Nociceptive neuroma Nociceptive neuroma is a common complication after peripheral nerve injury or amputation, and its intractable pain and high postoperative recurrence rate bring great pain to patients. Neuroma pain is related to nerve growth factor and tyrosine kinase B (TrkB) receptor, peripheral and central sensitization, cannabinoid CB2 receptor, α-smooth muscle actin (α-SMA), and structural changes of neuroma fibers. Its early intervention treatments include mirror theory application, ultrasound-guided local injection, and adriamycin application, as well as surgical nerve sparing and reconstruction of nerve continuity, and vascularized fasciocutaneous flap therapy. This article provides an overview of painful neuroma formation, related theories of analgesia and its prevention and treatment. The concept of neuroma was first proposed by Odier in 1811, and further reported by Wood, Virdow and Ched in the early 19th century. They believed that neuroma was the result of failure to rebuild normal continuity by severing the nerve. When a nerve is severed, the nerve fibers undergo ulceration and subsequently begin to regenerate on the basis of the ulceration. When the two severed ends of the nerve are too far apart, when there is too much scar tissue, or when there is no distal counterpart of the nerve after amputation, the nerve fibers grow erratically in all directions and become entangled with the proliferating fibrous connective tissue, forming a localized mass, i.e., a neuroma. Cravioto et al. concluded that only 10% of neuromas present with intractable pain, and Herndon et al. also concluded that not all severed nerves produce painful neuromas, and found that when both sides of the same amputated stump were treated in the same way, one nerve produced a painful neuroma, while the other side was asymptomatic. Foltan et al. classified the formation of painful neuromas into five stages: 1) nerve and adjacent tissue injury; 2) simultaneous nerve and wound repair, as well as cell proliferation and intermolecular signaling interactions; 3) wound and scar compression; 4) nerve defense response to compression; and 5) balanced development between nerve regeneration (proliferation) and injury (compression). They believed that if nerve fibers could not grow into sites where neuromas might develop, wound and scar contraction would not occur and neuromas could not form. There is a delicate and long-term balance between the protective effects of peripheral nerve epithelial proliferation and nerve injury, wound and scar compression. This balance can be easily disrupted by contact, compression, vibration, and temperature changes, leading to changes in extracellular signaling molecules, cytokines, and sudden release of ions from the neuroma cells, producing neuroma symptoms, which can be acutely exacerbated by repetitive stimulation or enlargement of the tumor. Nowadays, it is found that more and more medically induced nerve injuries lead to neuroma formation. The posterior branch of the medial cutaneous nerve of the forearm traveling close to the elbow canal is prone to intraoperative damage and develops a neuroma of the medial cutaneous nerve of the forearm, with an incidence of 81.6% (31/38), which is often misdiagnosed as a recurrence of elbow canal syndrome. Tiny traumatic neuromas formed after inner middle ear fibroplasty can cause intractable temporal pain in patients. Multiple neuromas of the abdominal wall form after abdominal wall myofascial flap reconstruction of the breast. The literature reports that 30% of neuromas are painful. However, from clinical experience, the incidence of painful neuromas is higher in cases of superficial cutaneous nerve damage. 2, Theories of neuroma-related pain 2.1 Nerve growth factor and its role Kotulska et al [10] studied that brain-derived nerve growth factor plays an important role in neuroma formation. Through animal experiments, it was found that all neuromas were formed in the tyrosine kinase B(TrkB)-deficient group after transecting the sciatic nerve of rats, and almost no neuroma was formed in the wild-type group; in the early stage of nerve regeneration, the reduced number of inhibited TrkB enhanced the role of brain-derived nerve growth factor and promoted axonal growth; in the chronic stage of nerve regeneration, TrkB deficiency increased the infiltration of mast cells in the site of injury and acted together with Brain-derived nerve growth factor acts together to attract mast cells, causing them to degranulate and release some substances (histamine, etc.); mast cell degranulation is closely related to fibrosis, and connective tissues composed of dispersed regenerative fibers are involved in the formation of a vicious cycle of neuroma pathogenesis. Funakoshi et al [11] also confirmed an increase in local neurotrophic factors and their mRNAs after peripheral nerve injury, and concluded that distal disconnected Schwann cells are the main source of neurotrophic factors, a kind of protective self-regulation of the organism. Atherton et al. concluded that nerve severance re-implantation into muscle or bone can inhibit neuroma formation, and one of the mechanisms is that neurotrophic factor increases the expression of ion channels and neuropeptides in sensory neurons during pain conduction; moving the proximal nerve severance from the neurotrophic factor-rich site (subcutaneous of injury or inflammation) to the site of less neurotrophic factor (such as muscle or bone) can improve the symptoms of neuroma ; by immunohistochemical techniques, the neurotrophic factor levels of 13 cases of painful neuromas were found to be increased compared with normal nerves in the control group, but the pain relief after implantation of the proximal severed ends of the neuromas into the muscle was found to be close to the level of the control group. 2.2 Peripheral and central sensitization According to Jensen et al [13], neuropathic pain should be understood with the understanding that, although nerve excitability is increased, afferents to nerve impulses are absent or reduced, and that the reduction in afferents due to damage to the nerve occurs in conjunction with the regeneration of secondary nerve hypersensitivity and disinhibition. The generation of this hypersensitivity is associated with the formation of new channels at the molecular level, up- and down-regulation of receptors, and new receptor or gene expression. An important clinical finding is that neuropathic pain and hypersensitivity at the damaged site are the result of alterations such as sensory deficits and neurological dysregulation caused by damage to nerve conduction pathways, which can be divided into peripheral sensitization and central sensitization. Peripheral sensitization mainly consists of injury receptor sensitization leading to spontaneous injury receptor activation, lowering of thresholds, and enhancement of responses to suprathreshold stimuli. The mechanisms of injury receptor sensitization are diverse. Immune receptors expressed on injury receptors after nerve injury, inflammatory mediators released by immune cells, and neurotrophic factors are involved in sensitization. Pain is often thought to be related to altered channel activity due to expression, regulation, and mutation of sodium channels, and current density of neurons located at injury receptors.Black et al [15] found multiple sodium channel isoforms (Nav1.3, Nav1.7, Nav1.8) and activated p38, extracellular signal-regulated kinase (ERK1) 1/ in human painful neuroma studies. 2, and mitogen-activated protein (MAP) kinase expression. These provide a molecular basis for peripheral nerve hypersensitivity and ectopic activation after amputation, and central sensitization may be related to a large number of intensive peripheral hypersensitivity inputs. However, mechanisms that do not rely on peripheral inputs have also been suggested. Perhaps the latter explains why focusing on peripheral sensitization as a therapeutic priority does not produce too long-lasting therapeutic effects. Nerve damage activates glial cells in the spinal cord, and activated glial cells release pro-inflammatory cytokines and act on neurons. This is an important mechanism by which neuropathic pain spreads beyond the damaged nerve to adjacent healthy tissue. 2.3 Cannabinoid CB2 Receptors Anand et al [17] demonstrated that cannabinoid CB2 receptors are present in a variety of tissues such as human dorsal root sensory neurons, damaged nerves such as neuromas. Studies [18] indicated that activation of CB2 receptors can act directly on sensory neurons and inhibit sensory neuron activity, and selective CB2 receptor agonists can reduce abnormal pain. Multiple complexes made from cannabinoids can target specific endogenous cannabinoid systems and are potentially valuable in neuropathic pain treatment. 2.4 α-Smooth muscle actin Desmouliere et al [20] suggested that painful neuromas produce spontaneous contractions, so they can cause paroxysmal or persistent pain without obvious triggers; due to the increased sensitivity to mechanical stimuli, neuromas have a significant increase in pain symptoms when subjected to collision, friction, and compression. Myofibroblasts decrease and disappear through apoptosis under normal conditions, but persist in proliferative paraplegia and fibrotic disease. Blocking neuroma formation, inhibiting fibrosis, reducing paralytic scar tissue production, and inhibiting α-smooth muscle actin (α-SMA) expression are important aspects of painful neuroma treatment. 2.5 Structural changes in neuroma fibers Battista et al[21] showed that there was a significant increase in unmyelinated fibers in the neuroma structure, and the ratio of unmyelinated fibers to myelinated fibers was 20:1, whereas nociceptive transmission depended on the unmyelinated fibers and the slender myelinated fibers. Pain was transmitted along the unmyelinated C fibers and the thinnest myelinated A fibers. Due to the absence of myelin sheath on the surface of the axon, the sensitivity to mechanical stimulation was increased, and pain would be induced by scar stimulation, external contact or percussion. Tay et al. showed that unmyelinated fibers in painful neuromas were 15 times greater than in normal nerves of the control group, and the thickness of myelin sheath in neuromas was significantly thinner, and the fine fibers embedded in them might be the cause of pain and sensory abnormalities during neuroma scar compression [23,24]. Gao Shichang et al. confirmed that the number of myelin plate layers of myelinated nerve fibers in the distal, proximal and central segments of neuromas varied greatly by pathology, and demyelinating lesions were common in neuromas, suggesting that the maturation of regenerating nerve fibers was inconsistent, and that regenerating nerve fibers, even if they grew into the distal nerve endothelial canal, could still have secondary damage due to the local scar tissue compression. This may be the reason why the neurological function could not be improved or even aggravated after neuroma resection and reanastomosis. 2.6 Other theories of pain associated with neuroma include the theory of increased loading, adrenaline sensitivity and destruction of neurophysiological function, and the theory of inter-fiber crosstalk. 3.1 Early prevention and intervention In order to prevent the development of painful neuroma after amputation, when dealing with the stump, cut the nerve with a fast knife at a relatively high place and let it retract into normal tissue. Intraoperatively, avoid roughly stripping, pulling and squeezing the nerve, or placing the nerve stump in scar tissue or infected area [27].Marcol et al. [28] suggested that cutting the nerve obliquely could prevent the formation of neuroma. In 10 rats, the unilateral sciatic nerve was cut obliquely at 30 degrees and compared with the control group, and it was found that there was almost no neuroma formation in the obliquely cut group. A study [29] from the direct inhibition of nerve stump regeneration ability, with high-frequency electric knife caramelization treatment of nerve stumps, can be very good to prevent the formation of painful neuroma. The mirror theory proposed by Rosen et al [30] may help improve the symptoms of painful neuroma. The mirror theory has potential for sensory reconstruction and has been used to treat patients with sensory hypersensitivity and painful inability to be touched due to nerve hypersensitivity. The mirror theory works by applying a mirror to the healthy side to create the optical illusion of touching the pain-free affected side. Repetition of this will attenuate the nerve hypersensitivity and eventually produce central desensitization. 3.2 Drug therapy Wang Tao et al. applied adriamycin nerve trunk injection combined with neuroma excision or release to treat painful neuroma, and achieved good results. Adriamycin nerve stem injection can play the role of corresponding ganglion drug resection, thus reducing the transmission of pain signals to the center and achieving the purpose of pain reduction. Adriamycin may be able to disable the regenerative ability of pain-producing nerve fibers and may become a commonly used drug against painful neuromas. The rise of ultrasound-guided injections of local anesthetics and steroids at the neuroma site in recent years has led to advances in the treatment of painful neuromas.Fischler et al[32] chose the ultrasound-guided nerve localization method for perineuromas in a 61-year-old sciatic neuroma patient requiring admission and opiates for pain control with injections of 0.75% ropivacaine (15 ml), 1: 2,000,000 epinephrine and methylprednisolone (20 mg), the patient had good pain relief after 4 injections and required only a small amount of oral analgesia to the patient’s satisfaction. Ultrasound-guided local injection is a diagnostic and therapeutic method for painful neuromas [33], and is considered an innovative technique for the treatment of painful neuromas. 3.3 Surgery Once a painful neuroma is formed, it should be treated surgically. There is a basic consensus on this [1]. Yin Weitian et al [34] proposed the method of nerve sparing and reconstruction of nerve continuity from the formation of neuroma and the cause of neuroma pain, and achieved relatively good efficacy. This method involves suturing the nerve stump to the nerve, muscle bond, vein, or skeletal muscle. The nerve is spared and regenerated along the sutured tissue to avoid neuroma formation and to re-establish nerve continuity. Tendon or skeletal muscle fibers can be used to guide the nerve along the tendon and muscle tissues in a sequential manner, and their epithelial tissues in turn prevent fibroblasts from interfering with the infiltration of fibroblasts in the surrounding tissues. Gross microanatomy and light microscopic observation confirmed that no neuroma formation was present. Dellon et al[35] reported a case of thumb reconstruction without sensory function after reconstruction, using absorbable nerve conduit to reconstruct radial and palmar nerve sensation of the thumb, after 30 months, the patient’s two-point discrimination and tactile sensation were recovered, and there was no formation of neuroma in the reconstructed site.Meek et al[36] reported the use of absorbable nerve conduit to repair the painful neuroma of the common nerve of the toe plantaris, and the patient did not complain of pain and discomfort of the neuroma after surgery, but sensation was recovered. tumor pain and discomfort, but the sensory recovery was unsatisfactory; it was concluded that the nerve conduit did not reestablish sensation, but treated the neuroma pain well. Atherton et al [37] performed proximal dissection implantation into the brachialis muscle in seven cases of isolated lateral dermatomal nerve neuroma of the forearm and achieved good results; they concluded that implantation of a lateral dermatomal nerve neuroma in the brachialis muscle has a shorter distance of nerve freedom than implantation in the brachioradialis muscle, and that even if the results of implantation of a proximal nerve in the brachioradialis muscle were unsatisfactory after the operation, the brachioradialis muscle could be implanted again with a better outcome. Kakinoki et al [38] demonstrated through animal experiments that neuromas can form 3 weeks after femoral nerve ligation. After the neuroma was removed, the proximal segment of the nerve was implanted into the femoral vein, and it was found that the regenerated nerve axons grew along the vein in 2-6 weeks, and the longest length could be 3 cm; they began to degenerate in the 8th week, and formed a hemispherical stump in the 12th week, with no neuroma formation; the proximal segment of the nerve did not have an accumulation of sodium channels, so stimulation of the implantation site of the vein would not easily depolarize the nerve segment and cause neuroma symptoms.Koch et al [39] also pointed out that the implantation of veins in the proximal segment of the nerve could inhibit the formation of neuroma through animal experiments. In 23 cases of painful neuroma patients, neuroma resection of the severed end and implantation of adjacent veins were performed, and 12 cases obtained complete and lasting pain relief at 26.5 months of follow-up, while 8 cases still had mild pain, with an excellent rate of 87%. From the above statistics, the effect of implantation of the severed vein is the best. Due to the abundance of veins, a suitable vein implantation can be found if the nerve severed end does not move more than 4 cm. There is no neurotrophic factor in the lumen of the vein to promote the formation of neuroma, and the blood flow can inhibit axonal regeneration, but it is necessary to loosen the free nerve and parallel nerve and vein solid fixation.Koch et al[40] performed neuroma excision combined with proximal vein implantation in 8 cases of neuromas of the lower limb, and 7 cases achieved satisfactory results.Balcin et al[41] conducted a double-blind controlled trial on 20 cases of painful neuroma of the lower limb, and the patients underwent neuroma excision combined with proximal vein implantation, and 7 cases achieved satisfactory results. Balcin et al [41] conducted a double-blind controlled trial of 20 patients with painful neuromas of the lower extremity who underwent neuroma excision combined with proximal intramuscular implantation or adjacent venous implantation, and reached similar conclusions regarding pain relief, sensory recovery, limb mobility, and functional recovery. Krishnan et al[42] used vascularized fasciocutaneous flap to treat 7 cases of painful neuroma with satisfactory results; 6 cases who needed regular opioid analgesics before surgery no longer needed them after surgery, and 5 cases resumed their previous work.Kakinoki et al[43] used retrograde vascularized island flap to treat 9 cases of painful neuroma of fingertip, and the patients’ pain was very well relieved and the functional recovery of the hand was relatively well improved after surgery; it was concluded that the degree of pain relief and sensory recovery of hand function had been improved; it was concluded that the patients’ pain was very much relieved and the functional recovery of hand function was relatively well improved. They concluded that the vascularized fasciocutaneous flap, although complicated, is a surgical method that should be considered as an option when multiple therapeutic methods are ineffective. In conclusion, it is reasonable to use different treatment methods for different parts of painful neuroma when the formation mechanism of painful neuroma is not completely clear. For example, for multiple neuromas formed after breast reconstruction, lateral gluteal neuroma should be neuromectomized, and the severed end should be implanted in soft tissue and blood-rich area; for intercostal neuroma, the severed end can be implanted in the rectus abdominis muscle; for ilioinguinal neuroma and inguinal neuroma, the severed end should not be left in the abdominal wall muscle, because somatic activities can make the pain symptoms recur, and it should be free from the nerve to the level of transversal abdominal fascia, and the accompanying blood vessels should be cauterized and appropriately pulled and then cut, so that it can be retracted to the level of abdominal fascia and then retracted back to the level of abdominal wall muscle. cut and retracted into the retroperitoneal space. For finger stumps, venous bridging and nerve grafting are preferred; for forearm stumps, neuromuscular robust suture is mostly used; for high limb neuromas, neuroskeletal muscle suture method can be considered. If the clinical condition permits, it can be considered to deal with the stump in emergency or initial surgery, and take the above corresponding methods to perform nerve sparing or rebuild nerve continuity to prevent neuroma formation [33]. If the above treatments are not effective, vascularized fasciocutaneous flap can be considered. 4. Prospect The treatment of painful neuroma is difficult, and the disposition of painful neuroma in some special areas is even more difficult. Different treatment methods should be adopted for neuromas in different parts, and the application of neuropathic pain-targeted therapeutic drugs may achieve satisfactory efficacy. For the basis of painful neuroma, further in-depth research on multiple sodium channel subtypes (Nav1.3, Nav1.7, Nav1.8) and activated p38, ERK1/2, MAP kinase, cannabinoid CB2 receptor and other related drugs will bring brighter prospects for painful neuroma pain treatment.