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5 INNOSC Theranostics and Pharmacological Sciences, 2022, Vol. 5, No. 2 Dhokne et al.

Table 1. First-line treatment for patients with neuropathic pain
Mechanism of action Dose (starting/ Side effects
maximum)
Selective serotonin-norepinephrine reuptake inhibitors (SSNRIs)
Venlafaxine [26] Inhibits both norepinephrine and 37.5 mg (once or twice Nausea
5-HT reuptake daily)/225 mg (daily)
Duloxetine [27] Inhibits both norepinephrine and 30 mg (once daily)/60 Nausea
5-HT reuptake mg (twice daily)
Tricyclic antidepressants (TCAs) [28]
Desipramine Inhibits the reuptake of 25 mg (bedtime)/150 Anticholinergic effects
Nortriptyline norepinephrine and/or mg (daily) (dryness of mouth,
5-HT, blocks Na channels, weight gain, urinary
+
anticholinergics retention, sedation)
Topical lidocaine [29]
5% lidocaine patch Blockade of Na channels 1–3 patches/3 patches Rash, local erythema
+
Calcium channel α2-δ ligands [30]
Pregabalin Decreases release of 50 mg (thrice daily or 75 Sedation, peripheral
norepinephrine, glutamate, and mg twice daily)/200 mg edema, dizziness
substance P, with ligands on the (thrice daily) or 300 mg
α2-δ subunit of voltage-gated (twice daily)
calcium channel
Gabapentin Decreases release of 100–300 mg (once to Sedation, peripheral
norepinephrine, glutamate and thrice daily)/1200 mg edema, dizziness
substance P, with ligands on the (thrice daily)
α2-δ subunit of voltage-gated
calcium channel
Opioid agonists [31]
Tramadol Agonist of μ-receptor inhibits 50 mg (once or twice Vomiting/nausea,
the reuptake of norepinephrine daily)/400 mg (daily as a constipation, dizziness
and serotonin long-acting drug)
Morphine, oxycodone, μ-receptor agonist (oxycodone 10–15 mg morphine Vomiting/nausea,
methadone, levorphanol also causes κ-receptor every 4 h or as needed constipation, dizziness
antagonism) (equianalgesic doses
should be used for other
opioids)/no maximum
doses
5-HT: 5-hydroxytryptamine (serotonin)

seems like the locus coeruleus which is a structure of presynaptic α2-adrenoceptors, which reduced
that prevents pain, some studies indicate that it central noradrenergic activity. The oxidative
may actually have a function in NP facilitation. and nitrosative stress elicited by persistent
There has been speculation that the coeruleospinal hyperglycemia in diabetes mellitus is regarded as
noradrenergic fibers are involved in the descending one of the key factors in the disease’s related brain
inhibition of spinal pain transmission. dysfunction. Increased oxidative stress promotes
Agmatine has been demonstrated to lower vascular dysfunction and endoneurial hypoxia,
3-methoxy-4-hydroxyphenyl ethylene glycol which impairs the function of the motor and sensory
(MHPG) and norepinephrine levels in the nerves. In addition, rats with diabetes caused
brainstem while increasing the norepinephrine by streptozotocin were also found to have an L-
(NP) pain threshold. It was suggested that the arginine shortage. Nitric oxide, agmatine [61], and
reduction of NP was due to agmatine’s activation glutamate all have similar effects on the CNS through

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