Evaluation of surgical treatment for neuropathic pain from neuroma in patients with injured peripheral nerves

OBJECTIVEChronic neuropathic pain after peripheral nerve injury is a major clinical problem. Its management is difficult, and therapeutic approaches vary and include oral medication, neurostimulation, and surgery. The aim of this study was to assess the adequacy of surgical nerve revision in a large series of patients with long-term follow-up.METHODSThe authors reviewed the charts of 231 patients (335 nerve injuries) who experienced neuropathic pain after peripheral nerve injury and underwent surgery for nerve revision at the authors’ institution between 1997 and 2012. The following parameters were recorded for each patient: history, location, duration, and severity of the pain and details of nerve revision surgery. In addition, patients were invited to participate in a follow-up consultation and were asked to score their pain at that time. Current medications and examination findings were also documented.RESULTSElective surgery was the source of nerve injury for 55.4% of the patients. The lower extremity was the most commonly involved anatomical region (54.3%), followed by the lower abdomen (16.4%) and the thoracic region (13%). The mean time between the onset of injury and revision surgery was 48 months. On average, 1.3 injured nerves per patient were explored, and surgery was performed 1.2 times per patient. Each nerve underwent revision 1.1 times on average. Neuromas-in-continuity and scar-tethered nerves were observed in 205 nerves (61%) and terminal neuromas were observed in 130 nerves (39%). The authors performed 186 (56%) neurolyses and 149 (44%) neuroma resections and translocations. The mean follow-up of the 127 (55%) patients who agreed to come back for a consultation was 68 months. These patients indicated an average pain decrease of 4 points in the visual analog scale (VAS) score. Pain relief greater than a 2-point decrease on the VAS, a criterion for a successful treatment according to the European Federation of Neurological Societies guidelines, was encountered in 80% of patients. Pain relief did not vary in a statistically significant way with regard to surgical technique, age and sex of the patient, affected nerve, or time between trauma and surgery. Before surgery, 76% of the patients were on a regimen of paracetamol and/or NSAIDs and 44% received opiates, while after nerve revision only 37% still required simple analgesia and 14% needed opiates.CONCLUSIONSBearing in mind that medication achieves satisfying pain relief in only 30%–40% of patients with neuropathic pain, surgery must be considered as an effective alternative therapy. No objective criteria were shown to be factors of poor prognosis. Systematic preoperative clinical mapping of the injured nerves and diagnostic nerve blocks could improve the primary success rate of the surgery.

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Changes in Crossed Spinal Reflexes After Peripheral Nerve Injury and Repair

Journal of Neurophysiology ◽

10.1152/jn.00305.2001 ◽

2002 ◽

Vol 87 (4) ◽

pp. 1763-1771 ◽

Cited By ~ 34

Author(s):

Antoni Valero-Cabré ◽

Xavier Navarro

Keyword(s):

Sciatic Nerve ◽

Action Potential ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Tibialis Anterior ◽

Tibial Nerve ◽

Spinal Reflexes ◽

Injury And Repair

We investigated the changes induced in crossed extensor reflex responses after peripheral nerve injury and repair in the rat. Adults rats were submitted to non repaired sciatic nerve crush (CRH, n = 9), section repaired by either aligned epineurial suture (CS, n = 11) or silicone tube (SIL4, n = 13), and 8 mm resection repaired by tubulization (SIL8, n = 12). To assess reinnervation, the sciatic nerve was stimulated proximal to the injury site, and the evoked compound muscle action potential (M and H waves) from tibialis anterior and plantar muscles and nerve action potential (CNAP) from the tibial nerve and the 4th digital nerve were recorded at monthly intervals for 3 mo postoperation. Nociceptive reinnervation to the hindpaw was also assessed by plantar algesimetry. Crossed extensor reflexes were evoked by stimulation of the tibial nerve at the ankle and recorded from the contralateral tibialis anterior muscle. Reinnervation of the hindpaw increased progressively with time during the 3 mo after lesion. The degree of muscle and sensory target reinnervation was dependent on the severity of the injury and the nerve gap created. The crossed extensor reflex consisted of three bursts of activity (C1, C2, and C3) of gradually longer latency, lower amplitude, and higher threshold in control rats. During follow-up after sciatic nerve injury, all animals in the operated groups showed recovery of components C1 and C2 and of the reflex H wave, whereas component C3 was detected in a significantly lower proportion of animals in groups with tube repair. The maximal amplitude of components C1 and C2 recovered to values higher than preoperative values, reaching final levels between 150 and 245% at the end of the follow-up in groups CRH, CS, and SIL4. When reflex amplitude was normalized by the CNAP amplitude of the regenerated tibial nerve, components C1 (300–400%) and C2 (150–350%) showed highly increased responses, while C3 was similar to baseline levels. In conclusion, reflexes mediated by myelinated sensory afferents showed, after nerve injuries, a higher degree of facilitation than those mediated by unmyelinated fibers. These changes tended to decline toward baseline values with progressive reinnervation but still remained significant 3 mo after injury.

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Effects of Nitric Oxide Synthase Inhibitor on Hindlimb Muscles in Rats with Neuropathic Pain Induced by Unilateral Peripheral Nerve Injury

Journal of Korean Academy of Nursing ◽

10.4040/jkan.2011.41.4.520 ◽

2011 ◽

Vol 41 (4) ◽

pp. 520 ◽

Cited By ~ 5

Author(s):

Myoung-Ae Choe ◽

Gyeong Ju An

Keyword(s):

Nitric Oxide ◽

Neuropathic Pain ◽

Nitric Oxide Synthase ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Nitric Oxide Synthase Inhibitor ◽

Hindlimb Muscles ◽

Synthase Inhibitor ◽

Oxide Synthase

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SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

Molecular Pain ◽

10.1177/17448069211006603 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110066

Author(s):

Orest Tsymbalyuk ◽

Volodymyr Gerzanich ◽

Aaida Mumtaz ◽

Sanketh Andhavarapu ◽

Svetlana Ivanova ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Thermal Sensitivity ◽

Gradual Improvement ◽

Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

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Role of the immune system in neuropathic pain

Scandinavian Journal of Pain ◽

10.1515/sjpain-2019-0138 ◽

2019 ◽

Vol 20 (1) ◽

pp. 33-37 ◽

Cited By ~ 16

Author(s):

Marzia Malcangio

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Immune Cells ◽

Peripheral Nerve Injury

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

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376 OLIGONUCLEOTIDE IMT504 REDUCES NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY

European Journal of Pain ◽

10.1016/j.ejpain.2007.03.391 ◽

2007 ◽

Vol 11 (S1) ◽

pp. S167-S167

Author(s):

M.F. Coronel ◽

A. Hernando-Insua ◽

J. Rodriguez ◽

F. Elias ◽

J. Flo ◽

...

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury

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Up-Regulation of P2X4 Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain

Journal of Neuroscience ◽

10.1523/jneurosci.2308-08.2008 ◽

2008 ◽

Vol 28 (44) ◽

pp. 11263-11268 ◽

Cited By ~ 305

Author(s):

L. Ulmann ◽

J. P. Hatcher ◽

J. P. Hughes ◽

S. Chaumont ◽

P. J. Green ◽

...

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

P2x4 Receptors

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A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Journal of Clinical Investigation ◽

10.1172/jci32371 ◽

2008 ◽

Vol 118 (1) ◽

pp. 161-172 ◽

Cited By ~ 33

Author(s):

Alban Gaultier ◽

Sanja Arandjelovic ◽

Xiaoqing Li ◽

Julie Janes ◽

Nikola Dragojlovic ◽

...

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Ldl Receptor ◽

Related Protein

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Sortilins in neuropathic pain

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2012.05.028 ◽

2012 ◽

Vol 3 (3) ◽

pp. 183-184

Author(s):

M. Richner ◽

O.J. Bjerrum ◽

Y. De Koninck ◽

A. Nykjaer ◽

C.B. Vaegter

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Mechanical Allodynia ◽

Molecular Mechanisms ◽

Intrathecal Injection ◽

Ion Concentration ◽

Down Regulation

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

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