Evaluation of an indirect Na_V1.7 inhibitor as adjunctive analgesic in burn-related neuropathic pain in a cat

Abstract

Burn-related neuropathic pain (BRNP) can arise following burn-induced nerve damage, affects approximately 6% of burned human patients and can result in chronic pain. Although widely studied in humans, data on BRNP or its treatment in animals is lacking. A 4-year-old domestic shorthair cat was presented with an infected, non-healing wound suspected to be a caustic burn. Initial treatments included surgical debridement, antimicrobials, and cortico-steroids, but the cat developed persistent pruritus leading to self-inflicted trauma. Despite various interventions, including prednisone, chloramphenicol and cyclosporine, clinical signs persisted, leading to a referral for suspected BRNP. Additional support for neuropathic pain was provided through thermal sensitivity testing and applying a modified Neuropathic Pain Symptoms Inventory. Treatment with gabapentin, amantadine, and acupuncture yielded little improvement, prompting an increasing escalation in gabapentin dosage. The cat was then treated with gabapentin compounded with compound 194, a small molecule that is a potent and selective inhibitor of voltage-gated sodium channel 1.7 (Na_V1.7). The cat exhibited significant pain relief and improvements in overall condition. After gabapentin was tapered, compound 194 effectively maintained pain control. The cat’s clinical condition stabilized with no adverse effects. Hematology and serum biochemistry results remained within reference intervals throughout the treatment period. This case highlights the potential of Na_V1.7 inhibitors in multimodal management of neuropathic pain in animals.

Introduction

Burn injuries in veterinary patients can lead to severe metabolic, coagulative, respiratory and cardiovascular complications (Sharpe et al. 2020). In addition, chronic neuropathic pain can develop following such injuries. This condition, known as burn-related neuropathic pain (BRNP), occurs when intense heat or chemical agents involved in a burn directly damage nerves, leading to persistent paresthesia or pain (Klifto et al. 2020). While the exact pathophysiology of BRNP remains unclear, it may involve increased neurotransmitter release from damaged nerve endings and alterations in nociceptive fiber density, although no significant difference in skin nerve density between burn scars and uninjured tissue has been observed (Hamed et al. 2011). A recent single-center, retrospective human study reported a 6% prevalence of BRNP, with symptoms developing post-injury (Klifto et al. 2020). However, no data are currently available regarding the incidence, clinical presentation or treatment of BRNP in cats.

Case description

A 4-year-old spayed female domestic shorthair stray cat was presented to the Veterinary Community Outreach Program of the University of Florida in January, 2023, with an infected, non-healing circumferential wound extending from the neck to the shoulder blades. The cause of the wound was suspected to be a caustic chemical burn, although its exact cause and duration remained unknown. On initial physical examination, heart rate was 220 beats minute⁻¹, respiratory rate 40 breaths minute⁻¹, mucous membranes were pink and moist, and the capillary refill time was <2 seconds. The cat appeared hydrated and rectal temperature after sedation was 37.1 °C. Blood tests, including a complete blood count and serum biochemistry, were within laboratory reference intervals. Initial treatment involved surgical debridement, honey bandages, and systemic antibiotics. The wound began healing, but the cat was brought back to the hospital due to persistent pruritus and self-inflicted trauma affecting the dorsal neck, lateral facial region, and convex surfaces of the ear pinnae. Histopathology from biopsies performed 10 months after the original presentation showed necro-ulcerative dermatitis and panniculitis consistent with feline idiopathic ulcerative dermatitis, and the cat was prescribed oral prednisone [3 mg mL⁻¹ suspension; PAI Pharma, SC, USA; 1.5 mg kg⁻¹ once daily (SID)] and chloramphenicol [250 mg mL⁻¹ suspension; University of Florida Pharmacy, FL, USA; 16.25 mg kg⁻¹ twice daily (BID)]. Despite 6 months of treatment, clinical signs persisted, and the cat was referred to the Dermatology Service. Thymoma was ruled out as a cause for the cat’s exfoliative dermatitis following thoracic radiographic examination. Fluoxetine (Fluoxetine HCl Compounded Oral Oil Liquid for Dogs & Cats; Chewy Pharmacy, FL, USA; 1 mg kg⁻¹ oral SID) and cyclosporine (Atopica for Cats, Elanco US, Inc., IN, USA; 10 mg kg⁻¹ oral SID) were prescribed, but discontinued after a month due to lack of efficacy and gastrointestinal adverse effects (anorexia, vomiting and diarrhea). Treatment was changed to oral dexamethasone (0.75 mg tablet; West-Ward Pharmaceuticals Corp., NJ, USA; 0.2 mg kg⁻¹ SID) and gabapentin [Ascend Laboratories LLC, CT, USA; 10 mg kg⁻¹ three times daily (TID)], which was increased to 20 mg kg⁻¹ TID after 15 weeks. Dexamethasone was replaced after 4 weeks with topiramate. Following approximately 1 month of unsuccessful treatment with topiramate (100 mg tablet; Zydus Cadila Healthcare, India; 5 mg kg⁻¹ BID), the case was referred to the Anesthesia and Pain Management Service in January, 2024.

Upon presentation, the cat had moderate alopecia extending from the eyes to the ears and ventral neck. The owner had fashioned a ‘hoodie’ which appeared to provide therapeutic mechanical stimulation through contact, leading to an improvement in pruritus. Once the hoodie was removed, the scratching behavior resumed, resulting in injury. Based on the history and clinical presentation, a tentative diagnosis of BRNP was made. The treatment plan involved continuing oral gabapentin (10 mg kg⁻¹ TID) and adding amantadine (University of Florida Pharmacy, FL, USA; 5 mg kg⁻¹ SID). Due to mild improvement of clinical signs, the gabapentin dose was increased to 20 mg kg⁻¹ after 8 weeks, and acupuncture was recommended, targeting large intestine (LI) 3, bladder (BL) 40, BL 62, kidney (KI) 3, spleen (SP) 3, and liver (LIV) 3 acupoints bilaterally, along surrounding affected areas. Acupuncture treatments were given twice weekly for 2 weeks, then weekly for maintenance. After 4 weeks without clinical improvement, amantadine was discontinued, and gabapentin was increased to 25 mg kg⁻¹ TID.

In May, 2024, thermal sensitivity (TT) was assessed (NTE-3 Thermal Sensitivity Tester; Physitemp, NJ, USA) at the midpoint of the shoulder blade, using an unaffected dorsal region for control. The starting temperature was 35–36 °C, increasing at 0.8 °C second⁻¹ until a response occurred (twitching of the skin, turning toward the heat source or avoidance of the heat source), with a cut-off at 55 °C. Cold thermal latency (CTL) was assessed with a 60-second cut-off at 0 ° C. The affected site reached both TT and CTL cut-offs, suggesting altered thermal sensitivity.

Three owner-based and one veterinarian-based clinical metrology instruments are available for assessment of feline osteoarthritis (Monteiro & Steagall 2019), but not neuropathic pain of different origin. Given the lack of a gold standard or specific set of methods or biomarkers to diagnose neuropathic pain in cats, a hierarchical grading system developed for humans, which assesses the strength of evidence for neuropathic pain, was applied. The cat in this report scored 14/38 on a modified Neuropathic Pain Symptoms Inventory (NPSI), with pain events occurring for 4–7 hours daily (Bouhassira et al. 2004; Table 1). This system, first introduced in 2008 and updated in 2016 (Finnerup et al. 2016), classified the cat as having probable neuropathic pain, further supported by the quantitative sensory testing.

Table 1.

Modified Neuropathic Pain Symptoms Inventory (NPSI), adapted from Bouhassira et al. (2004). The original questionnaire was revised to retain only questions 4, 7, 8, 9 and 10, excluding those that inquire about the quality of the painful sensation. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc. Please contact permissions@lww.com for further information

Severity of the spontaneous pain

During the past 24 hours, your pet’s spontaneous pain has been present:

Permanently

8 to 12 hours

4 to 7 hours

1 to 3 hours

<1 hour

Severity of the painful attacks

During the past 24 hours, how many of these pain attacks has your pet had?

More than 20

Between 11 −20

Between 6–10

Between 1–5

No pain attacks

Severity of provoked pain

Do you feel your pet’s pain is provoked or increased by brushing on the painful area?

Do you feel your pet’s pain is provoked or increased by pressure on the painful area?

Do you feel your pet’s pain is provoked or increased by provoked or increased by contact with something cold on the painful area?

After obtaining written, informed consent from the owner, the cat was prescribed oral gabapentin (10 mg kg⁻¹) compounded with compound 194 (0.5 mg kg⁻¹ TID). Compound 194 is a small molecule that is a potent and selective indirect inhibitor of voltage-gated sodium (Na_V) channel 1.7 expression and function in dorsal root ganglia (DRG) sensory neurons (François-Moutal et al. 2018; Cai et al. 2021). This dosage was based on allometric scaling from rodent studies (Cai et al. 2021). After 3 weeks of treatment, the owner reported a significant improvement, with pain events decreasing from 4–7 hours per day to less than 1 hour daily. This improvement was maintained over the following 3 months. Gabapentin was tapered and discontinued after 3 months, with the cat maintained on compound 194 (1 mg kg⁻¹ TID). At the time of writing, the cat is being given compound 194 on an ‘as-needed’ basis, with the owner administering a dose only during breakthrough crises. The cat’s condition is stable, with improvements in body mass, activity and playfulness. Blood tests performed 3 weeks and 6 months after introducing compound 194 remained within laboratory reference intervals. Follow-up quantitative sensory testing at 6 months recorded a TT of 44 °C and CTL of 14 seconds, which are consistent with values reported in healthy cats on a shaved thoracic region (Lascelles & Robertson 2004). The NPSI decreased to 10/38.

Discussion and conclusions

Na_V1.7 channels are predominately found in sensory neurons of the peripheral DRG (Shilo & Pascoe 2014). These channels play a key role in amplifying subthreshold stimuli and determining the threshold for action potential generation in nociceptors. The importance of Na_V1.7 in pain sensation is highlighted by human pain disorders: gain-of-function mutations in Na_V1.7 are linked to severe pain syndromes, while loss-of-function mutations result in congenital insensitivity to pain (Cai et al. 2021). This makes Na_V1.7 an attractive target for analgesic treatments. Despite promising in vitro pharmacological profiles, direct Na_V1.7 blockers have shown limited success in clinical trials (Siebenga et al. 2020). To address this, the small molecule compound 194 uses an alternative approach; indirectly modulating Na_V1.7 trafficking. It targets collapsin response mediator protein 2 (CRMP2), an accessory protein. By inhibiting CRMP2 SUMOylation via the E2 SUMO-conjugating enzyme UBC9, compound 194 promotes Na_V1.7 internalization, effectively reducing Na_V1.7 currents in DRG neurons across various species, including mice, rats, pigs and humans (Cai et al. 2021; Li et al. 2022) (Fig. 1). Compound 194 has shown efficacy in both reversing and preventing neuropathic pain in various models, including chemotherapy-induced peripheral neuropathy and inflammatory pain (Cai et al. 2021; Braden et al., 2022). In male rats undergoing spinal nerve ligation surgery, oral doses of compound 194 demonstrated synergy with parallel administration of gabapentin, improving the paw withdrawal threshold between 180 and 240 minutes after dosing compared with a similar dose of gabapentin alone (Cai et al. 2021). This case marks the first documented use of compound 194 in an animal with BRNP following natural exposure to a suspected caustic insult. The addition of compound 194 allowed reduction of the gabapentin dose, alleviating sedation and improving playfulness and quality of life, suggesting compound 194 may provide effective analgesia without drowsiness.

Figure 1.

An illustration of the mechanism of action for compound 194, which disrupts the interaction between collapsin response mediator protein 2 (CRMP2) and the E2 SUMO-conjugating enzyme UBC9 (capped line), thereby inhibiting the SUMOylation of CRMP2. This leads to a reduction in voltage-gated sodium channel 1.7 (Na_V1.7) localization at the cell surface, subsequently decreasing sodium currents and providing pain relief. Image created using BioRender.com.

Conclusion

Compound 194 may offer an alternative for multimodal neuropathic pain management in larger mammals. However, controlled studies are needed to better understand its pharmacokinetics, pharmacodynamics and long-term safety in cats and other animal species.

Multiple choice questions.

What is the terminal half-life of amantadine HCl in cats after a single oral dose of 5 mg kg⁻¹?

1. Approximately 2–3 hours.

2. Approximately 5–6 hours.

3. Approximately 8–10 hours.

4. Approximately 10–14 hours.

Reference.

Siao KT, Pypendop BH, Stanley SD, Ilkiw JE (2011) Pharmacokinetics of amantadine in cats. J Vet Pharmacol Ther 34, 599e604.

Which signaling pathways are associated with acupuncture analgesia?

1. Release of opioid peptides in the spinal cord.

2. Release of cholecystokinin-8 (CCK-8).

3. Activation of spinal glial cells.

4. Release of glutamate in the spinal cord.

Reference.

Cantwell S (2014) Mechanisms of acupuncture analgesia. In: Pain Management in Veterinary Practice (1st edn). Egger CM, Love L, Doherty T (eds). John Wiley & Sons, IA, USA. pp. 177–182.

In which tissue is the voltage-gated sodium channel (Na_V) 1.7 primarily found?

1. Skeletal muscle.

2. Cardiac muscle.

3. Peripheral sensory neurons and dorsal root ganglia (DRG).

4. Immature neurons.

Reference.

Shilo Y, Pascoe PJ (2014) Anatomy, physiology and pathophysiology of pain. In: Pain Management in Veterinary Practice (1st edn). Egger CM, Love L, Doherty T (eds). John Wiley & Sons, IA, USA. pp. 9–27.