Vitamin D for the treatment of painful diabetic neuropathy

The results from the current study suggest that a single high-dose intramuscular injection of vitamin D₃ provides significant relief in painful diabetic neuropathy by improving the associated symptoms.

A large population-based study has recently shown that the prevalence of painful diabetic neuropathy (PDN) is ∼21%, and painful symptoms are more prevalent in patients with type 2 diabetes, females, and South Asians. PDN is characterized by symmetrical lower limb paresthesiae, dysesthesiae, lancinating pains and allodynia, with nocturnal exacerbation and significant sleep disturbance, with a reduced quality of life. National and international guidelines advocate a range of therapies for symptom relief. However, the therapeutic efficacy for all recommended medications is at best ∼50% pain relief and is limited due to unwanted side effects. Several recent observational studies in patients with diabetes have demonstrated a significant association between vitamin D deficiency, and paraesthesiae and numbness, but also between neurological deficits and electrophysiology as well as parasympathetic dysfunction. Furthermore, a recent systematic review and meta-analysis of 1484 patients with type 2 diabetes has demonstrated a highly significant association (OR −2.68) between vitamin D deficiency and the development of diabetic peripheral neuropathy. In relation to a mechanistic link between vitamin D and pain, a recent study has shown that nociceptive calcitonin gene-related peptide-positive neurons have a distinct vitamin D phenotype with hormonally regulated ligand and receptor levels. In relation to the potential therapeutic benefits of vitamin D therapy, studies are limited. An open-label prospective study in 51 patients with type 2 diabetes and painful neuropathy showed that ∼2000 IU of cholecalciferol daily for 3 months resulted in an ∼50% decrease in the visual analog scale (VAS). Given the mechanistic link between vitamin D and neuropathy, and the known prevalence of vitamin D deficiency, this single-center open-label clinical trial was conducted to determine the effects of a single high-dose administration of intramuscular vitamin D on symptoms of PDN.

Rationale behind research:

In relation to the potential therapeutic benefits of Vitamin D therapy, studies are limited.

Therefore, this single-center open label clinical trial was conducted to determine the effects of a single high-dose administration of intramuscular vitamin D on symptoms of painful diabetic neuropathy.

Objective:

To assess the effect of high-dose vitamin D in patients with painful diabetic neuropathy.

Study outcomes

• Primary Outcomes: The primary efficacy parameter was the change in total McGill pain location (higher number indicating more severe pain) and McGill pain score
• Other Outcomes: Six questions that reflected positive symptoms for pain on the DN4 Neuropathic Pain Diagnostic Questionnaire, those being questions 1, 2, 3, 4, 5, and 10 (sensations of burning, painful cold, electric shocks, tingling, pins and needles, and brushing, respectively), were assessed in all participants at each visit. The Short Form McGill Pain Questionnaire (SFMPQ) was evaluated to establish the sensory dimensions of pain, which included pain sensations such as throbbing, shooting, stabbing, sharp, cramping, gnawing, hot, burning, aching, heavy, tender, and splitting; and affective dimensions of the pain experience, which included sensations such as tiring-exhausting, sickening, fearful, and punishing-cruel.

Time Points: Baseline and on four subsequent visits every 5±1 week

• A single intramuscular dose of 600 000 IU of vitamin D3 was administered at V1 by paramedical staff in accord with the results of a recent study indicating a good therapeutic effect with this dose
• Vitamin D levels were categorized as deficient (25(OH)D<20 ng/mL), insufficient (25(OH)D 20–30 ng/mL), and sufficient (25(OH)D>30 ng/mL)

Outcomes:

• Total McGill pain location: Total McGill pain location changed significantly between V1 and V2 (p=0.001), with a further significant reduction at V3 (p<0.0001), V4 (p<0.0001) and V5 (p<0.0001) compared with V1

Figure 1: Total McGill pain location from baseline to final visit

• McGill pain score: The McGill pain score did not change between V1 and V2 (p=not significant (NS)), however, there was a significant reduction at V3 (p<0.0001), V4 (p<0.0001), and V5 (p<0.0001), compared with V1.

Figure 2: McGill pain score from baseline to final visit

• Douleur Neuropathique 4: There was no significant change in the DN4 score between V1 compared with V2, V3, V4, and V5
• Questionnaire scores stratified on vitamin D status: There was an improvement in pain scores that was independent of baseline vitamin D status. Comparing patients based on deficient/insufficient vitamin D status (25(OH)D≤30 ng/mL) and sufficient vitamin D status (25(OH)D>30 ng/mL), there were no differences between pretreatment baseline scores and V5 scores for total McGill pain location, McGill pain score, DN4, and positive symptoms. However, there was a significant reduction in total McGill pain location (p<0.0001 and p<0.0001), McGill pain score (p=0.002 and p=0.0002), and positive symptoms (p=0.05 and p=0.002), when comparing pretreatment baseline scores to V5 scores within the stratified groups (deficient/insufficient vitamin D status (25(OH)D≤30 ng/mL) and sufficient vitamin D status (25(OH)D>30 ng/mL).
  

A single intramuscular dose of 600 000 IU of vitamin D appears to be a safe and efficacious treatment for painful diabetic neuropathy.

The administration of 600 000 IU of vitamin D results in a modest but significant increase in 25(OH)D levels measured at 20 weeks. This improvement in 25(OH)D levels was associated with an improvement in several independent measures of PDN, which became significant at Visit 3, approximately 10 weeks after administration of vitamin D. This would argue against a placebo effect, as this would have been expected to manifest immediately or at least at V2. Furthermore, a maximal placebo response from baseline of 33–36% has been shown in double-blind randomized controlled trials and our data show improvement of pain far in excess of a placebo response. However, we cannot exclude a placebo response particularly as patients received regular follow-up after a known active intervention.

Treatment options for PDN are currently limited due to the side effects from many of the current therapies. A single dose of vitamin D was found to be safe and effective. However, a longer placebo controlled study with more frequent assessment of vitamin D levels and objective measures of neuropathy is required to assess the optimal frequency, dose safety, and overall efficacy of Vitamin D in PDN, and perhaps, in diabetic neuropathy.