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Paul Lee, MBBS (Hons); Roger Chen, MBBS (Hons), FRACP, PhD

Arch Intern Med. 2008;168(7):771-772.

Treatment of neuropathic pain is generally unsatisfying for patients with type 2 diabetes mellitus,¹ and patients with debilitating residual symptoms may be given nonspecific diagnoses such as "chronic pain syndrome." Although hypovitaminosis D is highly prevalent in patients with type 2 diabetes,² to our knowledge, its impact on neuropathic pain has not been previously evaluated. Our objective was to evaluate the impact of vitamin D repletion on neuropathic pain in patients with type 2 diabetes and vitamin D insufficiency.

Methods
A total of 51 patients with type 2 diabetes with typical neuropathic pain, including burning, tingling, numbness, and throbbing sensations, and physical examination findings of reduced sensation to monofilament, were included. Severity of pain was evaluated by the short form of the McGill pain questionnaire (MPQ) and a 5-cm visual analog self-report scale (VAS) (0, no pain; 1, mild; 2, discomforting; 3, distressing; 4, horrible; and 5, excruciating). Baseline characteristics are summarized in the Table. Patients with myositis, connective tissue disorders, inflammatory arthropathies, and recent musculoskeletal trauma were excluded.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table. Characteristics, Biochemistry, and Pain Scores at Baseline and 3 Months After Treatment

Serum 25-hydroxyvitamin D (25D) concentration was measured by radioimmunoassay (Diasorin, Stillwater, Minnesota) and intact parathyroid hormone (iPTH) concentration by automated immunoassay (Roche E170; Roche Diagnositics, Mannheim, Germany).

Vitamin D–insufficient patients (serum 25D concentration <24 ng/mL³ [to convert to nanomoles per liter, multiply by 2.496]) were supplemented with cholecalciferol (vitamin D₃) tablets (mean dose, 2059 IU). Patients were reevaluated in 3 months with repeated biochemistry tests and reevaluation of pain by the questionnaires used at baseline.

The data were analyzed using SPSS statistical software (SPSS Inc, Chicago, Illinois). Main statistical analysis was descriptive. Differences between groups were assessed using analysis of variance for continuous variables. Pearson correlation was used to assess associations between continuous variables. P < .05 was considered statistically significant.

Results
All patients were vitamin D insufficient, with mean serum 25D concentration of 18 ng/mL (Table). The mean VAS score for pain at baseline was 3.3 ("distressing"). Pain scores for both the VAS (r² = 0.10) and MPQ (r² = 0.18) correlated negatively with serum 25D concentration but not with serum iPTH concentration. Vitamin D repletion resulted in a significant reduction in pain scores on both the VAS and MPQ at –48.5% and –39.4%, respectively.

Comment
Severe vitamin D deficiency leads to osteomalacic myopathy, as characterized in a case series demonstrating severe muscle weakness and pain in patients with serum 25D concentrations lower than 12 ng/mL, with prompt resolution of symptoms following vitamin D replacement.³ Vitamin D insufficiency (serum 25D concentration, 12-24 ng/mL), on the other hand, has not been reported to cause significant pain in patients.

To our knowledge, this is the first prospective observational study addressing the impact of vitamin D repletion on neuropathic pain in patients with type 2 diabetes mellitus. The mean serum 25D concentration in our patients was higher than "osteomalacic myalgic patients" reported in the literature (18 ng/mL vs <12 ng/mL). There is both in vitro⁴ and in vivo⁵ evidence that vitamin D is a neurotrophic substance and modulates neuromuscular function and neuronal growth and differentiation. Its role in diabetic neuropathic pain is uncertain. Vitamin D insufficiency may potentiate diabetic nerve damage and may impair nociceptor function, resulting in pain at a threshold of serum 25D concentration higher than that in the nondiabetic population.

While primary hyperparathyroidism has been associated with nonspecific musculoskeletal symptoms,⁶ the improvement of pain in our subjects following vitamin D repletion could not be attributed to a decrease in parathyroid hormone level. There was no evidence of secondary hyperparathyroidism at baseline, and the decrease in parathyroid hormone level following vitamin D repletion was not statistically significant, indicating that the improvement in symptoms was independent of parathyroid status.

The definition of vitamin D sufficiency is an ongoing debate in the literature. While vitamin D insufficiency is generally defined as a serum 25D concentration of less than 20 ng/mL,⁷ the optimal level of vitamin D most beneficial to bone health is not known. From the point of view of osteoporosis prevention, there is an argument in aiming at a serum 25D concentration of above 24 ng/mL, since bone resorption markers have been shown to be significantly higher in individuals below this threshold.⁸ The mean (SD) serum 25D concentration at 3 months in our study was 30 (5) ng/mL, which correlated with significant pain reduction. Achieving adequate serum 25D concentration (>24 ng/mL) may not only help to prevent osteoporosis in patients with type 2 diabetes but may also relieve neuropathic pain.

Our study was neither blinded nor randomized, resulting in the possibility of treatment bias. However, vitamin D has definite proven benefit in the prevention of osteoporosis, which is prevalent in the diabetic population. Vitamin D has been increasingly recognized for its pleiotropic effect, including improvement in glycemic control.⁹ It is also free of adverse effects. Because the treatment of diabetic neuropathic pain is generally unsatisfying for patients and is associated with significant adverse effects, we advocate a trial of vitamin D supplementation in vitamin D–insufficient patients with neuropathic pain. It is unlikely to have any harmful effects and may offer not only pain relief but also beneficial effects on bone health and glycemic control.

In conclusion, vitamin D insufficiency is underrecognized and may be a significant contributor to neuropathic pain in type 2 diabetes. Vitamin D supplementation may be an effective "analgesic" in relieving neuropathic pain.

Correspondence: Dr Lee, Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Hospital Road, Concord, New South Wales 2139, Australia (pcylee{at}gmail.com).

Author Contributions: Drs Lee and Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Lee and Chen. Acquisition of data: Lee and Chen. Analysis and interpretation of data: Lee. Drafting of the manuscript: Lee. Critical revision of the manuscript for important intellectual content: Lee and Chen. Statistical analysis: Lee. Administrative, technical, and material support: Lee and Chen. Study supervision: Chen.

Financial Disclosure: None reported.

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