Benefits of vitamin D as an additional therapy in painful diabetic neuropathy: Case report and recent literature review

The common chronic complication from diabetes mellitus (DM) is painful diabetic neuropathy. The available symptomat ic treatment with standard therapy is not sufficient for pain reduction. Previous studies showed that vitamin D deficiency was common in type 2 diabetes. Some studies report the benefit of vitamin D supplementation. We report a case of a type 2 diabetic 54-year-old obese female with painful diabetic neuropathy. The combination of lifestyle modifications and 2000 IU vitamin D supplementation improved neuropathy eight weeks of therapy symptoms. The literature search found a valid article that supports the use of combined exercise and vitamin D supplementation. Further research with a larger sample and better design is warranted.


INTRODUCTION
Diabetes mellitus is one of the most common non-communicable diseases. Data from the International Diabetes Federation (IDF) Diabetes Atlas in 2019 shows that there are 460 million diabetics and is predicted to increase by 51% by 2045. Sixty percent of people with diabetes will experience complications in diabetic peripheral neuropathy, with 54,000 people with diabetes experiencing amputation every year [1]. Diabetic peripheral neuropathy is one of the most common chronic complications of diabetes mellitus. Painful diabetic neuropathy is characterized by tingling, burning, shooting, numbness or even electric shock sensations that can decrease the patient's quality of life [2].
Symptomatic first-line treatment for diabetic neuropathic pain is adjuvant analgesics consisting of tricyclic antidepressants such as amitriptyline and imipramine, SNRIs (Serotonin Norepinephrine Reuptake Inhibitors) such as duloxetine and anticonvulsants such as pregabalin and gabapentin.
However, the available study data indicate that the current symptomatic therapy is not optimal in reducing pain and is only beneficial in one in three patients [3]. In addition, the use of this standard therapy is also limited due to the emergence of unwanted side effects so that the treatment of painful diabetic neuropathy patients is not limited to a single treatment [3,4].
Vitamin D deficiency is common in diabetic patients. Low vitamin D concentrations are associated with painful diabetic neuropathy through microvascular injury or direct neuronal metabolic injury [5,6]. Vitamin D deficiency is an independent predictor of painful diabetic neuropathy [7][8][9]. Vitamin D has a neuroprotective effect by regulating the VDR (vitamin D receptor) and L-type calcium channels [4]. Diabetic peripheral neuropathy is associated with decreased expression of the Nerve Growth Factor (NGF), while vitamin D is known to increase NGF synthesis in human nerve cells [10,11]. Moreover, at recommended doses, vitamin D tends to have low side effects, so vitamin D therapy is considered a promising intervention for treating painful diabetic neuropathy [12]. However, current evidence from randomized controlled trials on vitamin D in treating painful diabetic neuropathy is currently lacking, and relevant systematic reviews and meta-analyses are also minimal [4].
Symptomatic treatment of diabetes with existing therapies is still not optimal in reducing symptoms. An additional treatment that improves symptoms and plays a role in the pathomechanism of neuropathy in diabetes is urgently needed [11,13].

CLINICAL QUEsTION
A 54-year-old woman came to the neurological department in early March 2021 with complaints of tingling, burning pain and electric shock accompanied by numbness in the tips of her feet and hands since five months ago. The complaint has worsened in the last one month. Pain interferes with the patient's sleep and daily activities. Since six years ago, the patient is a type 2 diabetes mellitus patient with poor blood sugar control (last HbA1c was 7.2%). Patients take metformin two to three times daily and acarbose twice daily. The patient's lipid profile was as follows: LDL cholesterol 130 mg/dL, HDL 40 mg/ dL, and triglycerides 242 mg/dL. Blood pressure was controlled with candesartan 8 mg per day. The patient has a body mass index (BMI) value of 24.8 kg/ m 2 . Neurological physical examination leads to painful diabetic neuropathy. Examination of latency and nerve conduction velocity (electroneuromiograph) confirmed demyelinating type polyneuropathy.
Symptomatic therapy with gabapentin at a dose of 2 times 300 mg per day reduces pain by less than 30%. Additional therapy with mecobalamin three times daily did not significantly reduce pain. Adjunctive therapy with amitriptyline 10 mg at night improved sleep but did not significantly reduce pain. The daily pain intensity in patients with a numeric pain scale is 5-7 out of 10.
Examination of vitamin D levels in the patient showed a deficiency of 8 ng/ml (normal > 30 ng/ml). Non-pharmaceutical and pharmacological treatments are more intensive in patients to achieve the HbA1c and LDL targets. Non-pharmaceutical therapy with regular exercise and diet is carried out. Pharmacological management is added with vitamin D 1000 IU twice a day. In the evaluation of the first month, the complaints are much reduced. The daily pain intensity value is 4-5 from a 10 numeric pain scale. There was an improvement in the LDL value to 88 mg/dL. Patients claim to be more regular in exercising every day between 20-30 minutes with a morning walk around the housing complex.
On the second visit, the complaints got better. Sleep and daily activities improve. Measurement of vitamin D levels improved to 31 ng/ml (normal). The daily pain intensity value is 2-3 from a 10 numeric pain scale. Blood sugar levels ranged from 100-112 mg/dL, and current blood sugar levels ranged from 150-180 mg/dL. The patient's BMI value improved to 22.6 kg/m 2 .
The clinical question arises: "Can additional vitamin D therapy reduce pain in painful diabetic neuropathy?". The PICO (population-intervention-comparison-outcome) components of the clinical question were as follows: population: patients with painful diabetic neuropathy, intervention: supplementary vitamin D therapy, comparison: symptomatic therapy alone, and outcome: painful diabetic neuropathy.

METHODs
The literature search was performed in four databases, including PubMed, CENTRAL, EbscoHost, and ProQuest. Keywords included are vitamin D, neuropathy, painful diabetic neuropathy, therapy, pain, diabetes, type 2 diabetes.
After checking for duplication and elimination with endnote, the first screening stage was carried out by limiting the search to articles by design: in English, in humans, published in the last five years. Stage 1 screening received 11 articles. Based on the best and most current scientific evidence, only further research will be carried out with randomized controlled trial designs.
The second screening stage was carried out by entering the criteria for a randomized controlled trial and accessible full text, seven articles were obtained. By excluding the administration of high-dose vitamin therapy intramuscularly, three articles were found that fit the clinical question and matched the patient's characteristics [14][15][16].

Critical review
The first step after an article is selected is to determine the degree of scientific evidence and validity of the therapeutic article. The validity was based on the Canter of Evidence-Based Medicine Criteria at the University of Oxford [11,12]. There are several requirements for the validity of a therapeutic article: [1] randomization, [2] blinding, [3] the same characteristics at the beginning of the study, [4] there is no difference in treatment between groups except in terms of the drug/tool being tested, [5] reasonably complete follow-up, and [6] an intention-to-treat analysis was performed.

Unclear
There is no information about loss of follow-up and no information on the intention to treat analysis Are measurements still "blind"?
Unclear No blinding information Karonova, T, et al., 2020 Has the placement of each patient for treatment been randomized?
Yes, in the method section Randomization of patients using the even/ odd method into two groups of cholecalciferol treatment Were each group similar when the study began?
Yes, in the results section ,  table 1 There were no significant differences in the distribution of gender, age, BMI, duration of the history of type 2 diabetes mellitus, HbA1c, and other drugs. Were all patients enrolled in the study recorded? And were they analyzed for intention to treat?

Unclear
After randomization, three patients refused to participate in the study, and two patients with upper respiratory tract infections were excluded from the study. There is no information on the intention to treat analysis Are measurements still "blind"?
Unclear No blinding information Davoudi, M, et al., 2021 Has the placement of each patient for treatment been randomized?
Yes, in the method section Participants were randomized into five groups using a random table Were each group similar when the study began?
Yes, in the results section ,  table 1 There is no difference in terms of age and gender. There is no other information regarding HbA1c, duration of DM, BMI, and other drugs Were all patients enrolled in the study recorded? And were they analyzed for intention to treat?

Unclear
There is no information on loss of follow-up and no info on intention-to-treat analysis Are measurements still "blind"? Yes, in the method section Patients receiving vitamin D or placebo were blinded

DIsCUssION
Based on the journal search results, three articles matched the clinical questions posed, and then a critical study was conducted. After confirming that the article is valid and the results are essential, it is determined whether it can be applied. The questions that should be asked before using the study results to patients are: [1] Are our patients so different from the article reviewed that the results are not applicable? [2] Is the treatment feasible in the current situation? And [3] Will the potential benefits of the treatment outweigh the potential harm of the treatment to the patient?
The three studies found were randomized clinical trials to determine the effect of vitamin D administration on reducing the pain intensity of diabetic neuropathy. Nadi et al., 2017 combine training, and vitamin D administration for 12 weeks to improve sensory-motor neuropathy in 81 diabetic neuropathy patients. The subjects of this clinical trial were females aged 20-55 years who had a history of type II diabetes mellitus for more than five years and had no other comorbidities. Karonova et al., 2020 compared two doses of vitamin D for 24 weeks to improve microcirculation, decrease inflammation, and reduce pain in diabetic neuropathy patients. The subjects used were 67 patients (female predominance) aged 18-65 years and had a history of diabetes for five years. Research by Davoudi et al., 2021 combines vitamin D supplementation and mindfulness training on pain severity, pain-related disability, and neuropathy-specific quality of life dimensions in painful diabetic neuropathy. The subjects were 225 patients aged 20-70 years, had vitamin D insufficiency or deficiency, and had no severe comorbidities. The subjects used in the three articles reviewed were according to the basic characteristics of the patients in this study, namely a female patient aged 54 years and has a history of type II diabetes for six years.
The results of a clinical trial by Nadi et al., 2020 showed that after three months of combined training with vitamin D supplementation, there was a significant reduction in numbness (p=0.001), pain (p=0.002), tingling (p=0.001), and weakness (p=0.002) in the lower limbs. There was also an increase in the sense of touch intervention (p=0.005), detects the position of the fingers (p=0.001), and vibration perception (p=0.001). However, there was no significant change in the patellar reflex in the knee (p=0.77) and the Achilles tendon reflex in the ankle (p=0.47) after the intervention [14].
These results are similar to those experienced by patients reported in this study, is after patients were given additional vitamin D therapy, there was a decrease in daily intensity values from the baseline numeric pain scale of 5-7 to a scale of 4-5 in the first-month evaluation and a scale of 2-3 at the second-month evaluation.
The study by Karonova et al., 2020 after 24 weeks of intervention, found that the group was given highdose vitamin D supplementation of 40,000 IU/week showed a significant reduction in neurological deficits based on NDS points (p=0.001), decrease in pain severity as assessed by VAS (p=0.001), and a significant decrease in the neuropathic symptom score (NSS) (p=0.001). Meanwhile, no difference was found in the group given vitamin D 5000 IU/week [15]. Davoudi et al., 2021 showed that compared to the placebo group, giving an oral dose of vitamin D 4000 IU/day could significantly improve the total Quality of Life (QOL) score, especially on the pain, interpersonal, and emotional burden subscale. In addition, it can also significantly improve pain-related disability and reduce the severity of pain in diabetic neuropathy. However, the most significant improvement was in the combination group of vitamin D + Mindfulness training [16].
Between the three studies reviewed with our patients, differences were in the dose used. However, a search for articles had excluded high-dose vitamin D therapy administration intramuscularly according to our patient's clinical inquiry. Our patients received a higher dose of vitamin D, which is 2 x 1000 IU daily, Likewise, in our case, no side effects were reported by the subjects. Thus, the ratio of benefit to risk in the administration of vitamin D is good.
A prospective, placebo-controlled trial by Alam et al., 2017 included 112 diabetic patients with peripheral diabetic neuropathy and vitamin D deficiency [25(OH)D]. Subjects were divided into two groups: the intervention group with 57 people and the placebo group with 55 people. The intervention group was given 600,000 IU of vitamin D intramuscularly once a week, assessed using neuropathy specific quality of life (NeuroQoL) questionnaire for both groups. The results of this study were that there was a significant increase in 25(OH)D (p<0.0001), calcium (p=0.009), HDL (p=0.03), and a reduction in HbA1c (p=0.02). There was a significant improvement in the NeuroQoL score in the stress section. Still, there was no significant change in the NeuroQoL score in the paresthesias, temperature, and touch sensation [19].
A quasi-experimental trial (before-after) by Ghadiri-Anari et al., 2019 with subjects of 58 diabetic neuropathic pain patients, the results showed that after administration of vitamin D3 5000 IU/ week orally for 12 weeks, there was a significant increase in HbA1c, vitamin D levels, and Michigan Neuropathy Screening Instrument (MNSI) assessment (p<0.001) (17). A recent randomized placebo-controlled study by Sari et al., 2020, with 258 patients also showed similar results. The intervention group was given 300,000 IU intramuscular vitamin D supplementation showed a significant reduction in total DN4 score after 12 weeks. (p=0.008). Similar-ly, the Pinzon and Christi, 2020 study, also conducted at the same hospital as this study, showed that vitamin D supplement therapy was beneficial in reducing the painful symptoms of diabetic neuropathy compared to symptomatic therapy alone [20].
The results of a review of the available scientific evidence for vitamin D therapy show that there is a very promising potential benefit as an adjunct therapy for patients with diabetic neuropathic pain. Further research on a larger scale and more extended observations are needed. Research to assess the most optimum dose is also required. The administration of vitamin D therapy is following recent studies that state that pathognomonic treatment is required in painful diabetic neuropathy, not only focusing on symptom reduction [5,13].

CONCLUsION
A case of diabetic neuropathic pain has been reported in a 54-year-old woman that showed improvement after giving 2000 units of vitamin D per day. These results are supported by research with valid scientific evidence.