The potential of transdermal nitric oxide treatment for diabetic peripheral neuropathy and diabetic foot ulcers

Abstract The Center for Disease Control (CDC) estimates that 29 million Americans have diabetes, and 70% of diabetic patients develop diabetic peripheral neuropathy [1,2]. Up to 27% of the direct medical cost of diabetes may be attributed to DPN [3]. A 2013 article from the American Diabetes Association reported a $176 billion direct medical cost of diabetes in 2012 [4]. DPN patients often suffer from shooting and burning pain in their distal limbs and a severe loss of sensation. Diabetic foot ulcers, infections, and amputations may follow. Currently available treatments: tricyclic antidepressants, anticonvulsants such as gabapentin and pregabalin, serotonin and norepinephrine reuptake inhibitor, duloxetine, topical 5% lidocaine (applied to the most painful area) can manage painful symptoms but do not address the underlying pathologies of DPN and diabetic wound ulcers. A combination of pain-reducing medications can provide relief when individual medications fail, and opioids such as tramadol and oxycodone may be administered with these medications to reduce pain [5]. Due to the prevalence of diabetes, DPN, and diabetic foot ulcers, and because of the lack of available effective treatments to directly address the pathology contributing to these conditions, novel treatments are being sought. Our hypothesis is that a deficiency of nitric oxide synthase in diabetic patients leads to a lack of vascularization of the peripheral nerves, which causes DPN; and this could be treated with vasodilators such as nitric oxide. In this paper, the mechanisms of DPN are reviewed and analyzed to elucidate the potential of a transdermal nitric oxide application for the treatment of DPN and diabetic wound ulcers by increasing vasodilation.