What are the considerations for using Zynreleif (bupivacaine and meloxicam) in an adult cancer patient with moderate to severe pain, regarding Local Anesthetic Systemic Toxicity (LAST)?

Zynrelef and Local Anesthetic Systemic Toxicity (LAST) in Adult Cancer Patients

Direct Recommendation

Zynrelef (bupivacaine/meloxicam) can be used in adult cancer patients with moderate to severe pain, but requires heightened vigilance for LAST, particularly in patients with malignant bone lesions or extensive skeletal involvement, where cancer-related angiogenesis may increase systemic absorption and toxicity risk. 1

Critical Risk Factors Specific to Cancer Patients

Cancer patients with osteolytic bone lesions or extensive skeletal metastases face substantially elevated LAST risk due to increased tumor-associated angiogenesis at injection sites, which accelerates local anesthetic absorption into systemic circulation. 1 A documented case of multiple myeloma with extensive lytic vertebral lesions resulted in cardiovascular collapse requiring lipid emulsion rescue after standard-dose local anesthetic administration. 1

High-Risk Cancer Populations for LAST:

• Patients with multiple myeloma and diffuse bone involvement 1
• Those with osteolytic metastases at or near the surgical site 1
• Patients with malignant lesions in the thoracolumbar spine region 1
• Cancer patients on antiangiogenesis agents (e.g., bevacizumab) which increase bleeding risk and may alter local anesthetic pharmacokinetics 2

Zynrelef-Specific Considerations

Zynrelef contains 300 mg bupivacaine and 9 mg meloxicam in a novel polymer formulation designed for 72-hour sustained release. 3 While this extended-release formulation theoretically reduces peak plasma concentrations compared to immediate-release bupivacaine, LAST has been documented even with liposomal bupivacaine formulations, including cardiac arrest following transversus abdominis plane block. 4

Key Pharmacologic Differences:

• The polymer technology allows simultaneous diffusion over 72 hours, potentially creating a prolonged window of LAST vulnerability 3
• Unlike immediate LAST presentation (typically within minutes), extended-release formulations may cause delayed toxicity 4
• The combination with meloxicam (an NSAID) adds renal, gastrointestinal, and cardiovascular toxicity concerns in cancer patients already at high risk 2

Mandatory Precautions Before Zynrelef Administration

Pre-Administration Assessment:

• Image the surgical site to identify osteolytic lesions, tumor burden, or extensive skeletal involvement that increases vascular absorption 1
• Verify renal function (BUN, creatinine) as both bupivacaine metabolites and meloxicam are renally cleared; avoid in patients with creatinine doubling or GFR <30 mL/min 2, 5
• Review concurrent medications for antiangiogenesis agents, anticoagulants, or other NSAIDs that compound bleeding/toxicity risk 2
• Assess coagulation status as cancer patients often have thrombocytopenia or coagulopathy 2

Dose Modifications:

• Use fractionated dosing with incremental 3-5 mL aliquots when applying Zynrelef, allowing time between applications to detect early toxicity signs 5
• Consider dose reduction (below the standard 60 mL maximum) in debilitated, elderly, or acutely ill cancer patients 5
• Avoid maximum dosing in patients with extensive malignant bone involvement 1

LAST Recognition and Immediate Management

Early Warning Signs (Monitor Continuously):

• CNS toxicity (appears first): restlessness, anxiety, metallic taste, tinnitus, perioral numbness, lightheadedness, blurred vision, tremors, drowsiness 5, 6
• Cardiovascular toxicity (appears later): tachycardia, hypertension initially, then bradycardia, hypotension, arrhythmias, cardiovascular collapse 2, 5, 4
• Respiratory signs: tachypnea, hypoxia, respiratory depression, apnea 5, 4

Immediate Treatment Protocol (per AHA 2020 Guidelines):

At first sign of LAST, immediately administer 20% intravenous lipid emulsion (1.5 mL/kg bolus over 1 minute, then 0.25 mL/kg/min infusion) concomitant with standard ACLS. 2 This recommendation carries a Class 2b, Level C-LD evidence rating but is the only specific antidote for bupivacaine toxicity. 2

Step-by-Step LAST Management:

1. Stop local anesthetic administration immediately 2, 5
2. Call for help and lipid emulsion (must be immediately available) 2, 5
3. Establish airway with 100% oxygen via positive pressure ventilation to prevent hypoxia, hypercarbia, and acidosis that worsen cardiac toxicity 5
4. Administer 20% lipid emulsion: 1.5 mL/kg IV bolus over 1 minute, followed by 0.25 mL/kg/min infusion 2
5. If cardiovascular collapse: continue lipid infusion, increase to 0.5 mL/kg/min if needed, repeat bolus every 3-5 minutes up to 3 mL/kg maximum initial dose 2
6. Manage seizures with benzodiazepines (5-10 mg diazepam IV) or propofol, avoiding large doses that worsen cardiovascular depression 5
7. Avoid vasopressin, calcium channel blockers, beta-blockers, and local anesthetics during resuscitation 2
8. If cardiac arrest occurs, continue CPR and lipid emulsion; prolonged resuscitation may be required (>60 minutes) as bupivacaine dissociates slowly from cardiac tissue 2, 5

Resuscitation Equipment Requirements

Before administering Zynrelef, the following must be immediately available at the bedside: 5

• 20% intravenous lipid emulsion (minimum 500 mL) 2
• Oxygen delivery system with positive pressure capability 5
• Airway management equipment (bag-valve-mask, intubation supplies) 5
• Intravenous access with functioning catheter 5
• Standard ACLS medications and defibrillator 2, 5
• Benzodiazepines for seizure management 5

Multimodal Analgesia Context for Cancer Pain

While Zynrelef can reduce opioid consumption postoperatively 3, cancer pain management should prioritize systemic opioids as first-line therapy per ESMO and NCCN guidelines. 2, 7 Oral immediate-release morphine 5-15 mg every 4 hours remains the gold standard for moderate to severe cancer pain. 2, 7

When to Consider Zynrelef:

• Postoperative pain following cancer-related surgery (e.g., tumor resection, palliative procedures) as part of multimodal analgesia 3
• Adjunct to systemic opioids when localized surgical pain is a significant component 2
• NOT as primary treatment for diffuse cancer pain, bone metastases, or visceral pain 2

When Interventional Approaches Are Appropriate:

Per ESMO guidelines, nerve blocks and regional techniques should be considered when: 2

• Pain is well-localized and likely to respond to regional blockade 2
• Systemic opioids cause intolerable side effects despite dose optimization 2
• Life expectancy is sufficient to justify the intervention (generally >3 months for peripheral blocks) 2

Critical Contraindications

Absolute contraindications to Zynrelef in cancer patients: 2

• Active infection at the surgical site 2
• Coagulopathy or thrombocytopenia (common in cancer patients) 2
• Severe renal impairment (GFR <30 mL/min) due to meloxicam component 2
• History of hypersensitivity to amide local anesthetics or NSAIDs 5

Relative contraindications requiring extreme caution:

• Extensive osteolytic bone lesions at or near injection site 1
• Concurrent antiangiogenesis therapy 2
• Hepatic dysfunction (bupivacaine is hepatically metabolized) 5
• Cardiovascular disease or heart block 5
• Age >60 years with compromised fluid status 2

Post-Administration Monitoring

Continuous monitoring for minimum 30 minutes post-administration, then hourly for 4 hours: 5

• Vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation) 5
• Mental status and neurologic examination 5
• ECG monitoring if available, especially in high-risk patients 2, 4

Extended vigilance for 72 hours given the prolonged-release formulation, with patient/family education on LAST warning signs and immediate reporting instructions. 3