"Decreasing Postamputation Pain with the Regenerative Peripheral Nerve Interface (RPNI)".

Over 185,000 limb amputations are performed in the United States annually, many of which are due to the sequelae of peripheral vascular disease. Symptomatic neuromas remain a significant source of postamputation morbidity and contribute to both phantom limb (PLP) and residual limb pain (RLP). While many interventions have been proposed for the treatment of symptomatic neuromas, conventional methods lead to a high incidence of neuroma recurrence. Furthermore, these existing methods do not facilitate an ability to properly interface with myoelectric prosthetic devices. The Regenerative Peripheral Nerve Interface (RPNI) was developed to overcome these limitations. The RPNI consists of an autologous free muscle graft secured around the end of a transected nerve. The muscle graft provides regenerating axons with end organs to reinnervate, thereby preventing neuroma formation. We have shown that this simple, reproducible, and safe surgical technique successfully treats and prevents neuroma formation in major limb amputations. In this paper, we describe RPNI surgery in the setting of major limb amputation and highlight the promising results of RPNIs in our animal and clinical studies.

Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees.

BACKGROUND: Targeted muscle reinnervation is an emerging surgical technique to treat neuroma pain whereby sensory and mixed motor nerves are transferred to nearby redundant motor nerve branches. In a recent randomized controlled trial, targeted muscle reinnervation was recently shown to reduce postamputation pain relative to conventional neuroma excision and muscle burying. QUESTIONS/PURPOSES: (1) Does targeted muscle reinnervation improve residual limb pain and phantom limb pain in the period before surgery to 1 year after surgery? (2) Does targeted muscle reinnervation improve Patient-reported Outcome Measurement System (PROMIS) pain intensity and pain interference scores at 1 year after surgery? (3) After 1 year, does targeted muscle reinnervation improve functional outcome scores (Orthotics Prosthetics User Survey [OPUS] with Rasch conversion and Neuro-Quality of Life [Neuro-QOL])? METHODS: Data on patients who were ineligible for randomization or declined to be randomized and underwent targeted muscle reinnervation for pain were gathered for the present analysis. Data were collected prospectively from 2013 to 2017. Forty-three patients were enrolled in the study, 10 of whom lacked 1-year follow-up, leaving 33 patients for analysis. The primary outcomes measured were the difference in residual limb and phantom limb pain before and 1 year after surgery, assessed by an 11-point numerical rating scale (NRS). Secondary outcomes were change in PROMIS pain measures and change in limb function, assessed by the OPUS Rasch for upper limbs and Neuro-QOL for lower limbs before and 1 year after surgery. RESULTS: By 1 year after targeted muscle reinnervation, NRS scores for residual limb pain from 6.4 ± 2.6 to 3.6 ± 2.2 (mean difference -2.7 [95% CI -4.2 to -1.3]; p < 0.001) and phantom limb pain decreased from 6.0 ± 3.1 to 3.6 ± 2.9 (mean difference -2.4 [95% CI -3.8 to -0.9]; p < 0.001). PROMIS pain intensity and pain interference scores improved with respect to residual limb and phantom limb pain (residual limb pain intensity: 53.4 ± 9.7 to 44.4 ± 7.9, mean difference -9.0 [95% CI -14.0 to -4.0]; residual limb pain interference: 60.4 ± 9.3 to 51.7 ± 8.2, mean difference -8.7 [95% CI -13.1 to -4.4]; phantom limb pain intensity: 49.3 ± 10.4 to 43.2 ± 9.3, mean difference -6.1 [95% CI -11.3 to -0.9]; phantom limb pain interference: 57.7 ± 10.4 to 50.8 ± 9.8, mean difference -6.9 [95% CI -12.1 to -1.7]; p ≤ 0.012 for all comparisons). On functional assessment, OPUS Rasch scores improved from 53.7 ± 3.4 to 56.4 ± 3.7 (mean difference +2.7 [95% CI 2.3 to 3.2]; p < 0.001) and Neuro-QOL scores improved from 32.9 ± 1.5 to 35.2 ± 1.6 (mean difference +2.3 [95% CI 1.8 to 2.9]; p < 0.001). CONCLUSIONS: Targeted muscle reinnervation demonstrates improvement in residual limb and phantom limb pain parameters in major limb amputees. It should be considered as a first-line surgical treatment option for chronic amputation-related pain in patients with major limb amputations. Additional investigation into the effect on function and quality of life should be performed. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Painful Traumatic Neuromas in Subcutaneous Fat: Visibility and Morphologic Features With Ultrasound.

OBJECTIVES: Subcutaneous neuromas usually result from trauma and may lead to dissatisfaction in patients with a trigger point, loss of sensitivity in the relevant territory of innervation, and spontaneous neuropathic pain. Confirming clinically suspected cases of neuroma may prove difficult. The objective of this study was to evaluate the visibility and morphologic features of traumatic subcutaneous neuromas of the limbs with ultrasound (US). METHODS: Between January 2012 and August 2016, 38 consecutive patients clinically suspected of having subcutaneous neuromas were investigated with US. The diagnosis was confirmed on the basis of a focal morphologic abnormality of the nerve associated with trigger pain. Each neuroma was classified into 1 of 3 subtypes based on its injury pattern. The subtypes were terminal neuroma, spindle neuroma, and scar encasement, either isolated or associated with these subtypes. RESULTS: Forty-four lesions were found in the 38 patients, including 29 spindle neuromas (65.9%), 14 terminal neuromas (31.8%) and 1 scar encasement with no nerve caliber abnormality (2.3%). Fifteen neuromas (35% of all neuromas) were associated with scar encasement. In 13 cases that required surgery, the diagnosis of neuroma or scar encasement could be surgically proven and confirmed the validity of the US findings. CONCLUSIONS: Ultrasound can be used to show and classify subcutaneous nerves of the upper and lower limbs with high accuracy. The US trigger sign provides an indication of neuroma involvement in pain. This modality can play a substantial role both in the preoperative planning of neuroma surgery and in therapeutic US-guided procedures.

Neuroma of the Infrapatellar branch of the saphenous nerve following Total knee Arthroplasty: a case report.

BACKGROUND: Injury to the infrapatellar branch of the saphenous nerve (IBSN) is common during total knee arthroplasty (TKA) with a standard midline skin incision. Occasionally, painful neuromas form at the transection of nerve and cause pain and limitation of the range of motion of the knee joint. CASE PRESENTATION: A 70-year-old woman experienced right knee pain and stiffness for 4 years after TKA. Physical assessment revealed medial tenderness; Tinel's sign was positive. Radiographs revealed that the prosthesis was well-placed and well-fixed. She was diagnosed with arthrofibrosis and possible neuroma after TKA. She underwent right knee exploration, neurectomy, adhesiolysis and spacer exchange. The neuroma-like tissue was sent for pathological examination. The patient recovered uneventfully and at 3-month follow-up reported no recurrence of pain or stiffness. The pathological report confirmed the diagnosis of neuroma. CONCLUSIONS: IBSN injury should be a concern if surgeons encounter a patient who has pain and stiffness after TKA. Tinel's sign, local anesthetic injection, MRI and ultrasound could help the diagnosis and identify the precise location of neuroma. Surgical intervention should be performed if necessary.

Painful Neuroma Treatment of the Supraorbital Nerve and Forehead Neurotization Using Human Cadaveric Nerve Allograft.

Neuroma pain can be severe, persistent, and treatment-resistant. Forehead and scalp anesthesia is troublesome for patients. Following an iatrogenic ablative injury to the right supraorbital nerve, with subsequent painful neuroma formation, a human cadaveric nerve allograft (AxoGen, Alachua, FL) was used to restore sensation of the right forehead and treat pain. At 1-year follow-up, the patient was pain-free, and protective sensation to the right forehead was recovered with comparable static and dynamic 2-point discrimination between the injured (20 mm, 12 mm respectively) and the normal side (15 mm, 10 mm respectively). This is the first reported case of using a cadaver nerve allograft for successful direct neurotization of the skin and restoration of sensation in the upper part of the face, and for treating painful neuromas. Moreover, a brief review of the available techniques for treating neuromas of the supraorbital and supratrochlear nerves is provided.

Simple electrodiagnostic method for Morton neuroma.

INTRODUCTION: We describe a simple and quickly applied electrodiagnostic method for confirming the diagnosis of interdigital neuropathy caused by Morton neuroma (MN). METHODS: Interdigital nerves II-III and III-IV were stimulated with surface electrodes simultaneously touching the lateral side of 1 toe and the medial side of the other. Recording was also made with surface electrodes. The results of 20 normal controls and 14 patients with MN were evaluated. RESULTS: The amplitude and peak latency values elicited in the patients as well as the interside differences revealed an acceptable abnormality rate between 57.1% and 71.4%. CONCLUSIONS: Although the most popular and effective method of MN diagnosis is clinical evaluation supported by imaging, electrophysiological studies can, in selected patients, provide valuable information.

Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas.

BACKGROUND: Voltage-gated sodium channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the expression of these ion channels and the presence or absence of dysaesthesia investigated. RESULTS: Immunohistochemical processing and quantitative image analysis revealed that Nav1.8 and Nav1.9 were expressed in human lingual nerve neuromas from patients with or without symptoms of dysaesthesia. The level of Nav1.8 expression was significantly higher in patients reporting pain compared with no pain, and a significant positive correlation was observed between levels of Nav1.8 expression and VAS scores for the symptom of tingling. No significant differences were recorded in the level of expression of Nav1.9 between patients with or without pain. CONCLUSIONS: These results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. These data provide further evidence that changes in expression of Nav1.8 are important in the development and/or maintenance of nerve injury-induced pain, and suggest that Nav1.8 may be a potential therapeutic target.

A prospective randomized controlled trial of plantar versus dorsal incisions for operative treatment of primary Morton's neuroma.

BACKGROUND: There are a great number of studies on the outcome of surgery for Morton's neuroma. However, there is a lack of controlled trials to determine the outcome in general and for the 2 most used surgical approaches. This prospective and randomized trial studied the outcome and adverse events of resected primary Morton's neuromas, comparing plantar and dorsal incisions. METHODS: Seventy-six patients were randomized to treatment with either a plantar or a dorsal incision by 2 senior surgeons. Questionnaires were evaluated and physical examinations performed at baseline and at 3 and 12 months postoperatively by the treating surgeon and at a mean of 34 months (range, 28-42 months) by an independent surgeon. The follow-up rate was 93%. RESULTS: Histological examination of specimens verified resection of nerves in all cases except 1, which was in the dorsal group (artery). The main outcome variable, pain at daily activities, was significantly reduced by 96% (plantar) and 97% (dorsal) and restrictions in daily activities were reduced by 77% (plantar) and 67% (dorsal) at the final follow-up. Scar tenderness was noted by 3% (plantar) and 0% (dorsal) at the final evaluation. Clinically good results with surgery were noted in 87% (plantar) and 83% (dorsal) of cases. There were 5 complications in the plantar group and 6 in the dorsal group, with a difference in type of complications. CONCLUSIONS: This study demonstrated 87% (plantar) and 83% (dorsal) clinically good outcomes and no significant differences between the procedures in regard to pain, restrictions in daily activities, and scar tenderness. However, there was a difference between the groups in the type of complications. LEVEL OF EVIDENCE: Level I, prospective randomized trial.

Painful nodules and cords in Dupuytren disease.

PURPOSE: The etiology of Dupuytren disease is unclear. Pain is seldom described in the literature. Patients are more often disturbed by impaired extension of the fingers. We recently treated a series of patients who had had painful nodules for more than 1 year, and we therefore decided to investigate them for a possible anatomical correlate. METHODS: Biopsies were taken during surgery from patients with Dupuytren disease and stained to enable detection of neuronal tissue. RESULTS: We treated 17 fingers in 10 patients. Intraoperatively, 10 showed tiny nerve branches passing into or crossing the fibrous bands or nodules. Of 13 biopsies, 6 showed nerve fibers embedded in fibrous tissue, 3 showed perineural or intraneural fibrosis or both, and 3 showed true neuromas. Enlarged Pacinian corpuscles were isolated from 1 sample. All patients were pain free after surgery. CONCLUSIONS: Although Dupuytren disease is generally considered painless, we treated a series of early stage patients with painful disease. Intraoperative inspection and histological examination of tissue samples showed that nerve tissue was involved in all cases. The pain might have been due to local nerve compression by the fibromatosis or the Dupuytren disease itself. We, therefore, suggest that the indication for surgery in Dupuytren disease be extended to painful nodules for more than 1 year, even in the early stages of the disease in the absence of functional deficits, with assessment of tissue samples for histological changes in nerves.

Accumulation of Kv7.2 channels in putative ectopic transduction zones of mice nerve-end neuromas.

BACKGROUND: Modulation of M-type currents has been proposed as a new strategy for the treatment of neuropathic pain due to their role in regulating neuronal excitability. Using electrophysiological techniques we showed previously that the opening of Kv7 channels with retigabine, blocked ectopic discharges from axotomized fibers but did not alter transduction at intact skin afferents. We hypothesized that after nerve damage, accumulation of Kv7 channels in afferent fibers may increase M-type currents which then acquired a more important role at regulating fiber excitability. FINDINGS: In this study, we used an immunohistochemical approach to examine patterns of expression of Kv7.2 channels in afferent fibers after axotomy and compared them to patterns of expression of voltage gated Na+ channels (Nav) which are key electrogenic elements in peripheral axons known to accumulate in experimental and human neuromas.Axotomy induced an enlargement and narrowing of the nodes of Ranvier at the proximal end of the neuroma together with a dramatic demyelination and loss of structure at its distal end in which naked accumulations of Nav were present. In addition, axotomy also induced accumulations of Kv7.2 that co-localized with those of Nav channels. CONCLUSIONS: Whilst Nav channels are mandatory for initiation of action potentials, (i.e. responsible for the generation/propagation of ectopic discharges) an increased accumulation of Kv7.2 channels after axotomy may represent a homeostatic compensation to over excitability in axotomized fibers, opening a window for a peripheral action of M-current modulators under conditions of neuropathy.

An ultrasonographic and electromyographic evaluation of jumping stump possibly due to a neuroma in a patient with transradial amputation: A case report.

BACKGROUND AND OBJECTIVE: Jumping stump is an uncommon movement disorder characterized by involuntary movements and severe neuropathic pain in the stump. The pathophysiology and etiology of this phenomenon have not yet been clearly elucidated, and unfortunately, no proven treatment with successful recovery exists. This report aims to describe a severe painful jumping stump, possibly due to neuromas, in a traumatic transradial amputee. MATERIALS AND METHOD: We performed ultrasound examination of the painful stump depicted neuroma. Electromyographic evaluation of the stump revealed arrhythmic motor unit action potentials (MUAPs) with normal duration and amplitude; other movement disorders, such as myokymia and fasciculations, were excluded. Ultrasound should be preferred to magnetic resonance imaging (MRI) for evaluation of stumps in patients with painful stump because MRI may not be helpful due to motion artefacts. The involuntary movements ceased after surgical excision of the neuroma following failure of conservative treatments. CONCLUSION: This report confirms that neuromas are clearly associated with jumping stump. Ultrasonographic and electromyographic assessments are necessary to reveal the features of this pathology for treatment planning.

Neuromas of the hand and upper extremity.

The painful neuroma is an often debilitating sequela of nerve injury about the hand. The exact pathophysiology of this condition is poorly understood. After sharp trauma to a peripheral nerve, as nerve ends try to connect with their end organs and "find" the distal nerve stump, fascicular escape and scarring can lead to the development of a painful neuroma. Painful neuromas can even be associated with blunt trauma or retraction of a nerve when the nerve is not actually divided. Green's definition of a neuroma is "the inevitable, unavoidable, and biologic response of the proximal stump after it has been divided in situations where regenerating axons are impeded from re-entering the distal stump."(1) A number of unknown factors make certain patients more susceptible to neuroma formation. In addition, certain nerves such as the superficial radial nerve are more prone to the development of a painful neuroma. Treatment of neuromas of the hand is important because they can be quite debilitating and painful, often preventing patients from continuing with their normal daily activities. There are a number of approaches to the painful neuroma, and the treatment plan must be tailored to the individual patient.

The outcome of Morton's neurectomy in the treatment of metatarsalgia.

Morton's neuroma is a common cause of metatarsalgia caused by intermetarsal digital nerve thickening. This study reviews the pathology, presentation, symptoms and signs, and patient satisfaction with surgical treatment. Seventy-eight patients (82 feet) were treated for Morton's metatarsalgia by excision of the interdigital nerve. The patients were followed-up for a mean of 4.6 years (range 0.8-8.1 years) and scored using the Foot Functional Index and the American Orthopedic Foot Ankle Society scoring system. In 74 patients the Foot Functional Index was more than 85 (maximum score 100). Seventy-one patients scored more than 90 on the American Orthopedic Foot Ankle Society scoring system with two patients scoring 100 (maximum score). Postoperatively, 82% reported excellent or good results, 10% had a fair result with restriction of activities or pain and 8% had no improvement at all after surgery while 71% had restrictions with footwear.

Regenerative Peripheral Nerve Interfaces for Prevention and Management of Neuromas.

Symptomatic neuromas are a common cause of postamputation pain that can lead to significant disability. Regenerative peripheral nerve interface surgery is performed to treat symptomatic neuromas and prevent the development of neuromas. This review delineates the clinical problem of postamputation pain, describes the limitations of the available treatment methods, and highlights the need for an effective treatment strategy that leverages the biologic processes of nerve regeneration and muscle reinnervation. The evidence supporting use of regenerative peripheral nerve interface surgery to mitigate neuroma formation is discussed and the rationale behind the efficacy of regenerative peripheral nerve interfaces is explored.

Neuromas and postamputation pain.

Postamputation stump and phantom pain are highly prevalent but remain a difficult condition to treat. The underlying mechanisms are not fully clarified, but growing evidence suggests that changes in afferent nerves, including the formation of neuromas, play an important role. The main objective of this cross-sectional study was to investigate whether ultrasound-verified neuroma swellings are more frequent in amputees with postamputation pain than in amputees without pain (primary outcome). Sixty-seven amputees were included. Baseline characteristics including the frequency and intensity of spontaneous stump and phantom pain were obtained, and sensory characteristics and evoked responses were assessed. A high-frequency ultrasound examination of the amputated extremity was performed to obtain information on the presence, size, and elasticity of swollen neuromas and pressure pain thresholds. Swollen neuromas were present in 53 (79.1%) of the 67 amputees included in the study, in 47 (82.5%) of 57 amputees with pain and in 6 (60.0%) of 10 amputees without pain (P = 0.2). No difference was found in stump pain intensity (P = 0.42) during the last week or in phantom pain intensity in the last month (P = 0.74) between amputees with and without swollen neuromas. Our findings suggest that it is not the presence of swollen neuromas itself that drives postamputation pain. However, changes in the transected nerve endings may still be crucial for driving postamputation pain because a positive Tinel sign was significantly more frequent in amputees with pain, irrespectively of the degree of neuroma swelling.

Immunohistochemical analysis of the purinoceptor P2X7 in human lingual nerve neuromas.

AIMS: Recent evidence suggests that the purinoceptor P2X7 may be involved in the development of dysesthesia following nerve injury, therefore, the aim of the present study was to investigate whether a correlation exists between the level of P2X7 receptor expression in damaged human lingual nerves and the severity of the patients' symptoms. METHODS: Neuroma-in-continuity specimens were obtained from patients undergoing surgical repair of the damaged lingual nerve. Specimens were categorized preoperatively according to the presence or absence of dysesthesia, and visual analog scales scores were used to record the degree of pain, tingling, and discomfort. Indirect immunofluorescence using antibodies raised against S-100 (a Schwann cell marker) and P2X7 was employed to quantify the percentage area of S-100 positive cells that also expressed P2X7. RESULTS: P2X7 was found to be expressed in Schwann cells of lingual nerve neuromas. No significant difference was found between the level of P2X7 expression in patients with or without symptoms of dysesthesia, and no relationship was observed between P2X7 expression and VAS scores for pain, tingling, or discomfort. No correlation was found between P2X7 expression and the time between initial injury and nerve repair. CONCLUSION: These data show that P2X7 is expressed in human lingual nerve neuromas from patients with and without dysesthesia. It therefore appears that the level of P2X7 expression at the injury site may not be linked to the maintenance of neuropathic pain after lingual nerve injury.

Cold intolerance in surgically treated neuroma patients: a prospective follow-up study.

PURPOSE: Cold intolerance may impose great changes on patients' lifestyle, work, and leisure activities, and it is often severely disabling. This study aims to investigate the prevalence and severity of cold intolerance in patients with injury-related neuromas of the upper extremity and improvement of symptoms after surgical treatment. Furthermore, we try to find predictors for cold intolerance and correlations with other symptoms. METHODS: Between January 2006 and February 2009, 34 consecutive patients with surgically treated neuroma-specific neuropathic pain of the upper extremities were sent a questionnaire composed of general questions concerning epidemiologic variables and several specific validated questionnaires, including the Visual Analog Scale for pain. To estimate the prevalence of cold intolerance objectively in neuroma patients, we used the validated CISS (Cold Intolerance Symptom Severity) questionnaire with a prespecified cutoff point. RESULTS: The CISS questionnaire was filled out by 33 patients before and 30 after surgery for neuroma-specific neuropathic pain, with a mean follow-up time of 24 months. We found a prevalence of cold intolerance of 91% before surgery, with a mean CISS score above the cutoff point for abnormal cold intolerance. After surgery, the prevalence of cold intolerance and the mean CISS score were not significantly different, whereas the mean Visual Analog Scale score decreased significantly (p < .01). CISS scores were lower in patients with neuromas associated with sharp injury of the peripheral nerve (p = .02). A higher VAS score correlated significantly with a higher CISS score (p = .01). CONCLUSIONS: Cold intolerance is a difficult and persistent problem that has a high prevalence in patients with a painful injury-related neuroma. There seems to be a relationship between severity of cold intolerance as measured by CISS, pain as measured by the Visual Analog Scale, and type of injury. Cold intolerance may not disappear with time or surgical treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Time course of traumatic neuroma development.

This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA.

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins.

INTRODUCTION: Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. METHODS: We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. RESULTS: TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. CONCLUSIONS: Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT.

Vanilloid receptor 1 (TRPV1) expression in lingual nerve neuromas from patients with or without symptoms of burning pain.

The lingual nerve, a peripheral branch of the trigeminal nerve, can be damaged during the surgical removal of lower third molar teeth. This damage can lead to the development of dysaesthesia, with some patients complaining of burning pain. We investigated the hypothesis that vanilloid receptor 1 (TRPV1), a transducer of noxious heat stimuli, was involved in the development of this burning pain. Neuroma specimens were obtained from patients undergoing microsurgical repair of a damaged lingual nerve. Repair was undertaken where there was little evidence of spontaneous recovery, 7-41 months after the initial injury. Preoperatively the incidence of dysaesthesia was determined by reported symptoms and using visual analogue scales (VAS) for pain, tingling and discomfort. Nine neuromas were studied from patients with burning dysaesthesia and six from patients with a sensory deficit but no dysaesthesia. Indirect immunofluorescence for protein gene product (PGP) 9.5 and TRPV1 was used to quantify the percentage area of PGP 9.5 positive neuronal tissue that also expressed TRPV1. The results showed no significant difference between the mean percentage area of TRPV1 expression in neuromas from patients with or without burning dysaesthesia. Furthermore, there was no correlation between TRPV1 expression and the VAS scores for pain, tingling or discomfort. However, if data from all patients was pooled, there was a negative correlation between the level of TRPV1 expression and the time after initial injury. These data do not rule out involvement of TRPV1 in the aetiology of burning dysaesthesia following lingual nerve injury but suggest that TRPV1 at the injury site does not play a primary role.