A study recently published in Eye and Vision assessed the therapeutic potential of Vitamins B3, B12, and D as treatment for neuropathic corneal pain (NCP).
Give me some background.
NCP refers to aberrant corneal pain perception in the absence of stimuli arising from corneal nerve dysfunction and no clinically observable ocular surface abnormalities.
Hallmark features of NCP include:
- Burning
- Sensitivity to wind and light
- Electric-shock-like or stabbing pain
- Corneal hyperalgesia
- Allodynia
What is the pathogenesis of NCP?
The underlying etiology is multifactorial, which encompasses several pathological processes ranging from:
- Neuroinflammation
- Mitochondrial dysfunction
- Apoptosis
- Neurotoxicity
- Wound healing
- Neuronal degeneration
- Nociceptive dysfunction
Note: Each of these pathological processes, and their interactions, present potential therapeutic approaches for NCP management.
And how is NCP treated?
The primary goals of therapeutic paradigms in NCP are the mitigation of inflammation and promotion of corneal nerve regeneration. Both can involve:
However: The study authors noted that due to the diverse etiological spectrum, characteristic clinical-symptomatic disparity, and lack of standardized diagnostic and therapeutic frameworks, current insights into NCP remain fragmentary.
- “Given the established dual capacity of vitamins to provide neuroprotection and antioxidative effects in various neuropathies and associations between vitamin deficiencies and NCP in the literature, vitamin supplementation may be a potential therapeutic avenue,” they added.
Now to the study.
In this narrative review, investigators analyzed preclinical animal and clinical studies to outline the potential mechanisms of action provided by vitamin supplementation (specifically with Vitamins B3, B12, and D) in alleviating NCP.
The research team also offered insights into future directions needed for vitamin supplementation to serve as a mainstream treatment for NCP.
Let’s start with the role of Vitamin B3 in NCP.
Vitamin B3 belongs to the water-soluble B complex group, and is hypothesized to exert therapeutic effects in NCP through three mechanisms:
- Antioxidation: By generating nicotinamide adenine dinucleotide (NADH) production
- Neuroregeneration: Upregulation of sirtuin 2 activity
- Anti-inflammation: Via hydroxycarboxylic acid receptor 2 (Hcar2) agonism, which downregulates inflammatory cytokine production
What about Vitamin B12?
Vitamin B12 is the largest and most complex vitamin in the human body; its therapeutic impact on NCP management has been suggested to involve a combination of:
- Neuroregeneration: Upregulation of neurofilament and β-III tubulin expression, which improves nerve conduction velocity and inhibits spontaneous ectopic activity
- Antioxidation: Suppressing oxidative stress levels
- Antinociception: Increasing serotonin and dopamine levels in different brain regions, which enhance inhibitory regulation of the nociceptive system
And finally Vitamin D.
Vitamin D is a secosteroid that acts as an essential metabolite for various human physiological processes; its beneficial effects in NCP are thought to be mediated by:
- Anti-inflammation: Regulates toll-like receptor (TLR)-mediation inflammation and reduces proinflammatory cytokine expression
- Antioxidation: Upregulation of antioxidant enzymes (e.g., superoxide dismutase, catalase)
- Neuroregeneration: Promotes nerve growth factor production
- Antinociception: Inhibition of nitric oxide and prostaglandin E2 (PGE2) production and modulation of pain neurotransmitters (e.g., serotonin, dopamine)
What were the results from preclinical studies?
Several preclinical rodent studies have suggested that neuropathic pain can be relieved by nicotinamide riboside, a member of the Vitamin B3 family, due to its neuroprotective effects.
Plus: A study performed on male rats demonstrated the potential therapeutic benefit of Vitamin B3 in managing paclitaxel-associated neuropathic-like ocular pain.
What about clinical studies?
One retrospective study of 84 patients with NCP found that Vitamin B2 and D deficiencies were present in 31% and 15.8% of patients, respectively, while elevated Vitamin B6 and B12 levels were identified in 28.9% and 15.0% of subjects.
Plus: Two case reports of NCP patients, one with Vitamin B12 deficiency and the other with Vitamin D deficiency, were highlighted.
In both cases, addressing the respective vitamin deficiencies led to complete symptom resolution within 3 weeks (Vitamin B12) and 4 days (Vitamin D) of initiating supplementation.
Take home.
These findings demonstrate the viability of Vitamin B3, B12, and D supplementation as a therapeutic approach to managing NCP due to their anti-inflammatory, neuroregulatory, nerve regenerative, and antinociceptive effects.
Next steps?
The study authors explained that vitamin supplementation should be represented in larger, multicenter studies to further establish its therapeutic relevance in NCP and optimal treatment protocols, including:
- Dosing regimens
- Treatment duration
- Optimal methods of administration for each vitamin
Go on …
They hypothesized that topical vitamin formulations may offer advantages in achieving higher vitamin concentrations in the targeted tissue (cornea) compared to intramuscular and oral routes and may mitigate the risk of dose-dependent systemic adverse effects.
Finally: Other avenues for research may include dietary lifestyle interventions, such as low-fat plant-based, caloric-restricted, and potassium-reduced diets due to their neuroprotective and anti-inflammatory benefits in neuropathic pain.