Pathogenesis of diabetic neuropathy based upon oxidative/nitrosative stress and metabolic processes. AII, angiotensin II; AGE, advanced glycation end product; A-V, arteriovenous; DAG, diacylglycerol; EDHF, endothelium-derived hyperpolarizing factor; EFA, essential fatty acid; ET, endothelin-1; NO, nitric oxide; ONOO⁻, peroxynitrite; PGI₂, prostacyclin; PKC, protein kinase C; ROS, reactive oxygen species.(106).

Disabling Peripheral Neuropathies in Older Adults (38)

Schematic presentation of the physiologic function of different nerve fibers: Aα fibers are large myelinated fibers, in charge of motor functions and muscle control. Aα/β fibers are large myelinated fibers too, with sensory functions such as perception to touch, vibration and position. Aδ fibers are small myelinated fibers, in charge of pain stimuli and cold perception. C fibers can be myelinated or unmyelinated and have both sensory (warm perception and pain) and autonomic functions (blood pressure and heart rate regulation, sweating, etc.) GIT, GastroIntestinal Tract; GUT, GenitoUrinary Tract.(101)

C fibers are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord and cerebral cortex. Sympathetic blockers (e.g. clonidine) and depletion of axonal substance P used by C fibers as their neurotransmitter (e.g. by capsaicin) may improve pain. In contrast Ad fibers utilize Na+ channels for their conduction and agents that inhibit Na+ exchange such as antiepileptic drugs, tricyclic antidepressants and insulin may ameliorate this form of pain. Anticonvulsants (carbamazepine, gabapentin, pregabalin, topiramate) potentiate activity of g-aminobutyric acid, inhibit Na+ and Ca2+ channels and inhibit N-methyl-D-aspartate receptors and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. Dextromethorphan blocks N-methyl-D-aspartate receptors in the spinal cord. Tricyclic antidepressants, selective serotonin reuptake inhibitors (e.g. fluoxetine), and serotonin and norepinephrine reuptake inhibitors inhibit serotonin and norepinephrine reuptake, enhancing their effect in endogenous pain-inhibitory systems in the brain. Tramadol is a central opioid analgesic. α2 antag, α 2 antagonists; 5HT, 5-hydroxytryptamine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DRG, dorsal root ganglia; GABA: g-aminobutyric acid; NMDA, N-methyl-D-aspartate; SNRIs, serotonin and norepinephrine reuptake inhibitors; SP, substance P; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants;(101)

Schematic representation of different clinical presentations of diabetic neuropathy.

Pathogenesis of diabetic neuropathies based upon Autoimmunity, Metabolic and Microvascular Insufficiency. Ab, antibody; AGE, advance glycation end products; C¢, complement; DAG, diacylglycerol; ET, endothelin; EDHF, endothelium-derived hyperpolarizing factor; GF, growth factor; IGF; insulin-like growth factor; NFkB, nuclear factor kB; NGF, nerve growth factor; NO, nitric oxide; NT3, neurotropin 3; PKC, protein kinase C; PGI2, prostaglandin I2; ROS, reactive oxygen species; TRK, tyrosine kinase.(101)

Frequency of chronic inflammatory demyelinating polyneuropathy (CIPD)(38). There is an 11-fold greater frequency of CIPD in patients with diabetes.

A diagnostic algorithm for assessment of neurologic deficit and classification of neuropathic syndrome is given below. NSS; Neurological Symptom Score, NDS; Nerve Disability Score, QST; Quantitative Sensory Test, QAFT; Quantitative Autonomic Function Test, EMG; Electromyography, NCV; Nerve Conduction Velocity (1)

Non-pharmacological, topical, or physical therapies can be useful at any time (capsaicin, acupuncture, etc.). The only two drugs approved by in the US for the treatment of painful diabetic neuropathy are pregabalin and duloxetine. However, based on the NNT (number needed to treat), tricyclic antidepressants are the most cost-effective ones. SNRIs: serotonin and norepinephrine reuptake inhibitors.(101)