Suzetrigine Drug-Drug Interactions: Perioperative Anesthesia Considerations to Enhance Patient Safety

INTRODUCTION

Pain management for surgical patients remains a critical challenge, especially in the context of an ongoing opioid epidemic. Opioids have long been the cornerstone of perioperative analgesia, but widespread use has contributed to significant public health concerns, including opioid dependence, overdose, and addiction¹. The National Institute on Drug Abuse reported over 80,000 opioid-related overdose deaths occurred in the U.S. in 2022, emphasizing the urgent need for effective, non-opioid analgesic alternatives².

Suzetrigine (JOURNAVX), a selective Na_v1.8 sodium channel inhibitor, represents a novel, non-opioid approach to managing moderate to severe acute pain. Unlike opioids, which act on central μ-opioid receptors, suzetrigine targets peripheral pain-sensing neurons, inhibiting transmission of pain signals to the central nervous system thus offering effective analgesia without the risk of respiratory depression or addiction potential³.

Incorporation of suzetrigine into perioperative multimodal analgesia protocols presents an opportunity for anesthesiologists to reduce opioid exposure, enhance early recovery, and improve patient safety. However, given its metabolism via the cytochrome P450 3A (CYP3A) pathway, understanding its potential drug-drug interactions is essential to optimize its efficacy and prevent adverse effects⁴.

This article explores clinically relevant drug interactions of suzetrigine, emphasizing its preoperative considerations and perioperative safety for anesthesiologists.

PERIOPERATIVE DRUG-DRUG INTERACTION CONSIDERATIONS

CYP3A: Function and Clinical Relevance in Suzetrigine Metabolism

CYP3A is one of the most important drug-metabolizing enzymes in the human body. It belongs to the cytochrome P450 superfamily, which is responsible for the oxidation of various endogenous and exogenous compounds, including drugs, toxins, and steroids⁵. CYP3A is highly expressed in the liver and intestines, making it a key determinant of drug bioavailability and clearance⁶. It contributes to the metabolism of approximately 50% of all clinically used drugs, making it one of the most significant enzymes in pharmacokinetics⁷.

Factors Affecting CYP3A Activity

CYP3A activity is highly variable among individuals, influenced by genetic, physiological, and environmental factors:

1. Genetic Variability: Genetic polymorphisms in CYP3A genes contribute to inter-individual differences in enzyme activity. For example, the CYP3A41B allele and the CYP3A53 allele can influence enzyme expression and function^6,8.
2. Endogenous Substances: Hormones, bile acids, and inflammatory cytokines can regulate CYP3A expression. For instance, glucocorticoids can induce CYP3A activity, while inflammatory cytokines can downregulate it⁹.
3. Exogenous Substances: Drugs, environmental chemicals, and dietary factors can act as substrates, inhibitors, or inducers of CYP3A. Common inhibitors include macrolide antibiotics (e.g., erythromycin), antifungal agents (e.g., ketoconazole), and grapefruit juice. Inducers include rifampin and certain anticonvulsants like phenytoin^7,10.
4. Disease States: Conditions such as liver diseases and infections (e.g., COVID-19) can alter CYP3A expression and activity. Elevated liver enzymes and inflammatory markers are associated with reduced CYP3A activity^9,11
5. Sex Differences: Females generally have higher CYP3A expression levels compared to males, which can influence drug metabolism and clearance rates¹².
6. Age: CYP3A activity can vary with age, with neonates and elderly individuals often exhibiting different metabolic capacities compared to adults⁶.
7. Drug-Drug Interactions: Co-administration of drugs that are substrates, inhibitors, or inducers of CYP3A can lead to significant pharmacokinetic interactions, affecting drug efficacy and toxicity⁷.

CYP3A Inhibitors and Inducers

• Strong CYP3A Inhibitors (Contraindicated):
  Medications such as itraconazole, clarithromycin, and ritonavir can significantly increase suzetrigine plasma levels, increasing the risk of adverse effects⁴.
• Moderate CYP3A Inhibitors:
  Medications such as fluconazole and diltiazem can elevate suzetrigine exposure, potentially necessitating a dose reduction⁴
• CYP3A Inducers:
  Drugs like rifampin, carbamazepine, and phenytoin can reduce suzetrigine plasma concentrations, potentially decreasing its analgesic efficacy and concomitant use should be avoided⁴.

Interactions with Anesthesia Medications

Suzetrigine is metabolized by CYP3A and also acts as an inducer of CYP3A, as well as CYP2B6, CYP2C8, CYP2C9, and CYP2C19 to a lesser extent⁴.

Table: Anesthesia Drugs Metabolized by CYP3A

Hormonal Contraceptives and Preoperative Counseling

Suzetrigine can reduce the effectiveness of hormonal contraceptives containing progestins other than levonorgestrel and norethindrone⁴. Preoperative counseling should emphasize secondary contraception methods for patients while undergoing suzetrigine therapy and for 28 days after discontinuation.

ADVERSE REACTIONS AND PERIOPERATIVE MONITORING

Possible side effects of suzetrigine include:

• Constipation: This effect is unlikely to be severe, but therapy discontinuation could be considered³.
• Headache: This effect is unlikely to be severe, but therapy discontinuation could be considered³.
• Itching and Rash: May mimic allergic reactions, necessitating differentiation from true drug allergies in the perioperative setting⁴.
• Muscle Spasm and Elevated Creatine Kinase: The pathophysiology for suzetrigine-associated muscle spasms has not been elucidated and it has not been studied in conjunction with muscle relaxants⁴.

Monitoring:

• Assess renal and hepatic function preoperatively in patients receiving suzetrigine, as impaired function may prolong drug activity. Patients with moderate hepatic impairment (Childs Pugh Class B) have higher systemic exposures of suzetrigine and require dose adjustment while there is no change in dosage necessary for those with renal impairment (eGFR ≥ 15 mL/min by CKD-EPI equation with adjustment for the body surface area). Those with sever hepatic impairment (Childs Pugh Class C) or renal failure should avoid suzetrigine usage as it has not yet been studied in these populations⁴.

CONCLUSION

Suzetrigine represents a promising non-opioid option for acute pain management in surgical patients. However, its drug-drug interactions require careful attention from anesthesiologists.

To optimize perioperative safety, clinicians should:

1. Screen for CYP3A inhibitors/inducers in preoperative medication lists.
2. Consider alternative pain management strategies in patients on strong CYP3A modulators.
3. Screen for hepatic and renal function and consider usage accordingly.
4. Provide contraception counseling for patients on certain hormonal contraceptives.
5. Monitor for neuromuscular and sedative interactions during and after anesthesia.

By integrating these considerations into perioperative protocols, anesthesiologists can optimize the safe use of suzetrigine in surgical patients.

Daniel J. McCoy, (MD ’26)

Logan Olson, PharmD, BCCCP

Neil B. Sandson, MD

Lisa L. Sandson, BArch

Catherine Marcucci, MD

REFERENCES

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PHARMACOKINETICS OF SUZETRIGINE (JOURNAVX)

Below describes pharmacokinetic parameters of suzetrigine based on available data⁴.

1. Absorption

• • Time to Maximum Concentration (Tmax):
    • Suzetrigine: 3.0 hours (range: 1.5 – 5.03 hours)
    • M6-SUZ (Active Metabolite): 10.0 hours (range: 4.0 – 48.1 hours)
  • Bioavailability & Steady State:
    • Suzetrigine reaches 90% steady-state levels in ~3 days, while its active metabolite M6-SUZ takes 5 days.
    • Accumulation Ratio: 3.4 for suzetrigine, 4.5 for M6-SUZ, suggesting moderate accumulation with repeated dosing.

2. Distribution

• • Apparent Volume of Distribution (Vd):
    • Suzetrigine: 495 L (CV: 25.0%)
    • M6-SUZ: Not applicable
  • Protein Binding:
    • Suzetrigine: 99%
    • M6-SUZ: 96%

3. Metabolism

• • Primary Metabolic Pathway: CYP3A
    • Suzetrigine is metabolized by CYP3A, producing M6-SUZ as its major active metabolite.
    • M6-SUZ is 3.7 times less potent in inhibiting Na_v1.8 than suzetrigine.

4. Elimination

• • Primary Excretion Pathways:
    • Feces: 49.9% (only 9.1% as unchanged suzetrigine; majority as metabolites).
    • Urine: 44.0% (primarily as metabolites).
  • Effective Half-Life (T½):
    • Suzetrigine: 23.6 hours (CV: 36.2%)
    • M6-SUZ: 33.0 hours (CV: 34.9%)

Summary of Clinical Relevance for Anesthesia