The world of postoperative pain management is changing

Postoperative pain is a 72-hour problem

Pain management during the first 72 hours after surgery is critical. This is when pain is most severe and inflammation is most active.1,2 Until now, however, many local anesthetics have failed to manage postoperative pain consistently beyond 12 to 24 hours, contributing to the extensive use of opioids to fill the treatment gap.3-8 As the first and only extended-release dual-acting local anesthetic proven to last up to 72 hours, ZYNRELEF could positively impact the way we treat postoperative pain.9

Graph: level of pain patients report in first 72 hours after surgery: 72% rate moderate to severe in 48- to 72-hour window. Graph: level of pain patients report in first 72 hours after surgery: 72% rate moderate to severe in 48- to 72-hour window.
VAS mm
≥0 <40
≥40 <80
≥80 ≤100
Pain Intensity
Mild or No Pain
Moderate Pain
Severe Pain

Adapted from Svensson I. J Pain Symptom Manage. 2000;20(3):193-201.

The first 72 hours after surgery are when pain is most severe. During the 48- to 72-hour window, 72% of patients still rated their pain as moderate to severe.1

Graph showing the stages of inflammation from 1 hour to 10 days following surgery. Graph showing the stages of inflammation from 1 hour to 10 days following surgery.

Inflammation peaks around 24 hours but remains high through the first 72 hours.2

Learn how ZYNRELEF overcomes the challenges of local inflammation and acidity by introducing a low dose of the NSAID meloxicam.9

Many local anesthetics inconsistently provide pain relief beyond 12 to 24 hours

Chart showing the gap between how long common local anesthetics last and how long patient pain lasts. Chart showing the gap between how long common local anesthetics last and how long patient pain lasts.

3. Berde CB, Strichartz GR. In: Miller RD, Cohen NH, Eriksson LI, et al, eds. Miller’s Anesthesia. Vol 1. 8th ed. Philadelphia, PA: Saunders; 2015:1028-1054.e4. 4. Ali A, Sundberg M, Hansson U, et al. Acta Orthop. 2015;86(3):373-377. 5. Kim J, Burke SM, Kryzanski JT, et al. World Neurosurg. 2016;91:460-467. 6. Data on file. DRG physician survey. San Diego, CA: Heron Therapeutics Inc; 2017. 7. Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals Inc; 2021.

  • Generic local anesthetics are not designed to provide pain relief beyond 8 to 12 hours3,6
  • Most longer-acting local anesthetics inconsistently provide pain relief beyond 12 to 24 hours, in part because inflammation inhibits their ability to penetrate the nerve cell membrane3-7,10

View infographic on the limitations of some local anesthetics.

Opioids are not an ideal solution

The inability of most local anesthetics to last a full 72 hours has contributed to the extensive use of opioids to manage postoperative pain.3-8

But opioids come with a cost:
  More than 50 million surgical procedures are performed in the US each year.
Purple and blue pill capsule.

67%

of patients filled an opioid prescription associated with their surgery.12,a That equals more than 30 million opioid prescriptions each year.11,12

aBetween 30 days before through 14 days after surgery.

More than

2 million

patients per year may become persistent opioid users annually after surgery.11,12
In addition,

80%

of patients report unused opioid tablets.13

It’s time to redefine postoperative pain relief

ZYNRELEF provides patients with up to 72 hours of postoperative pain relief, decreasing the need for opioid analgesics following surgery and increasing the number of patients requiring no opioids through day 28.9,14,15

Important Safety Information and Indication

Indication

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.

Important Safety Information

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
  • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Contraindications

ZYNRELEF is contraindicated in patients with known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDS have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing coronary artery bypass graft (CABG) surgery.

Warnings and Precautions

Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after application of ZYNRELEF. When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours.

Hepatotoxicity: If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient.

Hypertension: Patients taking some antihypertensive medication may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure.

Heart Failure and Edema: Avoid use of ZYNRELEF in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.

Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal failure.

Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.

Methemoglobinemia: Cases have been reported with local anesthetic use.

Serious Skin Reactions: NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): If symptoms are present, evaluate clinically.

Fetal Toxicity: Due to the risk of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus with NSAIDS, limit use of ZYNRELEF between about 20 to 30 weeks gestation, and avoid use after about 30 weeks.

Hematologic Toxicity: Monitor hemoglobin and hematocrit in patients with any signs or symptoms of anemia.

Drug Interactions

Drugs That Interfere with Hemostasis: Monitor patients for bleeding who are using ZYNRELEF with drugs that interfere with hemostasis (eg, warfarin, aspirin, SSRIs/SNRIs). 

ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

ACE Inhibitors and ARBs: Use with ZYNRELEF in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function.

Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effect.

Use in Specific Populations

Infertility: NSAIDs are associated with reversible infertility. Consider avoidance of ZYNRELEF in women who have difficulties conceiving.

Severe Hepatic Impairment: Only use if benefits are expected to outweigh risks; monitor for signs of worsening liver function.

Severe Renal Impairment: Not recommended.

Adverse Reactions

Most common adverse reactions (incidence ≥10%) in controlled clinical trials with ZYNRELEF are constipation, vomiting, and headache.

Report side effects to Heron at 1-844-437-6611 or to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.

Please see full Prescribing Information, including Boxed Warning.

References: 1. Svensson I, Sjöström B, Haljamäe H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage. 2000;20(3):193-201. doi:10.1016/S0885-3924(00)00174-3. 2. Enoch S, Leaper DJ. Basic science of wound healing. Surgery (Oxford). 2008;26(2):31-37. doi:10.1016/j.mpsur.2007.11.005. 3. Berde CB, Strichartz GR. Local anesthetics. In: Miller RD, Cohen NH, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL, eds. Miller’s Anesthesia. Vol 1. 8th ed. Philadelphia, PA: Saunders; 2015:1028-1054.e4. 4. Ali A, Sundberg M, Hansson U, Malmvik J, Flivik G. Doubtful effect of continuous intraarticular analgesia after total knee arthroplasty: a randomized, double-blind study of 200 patients. Acta Orthop. 2015;86(3):373-377. doi:10.3109/17453674.2014.991629. 5. Kim J, Burke SM, Kryzanski JT, et al. The role of liposomal bupivacaine in reduction of postoperative pain after transforaminal lumbar interbody fusion: a clinical study. World Neurosurg. 2016;91:460-467. doi:10.1016/j.wneu.2016.04.058. 6. Data on file. DRG physician survey. San Diego, CA: Heron Therapeutics Inc; 2017. 7. Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals Inc; 2021. 8. Hill MV, McMahon ML, Stucke RS, Barth RJ Jr. Wide variation and excessive dosage of opioid prescriptions for common general surgical procedures. Ann Surg. 2017;265(4):709-714. doi:10.1097/SLA.0000000000001993. 9. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2021. 10. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53(3):98-109. doi:10.2344/0003-3006(2006)53[98:EOLAP]2.0.CO;2. 11. 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. doi:10.1001/jamasurg.2017.0504. 12. 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. doi:10.1016/j.surg.2019.04.016. 13. Bicket MC, Long JJ, Pronovost PJ, Alexander GC, Wu CL. Prescription opioid analgesics commonly unused after surgery: a systematic review. JAMA Surg. 2017;152(11):1066-1071. doi:10.1001/jamasurg.2017.0831. 14. Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee G-C. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: Phase III results from the randomized EPOCH 1 study. Reg Anesth Pain Med. 2019;44(7):700-706. doi:10.1136/rapm-2019-100531. 15. Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the Phase 3 EPOCH 2 study. Hernia. 2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6.