Cold Hyperalgesia: 

Cold Hyperalgesia – Journavx (Suzetrigine)

Because Cold hyperalgesia is a common problem for many chronic pain patients and there are few treatment options available and even those have limited research to support their use. The mechanism by which suzetrigine suppresses acute pain through its action on peripheral nerves suggest a potential mechanistic argument for its benefit in cold hyperalgesia. No studies have been performed, and it’s use would be purely experimental.

 

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Definitions and Terms Related to Pain

Cold Hyperalgesia – Journavx (Suzetrigine)

 

The Arguments for Suzetrigine’s Potential Benefit

There is a strong mechanistic argument for suzetrigine’s potential efficacy in cold hyperalgesia, based on the unique biophysical properties of Nav1.8 at low temperatures, though direct clinical evidence for this specific indication is currently lacking.

The Critical Role of Nav1.8 in Cold Pain Perception

A landmark 2007 Nature study established that Nav1.8 is essential for pain perception at low temperatures.[1] The key finding is that cooling progressively enhances voltage-dependent slow inactivation of tetrodotoxin-sensitive sodium channels (Nav1.1-1.7), effectively silencing them. In contrast, Nav1.8 inactivation properties are entirely cold-resistant. Additionally, low temperatures decrease the activation threshold of Nav1.8 and increase membrane resistance, augmenting voltage changes. Thus, in cold conditions, Nav1.8 remains available as the sole electrical impulse generator in nociceptors. Nav1.8-null mutant mice showed negligible responses to noxious cold and mechanical stimulation at low temperatures.[1]

Functional MRI studies in Nav1.8-deficient mice confirmed that these animals have dramatically reduced brain activity and connectivity upon noxious cold stimulation, with significantly reduced BOLD signal amplitudes in pain-relevant brain structures—effects far more pronounced for cold than heat stimulation.[2]

Nav1.8 and Cold Allodynia in Neuropathic Pain

A pivotal 2021 Brain study using in vivo calcium imaging revealed that in neuropathic pain states (oxaliplatin neuropathy, partial sciatic nerve ligation, ciguatera poisoning), normally silent large-diameter neurons become cold-sensitive.[3] Critically, many of these “unmasked” silent cold-sensing neurons express Nav1.8 and CGRPα (nociceptor markers). The study demonstrated that ablating Nav1.8-expressing neurons diminished cold allodynia, providing direct evidence that Nav1.8-positive neurons contribute to pathological cold sensitivity.[3]

This finding is particularly relevant because it suggests that Nav1.8 inhibition could specifically target the aberrant cold-sensing neurons that emerge in neuropathic pain states, rather than affecting normal cold sensation (which is primarily mediated by Nav1.8-negative neurons expressing TRPM8).[4]

Suzetrigine: Mechanism and Current Evidence

Suzetrigine is a highly selective Nav1.8 inhibitor (>31,000-fold selectivity over other sodium channel subtypes) that acts on peripheral nociceptors without crossing the blood-brain barrier.[5][6] It was approved by the FDA in January 2025 for moderate to severe acute pain—the first Nav inhibitor in this new therapeutic class of non-opioid analgesics.[5]

Preclinical studies in mice demonstrate that suzetrigine:

  • – Inhibits TTX-resistant sodium currents with IC50 = 0.35 μM
  • – Reduces nocifensive behaviors in the formalin test
  • – Attenuates CFA-induced thermal hypersensitivity
  • – Reverses mechanical hyperalgesia in partial sciatic nerve injury models
  • – Does not produce tolerance with repeated dosing[7]

 

The Argument for Cold Hyperalgesia Efficacy

The mechanistic rationale for suzetrigine’s potential efficacy in cold hyperalgesia is compelling:

  1. Nav1.8 is the only functional sodium channel at cold temperatures: When other Nav channels become inactivated by cooling, Nav1.8 remains the sole impulse generator. Blocking it should preferentially affect cold pain transmission.[1]
  2. Silent cold-sensing neurons express Nav1.8: The pathological neurons that become cold-sensitive in neuropathic pain states express Nav1.8, and their ablation reduces cold allodynia.[3]
  3. Nav1.8 is expressed in high-threshold cold cells: Under normal conditions, Nav1.8 is expressed in high-threshold cold-sensing cells that contribute to cold pain (as opposed to cool sensation), suggesting selective targeting of noxious cold pathways.[8]

Important Caveats

However, several factors temper enthusiasm:

  1. Normal cold sensing is Nav1.8-independent: Approximately 80% of neurons responsive to cold down to 1°C do not express Nav1.8, and Nav1.8 deletion does not affect transient cold-induced behaviors (cold-plantar, cold-plate ≥5°C, acetone tests). Nav1.8 appears critical only for prolonged extreme cold (<-5°C) and pain in the cold rather than cold sensation itself.[4]
  2. Incomplete analgesia in clinical trials: Human DRG neuron studies show that even with >99% Nav1.8 inhibition, repetitive firing often persists due to residual Nav1.8 current and Nav1.7 contribution—potentially explaining incomplete analgesia in clinical studies.[9]
  3. No direct clinical evidence for cold hyperalgesia: While trials for diabetic peripheral neuropathy and lumbosacral radiculopathy are ongoing, no published clinical data specifically address cold hyperalgesia or cold allodynia outcomes with suzetrigine.[10][1]
  4. Nav1.6 may be more important in some conditions: In oxaliplatin-induced cold allodynia specifically, Nav1.6 (not Nav1.7 or Nav1.8) plays an essential role through increased excitability of cold-sensitive neurons.[8]

Summary

  • Nav1.8 cold-resistance: Nav1.8 is sole impulse generator at low temperatures
  • Silent cold-sensing neurons:  Express Nav1.8; ablation reduces cold allodynia
  • Normal cold sensing: HOWEVER, 80% of cold-sensing neurons are Nav1.8-negative
  • Neuropathic cold allodynia: Nav1.8+ neurons contribute to pathological cold sensitivity and Nav1.6 may be more important in oxaliplatin neuropathy
  • Clinical evidence: No published data on cold hyperalgesia outcomes |
  • Mechanistic completeness: Unfortunately, >99% inhibition still allows repetitive firing |

[1][3][4][7][8][9]

 

Conclusion

There is a strong theoretical basis for suzetrigine’s efficacy in cold hyperalgesia based on Nav1.8’s unique role as the cold-resistant sodium channel and its expression in pathological cold-sensing neurons. However, direct clinical evidence is lacking, and the complexity of cold pain mechanisms (involving multiple ion channels and both peripheral and central sensitization) suggests that Nav1.8 inhibition alone may provide incomplete relief. The ongoing trials in diabetic peripheral neuropathy may provide relevant data if cold hyperalgesia is included as a secondary outcome measure.

References

  1. Meta-Analysis of Palmitoylethanolamide in Pain Management: Addressing Literature Gaps and Enhancing Understanding. Viña I, López-Moreno M. Nutrition Reviews. 2025;83(7):e1604-e1618. doi:10.1093/nutrit/nuae203.
  2. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Lang-Illievich K, Klivinyi C, Lasser C, et al. Nutrients. 2023;15(6):1350. doi:10.3390/nu15061350.
  3. The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-Alpha Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide. Lo Verme J, Fu J, Astarita G, et al. Molecular Pharmacology. 2005;67(1):15-9. doi:10.1124/mol.104.006353.
  4. Palmitoylethanolamide: A Natural Compound for Health Management. Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. International Journal of Molecular Sciences. 2021;22(10):5305. doi:10.3390/ijms22105305.
  5. Pharmacokinetic-Pharmacodynamic Influence of N-Palmitoylethanolamine, Arachidonyl-2′-Chloroethylamide and WIN 55,212-2 on the Anticonvulsant Activity of Antiepileptic Drugs Against Audiogenic Seizures in DBA/2 Mice. Citraro R, Russo E, Leo A, et al. European Journal of Pharmacology. 2016;791:523-534. doi:10.1016/j.ejphar.2016.09.029.
  6. Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer’s Disease. Beggiato S, Tomasini MC, Ferraro L. Frontiers in Pharmacology. 2019;10:821. doi:10.3389/fphar.2019.00821.
  7. A Novel Composite Formulation of Palmitoylethanolamide and Quercetin Decreases Inflammation and Relieves Pain in Inflammatory and Osteoarthritic Pain Models. Britti D, Crupi R, Impellizzeri D, et al. BMC Veterinary Research. 2017;13(1):229. doi:10.1186/s12917-017-1151-z.
  8. Effects of Palmitoylethanolamide (PEA) on Nociceptive, Musculoskeletal and Neuropathic Pain: Systematic Review and Meta-Analysis of Clinical Evidence. Scuteri D, Guida F, Boccella S, et al. Pharmaceutics. 2022;14(8):1672. doi:10.3390/pharmaceutics14081672.
  9. Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy. Gabrielsson L, Mattsson S, Fowler CJ. British Journal of Clinical Pharmacology. 2016;82(4):932-42. doi:10.1111/bcp.13020.
  10. Ultramicronized N-Palmitoylethanolamine Associated With Analgesics: Effects Against Persistent Pain. Nobili S, Micheli L, Lucarini E, et al. Pharmacology & Therapeutics. 2024;258:108649. doi:10.1016/j.pharmthera.2024.108649.

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