hyperpolarization inside the neuronal body that further begins apoptotic cascades.

Caspases are activated in the apoptotic pathways and cause damage to neuronal

bodies which ultimately cause cytotoxicity (Areti et al. 2016). Ultimately, A fibers

which are sensitive to cold and C fibers which are warm specific start decreasing

from the epidermis which is known as loss of intra-epidermal nerve fibers. Loss of

nociceptors have also been observed which will consequently result in the hyperre-

sponsive state of the remaining nociceptors (Bennett et al. 2014). TNF-α,

interleukin-1, and interleukin-6 are the inflammatory markers that are secreted

from the glial cells and macrophages present in DRG also seen to be involved in

this signaling cascade. Cytokines act on their receptors and further cause changes

that include activation of PKC (protein kinase C) and MAP (mitogen-activated

protein) kinase that further contribute to the development of neuropathic pain

(Gonçalves dos Santos et al. 2020). Also, inflammatory cytokines often increase

the level of expression of various ion channels, such as sodium ion channels, that

cause neuronal excitotoxicity and also cause an increase in the response of

nociceptors to noxious and even to the non-noxious stimuli and make a significant

contribution to neuropathic pain pathogenesis (Mamet et al. 2002). The pathogenesis

of DNP interlinking different pathways is represented in Fig. 20.1.

20.2.3 Present Treatment Strategies for Diabetic Neuropathic Pain

Diabetic neuropathy is an emerging outcome of diabetes that is seen to affect one out

of every five diabetic patients. PDN is difficult to assess objectively, making its

diagnoses a bit difficult (Javed et al. 2015). Treatment strategies recommended by

clinical guidelines are antidepressants like duloxetine, GABA analogues like

pregabalin, opioids, and topical agents like capsaicin to relieve PDN pain. The US

Food and Drug Administration (FDA) approved duloxetine and pregabalin for the

treatment of PDN in 2004, and extended release formulation of tapentadol was

approved in 2012 (Javed et al. 2015). Lowering HbA1c levels can increase the

activity of nerves present peripherally and conduction (Bertelsmann et al. 1987). The

HbA1c target for most DPN patients is less than 6.5% (American Diabetes Associa-

tion 2014). There also is clinical evidence that those who have had intensive

glycemic regulation in the past have a “metabolic memory” that may help avoid

DPN (Albers et al. 2010). Antidepressants, anticonvulsants, analgesics, and topical

drugs are among these remedies (Tan et al. 2010).

20.2.3.1 Antidepressants

The disturbance in the balance of release of norepinephrine and serotonin in neurons

has been linked to DPN in various studies (Sultan et al. 2008). Serotonin-norepi-

nephrine reuptake inhibitors (SNRIs) such as duloxetine, which comes under

antidepressants also used for treating DPN (Lindsay et al. 2010). TCAs (tricyclic

antidepressants) are typically less well received than SNRIs (Lindsay et al. 2010).

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