Neuropathic-like Pain Research Articles

Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain

ObjectiveTo evaluate how closely neuropathic-like ocular pain (NOP) symptoms align with a metric of central sensitisation (ie, the presence of persistent ocular pain after topical anaesthetic placement) in individuals with...

Assessment of Somatosensory Function in Patients With Idiopathic Dry Eye Symptoms

Somatosensory dysfunction likely underlies dry eye (DE) symptoms in many individuals yet remains an understudied component of the disease. Its presence has important diagnostic and therapeutic implications. To assess the integrity of nociceptive system processes in persons with DE and ocular pain using quantitative sensory testing (QST) techniques applied at a site remote from the eye. A cross-sectional study conducted at Miami Veterans Affairs Hospital included 118 individuals with a wide variety of DE symptoms and signs. The study was conducted from October 31, 2013, to January 28, 2016. Individuals completed questionnaires regarding ocular symptoms (5-Item Dry Eye Questionnaire [DEQ5], Ocular Surface Disease Index [OSDI], and Neuropathic Pain Symptom Inventory modified for the eye [NPSI-E]), psychological status, and medication use and underwent an ocular surface examination. The QST metrics included measures of vibratory and thermal thresholds and cold and hot pain temporal summation (surrogate measures of central sensitization) on the forearm. Correlations among DE and ocular pain symptom severity with QST metrics measured on the forearm. The OSDI score ranges from 0 to 100, with 100 indicating the most severe DE symptoms. The DEQ5 score ranges from 0 to 22, with the highest score indicating the most severe symptoms, and the NPSI-E score ranges from 0 to 100, with the highest score indicating the most severe symptoms. Psychological state was measured with the 9-item Patient Health Questionnaire, the PTSD Checklist-Military Version for PTSD, and the Symptom Checklist-90 for anxiety. Of the 118 patients who participated in the study, 105 (88.9%) were men (mean [SD] age, 60 [10] years), and a mean of 41% had PTSD, 10% depression, and 0.93% anxiety. Using stepwise linear regression analyses, significant associations were identified between overall DE symptom severity and posttraumatic stress disorder scores and tear breakup time (DEQ5 model: R = 0.54; OSDI model: R = 0.61, P < .001). All other variables (ie, demographics, comorbidities, medications, tear film factors, and QST metrics) dropped out of these models. When specifically considering neuropathic-like qualities of DE pain, however, anxiety and hot pain temporal summation at the forearm explained 17% of the variability in ocular burning (R = 0.41; P < .001), and PTSD score, tear breakup time, and hot pain temporal summation at the forearm explained 25% of the variability in sensitivity to wind (R = 0.50; P < .001) and 30% of the variability in total NPSI-E scores (R = 0.55; P < .001). Our findings demonstrate that neuropathic-like DE pain symptom severity correlates with quantitative measures of pain sensitivity at a site remote from the eye. This result provides additional evidence that DE symptoms are not only manifestations of a local disorder but also involve somatosensory dysfunction beyond the trigeminal system.

Pain, Quality of Life, and Clinical Outcomes after Robotic Lobectomy.

Background To evaluate pulmonary function, pain, and quality of life at midterm after robotic lobectomy performed in a single institution. Methods Sixty-five consecutive patients underwent robotic thoracic surgery over 32 months using a complete four-arm portal technique. Sixty-one patients underwent lobectomies predominantly for stage I non-small cell lung cancer. Pulmonary function tests were repeated at midterm follow-up. Pain and quality of life were evaluated during the follow-up on a subgroup of 39 patients, excluding the learning period. Results At a mean of 7-month follow-up, there was no significant difference in preoperative and midterm postoperative pulmonary function. A total of 62.5% of the patients reported a variable intensity of discomfort or pain at the surgical site, with a mean pain intensity score of 2.1 ± 1.4. Mean pain interference score were weak (1.8 ± 1.9), with patients with moderate pain reporting significantly higher pain interference scores than those with mild pain (p = 0.0025). Only one patient suffered from neuropathic-like pain. Quality of life was globally favorable and related to the pain level, with a significant interference on the physical component. Conclusion Robotic lobectomy does not appear to have an impact on midterm pulmonary function. Persistent postoperative pain is mild, nonneuropathic-like, with weak interference on daily activities. Quality of life is satisfactory but related to the pain level.

(464) Prior voluntary wheel running is protective for neuropathic-like pain

(464) Prior voluntary wheel running is protective for neuropathic-like pain

The Prevalence and Cross-Sectional Associations of Neuropathic-like Pain Among Older, Community-Dwelling Women with Arthritis.

To estimate the prevalence and examine the associations of neuropathic-like pain in a community-based sample of older Australian women with arthritis. Population based cross-sectional survey. Participants were recruited from the 1946-1951 cohort of the Australian Longitudinal Study of Women's Health. Women with self-reported arthritis (n = 147). Primary outcome measure was self-reported neuropathic-like pain, defined as scores ≥12 via the painDETECT screening tool. Descriptive statistics summarized health and socio-demographic characteristics, and comparisons made using student's t-test or Wilcoxon Rank Sum test, and Chi-square tests. Independent health and demographic variables were examined by univariable logistic regression, and significant variables included in multiple variable logistic regression modelling. Thirty-nine women (26.5%) were screened as having neuropathic-like pain. Women with neuropathic-like pain were more likely to have poorer health, worse pain, higher pain catastrophizing, more fatigue, and more depression than women with nociceptive pain. Neuropathic-like pain was significantly associated with higher scores on the SF-MPQ sensory scale and pain catastrophizing scale, and with more medication use. Neuropathic-like pain in women with arthritis was common and is associated with greater disability and poorer quality of life.

Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis.

IntroductionIncreasing evidence indicates that features suggestive of neuropathic pain may also be present in patients with common rheumatic conditions. The objective of this study was to examine neuropathic-like pain symptoms and associated factors in patients with rheumatoid arthritis.MethodsWe used the painDETECT screening tool to identify possible or likely neuropathic pain in 159 outpatients with rheumatoid arthritis. Patients additionally completed other self-reported measures, while clinical measures were assessed to calculate the 28-joint Disease Activity Score. Univariate analyses and multivariable logistic regression were used to identify factors associated with neuropathic pain features.ResultsAccording to the painDETECT, 27 patients (17.0 %) were classified as having likely neuropathic pain and 34 patients (21.4 %) as having possible neuropathic pain. Besides reporting more severe pain, patients with likely or possible neuropathic pain were more likely to meet the diagnostic criteria for fibromyalgia, to use analgesics, and to have more tender joints and a worse physical and mental health status as measured by the 36-item Short-Form health survey. In multivariable analysis, physical (P < 0.001) and mental health status (P = 0.006) remained significantly associated with neuropathic pain features, even after controlling for pain severity.ConclusionsThese findings suggest that a sizeable proportion of patients with relatively well-controlled rheumatoid arthritis report symptoms suggestive of neuropathic pain. Neuropathic-like pain symptoms are independently associated with worse self-reported physical and mental health.

Respective pharmacological features of neuropathic-like pain evoked by intrathecal BDNF versus sciatic nerve ligation in rats

Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague–Dawley male rats were either injected intrathecally with BDNF (3.0ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall–Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain.

Extreme Thermal Noxious Stimuli Induce Pain Responses in Zebrafish Larvae

Exposing tissues to extreme high or low temperature leads to burns. Burned animals sustain several types of damage, from the disruption of the tissue to degeneration of axons projecting through muscle and skin. Such damage causes pain due to both inflammation and axonal degeneration (neuropathic-like pain). Thus, the approach to cure and alleviate the symptoms of burns must be twofold: rebuilding the tissue that has been destroyed and alleviating the pain derived from the burns. While tissue regeneration techniques have been developed, less is known on the treatment of the induced pain. Thus, appropriate animal models are necessary for the development of the best treatment for pain induced in burned tissues. We have developed a methodology in the zebrafish aimed to produce a new animal model for the study of pain induced by burns. Here, we show that two events linked to the onset of burn-induced inflammation and neuropathic-like pain in mammals, degeneration of axons innervating the affected tissues and over-expression of specific genes in sensory tissues, are conserved from zebrafish to mammals.

Low-dose endotoxin potentiates capsaicin-induced pain in man: Evidence for a pain neuroimmune connection

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50μg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.

Pain is a salient “stressor” that is mediated by corticotropin-releasing factor-1 receptors

Corticotropin-releasing factor (CRF) plays a major role in controlling the body's response to stress. Because painful conditions are inherently stressful, we hypothesize that CRF may act via CRF-1 receptors to contribute to the pain experience. Studies were designed to investigate whether blocking CRF-1 receptors with selective antagonists or reducing their expression with CRF-Saporin, would attenuate ulcer, inflammatory- and neuropathic-like pain. Five experimental designs were undertaken. In experiment 1, ulcer pain was induced in mice following oral administration of indomethacin, while in experiments 2 and 3, inflammatory pain was induced in rats with either carrageenan or FCA, respectively. For these studies, animals were dosed with CP-154,526 (3, 10, 30 mg/kg) and NBI 27914 (1-30 mg/kg) 1 h prior to the assessment of tactile, thermal or mechanical hypersensitivity, respectively. In experiment 4, neuropathic pain was induced. Twenty-one days following spinal nerve ligation (SNL), animals received CRF-Saporin or control. Three weeks later tactile allodynia was assessed. Similarly, in experiment 5, a separate set of rats received CRF-Saporin or control. Twenty-one days later, mechanical hyperalgesia was assessed following intraplantar carrageenan. Results from the antagonist studies showed that CP-154,526 and NBI 27914 either fully or partially reversed the referred ulcer pain with minimal effective doses (MED) equal to 3 and 10 mg/kg, respectively. Similarly, both NBI 27914 and CP-154,526 reversed the thermal and mechanical hypersensitivity elicited by carrageenan and FCA with MEDs </= 5 and 10 mg/kg, respectively. Findings from the two CRF-Saporin studies determined that pre-treatment with this toxin significantly attenuated SNL- and carrageenan-induced tactile hypersensitivity. Together, these findings suggest that CRF-1 receptors mediate pain and implicate CRF in this regard.

Reactive oxygen species in rats with chronic post‐ischemia pain

An emerging theme in the study of the pathophysiology of persistent pain is the role of reactive oxygen species (ROS). In the present study, we examined the hypothesis that the exogenous supply of antioxidant drugs during peri-reperfusion would attenuate pain induced by ischemia/reperfusion (IR) injury. We investigated the analgesic effects of three antioxidants administered during peri-reperfusion using an animal model of complex regional pain syndrome-type I consisting of chronic post-ischemia pain (CPIP) of the hind paw. Application of a tight-fitting tourniquet for a period of 3 h produced CPIP in male Sprague-Dawley rats. Low-dose allopurinol (4 mg/kg), high-dose allopurinol (40 mg/kg), superoxide dismutase (SOD, 4000 U/kg), N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or SOD (4000 U/kg)+L-NAME (10 mg/kg) was administered intraperitoneally just after tourniquet application and at 1 and 2 days after reperfusion for 3 days. The effects of antioxidants in rats were investigated using mechanical and cold stimuli. Each group consisted of seven rats. Allopurinol caused significant alleviation in mechanical and cold allodynia for a period of 4 weeks in rats with CPIP. Both SOD and L-NAME, which were used to investigate the roles of superoxide (O2(-)) and nitric oxide (NO) in pain, also attenuated neuropathic-like pain symptoms in rats for 4 weeks. Our findings suggest that O2(-) and NO mediate IR injury-induced chronic pain, and that ROS scavengers administered during the peri-reperfusion period have long-term analgesic effects.

Anatomical localization and expression pattern for the NMDA-2D receptor subunit in a rat model of neuropathic pain

The N-methyl-d-aspartate receptor (NMDAR) has been implicated in the etiology of chronic pain. In this regard, this study sought to characterize the localization and expression pattern for the NMDAR-2D subunit in a rat model of neuropathic pain. To this end, one group of rats, 3 weeks post-dorsal root rhizotomy (DRR) and a second group, 3 weeks post-spinal nerve ligation (SNL) and sham surgery, were generated. Dorsal root ganglia (DRG) and/or lumbar spinal cord were excised from DRR, naïve, SNL and sham rats. Both immunohistochemical and real-time PCR analysis confirmed discrete NMDAR-2D subunit expression within the DRG and dorsal horn. However, no overt differences in staining intensity or expression were noted between DRG and spinal cord sections obtained from the different surgical groups. Results also demonstrated that the NMDAR-2D subunit was present within Neu N+ cells in the spinal cord and DRG, but excluded from cells labeled with the astrocytic marker, GFAP, and the microglial maker, OX-42. Lastly, the NMDAR-2D subunit was not co-expressed within neurokinin-1 (NK-1)+ or neurofilament-52 (N-52)+ neurons, but the antibody did co-label a number of isolectin B4+ (IB4) DRG cells. Together, these findings seem to suggest that the NMDAR-2D receptor subunit is present within the cell body region of a population of small diameter sensory afferents and post-synaptically within second order dorsal horn neurons. Although these data suggest that the NMDAR-2D subunit is well poised anatomically to modulate pain neurotransmission, the expression pattern for this subunit is not altered in rats demonstrating the presence of neuropathic-like pain behavior.

A Descriptive Review of Neuropathic-Like Pain After Burn Injury

This study reviews the natural history of neuropathic-like pain after burn injury. We undertook a retrospective chart review during a 24-month period of patients treated at an outpatient burn center. The medical records of patients with neuropathic-like pain complaints, including the sensation of pins and needles, burning, stabbing, shooting, or "electric" sensations, were included for analysis. Medical and demographic data were collected. We identified 72 patients for inclusion in the study. The age was 44 +/- 2 years (mean +/- SEM), and TBSA burned was 18 +/- 3%. The first complaint of neuropathic-like symptoms was at 4.3 +/- 0.5 months after injury. Documentation of improvement in the symptoms occurred at 7.0 +/- 0.8 months. Symptoms persisted for 13.1 +/- 2.2 months after the injury. Patients were followed for 14.5 +/- 2.2 months. Documented initial pain severity score was 7 +/- 1 of 10. Typical exacerbating factors included temperature change, dependent position, light touch, and weight-bearing activities. Common alleviating factors included rest, massage, compression garment use, and elevation. Treatment regimens often included gabapentin (38%) and steroid injections (21%). Hypertrophic scarring (43%), pruritus (40%), and psychiatric diagnoses (36%) were common associated problems. There is a patterned natural history for neuropathic-like pain after burn injury. This clinical entity involves significant pain complaints and persists, on average, for greater than 1 year after injury, which underscores the importance of long-term outpatient care after burn injury. Furthermore, an understanding of the natural history will assist clinicians in prognosticating and caring for burn survivors with pain after wound closure.

A Descriptive Review of Neuropathic-Like Pain Following Burn Injury

Neuropathic-like pain consisting of a pins and needles, burning or lancinating sensation is a common complaint of burn patients following healing of their open wounds. In our experience, this pain is often a significant complaint on long-term follow-up. However, there exists no published study outlining the clinical course of this common symptom following burns. A description of the natural history of this symptom would be useful to burn clinicians and their patients. A retrospective chart review over a twenty-four month period of patients treated at an outpatient burn center was performed. The medical records of patients with a complaint of pins and needles, burning, stabbing, or electric shock-like pain were included for analysis. Medical and demographic data was collected. We identified 72 patients for inclusion in the study. The age was 44 ± 2 (mean ± SEM) and total body surface area burned was 18±3%. The first complaint of neuropathic-like symptoms was at 4.3±0.5 months after injury. Documentation of improvement in the symptoms occurred at 7.0±0.8 months. Symptoms persisted for 13.1±2.2 months after the injury. Patients were followed for 14.5±2.2 months and 40% of patients still reported pain at their last clinic visit. Documented initial pain severity score was 7 ± 1 out of ten. Typical exacerbating factors included temperature change, dependent position, light touch and activity. Common alleviating factors included cool water immersion, massage, compression garment use and elevation. Treatment regiments often included gabapentin (38%) and steroid injections (21%). Hypertrophic scarring (43%), pruritis (40%) and psychiatric diagnoses (36%) were common associated problems.

Chronic post-ischemia pain (CPIP): a novel animal model of complex regional pain syndrome-Type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat

A neuropathic-like pain syndrome was produced in rats following prolonged hindpaw ischemia and reperfusion, creating an animal model of complex regional pain syndrome-Type I (CRPS-I; reflex sympathetic dystrophy) that we call chronic post-ischemia pain (CPIP). The method involves placing a tourniquet (a tight fitting O-ring) on one hindlimb of an anesthetized rat just proximal to the ankle joint for 3 h, and removing it to allow reperfusion prior to termination of the anesthesia. Rats exhibit hyperemia and edema/plasma extravasation of the ischemic hindpaw for a period of 2–4 h after reperfusion. Hyperalgesia to noxious mechanical stimulation (pin prick) and cold (acetone exposure), as well as mechanical allodynia to innocuous mechanical stimulation (von Frey hairs), are evident in the affected hindpaw as early as 8 h after reperfusion, and extend for at least 4 weeks in approximately 70% of the rats. The rats also exhibit spontaneous pain behaviors (hindpaw shaking, licking and favoring), and spread of hyperalgesia/allodynia to the uninjured contralateral hindpaw. Light-microscopic examination of the tibial nerve taken from the region just proximal to the tourniquet reveals no signs of nerve damage. Consistent with the hypothesis that the generation of free radicals may be partly responsible for CRPS-I and CPIP, two free radical scavengers, N-acetyl- l-cysteine (NAC) and 4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl (Tempol), were able to reduce signs of mechanical allodynia in this model.

Alpha-1 adrenoceptor hyperresponsiveness in three neuropathic pain states: complex regional pain syndrome 1, diabetic peripheral neuropathic pain and central pain states following spinal cord injury.

The pathophysiology of the pain associated with complex regional pain syndrome, spinal cord injury and diabetic peripheral neuropathy is not known. The pain of complex regional pain syndrome has often been attributed to abnormal sympathetic nervous system activity based on the presence of vasomotor instability and a frequently reported positive response, albeit a temporary response, to sympathetic blockade. In contrast, the pain below the level of spinal cord injury and diabetic peripheral neuropathy are generally seen as deafferentation phenomena. Each of these pain states has been associated with abnormal sympathetic nervous system function and increased peripheral alpha-1 adrenoceptor activity. This increased responsiveness may be a consequence of alpha-1 adrenoceptor postsynaptic hypersensitivity, or alpha-2 adrenoceptor presynaptic dysfunction with diminished noradrenaline reuptake, increased concentrations of noradrenaline in the synaptic cleft and increased stimulation of otherwise normal alpha-1 adrenoceptors. Plausible mechanisms based on animal research by which alpha-1 adrenoceptor hyperresponsiveness can lead to chronic neuropathic-like pain have been reported. This raises the intriguing possibility that sympathetic nervous system dysfunction may be an important factor in the generation of pain in many neuropathic pain states. Although results to date have been mixed, there may be a greater role for new drugs which target peripheral alpha-2 adrenoceptors (agonists) or alpha-1 adrenoceptors (antagonists).