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Neural Basis of Pain in Herpes Zoster and Postherpetic Neuralgia: The Ectopic Pacemaker Hypothesis

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Abstract

Pain in herpes zoster and postherpetic neuralgia is classically ascribed to irritable, inflammation-sensitized nociceptors in the cutaneous rash and to spinal cord deafferentation. After considering weaknesses in the evidence base underlying this view an alternative explanation is offered, based on hyperexcitability at ectopic pacemaker sites in affected primary sensory neurons, and central sensitization induced and maintained by the ectopic activity.

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... The ectopic pacemaker hypothesis of pain in HZ and PHN attempts to interpret the clinical facts surrounding HZ/PHN in light of recent advances in our understanding on the biology of neuropathic pain. 17 In a nutshell, the hypothesis has 2 elements: (1) spontaneous pain in both HZ and PHN is proposed to be due to spontaneous impulse discharge arising at ectopic pacemaker sites in the PNS, sites associated with the dying-back of axons ends and pathology in sensory somata in the VZV-infected DRG. Dying-back neuropathy also explains the dulling of response to warm stimuli as C fiber sensory endings are lost in the epidermis. ...
... Thus, if the DRG contributes a significant fraction of the impulses responsible for ongoing pain in a particular patient, diagnostic nerve block distal to the ganglion will not stop the pain, but block of the DRG itself (intraforaminal block), or centrally (dorsal root or spinal block), will. 17 If the reports on lidocaine patches, skin infiltration, and nerve block are to be taken at face value (section 3.1.2 and below), the signal in most patients originates distal to the DRG. ...
... The strategy would begin with diagnostic blocks needed to determine whether the primary driver in a given patient is in the skin, nerve trunk, or DRG. 17 Useful conclusions, of course, depend on the technical adequacy of the block. If incomplete, there is a risk of false-negative conclusions. ...
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Introduction Pain in herpes zoster (HZ) and postherpetic neuralgia (PHN) is traditionally explained in terms of 2 processes: irritable nociceptors in the rash-inflamed skin and, later, deafferentation due to destruction of sensory neurons in one virally infected dorsal root ganglion. Objectives and methods Consideration of the evidence supporting this explanation in light of contemporary understanding of the pain system finds it wanting. An alternative hypothesis is proposed as a replacement. Results This model, the ectopic pacemaker hypothesis of HZ and PHN, proposes that pain in both conditions is driven by hyperexcitable ectopic pacemaker sites at various locations in primary sensory neurons affected by the causative varicella zoster virus infection. This peripheral input is exacerbated by central sensitization induced and maintained by the ectopic activity. Conclusions The shift in perspective regarding the pain mechanism in HZ/PHN has specific implications for clinical management.
... Likewise, the DRG is implicated as a driver of pain in herpes zoster and postherpetic neuralgia, trigeminal neuralgia (TN), phantom limb pain, and complex regional pain syndrome. 5,8,14,[37][38][39][40]49 Ablative procedures aimed at the DRG and trigeminal ganglion are used frequently in the treatment of chronic pain, notably TN, chronic headaches, and occipital neuralgia. More recently, electrical counterstimulation directed at the DRG has been introduced as a therapeutic modality in a variety of chronic pain conditions. ...
... Conditions in which the DRG is implicated as a pain driver include postherpetic neuralgia, a pain state caused by viral infection of a single ganglion, TN where fifth nerve root compression triggers hyperexcitability within the trigeminal ganglion, phantom pain, complex regional pain syndrome, and radicular low back pain. 5,8,14,15,33,37 The principle also applies to pain generated at focal sites of nerve injury such as nerve-end neuromas and nerve entrapment sites. 12 The 5% lidocaine patch is an example of such focal targeting. ...
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Ectopic impulse discharge (ectopia) generated in the soma of afferent neurons in dorsal root ganglia (DRGs) following nerve injury is thought to be a major contributor to neuropathic pain. The DRG is thus a prime interventional target. The process of electrogenesis (impulse generation) in the DRG is far more sensitive to systemically administered Na channel blockers than the process of impulse propagation along sensory axons. It should therefore be possible to selectively suppress DRG ectopia with local application of membrane stabilizing agents without blocking normal impulse traffic. Results from in vivo electrophysiological recordings in rats showed that epidural application of lidocaine to the DRG surface within the intervertebral foramen at 0.02% or 0.2% substantially suppresses electrogenesis in the DRG with only a modest blocking effect on impulse propagation through the foramen. Topically applied opiates and GABA, in contrast, blocked neither ongoing discharge nor spike through-conduction. This suggests that sustained intraforaminal delivery of dilute lidocaine, and by extension other membrane stabilizing agents, is a potential new strategy for the control of chronic painful conditions in which ectopia in sensory ganglia is implicated as a key pain driver. Such conditions include postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, CRPS and radicular low back pain.
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Herpes zoster patients can develop persistent pain after rash healing, a complication known as postherpetic neuralgia. By preventing zoster through vaccination, the risk of this common complication is reduced. We searched Medline and Embase for studies assessing risk factors for postherpetic neuralgia, with a view to informing vaccination policy. Nineteen prospective studies were identified. Meta-analysis showed significant increases in the risk of postherpetic neuralgia with clinical features of acute zoster including prodromal pain (summary RR 2.29, 95%CI: 1.42-3.69), severe acute pain (2.23, 1.71-2.92), severe rash (2.63, 1.89-3.66) and ophthalmic involvement (2.51, 1.29-4.86). Older age was significantly associated with postherpetic neuralgia; for individual studies, relative risk estimates per ten-year increase ranged from 1.22-3.11. Evidence for differences by gender was conflicting, with considerable between-study heterogeneity. A proportion of studies reported an increased risk of postherpetic neuralgia with severe immunosuppression (studies, n=3/5) and diabetes mellitus (n=1/4). Systemic lupus erythematosis, recent trauma and personality disorder symptoms were associated with postherpetic neuralgia in single studies. No evidence of higher postherpetic neuralgia risk was found with depression (n=4) or cancer (n=5). Our review confirms a number of clinical features of acute zoster are risk factors for postherpetic neuralgia. It has also identified a range of possible vaccine-targetable risk factors for postherpetic neuralgia, yet aside from age-associated risks, evidence regarding risk factors to inform zoster vaccination policy is currently limited.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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• We treated 72 patients, referred to a pain clinic for acute herpes zoster neuralgia, with local anesthetics administered by nerve block and infiltration. Only those patients with severe pain initially proved to be at risk for the development of chronic postherpetic neuralgia (defined as pain in the involved dermatomes lasting at least six months). Although local anesthetic injections effectively relieved the acute pain of active herpes zoster, they did not prevent the development of chronic postherpetic neuralgia.(Arch Dermatol 1984;120:747-750)
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A 65-year-old man presents with a rash of 2 days' duration over the right forehead with vesicles and pustules, a few lesions on the right side and tip of the nose, and slight blurring of vision in the right eye. The rash was preceded by tingling in the area and is now associated with aching pain. How should this patient be evaluated and treated?
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THE PAIN which may follow herpes zoster may be so severe as to lead to suicide (Forget1). William Bowman2 wrote (1867): "I wish I could state anything very satisfactory as to the treatment of the after-pains, which are sometimes so severe as to make the patient weary of existence." In 1901 Mules3 reported a case in which the pains were so violent that the patient applied carriage varnish and liniment to the scalp; this caused severe dermatitis and eventual sloughing of the skin of the forehead down to the pericranium. When the man recovered, his pain had disappeared. It is common for pain to precede the outbreak of the vesicles which appear at the terminal ramifications of the sensory nerves in herpes zoster. It is usual for the pain to disappear at this time, or to linger on during the course of the eruption for a while
Article
Although unquestionably dedicated to the advancement of medical science, our profession apparently has failed to respond to pressing social needs. This failure is manifest by strong external forces striving to change the basic nature of medical practice and to impose upon each physician a different and perhaps more burdensome way of life. Medicine in the broad concept is a service; the doctor is a public servant. Whether his prime interest be patient care, teaching, or research, his goal must be to improve the health of the people. The profession's emphasis upon medical research has overtaxed and exceeded our ability to apply its abundant and significant advances. One of society's most urgent demands is the immediate application of these advances to the care of the people. This creates an enormous problem, for knowledge of inestimable value to the health of society has not been distilled to the degree that the practicing
Article
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.
Article
Unlabelled: We report a novel symptom in many patients with low back pain (LBP) that sheds new light on the underlying pain mechanism. By means of quantitative sensory testing, we compared patients with radicular LBP (sciatica), axial LBP (LBP without radiation into the leg), and healthy controls, searching for cutaneous allodynia in response to weak tactile and cooling stimuli on the leg and low back. Most patients with radicular pain (~60%) reported static and dynamic tactile allodynia, as well as cooling allodynia, on the leg, often extending into the foot. Some also reported allodynia on the low back. In axial LBP, allodynia was almost exclusively on the back. The degree of dynamic tactile allodynia correlated with the degree of background pain. The presence of allodynia suggests that the peripheral nerve generators of background leg and back pain have also induced central sensitization. The distal (foot) location of the allodynia in patients who have it indicates that the nociceptive drive that maintains the central sensitization arises paraspinally (ectopically) in injured ventral ramus afferents; this is not an instance of somatic referred pain. The presence of central sensitization also provides the first cogent account of shooting pain in sciatica as a wave of activity sweeping vectorially across the width of the sensitized dorsal horn. Finally, the results endorse leg allodynia as a pain biomarker in animal research on LBP, which is commonly used but has not been previously validated. In addition to informing the underlying mechanism of LBP, bedside mapping of allodynia might have practical implications for prognosis and treatment. Social media question: How can you tell whether pain radiating into the leg in a patient with sciatica is neuropathic, ie, due to nerve injury?
Article
Background: Lidocaine is a local anaesthetic that is sometimes used on the skin to treat neuropathic pain. Objectives: To assess the analgesic efficacy of topical lidocaine for chronic neuropathic pain in adults, and to assess the associated adverse events. Search methods: We searched CENTRAL, MEDLINE, and EMBASE from inception to 1 July 2014, together with the reference lists of retrieved papers and other reviews. We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal to identify additional published or unpublished data. Selection criteria: We included randomised, double-blind studies of at least two weeks' duration comparing any formulation of topical lidocaine with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only full journal publication articles. Data collection and analysis: Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks' duration, parallel design); second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with adequate numbers in the comparison; and third tier evidence from data involving small numbers of participants that we considered very likely to be biased or used outcomes of limited clinical utility, or both. Main results: We included 12 studies (508 participants) in comparisons with placebo or an active control. Six studies enrolled participants with moderate or severe postherpetic neuralgia, and the remaining studies enrolled different, or mixed, neuropathic pain conditions, including trigeminal neuralgia and postsurgical or post-traumatic neuralgia. Four different formulations were used: 5% medicated patch, 5% cream, 5% gel, and 8% spray. Most studies used a cross-over design, and two used a parallel-group design. Two studies used enriched enrolment with randomised withdrawal. Seven studies used multiple doses, with one to four-week treatment periods, and five used single applications. We judged all of the studies at high risk of bias because of small size or incomplete outcome assessment, or both.There was no first or second tier evidence, and no pooling of data was possible for efficacy outcomes. Only one multiple-dose study reported our primary outcome of participants with ≥ 50% or ≥ 30% pain intensity reduction. Three single-dose studies reported participants who were pain-free at a particular time point, or had a 2-point (of 10) reduction in pain intensity. The two enriched enrolment, randomised withdrawal studies reported time to loss of efficacy. In all but one study, third tier (very low quality) evidence indicated that lidocaine was better than placebo for some measure of pain relief. Pooling multiple-dose studies across conditions demonstrated no clear evidence of an effect of lidocaine on the incidence of adverse events or withdrawals, but there were few events and the withdrawal phase of enriched enrolment designs is not suitable to assess the true impact of adverse events (very low quality evidence). Authors' conclusions: This review found no evidence from good quality randomised controlled studies to support the use of topical lidocaine to treat neuropathic pain, although individual studies indicated that it was effective for relief of pain. Clinical experience also supports efficacy in some patients. Several large ongoing studies, of adequate duration, with clinically useful outcomes should provide more robust conclusions about both efficacy and harm.
Article
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.
Article
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.
Article
Topical analgesics applied locally to skin or to specialized compartments modify pain by actions on sensory nerve endings and/or adjacent cellular elements. With this approach, there are low systemic drug levels, good tolerability and few drug interactions, and combination with oral formulations is feasible. The goal of this review is to provide an overview of the potential for topical analgesics to contribute to improved management of neuropathic pain. Mechanistic and preclinical studies indicate much potential for development of novel topical analgesics for neuropathic pain. In humans, two topical analgesics are approved for use in post-herpetic neuralgia (lidocaine 5% medicated plaster, capsaicin 8% patch), and there is evidence for efficacy in other neuropathic pain conditions. Comparative trials indicate similar efficacy between topical and oral analgesics. Not all individuals respond to topical analgesics, and there is interest in determining factors (patient factors, sensory characteristics) which might predict responsiveness to topical analgesics. There is a growing number of controlled trials and case reports of investigational agents (vasodilators, glutamate receptor antagonists, α2-adrenoreceptor agonists, antidepressants, centrally acting drugs), including combinations of several agents, indicating these produce pain relief in neuropathic pain. There is interest in compounding topical analgesics for neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of neuropathic pain.
Article
The development of agents useful in local anesthesia, therapy of cardiac arrhythmias, and prevention of epileptic seizures has proceeded along independent pathways with use of appropriate pharmacological models for drug testing. William Catterall reviews recent studies of the mechanism of action of these agents in peripheral nerve, cardiac muscle cells and central neurons. These have focused on a common array of effects on voltage-sensitive Na+ channels which may underly much of their therapeutic utility. Na+ channels are found to be inhibited at therapeutic concentrations of these agents in a voltage- and frequency-dependent manner that selectively blocks excitability of abnormally firing cells while leaving normally functioning cells relatively unaffected. An allosteric or ‘modulated receptor’ model of drug action is sufficient to describe the major features of the voltage- and frequency-dependent action of all three classes of drugs.
Article
Neuropathic pain (NP) is often refractory to pharmacologic and non-interventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group (NeuPSIG), the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central post-stroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: (1) epidural injections for herpes zoster; (2) steroid injections for radiculopathy; (3) SCS for FBSS; and (4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor RF lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available of data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials; long-term studies; and head-to-head comparisons among different interventional and non-interventional treatments.
Article
Background: Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams.High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, normally under local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made. Objectives: To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-concentration (8%) capsaicin in chronic neuropathic pain in adults. Search methods: We searched CENTRAL, MEDLINE, EMBASE and clinicaltrials.gov to December 2012. Selection criteria: Randomised, double-blind, placebo-controlled studies of at least six weeks' duration, using topical capsaicin to treat neuropathic pain. Data collection and analysis: Two review authors independently assessed trial quality and validity, and extracted data on numbers of participants with pain relief (clinical improvement) after at least six weeks, and with local skin reactions. We calculated risk ratio and numbers needed to treat to benefit (NNT) and harm (NNH). We sought details of definition of pain relief and specific adverse events.Efficacy outcomes reflecting long-duration pain relief after a single drug application were from the patient global impression of change (PGIC) at specific points, usually eight and 12 weeks. We regarded these outcomes as first-tier evidence. We regarded average pain scores over weeks 2 to 8 and 2 to 12 and the number and/or percentage of participants with pain intensity reduction of at least 30% or at least 50% over baseline as second-tier evidence. Main results: We included six studies, involving 2073 participants; they were of generally good reporting quality; the control was 0.04% topical capsaicin to help maintain blinding. Efficacy outcomes were inconsistently reported between studies, however, resulting in analyses for most outcomes being based on less than complete data.Four studies involved 1272 participants with postherpetic neuralgia. All efficacy outcomes were significantly better than control. At both eight and 12 weeks there was a significant benefit for high-concentration over low-concentration topical capsaicin for participants reporting themselves to be much or very much better, with point estimates of the NNTs of 8.8 (95% confidence interval (CI) 5.3 to 26) and 7.0 (95% CI 4.6 to 15) respectively. More participants had average 2 to 8-week and 2 to 12-week pain intensity reductions over baseline of at least 30% and at least 50% with active treatment than control, with NNT values between 10 and 12.Two studies involved 801 participants with painful HIV-neuropathy. In a single study the NNT at 12 weeks for participants to be much or very much better was 5.8 (95% CI 3.8 to 12). Over both studies more participants had average 2 to 12-week pain intensity reductions over baseline of at least 30% with active treatment than control, with an NNT of 11.Local adverse events were common, but not consistently reported. Serious adverse events were no more common with active treatment (4.1%) than control (3.2%). Adverse event withdrawals did not differ between groups, but lack of efficacy withdrawals were somewhat more common with control than active treatment, based on small numbers of events. No deaths were judged to be related to study medication. Authors' conclusions: High-concentration topical capsaicin used to treat postherpetic neuralgia and HIV-neuropathy generates more participants with high levels of pain relief than does control treatment using a much lower concentration of capsaicin. The additional proportion who benefit over control is not large, but for those who do obtain high levels of pain relief there are additional improvements in sleep, fatigue, depression and an improved quality of life. High-concentration topical capsaicin is therefore similar to other therapies for chronic pain. In this case, the high cost of single and repeated applications suggest that high-concentration topical capsaicin is likely to be used when other available therapies have failed, and that it should probably not be used repeatedly without substantial documented pain relief. Even when efficacy is established, there are unknown risks, especially on epidermal innervation, of repeated application of long periods.
Article
A monograph which covers "… the traditional concepts of pain, the newer data respecting the phenomenology of pain,… " and an outline of a "… comprehensive theory of pain experience compatible with available information." 505-item bibliography. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Purpose: Adult studies have shown that sectioning the C2 nerve root and ganglion may facilitate placement of C1 lateral mass screws and lead to decreased operative time and blood loss. We report the functional outcomes and complications following routine sectioning of the C2 nerve root and ganglion, which have not been reported in pediatric patients. Methods: Fifteen consecutive pediatric patients underwent C1 lateral mass screw insertion and bilateral C2 nerve root and ganglion sectioning. Clinical and radiographic assessments were performed at follow-up. Numbness in the C2 distribution and/or occipital neuralgia, operative times, estimated blood loss (EBL), length of stay (LOS), and complications were recorded. Results: Average follow-up time was 35.7 months. Overall mean operative time was 250.5 min, LOS was 8.46 days, and EBL was 337 cc. When considering only atlantoaxial fusions, mean operative time was 180.7 min and EBL was 97.1 cc. There were no intraoperative complications, and no patient reported new onset occipital neuralgia or numbness in the C2 distribution that would interfere with daily living. Of the patients, 93 % achieved Lenke fusion grade A; one achieved Lenke fusion grade B. Conclusions: Routine C2 nerve root sectioning and ganglionectomy enhanced surgical exposure of the C1 lateral mass and C1-2 facet joint, potentially maximizing fusion rate and minimizing intraoperative complications. This technique may yield favorable operative times, EBL, and LOS in children undergoing C1 lateral mass screw insertion without negatively affecting functional outcome.
Article
Polyneuropathy can be linked to chronic pain but also to reduced pain sensitivity. We investigated peripheral C-nociceptors in painful and painless polyneuropathy patients to identify pain-specific changes. Eleven polyneuropathy patients with persistent spontaneous pain and 8 polyneuropathy patients without spontaneous pain were investigated by routine clinical methods. For a specific examination of nociceptor function, action potentials from single C-fibres including 214 C-nociceptors were recorded by microneurography. Patients with and without pain were distinguished by the occurrence of spontaneous activity and mechanical sensitization in C-nociceptors. The mean percentage of C-nociceptors being spontaneously active or mechanically sensitized was significantly higher in patients with pain (mean 40.5% and 14.6%, respectively, P=.02). The difference was mainly due to more spontaneously active mechanoinsensitive C-nociceptors (operationally defined by their mechanical insensitivity and their axonal characteristics) in the pain patients (19 of 56 vs 6 of 43; P=.02). The percentage of sensitized mechanoinsensitive C-nociceptors correlated to the percentage of spontaneously active mechanoinsensitive C-nociceptors (Kendall's tau=.55, P=.004). Moreover, spontaneous activity of mechanoinsensitive C-nociceptors correlated to less pronounced activity-dependent slowing of conduction (Kendall's tau=-.48, P=.009), suggesting that axons were included in the sensitization process. Hyperexcitability in mechanoinsensitive C-nociceptors was significantly higher in patients with polyneuropathy and pain compared to patients with polyneuropathy without pain, while the difference was much less prominent in mechanosensitive (polymodal) C-nociceptors. This hyperexcitability may be a major underlying mechanism for the pain experienced by patients with painful peripheral neuropathy.
Article
Peripheral injury can cause abnormal activity in sensory neurons, which is a major factor in chronic pain. Recent work has shown that injury induces major changes not only in sensory neurons but also in the main type of glial cells in sensory ganglia-satellite glial cells (SGCs), and that interactions between sensory neurons and SGCs contribute to neuronal activity in pain models. The main functional changes observed in SGCs after injury are an increased gap junction-mediated coupling among these cells, and augmented sensitivity to ATP. There is evidence that the augmented gap junctions contribute to neuronal hyperexcitability in pain models, but the mechanism underlying this effect is not known. The changes in SGCs described above have been found following a wide range of injuries (both axotomy and inflammation) in somatic, orofacial and visceral regions, and therefore appear to be a general feature in chronic pain. We have found that in cultures of sensory ganglia calcium signals can spread from an SGC to neighboring cells by calcium waves, which are mediated by gap junctions and ATP acting on purinergic P2 receptors. A model is proposed to explain how augmented gap junctions and greater sensitivity to ATP can combine to produce enhanced calcium waves, which can lead to neuronal excitation. Thus this simple scheme can account for several major changes in sensory ganglia that are common to a great variety of pain models.
Article
Previous definitions of dermatomes, in various species, have revealed a characteristic pattern of serial overlapping root areas. Most investigators have used either the method of “remaining sensibility” or recordings of dorsal nerve root potentials, and have sectioned the dorsal nerve roots within the spinal canal, proximal to the dorsal root ganglia. We have used the method of “remaining sensibility” in experiments in macaque monkeys. Section of the neighboring dorsal roots proximal to their ganglia produced dermatomes which resembled closely those isolated by Sherrington. However, we found consistently that when the neighboring spinal nerves were sectioned distal to their dorsal root ganglia, the isolated root areas on the trunk were approximately twice as large as before and now also showed persistent hyperesthesia. Re-sectioning of the dorsal roots of these nerves within the dura reduced the isolated root areas to their “classical” size, but usually only after a delay of three or four days. The injection of subconvulsive doses of strychnine sulfate solution produced an enormous expansion of an isolated dermatome, irrespective of whether the neighboring roots had been sectioned intradurally or beyond their ganglia; no change in area was observed after the injection of morphine sulfate solution. Conversely, the size of a dermatome which had been isolated by intradural section of three dorsal roots above and below was reduced by subsequent section of three additional roots above and below. We have concluded that the observed size of an isolated dermatome is a variable quantity and can be taken as an index of the efficiency of sensory transmission within the same and neighboring segments of the spinal cord.
Article
Pain to light touching of the skin is a hallmark sign of causalgia. The purpose of this study was to determine whether myelinated or unmyelinated afferent fibers signal this hyperalgesia. Sensory testing was performed in 17 patients with long-standing hyperalgesia after nerve injury. The patients underwent a differential ischemie block of nerve function of the involved area. At a time when touch sensation in adjacent normal skin was eliminated, but when sensibility to warming and cooling stimuli was unaffected, the hyperalgesia to mechanical stimuli was abolished in 15 of the subjects. In 2 of these 15 patients, a differential local anesthetic block of the injured nerve was performed proximal to the site of injury. When temperature sensibility was absent, but when touch sensation was intact, hyperalgesia was present. In a third study, latency measurements in response to 400 μm stepped displacement stimuli were made in two patients who had hyperalgesia on the foot. The mean latency for detection of pain in the hyperalgesic region was 414 ± 18 msec, compared to 458 ± 16 msec for the detection of touch to the same stimuli applied to the opposite normal foot. These 3 lines of evidence indicate that myelinated primary afferents, perhaps Aβ fibers, signal the hyperalgesic pain in causalgia. These fibers may be sensitized Aβ nociceptors or low-threshold mechanoreceptors.
Article
Post-herpetic neuralgia means pain which occurs for longer than one to three months after the resolution of the rash of herpes zoster. We conducted a study of 30 patients having post herpetic neuralgia. All the patients were treated with modified Jaipur block consisting of local subcutaneous infiltration of 2% Xylocaine, 0.5% bupivacaine and methylprednisolone. In our study, it was seen that 20% patients had complete relief of pain after first injection, 60% patients had complete relief of pain after second injection, 10% patients had complete relief of pain after third injection, and only 10% patients did not respond to treatment. The non-responders were either old (over 60 years) or had pain lasting for more than two years.