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Eftekari et al. Plast Aesthet Res 2022;9:43 https://dx.doi.org/10.20517/2347-9264.2022.33 Page 3 of 13

Figure 1. Illustration of neurovascular sphere growth following tibial nerve transection, leading to the eventual production of a neuroma.
Illustrated by Seitz AJ.

axons may innervate surrounding targets sporadically, such as the skin, which allows for propagation of
action potentials through anomalous pathways . Neuromas also express different transduction molecules,
[14]
upregulate sodium channels, and downregulate potassium channels embedded within the cell membranes
of axons . External stimuli such as cytokines and macrophages also trigger myofibroblast formation and
[14]
proliferation at the site of a neuroma causing contraction of scar tissue which in turn further aggravates the
disorganized bundle of nerves . These changes all contribute to creating hyperexcitable neural tissue that
[8]
can spontaneously discharge and produce inappropriate afferent pain signals for a patient . Over time,
[14]
these signals often lead to central nervous system imbalances between excitatory and inhibitory signaling
pathways, amplifying the intensity of each subsequent pain signal; this process is known as central
sensitization . From a clinical standpoint, a cross-sectional study that was conducted on 124 military
[2]
veterans with traumatic amputation injury showed that 64.5% of service members had clinically significant
pain following the amputation procedure, with 48.7% of these patients’ pain directly attributed to
symptomatic and sensitized neuroma formation . Although the growth of axons in the residual nerve is
[15]
considered physiologic in the regeneration of a peripheral nerve, the downstream effects have often shown
to manifest as pathologic pain [Figure 2].

TRADITIONAL TREATMENTS OF SYMPTOMATIC NEUROMAS
With such a high percentage of patients experiencing painful consequences of symptomatic neuromas, a
myriad of treatment options have been explored to help alleviate this pain. Conservative strategies such as
desensitization therapy, electrical biofeedback devices, anesthetic injections, and pharmacotherapy with
antidepressants, anticonvulsants, and opioids have all been attempted with varying degrees of short-term
success [13,16] . Although these treatment modalities may be less invasive, surgical intervention of symptomatic
neuromas has shown to provide superior pain management. A meta-analysis comparing surgical
interventions for symptomatic neuroma treatment found that 77% of patients undergoing neuroma
resection had significant improvement in patient-reported pain, depression, and quality of life shortly after
surgery regardless of the surgical technique used . However, even with this seemingly high initial success
[17]