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Resurgent neuropathic discharge: an obstacle to the therapeutic use of neuroma resection?
Abstract
Ectopic discharge ("ectopia") in damaged afferent axons is a major contributor to chronic neuropathic pain. Clinical opinion discourages surgical resection of nerves proximal to the original injury site for fear of resurgence of ectopia and exacerbated pain. We tested this concept in a well-established animal neuroma model. Teased fiber recordings were made of ectopic spontaneous discharge originating in the experimental nerve-end neuroma and associated dorsal root ganglia (DRGs) in rats that underwent either a single transection (with ligation) of the sciatic nerve, or two consecutive transections separated by 7, 14, 21 or 30 days. Ectopia emerged in afferent A- and C-fibers after a single cut with kinetics anticipated from prior studies. When resection was carried out during the early period of intense A-fiber activity a brief period of resurgence was observed. However, resection of neuromas of more than 14 days was followed by low levels of activity with no indication resurgence. This remained the case in trials out to 60 days after the first cut. Likewise, we saw no indication of resurgent ectopia originating in axotomized DRG neuronal somata and no behavioral reflection of resurgence. In summary, we failed to validate the concern that proximal resection of a problematic nerve would lead to intense resurgent ectopic discharge and pain. As the well-entrenched concept of resurgence is based more on case-reports and anecdote than on solid evidence, it may be justified to relax the stricture against resecting neuromas as a therapeutic strategy, at least within the framework of controlled clinical trials.
... In dental root-canal treatment as well, painful neuromas are a very rare complication. The reasons for this are uncertain [2,16]. For OA of the hip treating the femoral epiphysis might be sufficient, but for OA of the knee or digits both apposed bone ends would presumably need to be treated. ...
Pain in osteoarthritis (OA) results from erosion of joint cartilage, resulting in bone contacting bone without an intervening cushion. The periosteum, including its nociceptive innervation, ends at the border of the cartilage meaning that there is no extrinsic neuronal pathway between the opposing denuded bone surfaces to carry a bone-on-bone pain signal to the brain. The pain signaling pathway must therefore originate in nociceptive sensory endings within the subchondral bone itself. Selective ablation of this intrinsic nerve pathway, using any of a variety of approaches, is expected to permanently eliminate OA pain.
Pain perception can be powerfully influenced by an individual's expectations and beliefs. Whilst the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study employed ultra-high field 7 Tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25; 12 Male). Over two successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labelled 'lidocaine' (placebo) and 'capsaicin' (nocebo) were acting to modulate their pain relative to a third 'Vaseline' (control) cream. In a subsequent test phase, fMRI image sets were collected whilst participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain-modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG) - rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in their engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influence the experience of pain by modulating activity at the level of the dorsal horn.Significance StatementUnderstanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation, however due to their small size and complex organization, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of anti- and pro-nociceptive effects. We used ultra-high field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.
Purpose of Review
Radiofrequency ablation (RFA) has become an increasingly widespread treatment tool for various chronic pain syndromes within the last two decades with the majority of publications on the topic coming after 2006. Not only are clinicians using RFA to treat more peripheral nerve pain syndromes but the technology itself is evolving quickly to the point that it is nearly impossible to stay abreast on the complexity of such a diversely utilized instrument. This review summarizes studies that focus on the use of RFA for peripheral nerve neurotomy and anatomical studies regarding RFA published between 2015 and 2020.
Recent Findings
Topics in this review include anatomical regions or nerves of the body published since 2015. Significant findings are summarized in each section.
Summary
Peripheral nerve RFA is rapidly changing. Many studies have been performed over the last 5 years showing the usefulness of RFA.
Background. Knee osteoarthritis (KOA) is a common degenerative disease associated with joint dysfunction and pain. Ultrasound-guided radiofrequency (RF) may be a promising therapy in the treatment of chronic pain for KOA patients. Objective. To evaluate the efficacy and safety of ultrasound-guided RF treatment for chronic pain in patients with KOA. Design. A systematic review was conducted, and a meta-analysis was carried out when possible. Setting. We examined the studies evaluating the clinical efficiency of ultrasound-guided RF on chronic pain in KOA population. Method. A systematic review for the efficacy and safety of ultrasound-guided RF treatment for pain management of KOA patients was carried out in PubMed, EMBASE, Cochrane Library, Web of Science, Wanfang Data, and China National Knowledge Infrastructure (CNKI) from the date of inception to February 2020, and a meta-analysis was conducted. The primary outcomes of pain intensity (visual analogue scale or numerical rating scale) and knee function [the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)] were evaluated from baseline to various follow-up times by random-effects model. Heterogeneity was assessed by I² statistic and the potential sources of heterogeneity by subgroup and metaregression analyses, respectively. Results. Eight publications with 256 patients were included in the meta-analysis. RF could relieve pain with −4.196 of pooled mean difference and improve knee function by decreasing 23.155 points in WOMAC. Three patients had ecchymosis, two with hypoesthesia and one with numbness after the procedure, and improved within 6 months. Furthermore, study design and treatment target were the sources of heterogeneity by subgroup and metaregression analyses, accounting for 37% and 74% of variances, respectively. Target of genicular nerve achieved better pain relief than intra-articular or sciatic nerve. Sensitivity analysis showed that removal of any single study was unlikely to overturn the findings. Limitations. There were some limitations in the study. Firstly, the small number of relevant studies limited the confidence level of the meta-analysis. Also, the significant heterogeneity may not be explained due to the limited data. Secondly, the direct comparison of two different guidance methods (ultrasound vs. fluoroscopy) for RF therapy is lacking. In addition, the outcomes were blindly assessed in the meta-analysis from all studies according to evaluation of bias, which could affect the reality of the data. Finally, most of the studies only provided short follow-up times, so we could not analyze the long-term effectiveness of ultrasound-guided RF in the treatment of patients with KOA. Conclusions. Ultrasonography is an effective, safe, nonradiative, and easily applicable guidance method for RF in pain relief and functional improvement in KOA patients.
1. Introduction
Knee osteoarthritis (KOA) is a very common joint disease and associated with diverse factors including age, obesity, metabolic bone diseases, acute or chronic joint injuries, etc. [1]. The prevalence of KOA ranges from 4.2% to 15.5% and gradually increases with age. Approximately 80% of KOA patients could be diagnosed by imaging at the age of 65 years or older, while only 60% of patients have shown clinical manifestations [2, 3]. Pain and disabilities are the major consequences of KOA, with 25% of patients suffering from severe arthralgia. Furthermore, KOA was ranked 11th among the 291 disabling illnesses worldwide [4]. It is currently believed that failure of chondrocytes to maintain homeostasis between synthesis and degradation of extracellular matrix and subchondral bone leads to osteoarthritis [5–8]. Treatments of KOA include noninvasive therapies such as medication, physical therapy, and rehabilitation as well as minimally invasive strategies from intra‐ or periarticular injections to radiofrequency (RF) [9]. Multiple studies have shown that postoperative RF therapy could accelerate the early rehabilitation of the joints in patients with late stage of KOA after joint replacement surgery [10, 11].
Recently, minimally invasive RF has been extensively used in the treatment of different stages of KOA and has achieved convincing therapeutic benefits. However, conventional RF is routinely guided by X-rays, so it may increase the risk of radiation exposure to the patients and health care providers [12]. Thus, musculoskeletal ultrasonography has become a potential guidance method for RF instead of fluoroscopy in chronic pain management due to its unique advantages [13, 14]. For example, ultrasound guidance is very accurate in peripheral or paraspinal nerve blocks to avoid injury of blood vessels and pleura [15, 16]. The efficacy of ultrasound-guided intervention is associated with many factors such as the settings of ultrasound device, preoperative administration of diagnostic nerve block (DNB), the location of targeted site, the skill of physician, etc. [17]. In recent years, more studies have demonstrated its therapeutic effects on the improvements of soreness, pain, and functional impairments induced by KOA, including case reports, retrospective and prospective uncontrolled studies, and randomized controlled trials (RCTs). However, confounding factors from these studies such as sample size, different methods or procedures may affect the outcomes. Meanwhile, there is no systematic analysis for evaluating the efficacy and safety of ultrasound-guided RF in the treatment of chronic pain in KOA patients. Therefore, we searched several databases from relevant literature to perform a systematic review and meta-analysis to evaluate the efficacy and safety of ultrasound-guided RF for providing preliminary scientific evidence for its clinical application in the treatment of patients with KOA.
2. Methods
2.1. Design
A systematic review was conducted, and a meta-analysis was carried out when possible.
2.2. Search Strategy
We systematically searched several electronic databases including PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Wanfang Data, and China National Knowledge Infrastructure (CNKI) via strategies developed using the appropriate Medical Subject Headings (MeSH) terms from the date of inception to February 2020. Keywords such as “knee osteoarthritis,” “ultrasound guided,” “radiofrequency therapy,” “genicular nerve,” “intra-articular,” and “chronic knee pain” were used. No date, language, or country limitations were applied to the searching.
2.3. Inclusion Criteria
The inclusion criteria for the meta-analysis were as follows: (1) human clinical trials with or without control groups and cointervention were allowed if the trial was performed equally to both arms; (2) patients were diagnosed with KOA and suffered from chronic pain without satisfying pain relief by conservative therapies; (3) patients received RF therapy such as pulsed radiofrequency (PRF) or radiofrequency ablation (RFA); (4) minimally invasive procedure was completed under the guidance of ultrasound; and (5) necessary evaluation index was provided before and after RF therapy, for pain intensity and knee function including visual analogue scale (VAS), numerical rating scale (NRS), Oxford Knee Score (OKS), or Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and for quality of life including 36-Item Short-Form Health Survey (SF-36).
2.4. Exclusion Criteria
The exclusion criteria for the meta-analysis were as follows: (1) full text is not available; (2) patients received total knee arthroplasty (TKA) or other knee surgery; (3) case report; (4) studies with insufficient data or uncompleted RCT; and (5) studies with doubtful data such as illogical outcomes without reasonable explanation.
2.5. Study Selection
After targeted publications were found from different databases, the duplicates were removed first by two experienced investigators independently. Next, irrelevant studies were excluded by further scanning the title and abstract of publication by the inclusion criteria, and then the full text of remaining study was carefully screened to identify eligibility according to the exclusion criteria. Any uncertainty or disagreements were finally resolved via discussion between the two investigators and consulted with the third investigator to reach consensus.
2.6. Data Extraction
Two investigators independently extracted relevant data from each study including the first and corresponding authors, year of publication, country, study design, sample size, demographic characteristics (age and gender), grade of radiologic KOA (Kellgren–Lawrence grading system), follow-up time, type of RF, ultrasound transducer parameter, treatment targets and controls, primary outcomes such as the scores of pain intensity (VAS or NRS) and knee function (WOMAC or Lysholm knee scoring scale) at baseline and available follow-up times, complications or adverse effects, conclusion, and limitations. We contacted the first and/or corresponding authors of study to verify any unclear information and data by e-mails, and the data were considered to be irretrievable without a reply from the authors. All the information was recorded in a prepared spreadsheet, and data were fully analyzed after collection.
2.7. Quality Assessment
The quality and risk of bias for each study were independently assessed by at least two examiners. Additional investigators were consulted when discrepancies were present. RCTs were assessed by the criteria from the Cochrane Handbook for Systematic Reviews of Interventions [18]. The potential sources of bias include random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias were judged as “low risk,” “high risk,” or “unclear risk,” respectively. For nonrandomized studies, different biases were determined by the criteria according to “Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions” [19]. This specific form contains 9 questions, and each question represents a potential source of bias. Positive answer indicates low risk of bias, while negative answer means high risk of bias. Newcastle-Ottawa Scale (NOS) criteria were also used for reference [20].
2.8. Statistical Analysis
One of the primary outcomes from the studies was the pain intensity of patients as reported as the VAS (0–10 or 0–100 mm) or NRS (0–10) in different studies. To standardize the pain scale, the VAS (0–10 cm) was equivalent to the NRS (0–10) and transformed the scale from 0–10 cm to 0–100 mm. The 95% confidence interval (CI) for the difference in means was used to measure the scores of pain and knee function (WOMAC). For each analysis, the heterogeneity test was performed with I² statistics to measure the degree of data inconsistency as I² > 50% being statistically significant between studies. Data were also analyzed with the random-effects model for high heterogeneity. Subgroup analysis was conducted for study design (RCT vs. prospective vs. retrospective study), treatment target (intra-articular vs. genicular vs. sciatic nerve), the performance of DNB, and follow-up period (0 vs. 4, 12, or 24 weeks). Metaregression analyses were performed to evaluate the sources of heterogeneity based on all the covariates including age and gender in subgroup analysis. Sensitivity analysis was conducted to evaluate the impact of every single study on the pooled mean difference (MD). In addition, the publication bias was evaluated by Begg and Mazumdar rank correlation test and Egger’s regression test [21, 22]. Comprehensive meta-analysis (CMA version 3.0, Biostat, Englewood, NJ, USA) was used to analyze the pooled data.
3. Results
3.1. Study Selection
A total of 157 publications were identified from six electronic databases and 117 studies for further screening after removing 40 duplicates. Eighty-four irrelevant studies were removed through screening the titles and abstracts of publications, and 25 additional studies were excluded by exclusion criteria via full-text screening. Finally, eight eligible publications were included in the study of meta-analysis including 3 RCTs, 3 prospective trials, and 2 retrospective studies [23–30]. The screening method and results of the relevant studies are illustrated in Figure 1.
Selective denervation of sensory nerve branches to the wrist is a palliative surgical treatment option for patients with chronic wrist pain when preserving the range of motion and function is preferred. Treatment varies from partial isolated denervation of the posterior interosseous nerve to extensive ‘complete’ denervations. This study aimed to provide an overview of the literature regarding treatment outcomes in the domains of pain, grip strength, patient satisfaction and return to work. MEDLINE (PubMed), EMBASE and Cochrane databases were systematically searched and identified 993 studies, of which 12 were eligible for analysis. Denervation resulted in high ‘return to work’ rates (up to 94%), patient satisfaction (up to 92%), increased grip strength (7%–64%) and improved average pain scores (36%–92%). Treatment outcomes of both partial and complete denervations were favourable; however, variations in outcomes suggest the need for improving evidence regarding surgical technique and nerve identification.
Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
The primary sensory neurons of dorsal root ganglia (DRG) are a very useful model to study the neuronal regenerative program that is a prerequisite for successful axon regeneration after peripheral nerve injury. Seven days after a unilateral sciatic nerve injury by compression or transection, we detected a bilateral increase in growth-associated protein-43 (GAP-43) and superior cervical ganglion-10 (SCG-10) mRNA and protein levels not only in DRG neurons of lumbar spinal cord segments (L4-L5) associated with injured nerve, but also in remote cervical segments (C6-C8). The increase in regeneration-associated proteins in the cervical DRG neurons was associated with the greater length of regenerated axons 1 day after ulnar nerve crush following prior sciatic nerve injury as compared to controls with only ulnar nerve crush. The increased axonal regeneration capacity of cervical DRG neurons after a prior conditioning sciatic nerve lesion was confirmed by neurite outgrowth assay of in vitro cultivated DRG neurons. Intrathecal injection of IL-6 or a JAK2 inhibitor (AG490) revealed a role for the IL-6 signaling pathway in activating the pro-regenerative state in remote DRG neurons. Our results suggest that the pro-regenerative state induced in the DRG neurons non-associated with the injured nerve reflects a systemic reaction of these neurons to unilateral sciatic nerve injury.
Background
Chronic pain of the lower extremity remains challenging to manage. Radiofrequency treatment applies heat to nerve fibers with the goal of mitigating chronic pain conditions. The clinical efficacy has not yet been adequately established for pathologies of the ankle and foot. In this review paper, we report the use and efficacy of radiofrequency treatment applied to foot and ankle pain.
Recent Findings
PubMed and the Cochrane Controlled Trials Register were searched (final search 30 March 2018) using the MeSH terms “radiofrequency ablation,” “neurolysis,” “radiofrequency therapy,” “pain syndrome,” “analgesia,” “plantar heel pain,” “plantar fascitis,” and “chronic pain” in the English literature. Of the 23 papers screened, 18 were further investigated for relevance. Our final search methodology yielded 15 studies that investigated the use of radiofrequency treatment at the ankle. Of these 15 studies, there were three randomized control trials, four prospective studies, three retrospective studies, and five case reports. The quality of selected publications was assessed using the Cochrane risk of bias instrument.
Summary
The evidence from our studies suggests that radiofrequency treatment can be used safely for the management foot and ankle pain. The technique (continuous vs pulsatile), temperature, location of treatment, and duration of administration need more thorough evaluation. Randomized control trials are needed to establish the efficacy and safety profile of radiofrequency ablation and its long-term benefits in patients with chronic pain of the foot and ankle.
Conclusion
The evidence from our studies suggests that radiofrequency treatment can be used safely for the management foot and ankle pain. The technique (continuous vs pulsatile), temperature, location of treatment, and duration of administration need more thorough evaluation. Randomized control trials are needed to establish the efficacy and safety profile of radiofrequency ablation and its long-term benefits in patients with chronic pain of the foot and ankle.
Nearly all who review the literature conclude that the role of invasive procedures to treat chronic pain is poorly characterized because of the lack of “definitive” studies. The overt nature of invasive treatments, along with the risks, technical skills, and costs involved create challenges to study them. However, these challenges do not completely preclude evaluating invasive procedure effectiveness and safety using well-designed methods. This article reviews the challenges of studying outcomes of invasive therapies to treat pain and discuss possible solutions. Although the following discussion can apply to most invasive therapies to treat chronic pain, it is beyond the scope of the article to individually cover every invasive therapy used. Therefore, most of the examples focus on injection therapies to treat spine pain, spinal cord stimulation, and intrathecal drug therapies.
Object
In patients with focal nerve injury and neuropathic pain cutting the nerve to obtain permanent pain reduction can be considered. Surgery is indicated only if a diagnostic nerve block provides temporary pain relief. We evaluated the predictive value of a block on the outcome of surgery.
Methods
In total, three blocks were performed at two week intervals. Patients were blinded to injections containing lidocaine 1% and a placebo was included. Surgery was offered regardless of the effect of the blocks. Twenty-four patients received 72 blocks. Sixteen patients opted for surgery, 5 patients refrained from surgery, and in 3 the blocks provided permanent pain relief. The predictive ability of the block on the outcome of surgery was assessed by calculating the area under a Receiver Operating Characteristic curve (AUC).
Results
The AUC of the first lidocaine block was 0.35 with a 95% confidence interval from 0.077 to 0.62. At 95% confidence (two-sided), the AUC is less than 0.62, and hence the predictive ability of the block was poor. The outcome of the second lidocaine block and saline block did not change the conclusion of the first block.
Conclusions
We conclude that the use of blocks to select patients for surgery should be critically appraised.
Perspective
A pain relieving response to one open block is currently considered mandatory before patients with focal nerve injury and neuropathic pain are offered surgery. Blinded blocks including a placebo show that responses for selection should be carefully interpreted because they may not be as predictive as generally presumed.
Background:
Surgical management of neuromas is difficult, with no consensus on the most effective surgical procedure to improve pain and quality of life. This study evaluated the surgical treatment of neuromas by neurectomy, crush, and proximal transposition on improvement in pain, depression, and quality of life.
Methods:
Patients who underwent neuroma excision and proximal transposition were evaluated. Preoperative and postoperative visual analogue scale scores for pain (worst and average), depression, and quality of life were assessed using linear regression, and means were compared using paired t tests. The Disabilities of the Arm, Shoulder, and Hand questionnaire score was calculated preoperatively and postoperatively for upper extremity neuroma patients. Patients with long-term follow-up were analyzed using repeated measures analysis of variance comparing preoperative, postoperative, and long-term visual analogue scale scores.
Results:
Seventy patients (37 with upper extremity neuromas and 33 with lower extremity neuromas) met inclusion criteria. Statistically significant improvements in visual analogue scale scores were demonstrated for all four patient-rated qualities (p < 0.01) independent of duration of initial clinical follow-up. The change in preoperative to postoperative visual analogue scale scores was related inversely to the severity of preoperative scores for pain and depression. Neuroma excision and proximal transposition were equally effective in treating lower and upper extremity neuromas. Upper extremity neuroma patients had a statistically significant improvement in Disabilities of the Arm, Shoulder, and Hand questionnaire scores after surgical treatment (p < 0.02).
Conclusions:
Surgical neurectomy, crush, and proximal nerve transposition significantly improved self-reported pain, depression, and quality-of-life scores. Surgical intervention is a viable treatment of neuroma pain and should be considered in patients with symptomatic neuromas refractory to nonoperative management.
Clinical question/level of evidence:
Therapeutic, IV.
A continuous peripheral nerve block, also termed "perineural local anesthetic infusion," involves the percutaneous insertion of a catheter adjacent to a peripheral nerve, followed by local anesthetic administration via the catheter, providing anesthesia/analgesia for multiple days or even months. Continuous peripheral nerve blocks may be provided in the hospital setting, but the use of lightweight, portable pumps permits ambulatory infusion as well. This technique's most common application is providing analgesia after surgical procedures. However, additional indications include treating intractable hiccups; inducing a sympathectomy and vasodilation to increase blood flow after a vascular accident, digit transfer/replantation, or limb salvage; alleviating vasospasm of Raynaud disease; and treating peripheral embolism and chronic pain such as complex regional pain syndrome, phantom limb pain, trigeminal neuralgia, and cancer-induced pain. After trauma, perineural infusion can provide analgesia during transportation to a distant treatment center, or while simply awaiting surgical repair. Catheter insertion may be accomplished using many possible modalities, including nerve stimulation, ultrasound guidance, paresthesia induction, fluoroscopic imaging, and simple tactile perceptions ("facial click"). Either a nonstimulating epidural-type catheter may be used, or a "stimulating catheter" that delivers electrical current to its tip. Administered infusate generally includes exclusively long-acting, dilute, local anesthetic delivered as a bolus only, basal only, or basal-bolus combination. Documented benefits appear to be dependent on successfully improving analgesia, and include decreasing baseline/breakthrough/dynamic pain, supplemental analgesic requirements, opioid-related side effects, and sleep disturbances. In some cases, patient satisfaction and ambulation/functioning may be improved; an accelerated resumption of passive joint range-of-motion realized; and the time until discharge readiness as well as actual discharge from the hospital or rehabilitation center achieved. Lastly, postoperative joint inflammation and inflammatory markers may be decreased. Nearly all benefits occur during the infusion itself, but several randomized controlled trials suggest that in some situations there are prolonged benefits after catheter removal as well. Easily rectified minor complications occur somewhat frequently, but major risks including clinically relevant infection and nerve injury are relatively rare. This article is an evidence-based review of the published literature involving continuous peripheral nerve blocks.
A complex regional pain syndrome (CRPS)--multiple system dysfunction, severe and often chronic pain, and disability--can be triggered by a minor injury, a fact that has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently improved our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Variation in susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS.
Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.
Neuropathic pain in rodents can be driven by ectopic spontaneous activity (SA) generated by sensory neurons in dorsal root ganglia (DRG). The recent demonstration that SA in dissociated human DRG neurons is associated with reported neuropathic pain in patients enables detailed comparison of pain-linked electrophysiological alterations driving SA in human DRG neurons to alterations that distinguish SA in nociceptors from SA in low-threshold mechanoreceptors (LTMRs) in rodent neuropathy models. Analysis of recordings from dissociated somata of patient-derived DRG neurons showed that SA and corresponding pain in both sexes were significantly associated with the three functional electrophysiological alterations sufficient to generate SA in the absence of extrinsic depolarizing inputs. These include enhancement of depolarizing spontaneous fluctuations of membrane potential (DSFs), which were analyzed quantitatively for the first time in human DRG neurons. The functional alterations were indistinguishable from SA-driving alterations reported for nociceptors in rodent chronic pain models. Irregular, low-frequency DSFs in human DRG neurons closely resemble DSFs described in rodent nociceptors while differing substantially from the high-frequency sinusoidal oscillations described in rodent LTMRs. These findings suggest that conserved physiological mechanisms of SA in human nociceptor somata can drive neuropathic pain despite documented cellular differences between human and rodent DRG neurons.
Perspective: Electrophysiological alterations in human sensory neurons associated with patient-reported neuropathic pain include all three of the functional alterations that logically can promote spontaneous activity. The similarity of distinctively altered spontaneous depolarizations in human DRG neurons and rodent nociceptors suggests that spontaneously active human nociceptors can persistently promote neuropathic pain in patients.
There is a pressing need for more effective nonaddictive treatment options for pain. Pain signals are transmitted from the periphery into the spinal cord via dorsal root ganglion (DRG) neurons, whose excitability is driven by voltage-gated sodium (NaV) channels. Three NaV channels (NaV1.7, NaV1.8, and NaV1.9), preferentially expressed in DRG neurons, play important roles in pain signaling in humans. Blockade of these channels may provide a novel approach to the treatment of pain, but clinical translation of preclinical results has been challenging, in part due to differences between rodent and human DRG neurons. Human DRG neurons and iPSC-derived sensory neurons (iPSC-SNs) provide new preclinical platforms that may facilitate the development of novel pain therapeutics.
Objective:
The purpose of this study is to evaluate the effectiveness and safety of percutaneous radiofrequency thermocoagulation (PRT) via the foramen rotundum (FR) for the treatment of isolated maxillary (V2) idiopathic trigeminal neuralgia (ITN) and assess the appropriate puncture angle through the anterior coronoid process to reach the FR.
Methods:
Between January 2011 and October 2016, 87 patients with V2 ITN refractory to conservative treatment were treated by computed tomography (CT)-guided PRT via the FR at our institution. The outcome of pain relief was assessed by the visual analog scale (VAS) and Barrow Neurological Institute (BNI) pain grade and grouped as complete pain relief (BNI grades I-III) or unsuccessful pain relief (BNI grades IV-V). Recurrence and complications were also monitored and recorded. The puncture angle for this novel approach was assessed based on intraoperative CT images.
Results:
Of the 87 treated patients, 85 (97.7%) achieved complete pain relief, and two patients (2.3%) experienced unsuccessful pain relief immediately after operation. During the mean follow-up period of 44.3 months, 15 patients (17.2%) experienced recurring pain. No severe complications occurred, except for hypoesthesia restricted to the V2 distribution in all patients (100%) and facial hematoma in 10 patients (11.5%). The mean puncture angle to reach the FR was 33.6° ± 5.7° toward the sagittal plane.
Discussion:
CT-guided PRT via the FR for refractory isolated V2 ITN is effective and safe and could be a rational therapy for patients with V2 ITN.
A consensus on the optimal treatment of painful neuromas does not exist. Our objective was to identify available data and to examine the role of surgical technique on outcomes following surgical management of painful neuromas. In accordance with the PRISMA guidelines, we performed a comprehensive literature search to identify studies measuring the efficacy of the surgical treatment of painful neuromas in the extremities (excluding Morton's neuroma and compression neuropathies). Surgical treatments were categorized as excision-only, excision and transposition, excision and cap, excision and repair, or neurolysis and coverage. Data on the proportion of patients with a meaningful reduction in pain were pooled and a random effects meta-analysis was performed. The effects of confounding, study quality, and publication bias were examined with stratified, meta-regression, and bias analysis. 54 articles met inclusion criteria, many with multiple treatment groups. Outcomes reporting varied significantly and few studies controlled for confounding. Overall, surgical treatment of neuroma pain was effective in 77% of patients [95% confidence interval: 73-81]. No significant differences were seen between surgical techniques. Among studies with mean pain duration greater than 24 months, or median number of operations greater than 2 prior to definitive neuroma pain surgery, excision and transposition, or neurolysis and coverage were significantly more likely than other operative techniques to result in a meaningful reduction in pain (p<0.05). Standardization in the reporting of surgical techniques, outcomes, and confounding factors is needed in future studies to enable providers to make comparisons across disparate techniques in the surgical treatment of neuroma pain.
Objectives:
Painful stump neuromas in lower limb amputees are a significant burden on a person's quality of life due to interference with wearing prostheses and therefore the ability to walk. Treating painful stump neuromas is a challenge perhaps reflected by the lack of clinical guidelines both in the United Kingdom and internationally.
Methods:
A systematic review was conducted to evaluate the efficacy of all treatments tried in the management of symptomatic neuromas in the lower limb amputation stump in order to establish whether one treatment is superior.
Results:
Twenty-two studies were included in the final review which examined 14 different treatments both surgical and non-surgical. Results showed that no single treatment showed superiority.
Discussion:
The four treatments that showed most promise included targeted nerve implantation (TNI), traction neurectomy, nerve-to-nerve anastomosis and perineurial gluing. The short follow-up times and small sample sizes of the studies highlighted the need for more robust clinical studies.
Pain Genetics: Basic to Translational Science is a timely synthesis of the key areas of research informing our understanding of the genetic basis of pain. The book opens with foundational information on basic genetic mechanisms underlying pain perception and progresses recently discovered complex concepts facing the field. The coverage is wide-ranging and will serves as an excellent entry point into understating the genetics of pain as well as providing a single resource for established researchers looking for a better understanding of the diverse strands of research going on in the area. With contributors painstakingly selected to provide a broad range of perspectives and research, Pain Genetics will be a valuable resource for geneticists, neuroscientists, and biomedical professionals alike.
Basal lamina grafts for reconnecting severed nerves are prepared from muscle by removing cellular material therefrom while preserving the tubular structure of the basal lamina. When connected to nerve stumps the basal lamina surfaces promote axon regeneration therethrough, eventually reestablishing nerve function through the regenerated graft.
New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.
Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.
229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.
Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.
NeuPSIG of the International Association for the Study of Pain.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Central sensitization following peripheral nerve injury may result in ectopic neuronal activity in the spinal cord dorsal horn, implying a potential autonomous pain-generating mechanism. This study used peripheral nerve blockade and systemic lidocaine administration, with detailed somatosensory assessment, to determine the contribution of primary afferent input in maintaining peripheral neuropathic pain. Fourteen patients with neuropathic pain (seven with unilateral foot pain due to peripheral nerve injury and seven with bilateral pain in the feet due to distal polyneuropathy) underwent comprehensive characterization of somatosensory function by quantitative sensory testing. Patients were then administered an ultrasound-guided peripheral nerve block with lidocaine and intravenous lidocaine infusion in randomized order. The effect of these interventions on spontaneous pain intensity and on evoked cold, warm, pinprick, and brush responses was assessed at each session. All patients presented with sensory disturbances at baseline. The peripheral nerve block resulted in a complete abolition of ipsilateral pain within 10 min (median) in all patients, with lidocaine plasma concentrations being too low to account for a systemic effect of the drug. Intravenous lidocaine infusion reduced the spontaneous pain by 45.5% (± 31.7%), and reduced mechanical and thermal hypersensitivity in most patients who displayed such signs, but the improvement in evoked hypersensitivity was not related to the effect of the drug on spontaneous pain intensity. This study demonstrates that regardless of the individual somatosensory phenotype and signs of central sensitization, primary afferent input is critical for maintaining neuropathic pain in peripheral nerve injury and distal polyneuropathy.
This case report describes the remarkable recovery of a patient with very long‐standing, medically intractable and disabling, lower‐limb, complex regional pain syndrome type II (causalgia) following the resection, crushing, and relocation of sensory nerves. ABSTRACT: This case report describes the remarkable recovery of a patient with very long‐standing, medically intractable and disabling, lower‐limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves.
Objective:
To test the hypothesis that peripheral C nociceptor function may be abnormal in fibromyalgia and that C nociceptor dysfunction may contribute to the symptoms reported by these patients.
Methods:
Microneurography was used to record C nociceptors of 30 female patients meeting criteria for fibromyalgia and compared with recordings from 17 female patients with small-fiber neuropathy and 9 female controls.
Results:
We obtained stable recordings of 186 C nociceptors in the fibromyalgia group, 114 from small-fiber neuropathy patients, and 66 from controls. The mechanosensitive nociceptors in the fibromyalgia patients behaved normally, but the silent nociceptors in 76.6% of fibromyalgia patients exhibited abnormalities. Spontaneous activity was detected in 31% of silent nociceptors in fibromyalgia, 34% in small-fiber neuropathy, and 2.2% in controls. Sensitization to mechanical stimulation was found in 24.2% of silent nociceptors in fibromyalgia, 22.7% in small-fiber neuropathy, and 3.7% in controls. Abnormally high slowing of conduction velocity when first stimulated at 0.25Hz was more common in fibromyalgia.
Interpretation:
We show for the first time that the majority of fibromyalgia patients have abnormal C nociceptors. Many silent nociceptors exhibit hyperexcitability resembling that in small-fiber neuropathy, but high activity-dependent slowing of conduction velocity is more common in fibromyalgia patients, and may constitute a distinguishing feature. We infer that abnormal peripheral C nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain and tenderness suffered by patients with fibromyalgia.
Many pain states begin with damage to tissue and/or nerves in the periphery, leading to enhanced transmitter release within the spinal cord and central sensitization. Manifestations of this central sensitization are wind-up and long-term potentiation. Hyperexcitable spinal neurons show reduced thresholds, greater evoked responses, increased receptive field sizes and ongoing stimulus-independent activity; these changes probably underlie the allodynia, hyperalgesia and spontaneous pain seen in patients. Central sensitization is maintained by continuing input from the periphery, but also modulated by descending controls, both inhibitory and facilitatory, from the midbrain and brainstem. The projections of sensitized spinal neurons to the brain, in turn, alter the processing of painful messages by higher centers. Several mechanisms contribute to central sensitization. Repetitive activation of primary afferent C-fibers leads to a synaptic strengthening of nociceptive transmission. It may also induce facilitation of non-nociceptive Aβ-fibers and nociceptive Aδ-fibers, giving rise to dynamic mechanical allodynia and mechanical hyperalgesia. In post-herpetic neuralgia and complex regional pain syndrome, for example, these symptoms are maintained and modulated by peripheral nociceptive input. Diagnosing central sensitization can be particularly difficult. In addition to the medical history, quantitative sensory testing and functional magnetic resonance imaging may be useful, but diagnostic criteria which include both subjective and objective measures of central augmentation are needed. Mounting evidence indicates that treatment strategies which desensitize the peripheral and central nervous systems are required. These should generally involve a multimodal approach, so that therapies may target the peripheral drivers of central sensitization and/or the central consequences. ANN NEUROL 2013. © 2013 American Neurological Association.
This chapter describes pathophysiologic processes through which damaged nerves can come to contribute actively to chronic pain both by injecting abnormal discharge into the nervous system, and by amplifying and distorting naturally generated signals. Pathophysiologic changes in the peripheral nervous system (PNS) may cause neuropathic and radiculopathic pain. Thereafter irritation or damage to peripheral nerves or sensory roots triggers the development of distinctive clinical syndromes which include both negative and positive symptoms. The data presented in the chapter suggests that the primary pathophysiologic change in injured nerves, spinal roots, and dorsal root ganglias is an increase in electrical excitability. The probable cause is abnormal differentiation of the axonal membrane at the cut nerve end, at sites of demyelination, and in axotomized sensory neurons. Damaged nerves are capable of generating rhythmic discharge at ectopic pacemaker sites, providing a signal for detection. Also associated with abnormal impulse generation in damaged nerves are several processes that can amplify normal or pathophysiologic impulse discharge. There is a fundamental difference between the mechanisms of normal and neuropathic pain. Normal pain arises from acute or chronic stimulation of normal afferent nociceptor endings by intense stimuli, while neuropathic pain occurs spontaneously, or in response to weak stimuli because of abnormalities of neural excitability.
Spontaneous pain is difficult to measure in animals. One proposed biomarker of spontaneous pain is autotomy, a behavior frequently observed in rats with complete hindpaw denervation (the neuroma model of neuropathic pain). A large body of evidence suggests that this behavior reflects spontaneous dysesthesic sensations akin to phantom limb pain or anesthesia dolorosa. After partial paw denervation, such as in the spared nerve injury (SNI) model of neuropathic pain, autotomy is rare. Does this mean that spontaneous pain is absent? We denervated hindpaws in two stages: SNI surgery completed 7 or 28 days later by transection of the saphenous and sural nerves (SaSu). Minimal autotomy was evoked by the first stage. But it started rapidly after SaSu surgery rendered the limb numb, much more rapidly than after denervation in a single stage (neuroma model). The acceleration was proportional to the delay between the two surgeries. This "priming" effect of the first surgery indicates that the neural substrate of autotomy, spontaneous neuropathic pain, was not initiated by the onset of numbness, but rather by the first, SNI surgery. But the animal's pain experience was occult. The saphenous and sural nerves provided nociceptive sensory cover for the paw, preventing the behavioral expression of the spontaneous pain in the form of autotomy. The results support prior observations suggesting that partial nerve injury triggers spontaneous pain as well as allodynia, and illustrate the importance of nociceptive sensory cover in the prevention of self-inflicted limb injury.
Afferent fibers ending in nerve end neuromas in rats generate a substantial ectopic discharge and are sensitive to light pressure and to circulating adrenaline. Treatment of the nerve with colchicine or vinblastine at the time of the nerve section resulted in a dose-dependent reduction in the extent of this discharge. Such treatment also reduced neuroma discharge that had already gotten underway.
We undertook a retrospective study to evaluate the hypothesis that complex regional pain syndrome (CRPS) I, known as the "new" reflex sympathetic dystrophy, persists because of undiagnosed injured joint afferents, cutaneous neuromas, or nerve compressions, and is, therefore, a misdiagnosed form of CRPS II, which is known as the "new" causalgia. We used a research protocol, with institutional review board approval, to review medical records for the purpose of identifying 30 patients with lower extremity reflex sympathetic dystrophy, based on their history, physical examination, neurosensory testing, and response to peripheral nerve blocks, who were treated surgically at the level of the peripheral nerve. In this report, we describe long-term outcomes in 13 of these patients who were followed up for a minimum of 24 months (mean, 47.8 months; range, 25-90 months). Based primarily on the results of physical examination and the response to peripheral nerve blocks, surgery included a combination of joint denervation, neuroma resection plus muscle implantation, and neurolysis. Outcomes were measured in terms of decreased pain medication usage and recovery of function, and the results were excellent in 7 (55%), good in 4 (30%), and poor (failure) in 2 (15%) of the patients. Based on these results, we concluded that most patients referred with a diagnosis of CRPS I have continuing pain input from injured joint or cutaneous afferents, and chronic nerve compression, which is indistinguishable from CRPS II, and amenable to successful treatment by means of an appropriate peripheral nerve surgical strategy.
Keratinocytes play an important role in the dialog between skin and cutaneous sensory neurons. They are an essential source of cutaneous nerve growth factor (NGF), a neurotrophin that contributes to persistent pain in inflammation and neuropathy. We studied the interaction of human keratinocytes (hKTs) and regenerating afferent nerve fibers by transplanting hKTs into a ligated and transected peripheral nerve. The hKTs self-assembled into a multi-laminar spheroid cellular structure resembling the stratum spinosum of epidermis. Axonal sprouts surrounded the structure although they were excluded from entry. Levels of NGF were elevated at the transplant site. Whole cell patch-clamp recordings from primary afferent neurons whose cut axons were present near the transplanted hKTs displayed extreme hyperexcitability. These neurons generated high frequency trains of action potentials during step depolarization stimuli, and they sometimes showed afterdischarge and fired spontaneously at resting membrane potential. This spontaneous firing originated from subthreshold membrane potential oscillations. The animals with the hKT transplants exhibited spontaneous pain behavior manifest as autotomy. The results demonstrate that an interaction between injured/regenerating nerve fibers and keratinocytes such as may occur during wound healing, results in afferent hyperexcitability and pain. These results have implications for persistent pain associated with burn and traumatic skin injuries.
Injury of axons in the peripheral nervous system (PNS) induces transcription-dependent changes in gene expression and axonal transport that promote effective regeneration by increasing the intrinsic growth state of axons. Regeneration is enhanced in axons re-injured 1-2 weeks after the intrinsic growth state has been increased by such a prior conditioning lesion (CL). The intrinsic growth state does not increase after axons are injured in the mammalian central nervous system (CNS), where they lack the capacity for effective regeneration. Sensory neurons in the dorsal root ganglion (DRG) have two axonal branches that respond differently to injury. Peripheral branches, which are located entirely in the PNS, are capable of effective regeneration. Central branches regenerate in the PNS (i.e., in the dorsal root, which extends from the DRG to the spinal cord), but not in the CNS (i.e., the spinal cord). A CL of peripheral branches increases the intrinsic growth state of central branches in the dorsal columns of the spinal cord, enabling these axons to undergo lengthy regeneration in a segment of peripheral nerve transplanted into the spinal cord (i.e., a peripheral nerve graft). This regeneration does not occur in the absence of a CL. We will examine how changes in gene expression and axonal transport induced by a CL may promote this regeneration.
Ectopic discharge in axotomized dorsal root ganglion neurons is a key driver of neuropathic pain. However, the bulk of this activity is generated and carried centrally in large diameter myelinated Abeta afferents, a cell type that normally signals touch and vibration sense. Evidence is considered suggesting that following axotomy, Abeta afferents undergo a change in their electrical characteristics and also in the neurotransmitter complement that they express. This dual phenotypic switching renders them capable of (1) directly driving postsynaptic pain signaling pathways in the spinal cord, and (2) triggering and maintaining central sensitization.
This chapter describes microneurography as a neurophysiological method that allows microelectrode recordings of impulses in single nerve fibers in awake human subjects. It has been employed for recordings from afferent sensory nerve fibers, efferent sympathetic nerve fibers, and proprioceptive nerve fibers. It discusses that microneurography experiments in human experimental models of pain/neuropathic pain shed important light on pathophysiological mechanisms involved in primary and secondary hyperalgesia. The chapter reviews the principal findings in nociceptive systems of relevance for pathology. It also provides future perspective of microneurography. As microneurography does not allow recording directly from the sensory endings or of the membrane potential, molecular mechanisms of transduction cannot be investigated directly. The time course of post-excitatory hyperpolarization can be assessed by microneurography and, thus, there is an exciting perspective to finally bridge the gap between the cellular and systemic approach. Despite many limitations the microneurographic approach provides unique data from healthy human subjects and patients and has a mediative position between clinical science and basic research.
These findings, based upon the application to man of techniques for single unit recording, paresthesiae from peripheral nerve dysfunction signify abnormal impulse generation in the sensory unit. Our studies indicate that recognizable changes in perception of paresthesiae (sustained 'buzzing' versus intermittent 'tingling') can be the consequence of modulation of impulse frequency, and duration and rhythm of the discharges. Although the contribution ot paresthesiae from different fibre types has not been investigated, the sustained, very high frequency of discharge recorded in some fibres endorses participation of myelinated fibres.
(1) When hindlimb peripheral nerves are cut across in rats and mice, there is a tendency for the animal to attack the anaesthetic limb. We have called this attack "autotomy". In this paper we describe the time course and degree of autotomy following various types of nerve injury. (2) Four different types of lesion were applied to the sciatic nerve of rats. The most serious autotomy was produced by section of the nerve and encapsulation of its cut end in a polythene tube. Section followed by immediate resuturing also produced serious autotomy. Simple ligation of the nerve end was followed by less autotomy than encapsulation or cut and resuture. A crush lesion caused only minimal attack. (3) Section of the saphenous branch of the femoral nerve produced no autotomy. However, if the saphenous and sciatic nerves were ligated at the same time so that the entire foot became anaesthetic there was a great increase of autotomy over that seen when the sciatic nerve alone was ligated. This increase with the double lesion occurred even if the saphenous nerve was ligated more than 100 days after the sciatic nerve had been cut. (4) Mice showed autotomy very similar to that seen in rats but the onset was somewhat faster. (5) Reasons are given to propose that autotomy is triggered by an abnormal afferent barrage generated in the cut end of the nerve. Autotomy from peripheral nerve lesions is a different phenomenon from that seen after dorsal root section. Autotomy occurs under conditions which produce anaesthesia dolorosa in man. This simple model may be suitable for studies of the prevention of irritations originating from chronic lesions of peripheral nerves.
1. We recorded from single afferent axons ending in chronic sciatic nerve end neuromas in rats with the use of the teased-fiber method. Axons were sought that had ongoing impulse discharge originating in the neuroma. 2. Recording from myelinated (A-) fibers, tetanic stimulation of neighboring axons (50 Hz, 5 or 10 s, intensity adequate to drive A-fibers) caused an increase, and sometimes a decrease, in the rate of ongoing discharge in 68% of the fibers tested. In addition, some initially silent neuroma A-fibers (1.4%) were activated in this way. Both A beta and A delta fibers responded, although the likelihood of response was greater in A beta fibers. We call this form of interfiber cross-excitation "crossed afterdischarge." 3. In contrast to A-fibers, crossed afterdischarge was evoked with these stimulation parameters in < or = 5% of the spontaneously active unmyelinated (C-) fibers sampled. No initially silent C-fibers were activated. 4. C-fibers remained largely insensitive to cross-excitation by neighboring axons even when the strength of stimulus pulses was increased so as to include neighboring A + C-fibers. 5. The difference between A- and C-fibers could not be accounted for on the basis of the maturity of the neuroma, rate and pattern of ongoing discharge, or use of Flaxedil paralysis. 6. The difference between A- and C-fibers is discussed in terms of two alternative mechanisms that may underlie crossed afterdischarge: mediation by a neurotransmitter(s) in a nonsynaptic mode, and mutual K+ depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)
Systemic application of lidocaine in rats suppressed ectopic impulse discharge generated both at sites of experimental nerve injury and in axotomized dorsal root ganglion (DRG) cells. ED50 for DRGs was significantly lower than for the injury site. Lidocaine doses effective at blocking ectopic discharge failed to block the initiation or propagation of impulses by electrical stimulation, and only minimally affected normal sensory receptors. This selectivity may account for the effectiveness of systemic local anesthetics and other drugs that share the same mechanism of action (notably certain anticonvulsants and antiarrhythmics), in the management of neuropathic paresthesias and pain. In addition, it may account for the prolonged analgesia sometimes obtained using regional local anesthetic block.
Using the teased fiber recording method, we have compared pathophysiological properties of afferent axons injured in the infraorbital nerve (ION) vs the sciatic nerve in rats. Both myelinated and unmyelinated axons ending in ION neuromas produced much less ongoing discharge than those ending in sciatic nerve neuromas. Similarly, mechanosensitivity and acute injury discharge in ION neuromas were minimal. These differences may be related to the different spectrum of neuropathic symptomatology associated with nerve injury in the trigeminal vs the segmental innervation fields.
Injured sensory axons with endings trapped in a nerve-end neuroma become a source of abnormal impulse discharge and neuropathic pain. We have examined the ultrastructure of such endings anterogradely transported WGA-HRP and freeze-fracture replication, with emphasis on the postinjury period during which the abnormal neural discharge is maximal. Most axons ended in a terminal swelling, depleted of myelin but surrounded by Schwann cell processes. These 'neuroma endbulbs' were richly packed with membrane-bound organelles, and had a smoothly undulating surface with (in neuromas of several weeks standing) a moderate number of short filopodia. Massive sprouting did not occur until several months postinjury. Both p- and e-faces of endbulb axolemma had larger intramembranous particles, on average, than corresponding internodal membrane of control axons. This change, interpreted as indicating remodelling of axolemmal channel (and perhaps receptor) content, may be related to the abnormal electrical behavior of neuroma afferents.
La Forte et al. (this issue) failed to find an increase in the numbers of dorsal root ganglion (DRG) neurons in rats of advancing age. However, their conclusion that our data (Devor and Govrin-Lippmann, 1985) to this effect were methodologically flawed is based on an incorrect application of our counting method. In fact, both their counting method and ours provide similar results when applied to the same tissue sections. We believe that the difference in results is biological. Specifically, DRG neurogenesis in adulthood occurs in animals in which growth continues throughout life (including the male Wistar-derived rats we used), but not in those whose body size stabilizes soon after sexual maturity (including the female Sprague-Dawley rats they used). With this caveat in mind, recent data of Schmalbruch (1987a,b) and others can be understood as corroborating our conclusions. However, an adequate, independent replication of our 1985 study has yet to be carried out.
1. Experiments based on teased fiber recording from rat sciatic nerve have shown that a small proportion of primary afferent neurons in intact dorsal root ganglia (DRGs) fire spontaneously. The prevalence of this discharge is substantially increased if the sciatic nerve has been chronically injured. 2. We now show that in most cases this ongoing DRG activity can be augmented by tetanic stimulation of the axons of neighboring neurons, where the active neuron itself has not been stimulated. In addition, some previously silent DRG neurons can be cross-excited by neighbors. This novel form of neuron-to-neuron communication is termed "DRG crossed afterdischarge." Cross-excitation never occurred at fixed latency in response to single stimulus pulses and is therefore not a case of ephaptic cross talk. 3. Crossed afterdischarge occurred only if the spontaneously active neuron and the stimulated neighbors shared the same DRG. It occurred in 83.5% of the spontaneously active neurons sampled that had myelinated (A) axons, but in only 4.4% of spontaneously active neurons with unmyelinated (C) axons. Among initially silent neurons, stimulation of neighbors evoked firing in 3.1% of A-fibers but in no C-fibers. 4. Crossed afterdischarge responses began within 500 ms of stimulation onset (with the use of 50-Hz tetani) and increased in magnitude for about the first 30 s of stimulation, declining thereafter. Intense excitations were often followed by a short period of depression until the original rate of ongoing discharge was restored. 5. The magnitude of crossed afterdischarge responses increased with increasing stimulation frequency until saturation. Minimal responses occurred with the use of tetani of as little as 1 Hz. Maximal responses occurred with the use of 100-200 Hz tetani. 6. The inclusion of C-fibers in the afferent volley produced little if any augmentation of responses. 7. Cross-excitation was demonstrated in DRGs in which many or all peripheral afferent axons were intact and continued to innervate hind limb skin. In these preparations natural cutaneous stimulation was shown to be capable of evoking crossed afterdischarge responses. The most effective stimuli were gentle or firm rubbing of the foot. Noxious pinch, heat, cold, and chemical stimulation was ineffective. 8. DRG crossed afterdischarge is a mechanism whereby sensation in response to peripheral stimulation may be distorted in time, space, and modality. Because its prevalence is much increased after axotomy, it might contribute to neuropathic sensory abnormalities, including pain, in patients with nerve injury.
Male and female rats underwent transection and ligation of the sciatic and saphenous nerves, and the development of autonomy was monitored. The deafferented animals were then interbred, always selecting males and females that expressed relatively high and, alternatively, relatively low levels of autotomy. Offspring were similarly operated and interbred. By the sixth generation of selective breeding, lines were achieved in which autotomy was consistently high (HA) or consistently low (LA). There was no indication of sex linkage. Thermal and mechanical nocifensive responsiveness co-selected with propensity to express autotomy following nerve injury: response thresholds were lower in HA than in LA rats. F1 hybrids formed by crossing homozygous HA and LA animals showed low levels of autotomy, similar to LA stock. This indicates recessive inheritance of the autotomy trait. Backcrossing F1 hybrids onto the LA line yielded a low autotomy phenotype in almost all cases; backcrossing F1 hybrids onto HA stock yielded about 50% high autotomy and 50% low autotomy. These ratios are consistent with simple mendelian inheritance of a single gene. Taken together, the data suggest that autotomy is inherited as a single-gene autosomal recessive trait.