Himayapsill Batista Quevedo, PharmD

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.

 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.

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.

 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.

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.

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.

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.

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.

 Of note, the effects of enzyme induction are delayed about 3 weeks; enzyme inhibition, about 48 hours.

 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.

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.

 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.

, 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 paindr.com. 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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Articles

Oliceridine (Olinvyk) expands options for managing moderate to severe acute pain, but cost, drug-drug interactions, and other factors come into play.

Pharmacists Can Help Assess New FDA-Approved IV Opioid

The introduction of peripherally acting μ-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation brought opportunity for improved health and quality of life for patients on long-term opioid therapy.

Constipation is a bothersome, common, and underrecognized adverse effect (AE) of long-term opioid therapy. PAMORAs offer treatment for this condition and can improve patient adherence to the prescribed opioid therapy. However, it is crucial to understand the pharmacokinetic differences between the PAMORAs to aid in AE monitoring and minimize potentially strong drug-drug interactions (DDIs).

The 3 PAMORAs on the US market indicated for treating opioid-induced constipation from long-term opioid use are methylnaltrexone, naldemedine, and naloxegol. Each agent is available as oral tablets, and methylnaltrexone is also available as a subcutaneous injection. PAMORAs work by inhibiting the action of opioids in the gastrointestinal tract by combining with μ-receptors, thereby decreasing the constipating effects of opioids without compromising the analgesic effects in the central nervous system. These medications do not interfere with analgesia or cause opioid withdrawal, as they cannot cross the blood-brain barrier (BBB), because of their increased efflux across the BBB, large chemical structure, lipid solubility, and/or reduced permeability.

 Despite their overlapping mechanisms of action, the 3 PAMORAs differ in their pharmacokinetic properties. These properties can be harnessed based on a patient’s concomitant medications to help mitigate the risk of clinically relevant DDIs. The article “Peripheral Opioid Receptor Antagonists for Opioid-Induced Constipation: A Primer on Pharmacokinetic Variabilities with a Focus on Drug Interactions,” evaluates the subtle pharmacokinetic differences among these PAMORAs.

PAMORA DDIs may occur when a drug alters the absorption, distribution, metabolism, or elimination of another drug,

 such as with cytochrome P450 enzymes and P-glycoprotein (P-gp), the latter of which has significance within the gut and passage through the BBB. Evaluating each PAMORA’s unique profile can assist clinicians in selecting the optimal therapy for their patients, especially those with polypharmacy.

Study results have shown that methylnaltrexone does not significantly inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4 enzymes. Methylnaltrexone is metabolized by CYP2D6 to a small extent. However, this has no relevance nor is it affected by drug interactions. In healthy volunteers, methylnaltrexone did not affect the metabolism of dextromethorphan, a CYP2D6 substrate. Cimetidine is a moderate CYP3A4 inhibitor, and in healthy adults, cimetidine did not cause a clinically significant increase in the systemic exposure of methylnaltrexone.

 Therefore, methylnaltrexone’s pharmacokinetic profile is not affected by DDIs in a clinically significant manner (Table).

Naloxegol is a substrate of P-gp and is mainly metabolized by CYP3A4 enzymes. Moderate and strong CYP3A4 inhibitors significantly increase the plasma concentration of naloxegol, therefore potentiating the risk of AEs. In fact, concomitant use of naloxegol and strong CYP3A4 inhibitors, such as clarithromycin, itraconazole, and ketoconazole is contraindicated.

 Increasing the plasma concentration of naloxegol may precipitate opioid withdrawal symptoms. Similarly, moderate CYP3A4 inhibitors, such as diltiazem, erythromycin, and verapamil, should be avoided when using naloxegol. If coadministration of moderate CYP3A4 inhibitors cannot be avoided, naloxegol dose reduction is recommended, along with monitoring for toxicity, including opioid withdrawal symptoms, such as chills, diarrhea, hyperhidrosis, and irritability.

On the other hand, CYP3A4 inducers and P-gp inducers have not been shown to significantly decrease the plasma concentration of naloxegol. For example, efavirenz, a moderate CYP3A4 inducer, does not affect the concentration of naloxegol, whereas rifampin, a strong CYP3A4 inducer, may slightly decrease the exposure of naloxegol (but clinical significance has not been established) (Table). In healthy subjects, morphine and its major metabolites were not affected by naloxegol.

Although naldemedine is a substrate of CYP 3A4, it does not inhibit or induce CYP450 enzymes and does not inhibit P-gp. To prevent decreased efficacy, coadministration of naldemedine and strong CYP3A4 inducers, such as rifampin, should be avoided. Decreasing naldemedine’s dose to counteract the effects of rifampin is not recommended, as it puts the patient at risk of gastrointestinal-related AEs. CYP3A4 inhibitors and P-gp inhibitors moderately increase the plasma concentration of naldemedine but dose adjustments are not recommended (Table). In this case, clinicians should monitor for AEs, such as abdominal pain, diarrhea, and nausea.

PAMORAs can interact with other medications, resulting in decreased efficacy or toxicity. Understanding the pharmacokinetic relationship between each PAMORA and other medications could affect drug selection. Pharmacists play a pivotal role in identifying and preventing DDIs. Their detailed knowledge about drugs allows them to educate caregivers, health care professionals, and patients regarding clinically significant drug interactions. They can assist clinicians with therapy selection, as well as recommend appropriate course of action when DDIs occur. As a key part of the health care team, pharmacists can equip patients with knowledge about potential AEs, expectations, goals of therapy, and interactions to ensure safe medication administration.

, is a PGY-1 pharmacy resident at Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania.

, is a PGY-2 pain and palliative care pharmacy resident at Stratton VA Medical Center in Albany, New York.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB

, is president of Remitigate Therapeutics, LLC and the managing editor and owner of paindr.com. 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 Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

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Peripherally acting M-opioid receptor antagonists can improve quality of life but differ variably by impact from concomitant medications.