Differential development of sensory hypersensitivity and a measure of spinal cord hyperexcitability following whiplash injury

Widespread sensory hypersensitivity is present in acute whiplash and is associated with poor recovery. Decreased nociceptive flexion reflex (NFR) thresholds (spinal cord hyperexcitability) are a feature of chronic whiplash but have not been investigated in the acute to chronic injury stage. This study compared the temporal development of sensory hypersensitivity and NFR responses from soon after injury to either recovery or to transition to chronicity. It also aimed to identify predictors of persistent spinal cord hyperexcitability. Pressure and cold pain thresholds, NFR responses (threshold and pain VAS) were prospectively measured in 62 participants at <3 weeks, 3 and 6 months post whiplash injury and in 22 healthy controls on two occasions a month apart. Pain levels and psychological distress (GHQ-28; IES) were measured at baseline. Whiplash participants were classified at 6 months post-injury using the Neck Disability Index: recovered (?8%), mild pain and disability (10–28%) or moderate/severe pain and disability (?30%). All whiplash groups demonstrated spinal cord hyperexcitability (lowered NFR thresholds) at 3 weeks post-injury. This hyperexcitability persisted in those with moderate/severe symptoms at 6 months but resolved in those who recovered or reported lesser symptoms at 6 months. In contrast generalized sensory hypersensitivity (pressure and cold) was only ever present in those with persistent moderate/severe symptoms and remained unchanged throughout the study period. This suggests different mechanisms underlie sensory hypersensitivity and NFR responses. In multivariate analyses only initial NDI scores (p = 0.003) were a unique predictor of persistent spinal cord hyperexcitability indicating possible ongoing peripheral nociception following whiplash injury.     

Psychologic factors are related to some sensory pain thresholds but not nociceptive flexion reflex threshold in chronic whiplash

OBJECTIVES: Sensory hypersensitivity, central hyperexcitability [lowered nociceptive flexion reflex (NFR) thresholds], and psychologic distress are features of chronic whiplash. However, relationships between these substrates are not clear. This study tested the hypothesis that psychologic distress and catastrophization are correlated with sensory hypersensitivity and NFR responses in chronic whiplash. METHODS: Pressure and thermal pain thresholds (mean values across 3 body sites), NFR threshold, and pain at threshold Visual Analog Scale were measured in 30 participants with chronic whiplash and 30 asymptomatic controls. Pain and disability levels Neck Disability Index, psychologic distress (GHQ-28), and catastrophization (PCS) were also measured in the whiplash group. RESULTS: Whiplash injured participants demonstrated lowered pain thresholds to pressure and cold (P<0.05); lowered NFR thresholds (P=0.003), and demonstrated above threshold levels of psychologic distress (GHQ-28) and levels of catastrophization comparable with other musculoskeletal conditions. There were no group differences for heat pain thresholds or pain at NFR threshold. In the whiplash group, PCS scores correlated moderately with cold pain threshold (r=0.51, P=0.01). In contrast, there were no significant correlations between GHQ-28 scores and pain threshold measures or between psychologic factors and NFR responses in whiplash participants. There were no significant correlations between psychologic factors and pain thresholds or NFR responses in controls. DISCUSSION: We have demonstrated that psychologic factors have some association with sensory hypersensitivity (cold pain threshold measures) in chronic whiplash but do not seem to influence spinal cord excitability. This suggests that psychologic disorders are important, but not the only, determinants of central hypersensitivity in whiplash patients.     

Central hypersensitivity in chronic pain after whiplash injury.

OBJECTIVE: The mechanisms underlying chronic pain after whiplash injury are usually unclear. Injuries may cause sensitization of spinal cord neurons in animals (central hypersensitivity), which results in increased responsiveness to peripheral stimuli. In humans, the responsiveness of the central nervous system to peripheral stimulation may be explored by applying sensory tests to healthy tissues. The hypotheses of this study were: (1) chronic whiplash pain is associated with central hypersensitivity; (2) central hypersensitivity is maintained by nociception arising from the painful or tender muscles in the neck. DESIGN: Comparison of patients with healthy controls. SETTING: Pain clinic and laboratory for pain research, university hospital. PATIENTS: Fourteen patients with chronic neck pain after whiplash injury (car accident) and 14 healthy volunteers. OUTCOME MEASURES: Pain thresholds to: single electrical stimulus (intramuscular), repeated electrical stimulation (intramuscular and transcutaneous), and heat (transcutaneous). Each threshold was measured at neck and lower limb, before and after local anesthesia of the painful and tender muscles of the neck. RESULTS: The whiplash group had significantly lower pain thresholds for all tests. except heat, at both neck and lower limb. Local anesthesia of the painful and tender points affected neither intensity of neck pain nor pain thresholds. CONCLUSIONS: The authors found a hypersensitivity to peripheral stimulation in whiplash patients. Hypersensitivity was observed after cutaneous and muscular stimulation, at both neck and lower limb. Because hypersensitivity was observed in healthy tissues, it resulted from alterations in the central processing of sensory stimuli (central hypersensitivity). Central hypersensitivity was not dependent on a nociceptive input arising from the painful and tender muscles.     

Evidence, mechanisms, and clinical implications of central hypersensitivity in chronic pain after whiplash injury

OBJECTIVES: To provide insights into the mechanisms underlying central hypersensitivity, review the evidence on central hypersensitivity in chronic pain after whiplash injury, highlight reflections on the clinical relevance of central hypersensitivity, and offer a perspective of treatment of central hypersensitivity. METHODS: A review of animal and human studies focusing on the mechanisms of postinjury central sensitization, an analysis of psychophysical investigations on central hypersensitivity in patients with chronic pain after whiplash injury, and a review of possible treatment modalities. RESULTS: Animal data show that tissue damage produces plasticity changes at different neuronal structures that are responsible for amplification of nociception and exaggerated pain responses. Some of these changes are potentially irreversible. There is consistent psychophysical evidence for hypersensitivity of the central nervous system to sensory stimulation in chronic pain after whiplash injury. Tissue damage, detected or not by the available diagnostic methods, is probably the main determinant of central hypersensitivity. Psychologic distress could contribute to central hypersensitivity via imbalance of supraspinal and descending modulatory mechanisms. Although specific treatment strategies are limited, they are largely unexplored. IMPLICATIONS: Central hypersensitivity may explain exaggerated pain in the presence of minimal nociceptive input arising from minimally damaged tissues. This could account for pain and disability in the absence of objective signs of tissue damage in patients with whiplash. Central hypersensitivity may provide a common neurobiological framework for the integration of peripheral and supraspinal mechanisms in the pathophysiology of chronic pain after whiplash. Therapy studies are needed.     

Generalized expansion of nociceptive reflex receptive fields in chronic pain patients

Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25-75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38-0.54) and 0.33 (0.27-0.39), respectively (P = 0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P < 0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research.     

Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain

Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain-free volunteers (P < .001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P < .001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research.     

Evidence of spinal cord hyperexcitability as measured with nociceptive flexion reflex (NFR) threshold in chronic lateral epicondylalgia with or without a positive neurodynamic test

There is emerging evidence of altered pain signal processing as a likely underlying mechanism in chronic lateral epicondylalgia (LE), yet this remains to be assessed. Furthermore, it has been proposed that neurodynamic tests reflect nociceptive withdrawal responses. Therefore, the objective was to improve our understanding of spinal cord excitability as measured by nociceptive flexion reflex (NFR) threshold in chronic LE with and without a positive neurodynamic test. NFR threshold, pain-free grip, and pressure pain threshold were measured in 30 LE participants and 31 healthy controls. Test of neural tissue involvement (using upper limb neural tension, radial bias) was used to differentiate LE participants with or without a positive neurodynamic test. There were significant differences in NFR threshold between the control and LE with or without a positive neurodynamic test (F[2,54] = 5.68, P = .006), after adjusting for age, sex, pain rating at NFR threshold, and reflex size (NFR interval peak z score). The mean differences (95% confidence interval) in NFR threshold between the control and LE with or without a positive neurodynamic test were 3.74 mA (.637, 6.84) and 3.38 mA (.0245, 6.74) respectively. PERSPECTIVE: The results suggest evidence of spinal cord hyperexcitability, particularly sensory hypersensitivity, in LE with or without a positive neurodynamic test. Our data appear to support the hypothesis that continued peripheral afferent stimulation results in facilitation of nociceptive pathways in this patient population.     

Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury

At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine-induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above-level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI.

Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients

The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 ± 14 years) and 15 men (aged 48 ± 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2 mg, and tropisetron 5 mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity.     

Decrease of hypertonia after continuous passive motion treatment in individuals with spinal cord injury

OBJECTIVE: To examine the effect of ankle continuous passive motion on the reflex excitability and overall hypertonia of calf muscles in individuals with chronic spinal cord injury and without physical disabilities. DESIGN: Two-way repeated measure experimental design. SETTING: Inpatient rehabilitation department in general hospital. SUBJECTS: The spinal cord injury group comprised eight individuals with chronic complete spinal cord injury and the control group comprised eight healthy people without physical disabilities. An additional eight healthy people were recruited as the sham group. INTERVENTIONS: Each subject received 60 min of continuous passive motion on the ankle joint. MAIN MEASURES: The H-reflex of the soleus muscle was elicited by tibia nerve stimulation just before, immediately after, and 10 min after continuous passive motion. The Modified Ashworth Scale (MAS) score at the ankle joint was recorded for the spinal cord injury group just before and 10 min after continuous passive motion therapy. RESULTS. After 60 min of continuous passive motion of the ankle joint, the H-reflex amplitude at the soleus muscle was depressed in individuals with and without spinal cord injury (77.46 +/- 32.64%, P = 0.047 and 51.76 +/- 26.74% of initial, P<0.0001, respectively). This depression persisted up to 10 min after continuous passive motion only in individuals without spinal cord injury. In individuals with spinal cord injury, the median of MAS scores decreased from 2 to 1.25 after continuous passive motion. CONCLUSION: Sixty minutes of continuous passive motion of the ankle joint decreased reflex excitability and overall hypertonia in people with or without spinal cord injury. The depression of overall hypertonia persisted longer than the reflex excitability in people with spinal cord injury.     

Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls

Many chronic pain syndromes, including fibromyalgia (FM), show evidence of central nervous system hyperexcitability related to central sensitization. Windup (WU) of second pain reflects increased excitability of spinal cord neurons that is related to central sensitization. Psychophysical testing can help characterize this important central nervous system phenomenon because of the parallels between electrophysiological WU and WU of second pain. Animal experiments have shown that once WU has been established, only low frequency tonic nociceptive input is required to maintain the sensitized state of dorsal horn neurons (WU-maintenance or WU-M). The stimulus frequency necessary to maintain the hyperexcitability of spinal cord neurons can provide a measure of central sensitization. Because central sensitization plays an important role in many chronic pain syndromes including FM, we compared WU-M in 72 normal controls (NC) and 104 FM subjects. WU of second pain was produced by a train of 0.7 s duration thermal pulses applied to the glabrous surface of the hands at a frequency of 0.3 Hz. Enhanced second pain associated with WU could, thereafter, be maintained in FM but not NC subjects for up to 120 s by stimuli delivered at 0.16 and 0.08 Hz (WU-M stimuli). These two frequencies of stimulation do not produce WU when delivered alone. Thus, unlike NC subjects, FM subjects showed enhanced second pain during WU-M stimuli at very low stimulus frequencies, indicating central sensitization. Increased WU sensitivity, enhanced WU-M, and increased WU-related aftersensations help account for persistent pain conditions in FM subjects. In addition to WU, WU-M appears to be a useful tool to study mechanisms of pain in patients with characteristics of central sensitization.     

The nociceptive withdrawal reflex: Normative values of thresholds and reflex receptive fields

Assessments of spinal nociceptive withdrawal reflexes can be used in human research both to evaluate the effect of analgesics and explore pain mechanisms related to sensitization. Before the reflex can be used as a clinical tool, normative values need to be determined in large scale studies. The aim of this study was to determine the reference values of spinal nociceptive reflexes and subjective pain thresholds (to single and repeated stimulation), and of the area of the reflex receptive fields (RRF) in 300 pain‐free volunteers. The influences of gender, age, height, weight, body‐mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short‐Form 36 (SF‐36) were analyzed by multiple regressions. The 95% confidence intervals were determined for all the tests as normative values. Age had a statistically and quantitatively significant impact on the subjective pain threshold to single stimuli. The reflex threshold to single stimulus was lower on the dominant compared to the non‐dominant side. Depression had a negative impact on the subjective pain threshold to single stimuli. All the other analyses either did not reveal statistical significance or displayed quantitatively insignificant correlations. In conclusion, normative values of parameters related to the spinal nociceptive reflex were determined. This allows their clinical application for assessing central hyperexcitability in individual patients. The parameters investigated explore different aspects of sensitization processes that are largely independent of demographic characteristics, cognitive and affective factors.     

General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression

Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low- and high-intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high-intensity, but not low-intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low-intensity stimulation, too, induces a reversible cephalic allodynia, and high-intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high-intensity stimulation. Fos expression reveals that a single high-intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition-induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine.     

Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: Evaluation of pain-like behavior

Pain is a frequent consequence of spinal cord injury (SCI) which may profoundly impair the patients’ quality of life. Valid experimental models and methods are therefore desirable in the search for better treatments. Usually, experimental pain assays depend on stimulus-evoked withdrawal responses; however, this spinal-mediated reflex response may be particularly problematic when evaluating below-level SCI pain due to the development of hyperactive reflex circuitries. In this study, we applied and compared assays measuring cold (acetone), static (von Frey filaments), and dynamic mechanical (soft brush) hypersensitivity at different levels of the neuroaxis at and below the level of injury in a rat model of SCI. We induced an experimental SCI (MASCIS 25 mm weight-drop) and evaluated the development of spinal reflexes (withdrawal), spinal-brainstem-spinal reflexes (licking, guarding, struggling, vocalizing, jumping, and biting) and cerebral-dependent behavior (place escape/avoidance paradigm (PEAP)). We demonstrated increased brainstem reflexes and cerebrally mediated aversive reactions to stimuli applied at the level of SCI, suggesting development of at-level evoked pain behavior. Furthermore, stimulation below-level increased innate reflex responses without increasing brainstem reflexes or aversive behavior in the PEAP, suggesting development of the spasticity syndrome rather than pain-like behavior. While spinal reflex measures are acceptable for studying changes in the spinal reflex pathways and spinal cord, they are not suited as nociceptive behavioral measures. Measuring brainstem organized responses eliminates the bias associated with the spastic syndrome, but pain requires cortical involvement. Methods depending on cortical structures, as the PEAP, are therefore optimal endpoints in animal models of central pain.     

Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury

Functional magnetic resonance imaging (fMRI) has been used to map cerebral activations related to nociceptive stimuli in rodents. Here, we used fMRI to investigate abnormally increased responses to noxious or innocuous stimuli, in a well-established rat model of chronic neuropathic pain induced by photochemical lumbar spinal cord injury. In this model, a subpopulation of rats exhibits allodynia-like hypersensitivity to mechanical and cold stimulation of the trunk area. In those rats that do not develop overt hypersensitivity after identical spinal cord injury (i.e. non-hypersensitive rats), touch evoked pain can be triggered by the opioid receptor antagonist, naloxone. We show that cerebral activations in contralateral primary somatosensory cortex (SI) are markedly correlated with different behavioural characteristics of these animals. Identical electrical stimulation, applied on trunks of spinally injured hypersensitive and non-hypersensitive rats, evoked significantly higher responses in SI of the former than the latter. Although levels of fMRI signals in SI of the trunk territory were not significantly different between normal and spinally injured non-hypersensitive rats, the administration of naloxone significantly increased fMRI signals in the non-hypersensitive rats, but not in the normal rats. We conclude that increased activation of contralateral SI is a key feature of behavioural neuropathic pain in spinally injured rats and that fMRI is an effective method to monitor experimental neuropathic pain in small animals.     

Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings

Aiming at developing a new, noninvasive approach to spinal cord neuromodulation, we evaluated whether transcutaneous direct current (DC) stimulation induces long-lasting changes in the central pain pathways in human beings. A double-blind crossover design was used to investigate the effects of anodal direct current (2 mA, 15 min) applied on the skin overlying the thoracic spinal cord on the lower-limb flexion reflex in a group of 11 healthy volunteers. To investigate whether transcutaneous spinal cord DC stimulation (tsDCS) acts indirectly on the nociceptive reflex by modulating excitability in mono-oligosynaptic segmental reflex pathways, we also evaluated the H-reflex size from soleus muscle after tibial nerve stimulation. In our healthy subjects, anodal thoracic tsDCS reduced the total lower-limb flexion reflex area by 40.25% immediately after stimulation (T0) and by 46.9% 30 min after stimulation offset (T30). When we analyzed the 2 lower-limb flexion reflex components (RII tactile and RIII nociceptive) separately, we found that anodal tsDCS induced a significant reduction in RIII area with a slight but not significant effect on RII area. After anodal tsDCS, the RIII area decreased by 27% at T0 and by 28% at T30. Both sham and active tsDCS left all the tested H-reflex variables unchanged. None of our subjects reported adverse effects after active stimulation. These results suggest that tsDCS holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain.     

A comparison of diffuse noxious inhibitory controls in men and women.

Results from clinical and experimental pain studies provide consistent evidence of sex differences in pain perception, with women reporting more clinical pain and demonstrating lower pain threshold and tolerance levels than men. The present study was designed to assess the notion that sex differences in pain perception may be related to differential activation of supraspinal pain modulation systems. Specifically, the phenomenon of diffuse noxious inhibitory controls (DNIC) was examined in healthy young adult men (n = 39) and women (n = 44) using repeated assessment of nociceptive flexion reflex activity before, during and after exposure to forearm ischemia. Consistent with previous research, women exhibited significantly lower nociceptive flexion reflex thresholds than men, and reported significantly greater pain in response to both forearm ischemia and repeated electrocutaneous stimulation required to elicit the nociceptive flexion reflex. Application of forearm ischemia was associated with a significant decrease in nociceptive flexion reflex activity in both men and women, however, the degree of attenuation of nociceptive flexion reflex activity was not significantly different between the sexes. These findings suggest that men and women exhibit similar activation of diffuse noxious inhibitory controls, but they do not exclude the possibility of sex differences in other forms of central pain modulation.     

Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain.

The aim of the present study was to assess, compare, and correlate the pain response to an experimental pain stimulus (hyperalgesia to pressure pain threshold (PPT) measured from different body sites), the pain intensity (VAS) of the habitual pain, and quality of life parameters (SF-36) in groups of females with chronic non-malignant pain syndromes. Forty female pain patients with fibromyalgia/whiplash (n = 10), endometriosis (n = 10), low back pain (n = 10), or rheumatoid arthritis (n = 10), as well as 41 age-matched healthy female controls participated in the study. The fibromyalgia/whiplash patients scored significantly higher (p < 0.04) VAS ratings (median rating = 7.0) than the endometriosis (6.0), low back pain (6.0), and rheumatoid arthritis (3.5) patients. All fours patient groups had significantly lower PPTs at all sites as compared with controls. The fibromyalgia/whiplash patients experienced the highest influence of pain on their overall health status, particularly vitality, social function, emotional problems, and mental health. A significant negative correlation was found between VAS rating and quality of life (p < 0.04). Significant correlation (p < 0.05) was found between pressure hyperalgesia measured at lowest PPT sites and the impairment of SF-36 physical function as well as mental health parameters. This study demonstrates significant generalised pressure hyperalgesia in four groups of chronic pain patients, correlations between degree of pressure hyperalgesia and impairment of some quality of life parameters, and increased pain intensity of the ongoing pain is associated with decreased quality of life.     

Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn

Pain after burn injury can be intense and long lasting. Treatment is often ineffective, and there is a need for increased knowledge of the underlying pain mechanisms. In the present study, we established a unilateral partial-thickness burn injury model, which produces ipsilateral mechanical allodynia soon after injury, followed by contralateral allodynia. Chronic bilateral allodynia lasts up to 8 weeks postinjury in this model. In addition to the change in pain behavior, electrophysiological analyses showed that dorsal horn neurons become hyperexcitable and display significantly increased evoked activity with enlarged receptive fields, initially on the side ipsilateral to the injury, and subsequently on both sides of the spinal cord. It is known that, following nerve injury, activation of p38 mitogen-activated protein kinase (MAPK) pathways within spinal microglia contributes to the pathogenesis of pain. In our burn injury model, rapid and prolonged activation of phospho-p38-expressing microglia occurs bilaterally in the spinal cord dorsal horn. Taken together, these data demonstrate that a unilateral peripheral burn injury can produce long-lasting allodynia that can spread to the contralateral limb, together with dorsal horn neuronal hyperexcitability and microglial activation on both ipsilateral and contralateral sides of the spinal cord. Our results suggest that central neuropathic mechanisms can contribute to pain after burn injury.PerspectiveMechanisms contributing to pain following burn injury are incompletely understood. In a novel animal model of burn injury, we have demonstrated hyperexcitability of second-order sensory neurons, activation of microglia, and chronic bilateral pain following the burn injury. This work identifies potential therapeutic targets to alleviate pain after burn injury.     

Reduced cold pressor pain tolerance in non-recovered whiplash patients: a 1-year prospective study.

Whiplash injury and chronic whiplash syndrome represent major health problems in certain western communities, pain being the main symptom. Sensitization of the nociceptive system may play a role for non-recovery after whiplash injury. AIMS: This study examined if tolerance to endure pain stimuli may predict outcome in whiplash injury. In a prospective fashion, 141 acute whiplash patients exposed to rear-end car collision (WAD grade 1-3) and 40 ankle-injured controls were followed and exposed to a cold pressor test, respectively, 1 week, 1, 3, 6 and 12 months after the injury. VAS score of pain and discomfort was obtained before, during and after immersion of the dominant hand into cold water for 2 min. The McGill Pain Questionnaire showed that ankle-injured controls had higher initial pain scores than the corresponding whiplash group, while whiplash-injured subjects had higher scores at 6 months; pain scores being similar at other time points. No difference was found in cold pressor pain between recovered whiplash patients and ankle-injured subjects. Non-recovery was only encountered in whiplash injury. Eleven non-recovered whiplash patients (defined as: handicap after 1 year) showed reduced time to peak pain from 1 week to 3 months (P<0.001), 6 months (P<0.01), but not 12 months after the injury. A larger pain area was seen in non-recovered vs. recovered whiplash-injured subjects during the entire observation period (P<0.001). Non-recovery after whiplash was associated with initially reduced cold pressor pain endurance and increased peak pain, suggesting that dysfunction of central pain modulating control systems plays a role in chronic pain after acute whiplash injury.