New Post-Surgical Analgesic May Reduce Opioid Misuse

The National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) reports note that in 2019, nearly 50,000 people in the United States died from opioid-involved overdoses.¹ This serious national crisis affects public health as well as social and economic welfare. Estimates place the total "economic burden" of prescription opioid misuse in the United States at $78.5 billion per year, including the costs of health care, lost productivity, addiction treatment and criminal justice costs.²

Reports note that:¹

• Misuse of opioids prescribed for chronic pain takes place in roughly 21 to 29 percent of patients.³
• Between eight and 12 percent of people using an opioid for chronic pain develop an opioid use disorder.³
• Estimates suggest that between four and six percent of those who misuse prescription opioids transition to heroin.^4-6
• Developing an opioid use disorder depends on many factors, including duration of the opioid prescription for acute pain and length of time one continues to take opioids (whether as prescribed or misused).¹

The National Institutes of Health (NIH), a component of the U.S. Department of Health and Human Services (HHS), is leading the way in helping solve the opioid crisis. In 2017, the NIH met with pharmaceutical companies and academic research centers to discuss and promote discovery of new and better ways to manage pain safely, effectively and in a non-addictive fashion, as well as innovative ways to prevent opioid misuse and treat opioid use disorders.¹

In one study, patients aged 16 to 79 years undergoing a variety of elective surgical procedures cited the first 72 hours after surgery as the most painful, with 88 percent experiencing moderate-to-severe pain in the first 24 hours.⁷ For 72 percent of patients, pain remained moderate-to-severe through the 48- to 72-hour window.⁷ In fact, as the inflammatory process unfolds in the first 24 hours after surgery, the wound site becomes more acidic.⁸ This acidic microenvironment causes local anesthetics to ionize, preventing entering of the anesthetic to the nerve cell membrane, thus blocking pain signals to the brain.⁸

In my experience, local anesthetics do not typically provide consistent pain relief beyond 12 to 24 hours, and thus we often prescribe opioids to cover this subsequent time. We all remember from pharmacology class that opioids mask pain centrally (at the brain), which can reduce the sensation of said pain, but they do not block transmission of the pain signals at the source. Our clinical experience reinforces that opioids can cause serious adverse reactions, including respiratory depression, especially in our elderly population and those with cardiac and pulmonary co-morbidities. Other common adverse reactions we can see include nausea, vomiting, pruritus, somnolence, urinary retention and constipation. With greater than 50 million surgeries in the U.S. each year and 33 million opioid prescriptions each year, approximately 80 percent of patients report unused opioids.^9,10   This notably demonstrates a gap in local anesthetic efficacy and overreliance on opioids for post-surgical pain management.

We may have a new game changer in ZYNRELEF^™ (Heron Therapeutics), approved by the U.S. Food and Drug Administration (FDA) on May 12, 2021 for use in adults for soft tissue or periarticular instillation to produce post-surgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.¹¹ ZYNRELEF contains bupivacaine, an amide local anesthetic and meloxicam, a nonsteroidal anti-inflammatory drug (NSAID). The first and only extended-release dual-acting local anesthetic, ZYNRELEF’s novel mechanism of action uses a polymer to deliver postoperative pain relief.¹¹

Meloxicam in ZYNRELEF inhibits the pH-lowering effects of inflammation by reducing the concentration of hydrogen ions in the environment, normalizing the pH at the surgical site, and allowing more bupivacaine to penetrate the nerve cell membrane.¹¹ This allows the drug to provide continued pain relief in the critical 72-hour window, when pain is often most severe.¹¹ Surgeons apply ZYNRELEF without a needle into the surgical site following final irrigation and suction and prior to suturing. Considered extended-release and providing for reduction in pain intensity, in a Phase 3 placebo-controlled randomized trial, this drug resulted in fewer patients with severe pain, a significant reduction in opioid use and a significantly greater proportion of patients requiring no opioids through the first 72 hours following surgery.¹¹

The World Health Organization (WHO) introduced their three-step analgesic ladder in 1986 for cancer pain management. Current adaptations suggest the following approach:¹²

• STEP 1. Acetaminophen, NSAIDs or COX-2-selective inhibitors, gabapentinoids and local/regional anesthesia;   
• STEP 2. Step 1 and low doses of opioids; and
• STEP 3. Step 1 plus step 2 and higher doses of opioids.

With the modified WHO Analgesic Ladder, and now with FDA approval of a non-opioid option for post-management pain control, is there a new “ladder” we should consider?

Prescription drug monitoring programs (PDMPs), although findings are mixed, illustrate changes in prescribing behaviors, patient use of multiple providers and decreased substance abuse treatment admissions. With this new combination drug, we may find an opportunity for improvement in prescribing patterns and reduction in use or even need for opioids in patients for post-operative pain control.

Key Points To Know About ZYNRELEF¹¹

• The drug is a viscous liquid in a single-dose vial with 29.25 mg/mL bupivacaine and 0.88 mg/mL meloxicam;

• One should monitor cardiovascular and respiratory vital signs along with the patient’s state of consciousness after applying ZYNRELEF, due to dose-related toxicity.
• When using ZYNRELEF with other local anesthetics, one must consider overall total local anesthetic used, avoiding additional local anesthetics within 96 hours following administration of ZYNRELEF.
• Some of the most common adverse reactions in controlled clinical trials with ZYNRELEF are constipation, vomiting and headache.
• Bupivacaine and meloxicam are both metabolized in the liver.

Dr. Aung is Chief of the Podiatry Section of the Tenet Health System/St. Joseph’s Hospital in Tucson, Ariz. She is a member of the APMA Coding Committee, the APMA MACRA/MIPS Task Force and is on the Exam Committee of the American Board of Wound Management. Dr. Aung is also on the Editorial Review Board for Wound Management and Prevention. Her website is www.healthy-feet.com.

Disclaimer: The views and opinions expressed are those of the author(s) and do not necessarily reflect the official policy or position of Podiatry Today or HMP Global, their employees and affiliates. Any content provided by our bloggers or authors are of their opinion and are not intended to malign any religion, ethnic group, club, association, organization, company, individual, anyone or anything.

References

1. National Institute on Drug Abuse. Opioid overdose. Available at: https://www.drugabuse.gov/drug-topics/opioids/opioid-overdose-crisis . Accessed June 3, 2021.
2. Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care. 2016;54(10):901-906.
3. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4):569-576.
4. Muhuri PK, Gfroerer JC, Davies MC. Associations of nonmedical pain reliever use and initiation of heroin use in the United States. CBHSQ Data Rev. August 2013. Available at: https://www.samhsa.gov/data/sites/default/files/DR006/DR006/nonmedical-pain-reliever-use-2013.htm . Accessed May 24, 2021.
5. Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States: a retrospective analysis of the past 50 years. JAMA Psychiatry. 2014;71(7):821-826.
6. Carlson RG, Nahhas RW, Martins SS, Daniulaityte R. Predictors of transition to heroin use among initially non-opioid dependent illicit pharmaceutical opioid users: A natural history study. Drug Alcohol Depend. 2016;160:127-134..
7. Svensson I, Sjostrom B, Haljamae H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage. 2000;20(3):193-201
8. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53(3):98-109.
9. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152(6):e170504.
10. Santosa KB, Hu HM, Brummett CM, et al. New persistent opioid use among older patients following surgery: a medicare claims analysis. Surgery. 2020;167(4):732-742.
11. Heron Pharmaceutical Monograph Heron Pharmaceutical Web Site. https://www.herontx.com/  Accessed May 23, 2021.
12. World Health Organization Analgeic Ladder. UpToDate. Available at: https://www.uptodate.com/contents/image?imageKey=ONC%2F63298 . Accessed June 3, 2021.