Article

“Shooting pain” in lumbar radiculopathy and trigeminal neuralgia and ideas concerning its neural substrates

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Abstract

Patients with radicular low back pain (radicular LBP, sciatica) frequently describe their pain as "shooting" or "radiating." The dictionary meaning of these words implies rapid movement, and indeed, many sufferers report feeling pain moving rapidly from the lower back or buttock into the leg. But, others do not. Moreover, the sensation of movement is paradoxical; it is neither predicted nor accounted for by current ideas about the pathophysiology of radicular LBP. We have used a structured questionnaire to evaluate the sensory qualities associated with "shooting" and "radiating" in 155 patients, 98 with radicular LBP and 57 with trigeminal neuralgia, a second chronic pain condition in which shooting/radiating are experienced. Results indicated a spectrum of different sensations in different people. Although many sciatica patients reported rapid downward movement of their pain, even more reported downward expansion of the area of pain, some reported upward movement, and for some, there was no spatial dynamic at all. The velocity of movement or expansion was also variable. By cross-referencing sensations experienced in the sciatica and trigeminal neuralgia cohorts with known signal processing modes in the somatosensory system, we propose testable hypotheses concerning the pathophysiology of the various vectorial sensations reported, their direction and velocity, and the structures in which they are generated. Systematic evaluation of qualitative features of "shooting" and "radiating" pain at the time of diagnosis can shed light on the pain mechanism in the individual patient and perhaps contribute to a better therapeutic outcomes.

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... In particular, "shooting pain" is very commonly experienced by patients with radicular lower back pain (sciatica) or trigeminal neuralgia. In these patients, stimulus movement elicits so-called "traveling waves" in which neural activity sweeps across the bodypart representation in somatosensory maps 41 . The mechanisms of this have been attributed in part to Ca 2+ waves and gap junctions 41,42 . ...
... In these patients, stimulus movement elicits so-called "traveling waves" in which neural activity sweeps across the bodypart representation in somatosensory maps 41 . The mechanisms of this have been attributed in part to Ca 2+ waves and gap junctions 41,42 . Therefore, given the properties of the [Ca 2+ ] i fluctuations we have identified, they would make a good candidate for the neural substrate of shooting pain. ...
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Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5–6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of ‘silent’ neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.
... В клинической практике важно дифференцировать локальную боль (люмбалгия), радикулопатию и отраженную боль [5]. Для радикулярной боли характерно распространение боли в зону чувствительной (дерматомы) и двигательной (миотомы) иннервации пораженного спинномозгового нерва (корешка) [6,7]. В клинической практике отраженную боль в виде люмбоишиалгического синдрома отождествляют с радикулярной блью, что приводит к неправильной диагностике и лечению. ...
... Неврология, нейропсихиатрия, психосоматика. 2020;12(6):71-76 ...
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Nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants are used orally or intramuscularly (IM) to treat lumbar ischialgia caused by musculoskeletal disorders or radiculopathy. A comparative study has been conducted to investigate the efficacy and safety of the NSAID meloxicam (Amelotex®) injected intramuscularly and into the trigger points in combination with tolperisone and B-group vitamins for lumbar ischialgia. Patients and methods . The investigation enrolled 62 patients aged 30–60 years with lumbar ischialgia, who were randomized into three equal groups. Group 1 patients were injected with meloxicam 1.5 ml (15 mg of its active ingredient) into the trigger points daily for 3 days, followed by one 15-mg tablet daily for 14 days; Group 2 received IM meloxicam 15 mg daily for 3 days, followed by one 15-mg tablet daily for 14 days; Group 3 had IM meloxicam 15 mg daily for 3 days, followed by one 15-mg tablet daily for 14 days in combination with tolperisone (Calmirex®) as tablets: 150 mg (Day 1 of therapy), 300 mg (Day 2), and 450 mg daily (Day 3 until the end of therapy). All the patients received IM Vitamin B complex (Compligam B®) 2 ml for 5 days. The treatment efficiency was evaluated using the pain visual analogue scale (VAS), the Oswestry disability questionnaire, and the McGill pain questionnaire, the range of motion, and the severity of neurodystrophic syndrome. Results and discussion . All the patient groups showed a rapid and substantial pain reduction on the VAS and a functional activity improvement according to the Oswestry scale, which made it possible to complete the treatment within an average of 9.6 days. Groups 3 and 1 exhibited a faster improvement and, as a result, a shorter therapy duration on 8.6±1.2 and 9.2±0.9 days than did Group 2 (8.6±1.2 days). On day 2 of treatment, there was a more considerable pain reduction on the VAS in Group 1 that received meloxicam injections into the trigger zones. The administration of meloxicam intramuscularly and into the trigger zones in combination with tolperisone and vitamin B complex was noted to be safe and well tolerated. Conclusion . The injection of Amelotex into the trigger zones is highly effective and safe in treating lumbar ischialgia. An NSAID (meloxicam) in combination with a muscle relaxant (tolperisone) speeds up recovery and shortens the duration of NSAID intake.
... Low back pain (LBP), which has become a serious public health problem, ranking sixth in the global burden of disease, is a very common clinical symptom, and more than 80% of people have experienced LBP torture during their lifetime [1][2][3]. Intervertebral disc (IVD) degeneration is the main pathogenic factor of LBP [4]. IVD is a fibrocartilage disc located between two adjacent vertebral bodies. ...
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... Радикулопатия является серьезным осложнением дегенеративного поражения пояснично-крестцового отдела позвоночника, сопровождающимся болевым синдромом, который включает ноцицептивный и нейропатический компоненты, а также приводит к нарастанию неврологического дефицита [37,[46][47][48][49][50]. Хронический радикулярный болевой синдром не только физически инвалидизирует пациента, но и вовлекает его эмоциональную сферу, снижая адаптивный ресурс и качество жизни [38,51]. ...
Article
Study Objective: To study the prevalence of depressive syndromes in patients with chronic lumbosacral radiculopathy and pain syndrome, and to identify correlations between neuropathic pain and psychoemotional disturbances. Study Design: open perspective study. Materials and Methods. The study included 126 patients (45 (35.7%) males and 81 (64.3%) females) of 19 to 78 years old with verified unilateral lumbosacral radiculopathy of L4, L5, S1 radicules resulting from degenerative damage of the spine lasting for more than 12 weeks. For assessment, we used the Pain Detect Questionnaire, visual analogue scale for pain syndrome, Oswestry Disability Index, and Beck Depression Inventory. Study Results. Among patients with chronic lumbosacral radiculopathy, depressive syndromes were diagnosed in 74 (587%) cases as follows: 26 (20.6%) patients had mild (subclinical) depression, 33 (26.2%) cases were of moderate intensity, 12 (9.5%) patients had marked, and 3 (2.4%) had severe depression. We used Spearmen’s rank-order correlation to identify statistically significant correlations between Beck Depression Inventory score and neuropathic pain syndrome intensity (Pain Detect Questionnaire) (r = 0.861; p = 0.006). Pain Detect Questionnaire and Oswestry score correlated as well (r = 0.745; p = 0.001). Conclusion. Chronic pain syndrome in patients with lumbosacral radiculopathy resulting from degenerative damage of the spine is characterised by high comorbidity with depression. The results justify inclusion of psychoemotional assessment into a routine screening program for patients with lumbosacral radiculopathy. Keywords: depression, chronic back pain, lumbosacral radiculopathy, neuropathic pain syndrome.
... Devor and his colleagues have studied the nature of the 'shooting pain' and its neural substrates [37]. Background pain was found in 39% of their patients. ...
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Astrocytes communicate with neurons, endothelial and other glial cells through transmission of intercellular calcium signals. Satellite glial cells (SGCs) in sensory ganglia share several properties with astrocytes, but whether this type of communication occurs between SGCs and sensory neurons has not been explored. In the present work we used cultured neurons and SGCs from mouse trigeminal ganglia to address this question. Focal electrical or mechanical stimulation of single neurons in trigeminal ganglion cultures increased intracellular calcium concentration in these cells and triggered calcium elevations in adjacent glial cells. Similar to neurons, SGCs responded to mechanical stimulation with increase in cytosolic calcium that spread to the adjacent neuron and neighboring glial cells. Calcium signaling from SGCs to neurons and among SGCs was diminished in the presence of the broad-spectrum P2 receptor antagonist suramin (50 muM) or in the presence of the gap junction blocker carbenoxolone (100 muM), whereas signaling from neurons to SGCs was reduced by suramin, but not by carbenoxolone. Following induction of submandibular inflammation by Complete Freund's Adjuvant injection, the amplitude of signaling among SGCs and from SGCs to neuron was increased, whereas the amplitude from neuron to SGCs was reduced. These results indicate for the first time the presence of bidirectional calcium signaling between neurons and SGCs in sensory ganglia cultures, which is mediated by the activation of purinergic P2 receptors, and to some extent by gap junctions. Furthermore, the results indicate that not only sensory neurons, but also SGCs release ATP. This form of intercellular calcium signaling likely plays key roles in the modulation of neuronal activity within sensory ganglia in normal and pathological states.
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Objective: Pain is a universal phenomenon, but is also inherently private and subjective – there’s no objective test for its existence. Sufferers rely on language to describe their pain experience. The McGill Pain Questionnaire paved the way for incorporating language into pain assessment and recent research has explored aspects of pain language such as metaphors and grammatical patterns. This study investigated how chronic pain sufferers use language to describe their pain experience. Design: Three focus groups were conducted (N = 16, age 22–74 years, M = 46.6 years) with participants attending an outpatient chronic pain management program in Sydney, Australia. Participants were asked to describe aspects of their pain experience. Main outcome measure: The language which participants utilized to talk about their pain experience. Results: Thematic analysis identified five superordinate themes: Isolation, Physical Sensations of Pain, Pain Personified, Pain as Overwhelming, and Coping with Pain. Across themes, participants relied on metaphorical language, which reflects the complex, multidimensional aspects of pain as well as the desire to effectively communicate it to others. Conclusions: This study underscores research indicating the complexity of pain experience and hence pain language, and suggests that single word adjectival measures are inadequate to completely capture its complexity. • IMPLICATIONS FOR REHABILITATION • Chronic pain is now considered a disease in and of itself, with patient’s pain language being an important study area due to the lack of objective tests for pain. • In both assessment and rehabilitation, patients rely on metaphorical pain language in order to facilitate understanding and garner support from others. • Pain metaphors may provide a useful target for interventions such as Acceptance and Commitment Therapy and Cognitive Behavioural Therapy, particularly when addressing catastrophic thinking patterns.
Article
Neuropathic pain is frequently driven by ectopic impulse discharge (ectopia) generated in injured peripheral afferent neurons. Observations in the spinal nerve ligation (SNL) model in rats suggest that cell bodies in the dorsal root ganglion (DRG) contribute three times more to the ectopic barrage than the site of nerve injury (neuroma). The DRG is therefore a prime interventional target for pain control. Since DRG ectopia is selectively suppressed with lidocaine at concentrations too low to block axonal impulse propagation, we asked whether targeted delivery of dilute lidocaine to the L5 DRG can relieve L5 SNL-induced tactile allodynia without blocking normal sensation or motor function. Results showed that intraforaminal injection of 10 µL bolus doses of 0.2% lidocaine suppressed allodynia transiently, while sustained infusion over 2 weeks using osmotic minipumps suppressed it for nearly 2 weeks. Bolus injections of morphine or fentanyl were ineffective. Lidocaine applied to the cut spinal nerve end or the L4 DRG did not affect allodynia suggesting that discharge originating in the neuroma and in neighboring "uninjured" afferents makes at best a minor contribution. Spike electrogenesis in the DRG is apparently the primary driver of tactile allodynia in the SNL model of neuropathic pain and it can be controlled selectively by superfusing the relevant DRG(s) with non-blocking concentrations of lidocaine. This approach has potential clinical application in conditions such as postherpetic neuralgia and phantom limb pain in which one or only a few identifiable ganglia are implicated as pain drivers.
Article
Residual lower limb pain after low back surgery (post-surgical sciatica) and complex regional pain syndrome involving a lower limb (CRPS) are separate conditions, but may share some mechanisms (e.g., tissue inflammation, neuro-immune disturbances and central neuro-plasticity). As adrenergically-evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to post-surgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with post-surgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all four limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in post-surgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuro-plastic changes are involved not only in the pathophysiology of CRPS but also in post-surgical sciatica. This may have treatment implications for patients with post-surgical sciatica.
Article
Spreading depolarization is assumed to be the mechanism of migraine with aura, which is accompanied by an initial predominant hyperaemic response followed by persistent vasoconstriction. Cerebral blood flow responses are impaired in patients and in experimental animals after spreading depolarization. Understanding the regulation of cortical blood vessels during and after spreading depolarization could help patients with migraine attacks, but our knowledge of these vascular mechanisms is still incomplete. Recent findings show that control of cerebral blood flow does not only occur at the arteriole level but also at capillaries. Pericytes are vascular mural cells that can constrict or relax around capillaries, mediating local cerebral blood flow control. They participate in the constriction observed during brain ischaemia and might be involved the disruption of the microcirculation during spreading depolarization. To further understand the regulation of cerebral blood flow in spreading depolarization, we examined penetrating arterioles and capillaries with respect to vascular branching order, pericyte location and pericyte calcium responses during somatosensory stimulation and spreading depolarization. Mice expressing a red fluorescent indicator and intravenous injections of FITC-dextran were used to visualize pericytes and vessels, respectively, under two-photon microscopy. By engineering a genetically encoded calcium indicator we could record calcium changes in both pericytes around capillaries and vascular smooth muscle cells around arterioles. We show that somatosensory stimulation evoked a decrease in cytosolic calcium in pericytes located on dilating capillaries, up to the second order capillaries. Furthermore, we show that prolonged vasoconstriction following spreading depolarization is strongest in first order capillaries, with a persistent increase in pericyte calcium. We suggest that the persistence of the ‘spreading cortical oligaemia’ in migraine could be caused by this constriction of cortical capillaries. After spreading depolarization, somatosensory stimulation no longer evoked changes in capillary diameter and pericyte calcium. Thus, calcium changes in pericytes located on first order capillaries may be a key determinant in local blood flow control and a novel vascular mechanism in migraine. We suggest that prevention or treatment of capillary constriction in migraine with aura, which is an independent risk factor for stroke, may be clinically useful.
Article
Neurons responding to different whiskers are spatially intermixed in the superficial layer 2/3 (L2/3) of the rodent barrel cortex, where a single whisker deflection activates a sparse, distributed neuronal population that spans multiple cortical columns. How the superficial layer of the rodent barrel cortex is organized to support such distributed sensory representations is not clear. In a computer model, we tested the hypothesis that sensory representations in L2/3 of the rodent barrel cortex are formed by activity propagation horizontally within L2/3 from a site of initial activation. The model explained the observed properties of L2/3 neurons, including the low average response probability in the majority of responding L2/3 neurons, and the existence of a small subset of reliably responding L2/3 neurons. Sparsely propagating traveling waves similar to those observed in L2/3 of the rodent barrel cortex occurred in the model only when a subnetwork of strongly connected neurons was immersed in a much larger network of weakly connected neurons.
Article
Introduction Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.
Article
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.
Article
Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (e.g., microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared to healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18kDa translocator protein (TSPO), in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared to both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared to more superior segments). Furthermore, the neuroforaminal TSPO signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.
Article
Single-unit exploration of the dorsal horn of segments L4-S2 of unanesthetized cats with the neuraxis transected at lower thoracic levels reveals a somototopic organization in the horizontal plane. The dorsal horn dermatomes correspond closely to the dermatomes of the corresponding dorsal roots, and the ML gradient is equally well described by two different projection schemes: a distoproximal gradient and a ventrodorsal one (5, 33). There is no evidence of segmental discontinuity of the map. As is the case in other nuclear regions of the CNS, the relative area devoted to projections from the foot is disproportionately large relative to the area devoted to skin regions of similar size which are located more proximally on the limb. From our data, and from the close correspondence to anatomical data obtained by others, we suggest that at least some cutaneous afferent fibers from a given skin area project directly to any dorsal horn region where that skin area is represented. This assumption, together with the organization of the dorsal horn map, yields a model which predicts a precise somatotopic organization of presynaptic neuropil in the substantia gelatinosa.
Article
Therapeutic duration of traditional local anesthetics when used in peripheral nerve blocks is normally limited. This article describes novel approaches to extend the duration of peripheral nerve blocks currently available or in development. Three newer approaches on extending the duration of peripheral nerve blocks include site-1 sodium channel blockers, novel local anesthetics delivery systems, and novel adjuvants of local anesthetics. Compared with plain amide-based and ester-based local anesthetics, alternative approaches show significant promise in decreasing postoperative pain, rescue opioid requirement, hospital length-of-stay, and overall health care cost, without compromising the established safety profile of traditional local anesthetics.
Article
Facilitated pain mechanisms and impaired pain inhibition are often found in chronic pain patients. This study compared clinical pain profiles, pain sensitivity, as well as pro-nociceptive and anti-nociceptive mechanisms in patients with localized low back pain (n=18), localized neck pain (n=17), low back and radiating leg pain (n=18), or neck and radiating arm pain (n=17). It was hypothesized that patients with radiating pain had facilitated pain mechanisms and impaired pain inhibition compared with localized pain patients. Cuff algometry was performed on the non-painful lower leg to assess pressure pain threshold (cPPT), tolerance (cPTT), temporal summation of pain (TSP: increase in pain scores to ten repeated stimulations at cPTT intensity), and conditioning pain modulation (CPM: increase in cPPT during cuff pain conditioning on the contralateral leg). Heat detection (HDT) and heat pain threshold (HPT) at the non-painful hand were also assessed. Clinical pain intensity, psychological distress, and disability were assessed with questionnaires. TSP was increased in patients with radiating back pain compared with localized back pain (P<0.03). Patients with radiating arm pain or localized low back pain demonstrated hyperalgesia to heat and pressure in non-painful body areas (P<0.05), as well as well as a facilitated clinical pain profile compared with patients with localized neck pain (P=0.03). Patients with radiating pain patterns demonstrated facilitated temporal summation suggesting differences in the underlying pain mechanisms between patients with localized back pain and radiating pain. Perspective: These findings have clinical implications as the underlying mechanisms in different back pain conditions may require different treatment strategies.
Article
A 41-year-old man reports the sudden onset of low back and left leg pain. The symptoms began while he was doing yard work and pulling out large bushes. Since the onset of the pain 2 days ago, it has worsened, although he took a single dose of ibuprofen when the pain began. The patient has no clinically significant medical history, and the physical examination is normal other than severe pain in the left leg with a straight-leg-raising maneuver to 40 degrees. He says, "I'm sure I slipped a disk," and he requests magnetic resonance imaging (MRI) of the low back. What testing and treatment would you recommend?
Article
Objective: This study was conducted to determine whether mechanical allodynia (MA) acts as a predictor of outcome after microvascular decompression (MVD) for trigeminal neuralgia (TN) and discuss the potential pathological mechanisms involved. Methods: A series of 246 patients who underwent MVD for TN were involved in the study. The classifications were based on the characteristic of pain (shock-like or constant), and the presence of MA was defined from the chart review, retrospectively. The surgical outcome is defined as excellent, good, and poor. Immediate and long-term outcomes were compared to provide the information on recurrence and delayed relief. The relationship among the groups was investigated, and the strength was determined. Results: Both presence of MA and type of TN pain are significant predictors of surgical outcome (P < 0.05). MA was proven to be an independent predictor of surgical outcome and also a significant predictor of existence of neurovascular compression (P < 0.05) and lower rate of recurrence (P < 0.05). No statistically significant predictors of delayed relief were detected in this study. Conclusions: The presence of MA is a reliable predictor of immediate and long-term outcome after MVD for TN. Compared to the patients without MA, the incidence rate of intraoperative neurovascular compression (NVC) was higher in MA-positive patients, who were more likely to achieve a better outcome and lower rate of recurrence after MVD for TN. Application of the information in this study will be helpful in patient selection of MVD for TN.
Article
Low back pain is one of the four most common disorders in all regions, and the greatest contributor to disability worldwide, adding 10.7% of total years lost due to this health state. The etiology of chronic low back pain is, in most of the cases (up to 85%), unknown or nonspecific, while the specific causes (specific spinal pathology and neuropathic/radicular disorders) are uncommon. Central sensitization has been recently recognized as a potential pathophysiological mechanism underlying a group of chronic pain conditions, and may be a contributory factor for a sub-group of patients with chronic low back pain. The purposes of this narrative review are twofold. First, to describe central sensitization and its symptoms and signs in patients with chronic pain disorders in order to allow its recognition in patients with nonspecific low back pain. Second, to provide general treatment principles of chronic low back pain with particular emphasis on pharmacotherapy targeting central sensitization.
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
Neuropathic pain-that is, pain arising directly from a lesion or disease that affects the somatosensory system-is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development.
Article
Moving stimuli activate all of the mechanoreceptive afferents involved in discriminative touch but their signals covary with several parameters, including texture. Despite this, the brain extracts precise information about tactile speed, and humans can scale the tangential speed of moving surfaces as long as they have some surface texture. Speed estimates, however, vary with texture: lower estimates for rougher surfaces (increased spatial period, SP). We hypothesized that the discharge of cortical neurones playing a role in scaling tactile speed should covary with speed and SP in the same manner. Single-cell recordings (n=119) were made in the hand region of primary somatosensory cortex, S1, of awake monkeys while raised-dot surfaces (longitudinal SPs, 2-8 mm; periodic or nonperiodic) were displaced under their fingertips at speeds of 40-105 mm/s. Speed-sensitivity was widely distributed (areas 3b, 13/25; 1, 32/51; and 2, 31/43) and almost invariably combined with texture-sensitivity (82% of cells). A subset of cells (27/64 fully tested speed-sensitive cells) showed a graded increase in discharge with increasing speed for testing with both sets of surfaces (periodic, non periodic), consistent with a role in tactile speed scaling. These cells were almost entirely confined to caudal S1 (areas 1 and 2) None of the speed-sensitive cells, however, showed a pattern of decreased discharge with increased SP, as found for subjective speed estimates in humans. Thus, further processing of tactile motion signals, presumably in higher order areas, is required to explain human tactile speed scaling.
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
Mechanisms responsible for neuropathic pain are still unclear. By using microneurography we have been able to record from single C-nociceptive and sympathetic fibers in patients and attempted to uncover possible abnormal functional properties of these fibers of relevance for pain. In two previously published studies conducted on patients with erythromelalgia and patients with diabetic neuropathy, some of the major findings were: (1) spontaneous activity in nociceptive fibers, (2) sensitization of mechano-insensitive C-fibers, and (3) an altered distribution of C-afferent nerve fibers with a reversal of the proportion of the two main subtypes of C-nociceptive fibers, indicating a loss of function of polymodal nociceptors. Although some degree of spontaneous activity and sensitization also was found in patients without pain, these mechanisms may still be of importance for the development and maintenance of neuropathic pain. A change in the distribution of C-nociceptive fibers in the skin as shown in the patients with diabetic neuropathy may help to reveal mechanisms responsible for small-fiber dysfunction.
Article
A novel approach for sustained production of therapeutic proteins is described, using genetic modification of intact autologous micro-organ tissue explants from the subject's own skin. The skin-derived micro-organ can be maintained viable ex vivo for extended periods and is transduced with a transgene encoding a desired therapeutic protein, resulting in protein-secreting micro-organ (biopump (BP)). The daily protein production from each BP is quantified, enabling drug dosing by subcutaneous implantation of the requisite number of BPs into the patient to provide continuous production to the circulation of a known amount of the therapeutic protein. Each implanted BP remains localized and is accessible, to enable removal or ablation if needed. Examples from preclinical and clinical studies are presented, including use of associated virus vector 1 and helper-dependent adenoviral vectors producing BPs to provide long-term sustained secretion of recombinant interferon-α and erythropoietin.
Article
Considerable overlap exists in nerve root innervation of various muscles. Knowledge of myotomal innervation is essential for the interpretation of neurological examination findings and neurosurgical decision-making. Previous studies relied on cadaveric dissections, animal studies, and cases with anomalous anatomy. This study investigates the myotomal innervation patterns of cervical and lumbar nerve roots through in vivo stimulation during surgeries for spinal decompression. Patients undergoing cervical and lumbar surgeries in which nerve roots were exposed in the normal course of surgery were included in the study. Electromyography electrodes were placed in the muscle groups that are generally accepted to be innervated by the roots under study. These locations included levels above and below the spinal levels undergoing decompression. After decompression, a unipolar neural stimulator probe was placed directly on the nerve root sleeve and constant current stimulation in increments of 0.1 mA was performed. Current was raised until at least a 100 μV amplitude-triggered electromyographic response was noted in 1 or more muscles. All muscles that responded were recorded. A total of 2295 nerve root locations in 129 patients (mean age 57 ± 15 years, 47 female [36%]) were stimulated, and 1589 stimulations met quality criteria and were analyzed. Four hundred ninety-five stimulations were performed on roots contributing to the cervical and brachial plexus from C-3 to T-1 (31.2%), and 1094 (68.8%) were roots in the lumbosacral plexus between L-1 and S-2. The authors were able to construct a statistical map of the contributions of each cervical and lumbosacral nerve root for the set of muscle groups monitored in the protocol. In many cases the range of muscles innervated by a specific root was broader than previously described in textbooks. This is the largest data set of direct intraoperative nerve root stimulations during decompressive surgery, demonstrating the relative contribution of root-level motor input to various muscle groups. Compared with classic neuroanatomy, a significant number of roots innervate a broader range of muscles than expected, which may account for the variability of presentation between patients with identical number and location of compressed roots.
Article
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.
Article
Trigeminal neuralgia (TN) presents a diagnostic challenge because of the variety of symptoms, findings during microvascular decompression (MVD), and postsurgical outcomes observed among patients who suffer from this disorder. Recently, a new paradigm for classification of TN was proposed, based on the quality of pain. This study represents the first clinical analysis of this paradigm. The authors analyzed 144 consecutive cases involving patients who underwent MVD for TN. Preoperative symptoms were classified into 1 of 2 categories based on the preponderance of shocklike (Type 1 TN) or constant (Type 2 TN) pain. Analysis of clinical characteristics, neurovascular pathology, and postoperative outcome was performed. Compared with Type 2 TN, Type 1 TN patients were older, were more likely to have right-sided symptoms, and reported a shorter duration of symptoms prior to evaluation. Previous treatment by percutaneous or radiosurgical procedures was not a predictor of symptoms, surgical findings, or outcome (p = 0.48). Type 1 TN was significantly more likely to be associated with arterial compression. Venous or no compression was more common among Type 2 TN patients (p < 0.01). Type 1 TN patients were also more likely to be pain-free immediately after surgery, and less likely to have a recurrence of pain within 2 years (p < 0.05). Although a subset of patients progressed from Type 1 to Type 2 TN over time, their pathological and prognostic profiles nevertheless resembled those of Type 1 TN. Type 1 and Type 2 TN represent distinct clinical, pathological, and prognostic entities. Classification of patients according to this paradigm should be helpful to determine how best to treat patients with this disorder.
Article
Microneurography is a method for recording single unit action potentials with microelectrodes from the nerves of awake cooperating humans. Although this method is now in use since almost 40 years, its potency has been strengthened by the recent technical developments. A great progress was the discovery that different functional groups of nociceptors are characterized by a distinctly different post-excitatory slowing of their conduction velocities. Microneurography is now powerful enough to analyze the nerve activity pattern of enigmatic sensations such as pruritus. Furthermore, it is the only method providing direct insight in the changes which human nerves undergo with aging. Recently, reliable recordings from patients suffering from painful neuropathies came into reach. It has been shown that different types of neuropathies are characterized by different patterns of abnormal nociceptor functions. Although some of them are characterized by abnormal spontaneous activity in C-nociceptors, others show mainly signs of denervation. Microneurography is, therefore, a tool for translational studies on human nociceptor functions by linking direct animal studies on experimental neuropathies with human diseases.
Article
Single-unit exploration of the dorsal horn of segments L4-S2 of unanesthetized cats with the neuraxis transected at lower thoracic levels reveals a somototopic organization in the horizontal plane. The dorsal horn dermatomes correspond closely to the dermatomes of the corresponding dorsal roots, and the ML gradient is equally well described by two different projection schemes: a distoproximal gradient and a ventrodorsal one (5, 33). There is no evidence of segmental discontinuity of the map. As is the case in other nuclear regions of the CNS, the relative area devoted to projections from the foot is disproportionately large relative to the area devoted to skin regions of similar size which are located more proximally on the limb. From our data, and from the close correspondence to anatomical data obtained by others, we suggest that at least some cutaneous afferent fibers from a given skin area project directly to any dorsal horn region where that skin area is represented. This assumption, together with the organization of the dorsal horn map, yields a model which predicts a precise somatotopic organization of presynaptic neuropil in the substantia gelatinosa.
Article
Optical imaging of animal somatosensory, olfactory and visual cortices has revealed maps of functional activity. In non-human primates, high-resolution maps of the visual cortex have been obtained using only an intrinsic reflection signal. Although the time course of the signal is slower than membrane potential changes, the maximum optical changes correspond to the maximal neuronal activity. The intrinsic optical signal may represent the flow of ionic currents, oxygen delivery, changes in blood volume, potassium accumulation or glial swelling. Here we use similar techniques to obtain maps from human cortex during stimulation-evoked epileptiform afterdischarges and cognitively evoked functional activity. Optical changes increased in magnitude as the intensity and duration of the afterdischarges increased. In areas surrounding the afterdischarge activity, optical changes were in the opposite direction and possibly represent an inhibitory surround. Large optical changes were found in the sensory cortex during tongue movement and in Broca's and Wernicke's language areas during naming exercises. The adaptation of high-resolution optical imaging for use on human cortex provides a new technique for investigation of the organization of the sensory and motor cortices, language, and other cognitive processes.
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The proto-oncogene c-fos is activated in the brain by a variety of stimuli including brain injury. In unilateral brain injury, c-fos immunoreactivity is confined to the damaged hemisphere, an effect reminiscent of spreading depression. Here we show that topical application of KCl (3 M) to the brain surface (which induces spreading depression) is accompanied by ipsilateral increase in c-fos immunolabeling. The activation of c-fos, like spreading depression, is markedly reduced by the non-competitive NMDA antagonist MK-801 (3 mg/kg i.p.).
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The diagnostic value of pain mapping in patients with lumbago sciatica and herniated intervertebral discs is evaluated, somatosensory pain descriptions being compared with surgical findings. Information has been extracted from complex data sets using a multivariate data analysis program (FCVPC-87). Superficially experienced pain may represent pronounced nerve root affliction. Pain relief in particular body positions was related to extruded discs and additional osseous stenosis, and rarely occurring relief to derangement of nerve root circulation. Neither somatosensory pain quality descriptions nor pain intensity variables were found to be of diagnostic value. Long duration of symptoms was found together with nerve root atrophy. Affliction of the L5 and S1 nerve roots showed differences with regard to pain localization and intensity and some surgical findings. Pain mapping may represent an indication of the patho-anatomical substratum in patients with herniated lumbar intervertebral discs.
Article
Sensory fibers trapped in nerve-end neuromas become abnormally excitable, and produce an ectopic discharge which is believed to contribute to paresthesias and pain associated with chronic nerve injury in man. Here we report that stimulation of injured nerves can alter this discharge, directly by antidromic invasion of active neuroma fibers, and indirectly through interactions with neighboring fibers. Antidromic stimulation of spontaneously active fibers in experimental neuromas in the rat sciatic nerve, using single electrical stimulus pulses, produced time-locking of rhythmic spontaneous firing and of spontaneous impulse bursts. Some initially silent fibers generated a burst of rhythmic afterdischarge when stimulated in this way. Stimulation delivered in brief trains (tetani) produced more prolonged alterations in spontaneous neuroma discharge, including excitation, suppression and combinations of the two. In some cases initially silent fibers were activated for extended periods. These responses to tetanic stimulation occurred even when the active fibers were not themselves stimulated, and reflect a novel form of fiber-fiber interaction in neuromas that we term 'crossed afterdischarge'. This interaction probably results from the accumulation of potassium ions within the extracellular compartment adjacent to active neuroma fibers during activation of their neighbors. It differs fundamentally from the high safety factor ephaptic cross-talk seen in acutely cut nerves and in neuromas of 30 or more days standing.
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In order to classify movement-sensitive neurons in SI cortex, and to estimate their relative distribution, we have developed a new simple method for controlled motion of textured surfaces across the skin, as well as a set of objective criteria for determining direction selectivity. Moving stimuli were generated using 5 mm thick precision gear wheels, whose teeth formed a grafting. They were mounted on the shafts of low-torque potentiometers (to measure the speed and direction of movement) and rolled manually across the skin using the potentiometer shaft as an axle. As the grafting wheel was advanced, its ridges sequentially contacted a specific set of points on the skin, leaving gaps of defined spacing that were unstimulated. This stimulus was reproducible from trial to trial and produced little distention of the skin. Three objective criteria were used to categorize responses: the ratio of responses to motion in the most and least preferred directions [direction index (DI)], the difference between mean firing rates in the two directions divided by the average standard deviation [index of discriminability (delta'e)], and statistical tests. Neurons were classified as direction sensitive if DI greater than 35, delta's greater than or equal to 1.35 (equivalent to 75% correct discrimination by an unbiased observer), and firing rates in most- and least-preferred directions were significantly different (P less than 0.05). Good agreement was found between the three classification schemes. Recordings were made from 1,020 cortical neurons in the hand and forearm regions of primary somatosensory cortex (areas 3b, 1 and 2) of five macaque monkeys. Tangential motion across the skin was found to be an extremely effective stimulus for SI cortical neurons. Two hundred eighty six of 757 tactile neurons (38%) responded more vigorously to moving stimuli than to pressure or tapping the skin. One hundred twenty-one cells were tested with moving gratings and were classified according to their ability to differentiate movement in longitudinal and transverse directions. Responses to the moving gratings resembled those observed when stroking the skin with brushed, edges, or blunt probes. Three major types of firing patterns were found: motion sensitive, direction sensitive, and orientation sensitive. Motion-sensitive neurons (37%) responded to movement in both longitudinal and transverse directions with only slight difference in firing rates and interval distributions. Responses throughout the field were fairly uniform, and no clear point of maximum sensitivity was apparent. Direction-sensitive neurons (60%) displayed clear preferences for movement in one or more directions.4
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This paper aims at elucidating to what extent patients with lumbago-sciatica in the presence of an herniated intervertebral disc, are inclined to describe their pain in a characteristic way. The material comprised 50 patients with clinical and radiological signs indicating herniation of the L4/5 or L5/S1 discs. The assessment of pain was performed by formal oral interview, focussing on spatial distribution and somatosensory dimensions of pain in various regions of the back and leg. In conformity with the fact that a range of sensible nerves are affected by the herniation pain description is represented by a variety of pain qualities. The pattern of pain description tends to exhibit certain characteristic traits: only half of the patients had low-back pain, and pain was most frequently occurring in the gluteal region, thigh and calf. The frequency of superficially localized pain tended to increase in the proximo-distal direction. Aching-like pain was the most common pain quality, and this variant of pain as well as flashing and jerking sensations were commonly reported in the gluteal region, thigh and calf. Warmth was most frequently experienced in these regions, cold sensations in distal parts. A feeling of punctate pressure was common in the gluteal region, incisive pressure and paraesthesia in the thigh and calf, and a cramp-like feeling in the calf region. Reduced sensibility was frequently experienced in distal parts and never in the lumbar region. Pain quality differs in patients with a short and a long duration of the actual attack of sciatica. The mapping of pain seems to represent a diagnostical aid. A high degree of homogeneity of the patients is required for pain description to be a valid and reliable instrument. The clinical application of pain mapping is to be shown through a paper-and-pencil administration of a questionnaire based upon the findings from this study.