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Expert Critique

FROM THE ASCO Reading Room

Justin B. Echouffo Tcheugui MD, PhD Johns Hopkins University

Emerging evidence suggest that serum vitamin D levels may contribute to the detection and treatment of painful diabetic neuropathy.

A recent British-based study reported significant lower levels of vitamin D levels among individuals with painful diabetic peripheral neuropathy, after accounting for a multitude of confounding factors. In this study, there was an inverse monotonic association between blood vitamin D levels and the extent of neuropathic pain, as well as the degree of blood glucose control. Lower vitamin D levels correlated with lower cold detection thresholds (a measure of small nerve fiber function) and subepidermal nerve fiber densities. These results suggest that vitamin D contributes to the underlying nerve damage among diabetic patients with painful neuropathy.

Contrary to prior studies, the newly published study was well conducted with a robust design. It corrected for confounding factors not accounted for in previous research; these factors that affect vitamin D levels include age, adiposity, sun exposure, and activity patterns of the subject. Moreover, the authors compared three groups of carefully phenotyped (through clinical and neurophysiological assessments) patients - a group of diabetic patients with neuropathy (further divided into those with pain and those without pain), a group of diabetic patients without neuropathy, and a group of healthy volunteers without diabetes. They relied on skin biopsy to differentiate between painful and painless peripheral neuropathy.

The aforementioned newly reported findings are consistent with those of a prior case report documenting an improvement in severe diabetic neuropathy symptoms in a patient after correction of vitamin D deficiency. Furthermore, the newly published results reinforce the case for considering vitamin D as a therapy for painful diabetic neuropathy. The findings suggest that correcting of vitamin D deficiency has the potential of arresting and reversing neuronal destruction, thus alleviating neuropathic symptoms and reducing the need for medications such as narcotics, which may exhibit severe side effects. Indeed, a prior study showed that a single intramuscular dose of 600,000 international units of vitamin D significantly reduced the symptoms of painful diabetic neuropathy.

Improvement of painful neuropathic symptoms points to the potential necessity for screening for vitamin D deficiency among individuals with painful diabetic peripheral neuropathy, as a replacement would lead to symptom improvement. However, prior to using vitamin D replacement for treating painful diabetic neuropathy in clinical practice, additional experimental evidence is needed. Such evidence would ideally originate from a randomized controlled trial that includes patients with painful diabetic peripheral neuropathy with low vitamin D levels, and shows that vitamin D supplementation significantly improves neuropathic pains.

Full Critique

Vitamin D levels have a considerable effect on painful diabetic neuropathy, even when adjusting for sun exposure and other factors, according to new research.

A study in found a significant difference in vitamin D levels in people with well-characterized painful diabetic peripheral neuropathy, which can be difficult to treat with existing options.

"We found that vitamin D levels were significantly reduced in those with painful neuropathy," said the lead author of the study, Solomon Tesfaye, MD, of Royal Hallamshire Hospital in England. "Moreover, the lower the blood vitamin D levels, the worse the pain and the poorer the glucose control."

The investigation builds on several prior reports with similar findings, Tesfaye and colleagues said. For example, a 2012 case report in initially documented improvement in severe diabetic neuropathy symptoms in a single patient after correcting a vitamin D deficiency.

"The correction of vitamin D deficiency cannot be harmful and has the potential to alleviate neuropathic symptoms and lower the need for medications, especially narcotics, with their often severe side effects," said the author of the case report, David Bell, MB, an endocrinologist based in Alabama. "In addition, with correction of vitamin D deficiency, there is the potential of arresting and perhaps reversing the progression of neuronal destruction."

In addition, a of 143 participants found that a single intramuscular dose of 600,000 international units of vitamin D significantly reduced painful diabetic neuropathy symptoms.

The new study, however, corrected for several confounding factors from previous research, such as those that tend to affect vitamin D levels, including sun exposure, Tesfaye explained. "These studies were not conducted properly as they did not evaluate sunlight exposure or activity patterns of the subjects that were studied. They also did not carefully phenotype the peripheral neuropathy to differentiate between whether the patient had painful or painless peripheral neuropathy."

"We recruited very carefully phenotyped patients and divided our neuropathy group into those with and without pain, and we also had a control group of diabetic patients without any neuropathy, as well as another group of healthy volunteers without diabetes," he said.

Tesfaye and co-authors followed 45 white European patients with type 2 diabetes and 14 healthy volunteers who underwent clinical and neurophysiological assessments. Patients with type 2 diabetes were divided into three groups: those with painful diabetic peripheral neuropathy (17 patients), those with painless diabetic peripheral neuropathy (14), and those with no diabetic peripheral neuropathy (also 14).

All patients had seasonal sunlight exposure and daily activity measured, underwent a lower limb skin biopsy, and had 25‐hydroxyvitamin D measured during July to September.

After adjusting for age, body mass index, activity score, and sunlight exposure, the team found that vitamin D levels [nanomoles/liter (se)] were lower in people with painful diabetic peripheral neuropathy [34.9 (5.8)] compared with healthy volunteers [62.05 (6.7)], no diabetic peripheral neuropathy [49.6 (6.1)], and painless diabetic peripheral neuropathy [53.1 (6.2)] (P=0.03).

Tesfaye and colleagues then assessed the impact of vitamin D and six other independent variables on painful diabetic peripheral neuropathy. Vitamin D was the only variable that significantly contributed to the symptoms. Lower vitamin D levels also correlated with lower cold detection thresholds (r=0.39, P=0.02) and subepidermal nerve fiber densities (r=0.42, P=0.01).

"We found abnormal cooling detection thresholds, a measure of small nerve fiber function, with lower vitamin D levels," Tesfaye said. "Therefore, vitamin D appears to be low in those with painful neuropathy, and this may be contributing to the underlying nerve damage in those with painful neuropathy."

The study results could further bolster the case for considering vitamin D as part of an overall treatment strategy for type 2 diabetes patients with painful diabetic neuropathy, Tesfaye said.

"The crucial point will be if vitamin D supplementation does improve painful neuropathic symptoms. If it does, then our current practice will change in that we will have to screen patients with painful diabetic peripheral neuropathy to see if they have vitamin D deficiency, as a replacement would be helpful."

Although the study provides more evidence for that case, more research may be needed to solidify the role of vitamin D levels in understanding and addressing these symptoms and their underlying causes, Tesfaye cautioned.

"I think there is a great need now to do a randomized controlled trial of patients with painful diabetic peripheral neuropathy who have low vitamin D levels to see if vitamin D supplementation would improve their neuropathic pains significantly," he said. "Previous studies showed very positive effects, but none of them were large randomized and controlled trials and we do need an adequately powered, carefully conducted, randomized controlled trial to confirm the findings of these previous studies."