elevating drugs, such as fluoroquinolones. They can also present cost considerations and a risk-versus-benefit evaluation to the team.
Emily Uebbing, PharmD, is a PGY-1 pharmacy resident, and Himayapsill Batista Quevedo, PharmD is a PGY-2 pain and palliative care pharmacy resident, both at Albany Stratton VA Medical Center in New York. 

Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB, is CEO and founder of Remitigate Therapeutics, LLC, and the owner and managing editor of He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts; an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in New York; and the director of the PGY-2 pain and palliative care residency at Albany Stratton VA Medical Center.

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