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The Case for IV Opioid Use in Acute Postoperative Pain
This episode discusses evolving clinical strategies in acute postoperative pain management with a focus on OLINVYK as an IV opioid option. Hear from Dr. Sabry Ayad, Professor of Anesthesiology at the Cleveland Clinic Lerner College of Medicine.
Pressure to reduce opioid use perioperatively has led to gaps in acute postoperative pain control.1,2 While IV opioids are still a critical component of recovery for some postoperative patients, there’s a clear need to balance pain control with minimizing the risk of adverse events.1-4 So how do surgeons and anesthesiologists maintain this balance, especially in clinically challenging patients?
Today, we’ll be discussing evolving clinical strategies in acute postoperative pain management, with a focus on a new treatment option, OLINVYK, the first IV opioid advancement in decades.5
And I’m your host Dr. Jennifer Caudle. And joining me is Dr. Sabry Ayad, Professor of Anesthesiology at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University in Cleveland, Ohio.
Dr. Ayad, welcome to the program.
Great to be with you!
Before we begin, let’s take a moment to review some important safety information about OLINVYK.
OLINVYK is an opioid agonist indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.6 OLINVYK has a black box warning with risks of addiction, abuse, and misuse; life-threatening respiratory depression; neonatal opioid withdrawal syndrome; and risks from concomitant use with benzodiazepines or other central nervous system depressants.6
Dr. Ayad, to start, can you put the current landscape of acute postoperative pain management into perspective for us and the challenges that you and your colleagues face on your patients’ behalf?
- a) Thanks, Dr. Caudle. I think we first need to consider the current societal opioid crisis in context, since this crisis is both large and pervasive.1 But while it emanated largely from inappropriate prescribing, marketing, and misuse of oral prescription opioids,2 it’s become common in the current environment to lose sight of a key factor giving rise to this crisis, which is poorly controlled pain.1
- b) And this is very much an ongoing issue in surgery and anesthesiology since acute postoperative pain remains poorly treated.1 In a US survey of 300 adults who had undergone surgery within 5 years of the survey date, 75% reported experiencing moderate to severe postoperative pain.4 But unfortunately, despite this takeaway, we also know that more than 80% of postoperative patients report inadequate pain relief, and that metric has remained largely unchanged over the past 20 years.7
- c) So this underscores an important role that opioids still play for postoperative analgesia, especially for moderate to severe pain.3
But I take it, despite those takeaways, procedural practice is still complicated when it comes to the use of opioid analgesics, is that correct?
- a) That’s right. The opioid crisis has put an important emphasis on thoughtfully scrutinizing perioperative opioid use and prescribing, but what we’ve also seen is a trend toward precipitously reducing or eliminating opioid use in these settings altogether.1 And this has gone on despite there being no clear evidence that opioid-free strategies benefit patients above and beyond opioid-sparing strategies.8 Those aren’t synonymous terms or approaches, and it’s important to distinguish them in practice.
- b) Consider non-opioid analgesic agents such as acetaminophen, NSAIDs, local/regional analgesic techniques, and adjuncts such as steroids, gabapentinoids, and ketamine.8 In the setting of opioid-free analgesia, there is a ceiling effect with these agents and a small therapeutic index for safety8; and other than the local/regional analgesic options, we can’t titrate these agents to individual patient requirements, which is a necessity during the intraoperative period.8 These limitations can render non-opioid agents insufficient against moderate to severe pain.2
- c) So I think there’s a lot at stake here in the intraoperative and postoperative settings because, in my experience, if acute surgical pain isn’t managed promptly, it can be even more difficult to address later or when this acute pain turns into chronic pain.1 Some of the patients develop chronic pain following invasive procedures such as laminectomy, hernia repair, thoracotomy, and breast surgery, and these patients are very hard to manage. That’s why tackling acute surgical pain in a controlled surgical setting is extremely important.1
Can you give us a better sense of the patient populations and factors that influence your postoperative pain management decisions?
- a) Sure. In any assessment of acute postoperative pain management of our patients, we need to balance expected benefits with potential risks. And with IV opioids, that balance centers on delivering effective analgesia alongside acceptable tolerability.9 So we focus on risks of opioid-related adverse events, or ORAEs, such as nausea, vomiting, ileus, confusion or delirium, and the most serious side effect, respiratory depression.3
- b) And we’ve found that certain patient types may be at higher risk for these ORAEs, which can make for much more challenging clinical management.10
- c) A large, retrospective database analysis of patients who underwent inpatient surgical procedures and received conventional opioids found several factors that put patients at higher risk of opioid-induced respiratory depression, including comorbid obesity, respiratory conditions, sleep apnea, and older age.10
- d) Patients who are older, obese, and/or have multiple comorbidities are particularly challenging for us since they’re more likely to experience respiratory depression,10 so good providers need to keep these factors in mind when evaluating patients ahead of surgery.
And do these postoperative adverse events with conventional opioids impact healthcare systems as well?
- a) Absolutely. The care complications and close management required after patients experience ORAEs can also be associated with substantial increases in healthcare utilization.3
- b) A large, retrospective study that assessed clinical and administrative data of patients who underwent inpatient surgery and received opioids found a 25% increase in 30-day readmissions, a 30% increase in length of hospital stay, and a 47% greater total cost of hospitalization in patients who experienced an opioid-related adverse event.3
- c) So clearly, from both patient care and healthcare system standpoints, there’s an ongoing need to monitor patients carefully to reduce the risk of ORAEs.3
Well given this foundation you’ve provided on the clinical priorities and challenges concerning opioid use in surgical settings, I want to focus now on the emerging role of OLINVYK, which as we talked about earlier, represents the first IV opioid advancement in decades.5 Dr. Ayad, what makes this a novel treatment option among opioids, mechanistically?
- a) a) OLINVYK, or oliceridine, is a full opioid agonist that features what’s called a biased ligand technology which preferentially targets not just specific opioid receptors such as the μ-opioid receptor, but the specific signaling pathways downstream of those receptors.11,12 And this is a novel level of selectivity that may lead to a differentiated pharmacology.13,14
So let’s dive into that pharmacological profile for a moment. What are some key clinical characteristics that stand out for you regarding this treatment option?
- a) OLINVYK has been very well-studied from a strong clinical program consisting of more than 1900 patients.6,15-17
- b) Early phase trials have shown that OLINVYK has a rapid onset of analgesia, with the median onset of pain relief at one to three minutes after the first dose.6,18
- c) We talked about clinically challenging patients earlier, including the elderly, obese, and those with comorbidities. And based on the results of a phase 3 open-label study called the ATHENA trial,17 OLINVYK’s safety profile was established in these patient populations.6,17
- d) It also has no active metabolites, which provides a predictable level of analgesia and reduced dose stacking concerns.6,19
- e) Plus, with simple flexible dosing, there are no dose adjustments needed in patients with renal impairment,6,19 which is different from the conventional opioids that we use. So features like these are actually very exciting when seen in clinical practice.
You spoke to the ATHENA trial just now. Can you give us some more details on that study and what was uncovered there?
- a) Sure. ATHENA was a phase 3, multicenter, open-label clinical study that evaluated the safety and tolerability of OLINVYK in 768 patients with moderate to severe acute pain warranting the use of a parenteral opioid.6,17
- b) Treatment duration for each patient was determined by the clinical need for parenteral opioid therapy, but the maximum duration of treatment was limited to 14 days.17
- c) The “End of treatment” period was within 24 hours after the last dose of OLINVYK, while the posttreatment follow-up period was limited to 3 days unless any serious adverse events occurred, at which point that patient would be followed until it was resolved.17
- d) I mentioned an important differentiator in this study compared to what’s usually seen in controlled clinical trials, in that the ATHENA study population included a good representation of clinically challenging patients.6,17
- e) Many of these patients had a BMI greater than 30 and were older than 65, and all patients included in ATHENA had at least one underlying comorbidity, providing a good representation of what happens in the real world.6,17
- f) Many patients also received prophylactic antiemetics and multimodal analgesics such as acetaminophen, NSAIDs, or gabapentinoids along with OLINVYK.17 But those receiving OLINVYK didn’t receive other opioids during their treatment period.17
- g) The data from ATHENA showed that OLINVYK was very well tolerated.17 Most adverse events reported were mild or moderate in severity, and the most common ones were nausea, constipation, and vomiting.6
- h) Interestingly, the incidence of adverse events in the obese and elderly population was similar to that of the overall population,17 which was something that differentiated OLINVYK from what is seen in the literature with conventional opioids.20
- i) Only 2 percent of patients had adverse events leading to early discontinuation,17 and none of the patients receiving OLINVYK needed to use naloxone during treatment,17 which further highlights this treatment’s safety profile.
Great insights on that clinical trial, Dr. Ayad, thank you. Now, my last question to you: looking ahead, how do you see OLINVYK changing the practice of acute pain management where an IV opioid is needed, especially for patients with complex clinical needs?
- a) Well, from my vantage point, OLINVYK, with its unique pharmacology13,14 and established safety profile, is a new option to treat moderate to severe acute intraoperative or postoperative pain for the clinically challenging adult patients that I see in practice every day.
- b) So I think that adding OLINVYK to our ERAS protocols will be a very good way of enhancing our acute post-surgical pain management, and I’m looking forward to seeing the impacts of this treatment across all types of surgeries.
- c) But as a reminder, as with all opioids and other Black Box Warning products, there are certain risks associated with use, including respiratory depression, neonatal withdrawal syndrome, and the risk of misuse and addiction.
Well, with those forward-looking insights in mind, I very much want to thank my guest, Dr. Sabry Ayad, for helping us better understand the role of IV opioids in acute postoperative pain management, and the emergence of OLINVYK as a treatment option for clinically challenging patients.
Dr. Ayad, it was great speaking with you today.
It’s been a pleasure. Thank you so much.
References: 1. Kharasch ED, Avram MJ, Clark JD. Rational Perioperative Opioid Management in the Era of the Opioid Crisis. Anesthesiology. 2020;132(4):603-605. doi:10.1097/ALN.0000000000003166 2. Kharasch ED, Clark JD. Opioid-free Anesthesia: Time to Regain Our Balance. Anesthesiology. 2021;134(4):509-514. doi:10.1097/ALN.0000000000003705 3. Shafi S, Collinsworth AW, Copeland LA, et al. Association of Opioid-Related Adverse Drug Events with Clinical and Cost Outcomes Among Surgical Patients in a Large Integrated Health Care Delivery System. JAMA Surg. 2018;153(8):757-763. doi:10.1001/jamasurg.2018.1039 4. Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL. Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin. 2014;30(1):149-160. doi:10.1185/03007995.2013.860019 5. Trevena, Inc. Data on File; 2020. 6. Trevena, Inc. OLINVYK [Prescribing Information].; 2021. 7. Gan TJ: Poorly controlled postoperative pain: Prevalence, consequences, and prevention. J Pain Res 2017;10:2287-98. 8. Shanthanna H, Ladha KS, Kehlet H, Joshi GP: Perioperative opioid administration: A critical review of opioid-free versus opioid-sparing approaches. Anesthesiology 2021;134:645-59 9. Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84:613-624. 10. Oderda GM, Senagore AJ, Morland K, et al. Opioid-related respiratory and gastrointestinal adverse events in patients with acute postoperative pain: prevalence, predictors, and burden. J Pain Palliat Care Pharmacother. 2019;33(3-4):82-97. doi:10.1080/15360288.2019.1668902 11. Benovic JL. G-protein-coupled receptors signal victory. Cell. 2012;151(6):1148-1150. 12. Violin JD, Crombie AL, Soergel DG, Lark MW. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci. 2014;35(7):308-316. doi:10.1016/j.tips.2014.04.007 13. Schmid CL, Kennedy NM, Ross NC, et al. Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell. 2017;171(5):1165-1175.e13. doi:10.1016/j.cell.2017.10.035 14. Siuda ER, Carr R, Rominger DH, Violin JD. Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics. Curr Opin Pharmacol. 2017;32:77-84. doi:10.1016/j.coph.2016.11.007 15. 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 16. 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 17. 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 18. Viscusi ER, Webster L, Kuss M, et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain. Pain. 2016;157(1):264-272. doi:10.1097/j.pain.0000000000000363 19. Gan TJ, Wase L. Oliceridine, a G protein-selective ligand at the μ-opioid receptor, for the management of moderate to severe acute pain. Drugs Today (Barc). 2020;56(4):269-286. doi:10.1358/dot.2020.56.4.3107707 20. Gupta K, Prasad A, Nagappa M, Wong J, Abrahamyan L, Chung FF. Risk factors for opioid-induced respiratory depression and failure to rescue: a review. Curr Opin Anaesthesiol. 2018. Feb;31(1):110-119.
Register for an OLINVYK lecture program facilitated and led by expert surgeons and anesthesiologists.
- 1. Present the promise of G-protein biased ligand technology as an advancement to the IV opioid class
- 2. Review the efficacy and safety data from the OLINVYK clinical development program
- 3. Discuss the appropriate clinical use of OLINVYK through hypothetical patient cases