PPM ACCESS
Access to the PPM Journal and newsletters is FREE for clinicians.
16 Articles in Volume 20, Issue #5
20/20 with Drs. Carmen R. Green and Johnathan Goree: Racial Disparities in Pain Care
A Kratom Primer: Miracle Medicine or Herb of Abuse?
A Pilot Study: Incidence and Prediction of Diversion among Opioid Therapy Patients
Analgesics of the Future: G-Protein Biased Mu-Opioid Receptor Ligands
Application Note: Decellularized Human Placenta in the Treatment of Infracalcaneal Heel Pain
Are Clinicians Effectively Counseling Patients on Safe Opioid Storage and Disposal? Survey Results
Ask the PharmD: How to Manage Pain Meds During Pregnancy?
Behavioral Medicine: Managing Anxiety and Maladaptive Behaviors
Case Report: Spinal Cord Stimulation for the Treatment of Pain Associated with Chronic Pancreatitis
Differential Diagnoses: Inflammatory or Non-inflammatory Chronic Back Pain?
Pelvic Inflammatory Disease: Diagnosis, Education, and Treatment Options
Product Review: Non-Invasive Neuromodulation for the Treatment of the Most Difficult Pain Conditions
Provider Perspective: Carpal Tunnel's Association with Hypothyroidism
Research Insights: Opioid Use During the Peripartum Period – What to Expect
Special Report: Race, Pain Management, and the System
When Patients Become Pregnant: How to Maintain Chronic Pain Management

Analgesics of the Future: G-Protein Biased Mu-Opioid Receptor Ligands

With oliceridine recently approved by the FDA, are these receptor ligands pain management’s newest breakthrough or a traditional therapy in disguise?

 

Background

Although one G-protein biased mu-opioid receptor ligand (oliceridine) recently gained FDA approval, knowledge of the possibilities with these compounds has been around for over 20 years. In 1999, Bohn, et al, observed increased analgesia with morphine in B-arrestin 2-knockout mice, and in 2000, they published their finding of reduced GI and respiratory depression in these same mice.1-4

To step back for a second, opioid receptors are G-protein coupled receptors (GPCRs), with mu, kappa, and delta subtypes. While all subtypes have some activity on analgesia, the mu-receptor is the primary target in traditional opioid therapy for analgesia. These receptors also have additional activity at B-arrestin. Since the findings of Bohn, et al, it has been hypothesized that the adverse effects of opioids may be linked to excessive recruitment of B-arrestin.5

This hypothesis is supported by naturally occurring substances. For instance, rubisco in spinach is metabolized to two peptides with high affinity and potency in vitro at the delta-opioid receptor. Rubiscolin-6 has been shown to prevent delta-opioid receptor internalization, which is an activity associated with B-arrestin recruitment. There is data to suggest that rubiscolin’s bias toward the delta-opioid receptor may have benefit in alcohol use disorder (AUD).5

GPCR-bias has also been characterized in kratom (naturally synthesized to mitragynine6) and salvinorin.5 There is evidence in mice to suggest that this bias of kratom alkaloids for the mu and kappa opioid receptors may reduce moderate and binge alcohol intake, further supporting the potential role of GPCR-biased agents in the management of AUD.6 Salvinorin is used to derive semi-synthetic opioid herkinorin, which is also a GPCR-biased ligand.5

To date, the data on these ligands is inconclusive and no known attempts at prescription medication research is known at this time.7 PMZ21 was a ligand that gained traction in 2016 when it showed analgesia without respiratory depression in mice. However, a subsequent study showed tolerance similar to morphine with no analgesia demonstrated by Day 4. With little to no benefit noted over traditional opioid therapy, no further action has been taken to date.7

Oliceridine’s Road to the FDA

Trevena, Inc will be the first company to take a GPCR-biased ligand to market. TRV130 oliceridine (Olinvyk) was approved in August 2020 and was found in preclinical trials to provide potent analgesia with reduced GI and respiratory dysfunction when compared to morphine.8

Oliceridine is s an IV solution administered as a short infusion. It is primarily metabolized by CYP2D6 and CYP3A4 to inactive byproducts and excreted in urine (70%) and feces (30%).9

In Trevena’s preclinical findings,8,9 researchers found a reduced respiratory drive at all doses tested, similar to the comparator dose of morphine. However, this was transient in TRV130 (peaked at 30 minutes) whereas morphine was persistent (still present at 4 hours). For analgesia, TRV130 at doses of 3 mg and 4.5 mg were significantly greater than morphine 10 mg, at times <1 hour, however, analgesia was significantly higher in morphine compared to TRV130 1.5 mg beginning at 1 hour. While hypothesized that GI adverse effects should occur less in the TRV130 group, more patients experienced nausea in the 3 mg and 4.5 mg groups compared to morphine.

The developer’s first studies in patients with acute pain were randomized, double-blind trials in patients undergoing bunionectomy10 and abdominoplasty.11Patients were almost entirely female, which is a stark contrast to the Phase 1 trials in which the enrolled population was entirely male. The doses of TRV130 included in the trials were further reduced due to poor tolerability in previous trials. Patient-controlled analgesia dosing was first analyzed in the abdominoplasty trial, however, the authors did not report the number of demand doses required in each arm, making the data difficult to analyze. As would be expected, these trials showed an increased incidence of adverse effects with increasing doses of oliceridine.

In preclinical findings, researchers of oliceridine found a reduced respiratory drive at all doses tested, similar to the comparator dose of morphine. (Image: iStock)

In October 2018, FDA’s Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) voted 8 to 7 against the approval of oliceridine for market.12 Committee members noted that while the drug demonstrated superiority over placebo, it did not demonstrate superiority overactive comparator, and they issued concern about the side effects that may be seen at higher doses, such as respiratory depression and QTc prolongation. Those voting against approval pointed to possible lower abuse potential and favorable side effect profile, however, remained concerned about real-world application; for instance, what might be the outcome when used at higher doses than included in trials, with providers under the possible guise that it is “safer” despite respiratory depression noted in pre-clinical trials.

Since the release of the FDA’s denial, researchers published the findings of the APOLLO-110 and APOLLO-211 trials, which are Phase 3 trials investigating the use of oliceridine for the management of moderate-to-severe pain following bunionectomy and abdominoplasty, respectively. These studies utilized the same dosing scheme for patient-controlled analgesia as the Phase 2B trial,13 however, both added an oliceridine 0.5 mg dosing scheme. As with the previous trials, enrolled patients were primarily female. Interestingly, APOLLO-1 found the highest rate of treatment responders was in the morphine group, without a statistically significant difference in respiratory depression, but less use of antiemetics with oliceridine. APOLLO-2 showed at least one adverse effect experienced by less than 89% of participants across all treatment arms (excluding placebo). Somnolence and dizziness were notably less in the oliceridine arms. The researchers concluded that these trials demonstrated the safety and efficacy of oliceridine when used PRN for post-surgical pain, and support findings of less adverse effects when used with comparable doses of morphine.  

Trevena also released kinetic, safety, and tolerability data on the influence of renal or hepatic impairment.14 Men and women age 18 to 80 years were included in this study. A creatinine clearance of 90 mL/min or greater was required for the healthy subjects' control arm in the renal impairment study, but only 60 mL/min or greater in the healthy subjects control arm in the hepatic impairment study. In addition to various medical exclusions, patients were excluded if they had drug or alcohol abuse in the preceding 6 months, or were positive for Hepatitis B, Hepatitis C, or HIV. These were both Phase 1, open-label trials. To be enrolled in the renal impairment trial, the patients must have Stage 5 Chronic Kidney Disease (CKD)/End Stage Renal Disease (ESRD) on hemodialysis.  ESRD patients received one dose of 0.5 mg infused over 2 minutes, whereas the healthy individuals received 1 mg infused over 2 minutes. No clinically meaningful kinetic differences were found; clearance in ESRD was ~80% that of healthy participants, and exposure was ~20% higher.  The hepatic impairment study stratified patients based on the Child-Pugh score, and found a nearly 3-fold increase in half-life and volume of distribution in patients with severe hepatic impairment compared to healthy subjects. Based on these findings, the authors conclude that no dose adjustments are necessary for renal dysfunction, or mild to moderate hepatic dysfunction, and lower initial doses and close monitoring should be utilized in severe hepatic impairment, as fewer doses of oliceridine will be required.

An additional Phase 3 trial was completed, the ATHENA trial, which expanded uses of oliceridine to better represent a real-world population.15 This included non-surgical pain of 4 or greater on the numeric rating scale, or following surgery, including orthopedic, gynecologic, colorectal, plastic, urologic, neurologic, and cardiothoracic procedures, among others. The dosing limit in this study was 60 mg in the first 12 hours, and treatment was limited to 14 days. Interestingly, there was no restriction on the use of local anesthetic, epidural or intrathecal opioids, nor concomitant anxiolytics, sedatives, or hypnotics. Sixty-four percent of patients experienced adverse effects, with most common being nausea, constipation, and vomiting. The incidence increased with increasing doses, as well as the need for medical management of these adverse effects. The goal of ATHENA was to assess the safety of oliceridine however it was not powered to do so.

In 2020, three studies were released that re-evaluated previously published data by Trevena,16-18 and the NDA for oliceridine was resubmitted in February 2020. FDA agreed to labeling for oliceridine with a max dose of 27 mg in 24 hours based on published safety and QT data. Trevena notes in one publication that an important future step for oliceridine will be its evaluation as a part of ERAS protocols, however, this has not yet been published as of this writing.

As noted, FDA approved Olinvyk (oliceridine)1 on August 7, 2020 “for short-term intravenous use in hospitals or other controlled clinical settings, such as during inpatient and outpatient procedures. It is not indicated for at-home use.” On August 10, 2020, Trevena hosted a conference call to provide updates.19 In this call, they commented that DEA Scheduling is anticipated within 90 days of approval. They also noted that they have >1000 target hospitals and facilities to begin introducing oliceridine in, and that these facilities were selected due to historically higher use of IV opioids, as well as for being early adopters of new products. No firm comments regarding price have been made, but they did state that based on early research, their goal price point is ~$100/day (volume and dose unclear).

Expanding on GPCR-biased Ligands

Trevena has two other GPCR-biased ligands making their way into the medical literature: TRV250, a GPCR-delta opioid receptor biased ligand, both orally and subcutaneously, for the treatment of acute migraine, and TRV734, an orally bioavailable GPCR-biased ligand for the treatment of opioid use disorder. Both products are in early clinical trials.

 

Discussion

The FDA’s 2018 ruling against allowing oliceridine to market, based on Trevena’s data available at that time, is not surprising. More than anything, the trials published by Trevena suggest that B-arrestin’s role in the adverse effects of opioids is likely much less significant than the original knock-out mice trials led us to believe. These compounds have been investigated under the hypothesis that the primary mechanism for the undesirable effects of opioids, most namely, gastrointestinal effects and respiratory depression, lies in the recruitment of B-arrestin.

However, each phase of trials noted these effects, which appears to be linear with increasing dose. While data suggests respiratory depression had a shorter duration and was reversible with naloxone, these authors agree with the FDA’s original concern that this may provide practitioners with a false sense of safety when using this product. Practically, however, this is circumvented by the fact that this is an IV medication intended for use only in the post-operative setting, suggesting that patients will be in a setting with close monitoring and therefore mitigating associated risks in a way that outpatient, patient-controlled use would not. The developer’s 2019 data certainly improves confidence in the safety profile of this medication as a reasonable IV opioid analgesic, however, these authors feel that the company’s renal and hepatic dosing instructions are inadequate. Patients with ESRD were initiated on half the dose of their healthy counterparts and achieved roughly similar kinetics, however, no recommendation was made by the authors for smaller starting doses, as were made in the setting of hepatic impairment. That said, these authors do not feel that an adjustment to the max recommended dose should be prophylactically set, but rather doses titrated based on clinical response.

Although the evidence leaves us wanting more in terms of improved side effect profiles, the impact on analgesia cannot be ignored. In the face of the opioid crisis, having an IV analgesic without an oral equivalent may initially seem like an ideal option for post-surgical pain. However, with limited comparison data, this could lead to inappropriate transitions to oral opioid analgesics and increase risks associated with inappropriate oral prescribing, including dependence and respiratory depression.

Phase 1 trial data suggested an oliceridine dose between 1.5 mg and 3 mg to be roughly equivalent to 10 mg of IV morphine, however, in subsequent trials, a comparator of morphine 4 mg was used. In trials with demand dosing, 0.1 mg to 0.35 mg oliceridine was compared with 1 mg morphine, which is a more appropriate comparison based on initial trial data. However, no data was reported on the number of demand doses required by patients in each arm, therefore masking the true comparison of dose requirements, and making the comparison mute. With no clear way to convert to orally available agents following use of oliceridine post-surgically, researchers have inadvertently limited the integrability of oliceridine into medical practice. However, the FDA’s limitation of oliceridine to a max of 27 mg/24 hours does provide guidance and limitation that these authors hope will reduce inappropriate dose escalation and unintentional patient harm.

The FDA’s commentary on oliceridine at the time of approval1 mirrors the opinions of these authors: “Its safety and efficacy were established by comparing Olinvyk to placebo in randomized, controlled studies of patients who had undergone bunion surgery or abdominal surgery. Patients administered Olinvyk reported decreased pain compared to placebo at the approved doses. The safety profile of Olinvyk is similar to other opioids. As with other opioids, the most common side effects of Olinvyk are nausea, vomiting, dizziness, headache, and constipation.” FDA has also included black box warnings for oliceridine including addiction, abuse and misuse, life-threatening respiratory depression, neonatal opioid withdrawal syndrome, and risk of combination use with other central nervous system depressants, which align with those of traditional opioids.

In summary, oliceridine shows promise for the use of post-surgical acute pain. However, current data suggests very little benefit over traditional therapy, and many questions allowing for the safe use of oliceridine remain unanswered. These authors feel that evidence regarding dose equivalency to traditional opioid therapy, and clear pharmacokinetic and mechanistic clarity on oliceridine’s mechanism by which it causes respiratory depression are required prior to oliceridine being safely used in medical practice for the management of acute, post-surgical pain.

 

Experts Weigh In: Review by PPM Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD

Commensurate with the star rating criteria, oliceridine deserves a high rating for novelty. Considering that we have known about potential attributes of dodging beta-arrestin recruitment for more than 20 years, and we are just now seeing the first fruits of that labor, Trevena Inc deserves kudos in that regard! The risk-benefit ratio remains a bit of a conundrum, as the side effect profile is bothersome, particularly the risk for elevated QTc interval and opioid-induced respiratory depression (OIRD) with elevated doses. Although we are excited that the risk of oliceridine induced OIRD is transient compared to morphine and reversible by naloxone, there still is risk.  But perhaps an even bigger risk is that institutions may go to great lengths to reduce morphine equivalent daily dose (MEDD) in an effort to satisfy opioid stewardship initiatives, leveraging the lack of an MEDD without a fair balance to real-world morbidity.

The scientific rigor of these the pivotal trials in our mind were average, particularly since the majority of all study subjects were women and we still have no sense of how those on strong CYP2D6 or  CYP3A4 inhibitors will tolerate this new drug, nor do we know if tolerability may be affected by phenotypic outliers. Notwithstanding, oliceridine may be just what the doctor ordered to catapult industry-driven development of new and improved drugs that resist beta-arrestin recruitment (similar to buprenorphine) in an effort to reduce toxicity, particularly with regard to the development of physical opioid tolerance. Trevena’s oliceridine (branded Olinvyk) is in fact a novel therapeutic option that we will continue to watch closely.

Overall, we give oliceridine 3.75 STARS* for its novel mechanism of action. We hope that the manufacturer will perform human respiratory depression studies rather than use soft surrogate markers such as dosing interruptions or an analgesic/(resp) AE ratio. We are looking forward to future biased opioid ligands and support any and all novel, nonaddictive and effective analgesics in development. 

*Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewer’s expertise and opinion. 

 

Prior Analgesics of the Future columns

 

 

 

Last updated on: October 5, 2020
Continue Reading:
Are Nerve Growth Factor Inhibitors the Future of Hip, Knee, or Back Pain Relief?
close X
SHOW MAIN MENU
SHOW SUB MENU