Vitamin D Deficiency–Associated Neuropathic Pain Examined in a Chronic Pain Management Program

Introduction

Neuropathic pain is a complex and often debilitating sequelae resulting from damage or disease of the central or peripheral nervous system.¹ Numerous conditions associated with neuropathic pain or neuralgia include traumatic injury, nerve compression, musculoskeletal structural changes, diabetes, autoimmune disorders, chronic alcohol use, metabolic imbalances, organ dysfunction, neoplasms, infections, medications, vascular problems, and iatrogenic complications. Underlying mechanisms of neuralgia remain unclear. However, theories often involve neuronal dysfunction causing abnormal pain signaling and processing. This proposed dysfunction results in nerves becoming hypersensitive, often sending pain signals in response to mild nonpainful stimuli or firing spontaneously.² Furthermore, pain exacerbation may be the result of suppression of inhibitory synaptic connections.³ Neuropathic pain is typically described as a radiation experience of shocking, burning, and stabbing quality. It can be associated with numbness, paresthesia, weakness, spasticity, and abnormal reflexes. Depending on severity, neuralgia can substantially impede patients’ independence and degrade their overall quality of life. Due to its diverse presentations and multifactorial etiologies, neuropathic pain proves to be an elusive challenge to manage.^1,3

Vitamin D is an essential metabolite for various physiological processes including calcium homeostasis. Vitamin D comes in 2 primary forms: vitamin D2 and vitamin D3.⁴ Ergocalciferol (vitamin D2) is typically supplemented through dietary sources, including mushrooms, supplements, and enhanced fortified foods. Cholecalciferol (vitamin D3) is primarily synthesized in the skin through ultraviolet B exposure from sunlight, during which 7-dehydrocholesteol is converted to previtamin D3 via ultraviolet B radiation, but it can also be found in foods including fish, meat, eggs, and dairy products.⁵ Vitamin D is absorbed and synthesized in its inactive form and undergoes hydroxylation in the liver, creating calcidiol (25-hydroxyvitamin D [25(OH)D]), and in the kidneys, creating calcitriol (1,25-dihydroxyvitamin D [1,25(OH)2D]), bringing it to its active form.⁶ Vitamin D deficiency is often seen in patients presenting with neuropathic pain.

The authors have presented a clinical case of neuropathy and neuralgia associated with hypovitaminosis D.

Case Presentation

A 46-year-old right-handed Black male patient with past medical history of severe obesity, viral cardiomyopathy, left ocular prosthesis, meningitis, lumbar stenosis with radiculopathy, chronic low back pain status after right L5-S1 foraminotomy, and microdiscectomy 10 months prior, was referred to the chronic pain management clinic for evaluation by neurology after inconclusive findings. Per neurology, the patient complained of continued but improved chronic back pain with persistent difficulty walking due to right leg weakness. The patient also admitted to hyperalgesia in the lower extremity inconsistent with lumbar radiculopathy. Previous neurology examination showed right hand clumsiness and weakness, right leg proximal and distal weakness, and brisk right upper and lower extremity reflexes. An MRI of the cervical and thoracic spine postdecompression revealed C4-5 signal enhancement appearing to be more inflammatory in origin than compressive. Lumbar puncture revealed mildly elevated protein of 56 mg/dL with no white blood cells. Workup for autoimmune, infectious, and metabolic causes of myelopathy was unremarkable.

At the visit assessment, the patient reported bilateral low back pain, numbness and paresthesia in the right dorsal foot, hyperalgesia in the right lower extremity, right extremity incoordination and “sensation” of weakness, and difficulty ambulating, for which he used a cane. For pain medications, the patient had been on a regiment of oxycodone 30 mg per day, nortriptyline 40 mg per day, and topical diclofenac gel. Despite best efforts, the pain was still substantially interfering with day-to-day activities. The patient used to work in the shipping industry but had to stop all activity due to the debilitating pain. Overall, he had been out of work for more than a year. He expressed a feeling of depression with his outlook and frustration because he had difficulty financially providing for his family.

On physical examination, the patient had typical muscle bulk and tone with 5/5 strength in bilateral upper and lower extremities. He had decreased sensation in the right dorsal foot and hyperalgesia in the entire right extremity. Ankle clonus and upper motor neuron signs were negative. The patient also had an antalgic wide-based gait and pain with weight bearing in the right lower extremity. Examining spinal range of motion, the patient had increased pain with lumbar extension. On palpation, there was local tenderness in the right sacroiliac joint with a positive flexion, abduction, and external rotation test on the right side. With the hip examination, pain with internal rotation of the left hip was present. Recent relevant labs showed complete blood count, vitamin B12, and hemoglobin A1c were unremarkable. Based on recent lumbar spine MRI imaging, there was no clear spinal nerve etiology for his persistent numbness and tingling pain in the right dorsal foot.

Verbal and written informed consent was received formally by the patient described in the case and stored in the authors' files appropriately.

Treatment Pathway

The patient was admitted to the chronic pain program and assessed for neuropathic pain in the right lower extremity and right sacroiliac joint pain. For the pain management plan, the patient was referred to physical therapy, pain psychology, and pain management courses. In the meantime, the patient was advised to try topical pain creams including Arnica and over-the-counter pain relief patches. Updated comprehensive labs were ordered including complete nutritional labs to assess levels of vitamin D, B1, B6, and B12, along with fructosamine, thyroid-stimulating hormone, and magnesium. Sacroiliac joint injections were proposed as a future consideration.

Comprehensive laboratory results obtained after the visit were unremarkable except for vitamin D, which showed abnormally low levels at 6 ng/mL. The patient was then prescribed a vitamin D supplementation regimen with a high loading dose of vitamin D3 at 300,000 IU, followed by vitamin D3 at 5000 IU once daily.

Outcomes

At the 1-month follow-up clinic visit, the patient reported that symptoms of neuropathy (including pain, numbness, hyperalgesia, and paresthesia) had improved "tremendously" since starting vitamin D3 supplementation. The patient no longer needed a cane for walking support, including walking on the treadmill and up hills, and he was looking to return to work immediately. He was also able to work out using kettle bells, which previously was not feasible. Vitamin D levels were trending up at 32 ng/mL. The patient was also using less oxycodone, which was reduced from 20 mg per day to 10 mg per day. Targeting a vitamin D level of < 40 ng/mL, vitamin D3 supplementation was increased to 6000 IU once daily and rechecked, showing 34 ng/mL. Upon subsequent visits, supplementation was gradually increased up to 10,000 IU once daily, with a corresponding vitamin D level of 41 ng/mL. A total of 10 months after the initial encounter, the patient was able to be weaned off oxycodone and alternatively prescribed naproxen instead for chronic pain.

Discussion

Vitamin D deficiency has been seen in patients with neurocognitive dysfunction and neurodegeneration.⁷ Epidemiological literature has been shown to have inconsistent findings with direct causal and observational evidence between hypovitaminosis D and neuropathies.^8,9 Additionally, it remains unclear whether or not vitamin D deficiency is the cause or the result of peripheral neuropathy (PN) and its underlying conditions.¹⁰ Studies have investigated the prominent existence of vitamin D deficiency in various neuropathic-associated disorders. In the study by Demiryurek et al examining carpal tunnel syndrome (CTS) and vitamin D levels in patients, serum vitamin D was significantly lower in those patients with mild CTS than in those patients without it (p = 0.02). Patients with both mild CTS and high subjective pain levels were also correlated with hypovitaminosis D (p = 0.03).¹¹ A study examining a multiple myeloma cohort showed a high incidence of PN and vitamin D deficiency in total (p = 0.035) and active (p = 0.016) patients with multiple myeloma, indicating supplementation could be beneficial to PN improvement.¹² Elf et al documented that all patients in the study with immune-mediated PN had significantly lower 25(OH)D than their healthy counterparts.¹³ Additionally, other studies have examined close relationships between vitamin D deficiency and demyelinating disorders, with evidence of supplement efficacy for immunomodulation including neuromyelitis optica, multiple sclerosis, and Guillain–Barré syndrome.^10,14

Supplementation with vitamin D has promise in improving neuropathic symptoms, especially in patients with diabetic PN (DPN). Findings have shown a strong relationship between hypovitamosis D and diabetic neuropathy.¹⁵ In a randomized, placebo trial examining patients with combined DPN and vitamin D deficiency, the treatment group (which received 300,000 IU intramuscular vitamin D at week 0 and week 12) appeared to have significantly improved Douleur Neuropathique 4 neuropathic pain scores (p = 0.008), Berg Balance Scale test scores (p = 0.001), and electric shock or burning sensations.¹⁶ In a study by Basit et al, the investigators found that in the 58 participants with painful DPN and vitamin D deficiency, a single high dose of 600,000 IU of vitamin D significantly increased serum 25(OH)D and showed reduced Douleur Neuropathique 4 scores (p < 0.0001), total McGill Pain scores (p < 0.0001), and McGill Pain Questionnaire scores (p < 0.0001).¹⁷ Pinzon et al indicated that for experimental patients with DPN, the benefits of vitamin D adjunct with 5000 IU improved burning pain (1.76 ± 7.16 vs 6.18 ± 13.93, p = 0.046), mood scores (88.2% vs 70.6%, p = 0.031), and vitamin D levels (40.02 ± 15.33 ng/mL vs 18.73 ± 6.88 ng/mL; p < 0.001) over standard therapy alone.¹⁸

Although not typically solely contributory to neuropathic presentation, vitamin D deficiency has been associated with neurologic dysfunction and inflammatory expression that may be involved with exacerbating and intensifying neuropathic and musculoskeletal pain.¹⁹ Vitamin D and its receptor have potential pain signaling capabilities of inducing nerve growth factor, glial-derived neurotrophic factor, epidermal growth factor receptor, and opioid receptors expression and restricting neurotrophic deficits to promote nerve healing and prevent PN.^20–22 Studies have suggested that vitamin D regulates expression of inflammatory cytokines involved in pain processing, along with interferon 6 and tumor necrosis factor alpha.²³ As stated previously, vitamin D also has been associated with immunomodulation and preventing autoimmune disorders.²⁴ Therefore, hypovitaminosis D plays an integral role in amplified inflammation response, pain sensitization, and pain signaling. Based on initial studies, supplementation with vitamin D may prove to be an effective alternative therapeutic for modulating neuropathic pain and impeding the progression of worsening neuropathy and chronic pain.

Vitamin D deficiency is often associated with lack of sunlight exposure, obesity, elderly populations, and malabsorption disorders.²⁵ Furthermore, due to melanin’s protective effects against ultraviolet radiation, those with darker skin tones, including those in African, Middle Eastern, Indian, and South American populations, are more prone to deficiency.²⁶ Vitamin D deficiency is prevalent but highly curable with nutritional supplementation. Supplementation should be considered in populations with darker skin tones, with lack of outdoor exposure, in high latitude areas, and with nutrient-associated health disparities including poverty, high crime rates, and lack of appropriate health care access.²⁷ In the clinical setting, patients in long-term hospitalization or patients with compromised skin surface area (ie, postburn) may also require additional vitamin D.^28,29

Target levels of serum 25(OH)D are typically < 30 ng/mL. However, literature has trended toward 40–80 ng/mL as the optimal target range.³⁰ High bolus doses of vitamin D at 300,000 IU, with daily doses of 5000 IU, have been efficaciously seen as sufficient supplementation to improve deficiency status without causing adverse side effects.^31–33 Standardized supplementation regiments and duration for treatments remain unclear and require further evaluation. However, the regiment may be variable on a case-by-case basis.^17,34,35 Due to their metabolic relationship, calcium, phosphorus, and parathyroid hormone levels should continue to be monitored regularly during high-dose vitamin D supplementation.³⁶ Overall, advocating for comprehensive nutritional panels, especially levels of vitamin D, as an essential part of the diagnostic process for neuropathic pain is a logical and proactive approach. The authors call for future prospective and retrospective studies to comprehensively investigate both the mechanisms and efficacy of vitamin D supplementation in alleviating neuropathy and neuropathic pain.