The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization

The ultraviolet B (UVB) sunburn model was characterized with a comprehensive battery of quantitative sensory testing (QST). Primary hyperalgesia in UVB-irradiated skin and secondary hyperalgesia in adjacent nonirradiated skin were studied in 22 healthy subjects 24 h after irradiation with UVB at 3-fold minimal erythema dose of a skin area 5 cm in diameter at the thigh and compared to mirror-image contralateral control areas. The time course of hyperalgesia over 96 h was studied in a subgroup of 12 subjects. Within the sunburn area, cold hyperesthesia (P = .01), profound generalized hyperalgesia to heat (P < .001), cold (P < .05), pinprick and pressure (P < .001), and mild dynamic mechanical allodynia (P < .001) were present. The finding of cold hyperalgesia and cold hyperesthesia is new in this model. The sunburn was surrounded by large areas of pinprick hyperalgesia (mean ± SEM, 218 ± 32 cm²) and a small rim of dynamic mechanical allodynia but no other sensory changes. Although of smaller magnitude, secondary hyperalgesia and dynamic mechanical allodynia adjacent to the UVB-irradiated area were statistically highly significant. Primary and secondary hyperalgesia developed in parallel within hours, peaked after 24–32 h, and lasted for more than 96 h. These data reveal that the UVB sunburn model activates a broad spectrum of peripheral and central sensitization mechanisms and hence is a useful human surrogate model to be used as a screening tool for target engagement in phases 1 and 2a of drug development.     

Heterogeneous sensory processing in persistent postherniotomy pain

Previous studies on sensory function in persistent postherniotomy pain (PPP) have only identified pressure pain threshold to be significantly different from pain-free patients despite several patients reporting cutaneous pain and wind-up phenomena. However the limited number of patients studied hinders evaluation of potential subgroups for further investigation and/or treatment allocation. Thus we used a standardized QST protocol to evaluate sensory functions in PPP and pain-free control patients, to allow individual sensory characterization of pain patients from calculated Z-values. Seventy PPP patients with pain related impairment of everyday activities were compared with normative data from 40 pain-free postherniotomy patients operated >1 year previously. Z-values showed a large variation in sensory disturbances ranging from pronounced detection hypoesthesia (Z = 6, cold) to pain hyperalgesia (Z = −8, pressure). Hyperalgesia for various modalities were found in 80% of patients, with pressure hyperalgesia in ∼65%, and cutaneous (mechanical or thermal) hyperalgesia in ∼35% of patients. The paradoxical combination of tactile hypoesthesia and hyperalgesia was seen in ∼25% of patients. Increased pain from repetitive tactile and/or brush stimulation was found in 51%, suggesting a role of altered central nociceptive function in this subpopulation. A high incidence (26%) of pressure hyperalgesia was found in the contralateral groin, with a significant correlation (rho = 0.58, p = 0.002) to the hyperalgesic level on the painful side, again suggesting central nervous mechanisms in PPP. In conclusion, this study shows that a standardized trauma results in heterogeneous combinations of hypo- and hyperalgesia. Z-score evaluation of sensory function identifies subpopulations in PPP, which may be used in selecting surgical and/or pharmacological treatment strategies.     

Quantitative sensory testing somatosensory profiles in patients with cervical radiculopathy are distinct from those in patients with nonspecific neck–arm pain

The aim of this study was to establish the somatosensory profiles of patients with cervical radiculopathy and patients with nonspecific neck–arm pain associated with heightened nerve mechanosensitivity (NSNAP). Sensory profiles were compared to healthy control (HC) subjects and a positive control group comprising patients with fibromyalgia (FM). Quantitative sensory testing (QST) of thermal and mechanical detection and pain thresholds, pain sensitivity and responsiveness to repetitive noxious mechanical stimulation was performed in the maximal pain area, the corresponding dermatome and foot of 23 patients with painful C6 or C7 cervical radiculopathy, 8 patients with NSNAP in a C6/7 dermatomal pain distribution, 31 HC and 22 patients with FM. For both neck–arm pain groups, all QST parameters were within the 95% confidence interval of HC data. Patients with cervical radiculopathy were characterised by localised loss of function (thermal, mechanical, vibration detection P < .009) in the maximal pain area and dermatome (thermal detection, vibration detection, pressure pain sensitivity P < .04), consistent with peripheral neuronal damage. Both neck–arm pain groups demonstrated increased cold sensitivity in their maximal pain area (P < .03) and the foot (P < .009), and this was also the dominant sensory characteristic in patients with NSNAP. Both neck–arm pain groups differed from patients with FM, the latter characterised by a widespread gain of function in most nociceptive parameters (thermal, pressure, mechanical pain sensitivity P < .027). Despite commonalities in pain characteristics between the 2 neck–arm pain groups, distinct sensory profiles were demonstrated for each group.     

Test-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): a multi-centre study

Quantitative sensory testing (QST) is an instrument to assess positive and negative sensory signs, helping to identify mechanisms underlying pathologic pain conditions. In this study, we evaluated the test-retest reliability (TR-R) and the interobserver reliability (IO-R) of QST in patients with sensory disturbances of different etiologies. In 4 centres, 60 patients (37 male and 23 female, 56.4 ± 1.9 years) with lesions or diseases of the somatosensory system were included. QST comprised 13 parameters including detection and pain thresholds for thermal and mechanical stimuli. QST was performed in the clinically most affected test area and a less or unaffected control area in a morning and an afternoon session on 2 consecutive days by examiner pairs (4 QSTs/patient). For both, TR-R and IO-R, there were high correlations (r = 0.80-0.93) at the affected test area, except for wind-up ratio (TR-R: r = 0.67; IO-R: r = 0.56) and paradoxical heat sensations (TR-R: r = 0.35; IO-R: r = 0.44). Mean IO-R (r = 0.83, 31% unexplained variance) was slightly lower than TR-R (r = 0.86, 26% unexplained variance, P < .05); the difference in variance amounted to 5%. There were no differences between study centres. In a subgroup with an unaffected control area (n = 43), reliabilities were significantly better in the test area (TR-R: r = 0.86; IO-R: r = 0.83) than in the control area (TR-R: r = 0.79; IO-R: r = 0.71, each P < .01), suggesting that disease-related systematic variance enhances reliability of QST. We conclude that standardized QST performed by trained examiners is a valuable diagnostic instrument with good test-retest and interobserver reliability within 2 days. With standardized training, observer bias is much lower than random variance.     

Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements

Quantitative sensory testing (QST) is commonly used to evaluate peripheral sensory function in neuropathic conditions. QST measures vary in repeated measurements of normal subjects but it is not known whether QST can reflect small changes in epidermal nerve fiber density (ENFd). This study evaluated QST measures (touch, mechanical pain, heat pain and innocuous cold sensations) for differences between genders and over time using ENFd as an objective-independent measure. QST was performed on the thighs of 36 healthy volunteers on four occasions between December and May. ENFd in skin biopsies was determined on three of those visits. Compared to men, women had a higher ENFd, a difference of 12.2 ENFs/mm. They also had lower tactile and innocuous cold thresholds, and detected mechanical pain (pinprick) at a higher frequency. Heat pain thresholds did not differ between genders. By the end of the 24-week study, men and women showed a small reduction (p < 0.05) in the frequency of sharp mechanical pain evoked by pinprick whereas tactile and thermal thresholds showed no change. This coincided with a small decrease in ENFd, 4.18 ENFs/mm. Variation in measurements over time was large in a fraction of normal subjects. We conclude that most QST measures detect relatively large differences in epidermal innervation (12.2 ENFs/mm), but response to mechanical pain was the only sensory modality tested with the sensitivity to detect small changes in innervation (4.18 ENFs/mm). Since some individuals had large unsystematic variations, unexpected test results should therefore alert clinicians to test additional locations.     

Experimental characterization of the effects of acute stresslike doses of hydrocortisone in human neurogenic hyperalgesia models

Relative hypothalamic-pituitary-adrenal axis dysfunction has been described as a common feature of several dysfunctional pain syndromes, and its end hormone cortisol may thus constitute a protective factor against the development of chronic pain. We investigated the potential influence of experimentally induced stresslike hypercortisolism on the induction of neurogenic hyperalgesia using 2 human surrogate models: secondary hyperalgesia after intradermal capsaicin injection into the volar forearm, and perceptual windup in normal skin. In a double-blind, placebo-controlled, randomized, crossover study, a psychophysical study was performed in 10 healthy subjects (median age 23 years) examining the effects of 40 mg orally administered hydrocortisone. Numeric pain ratings were assessed for punctate pinprick and light touch stimuli applied to the zone of secondary hyperalgesia adjacent to the capsaicin injection and to the contralateral control side. In addition, visual analog ratings were assessed for repetitive pinprick stimulation of the noninjected arm. Hydrocortisone significantly attenuated the late phase of capsaicin-induced pain by nearly 50%, and hyperalgesia to pinprick stimuli by 33% (both P < .05). Baseline mechanical pain and dynamic mechanical allodynia remained unaltered. Temporal summation (windup) to mechanical pain stimuli and electrically induced windup of second pain (tested in an independent cohort of 10 other subjects) were also unchanged. The selective effects of hydrocortisone on pinprick hyperalgesia but not pinprick pain suggest an antihyperalgesic rather than analgesic effect. The findings suggest that hypothalamic-pituitary-adrenal axis reactivity might be an important mechanism in resilience to dysfunctional pain syndromes.     

One night of total sleep deprivation promotes a state of generalized hyperalgesia: A surrogate pain model to study the relationship of insomnia and pain

Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P < 0.001) and resulted in higher scores of the State Anxiety Inventory (P < 0.01). In addition to previously reported hyperalgesia to heat (P < 0.05) and blunt pressure (P < 0.05), study participants developed hyperalgesia to cold (P < 0.01) and increased mechanical pain sensitivity to pinprick stimuli (P < 0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.     

Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans

Opioids may enhance pain sensitivity resulting in opioid-induced hyperalgesia (OIH). Activation of spinal cyclooxygenase may play a role in the development of OIH. The aim of this study was to demonstrate remifentanil-induced postinfusion hyperalgesia in an electrical pain and a cold pain model, and to investigate whether COX-2 (parecoxib) or COX-1 (ketorolac) inhibition could prevent hyperalgesia after remifentanil infusion. Sixteen healthy males were enrolled in this randomized, double-blind, placebo-controlled crossover study. Each subject went through 4 sessions: control, remifentanil, parecoxib + remifentanil, and ketorolac + remifentanil. Transcutaneous electrical stimulation induced acute pain and areas of pinprick hyperalgesia. The areas of pinprick hyperalgesia were assessed before, during, and after a 30-minute infusion of either remifentanil or saline. The cold-pressor test (CPT) was performed before, at the end of, and 1 hour after the infusions. The subjects received a bolus of either saline, 40 mg parecoxib, or 30 mg ketorolac intravenously after the first CPT. The areas of pinprick hyperalgesia and CPT pain after the end of remifentanil infusion increased significantly compared to control (P < 0.001 and P = 0.005, respectively). Pretreatment with parecoxib or ketorolac reduced the postinfusion area of pinprick hyperalgesia (P < 0.001 and P = 0.001, respectively), compared to the remifentanil group. Parecoxib reduced the area significantly more than ketorolac (P = 0.009). In the CPT, pretreatment with parecoxib or ketorolac did not prevent postinfusion hyperalgesia. These results demonstrated OIH in both models, and may suggest that COX-2 inhibition is more important than COX-1 inhibition in reducing hyperalgesia.     

Quantitative sensory testing: a comprehensive protocol for clinical trials.

We have compiled a comprehensive QST protocol as part of the German Research Network on Neuropathic Pain (DFNS) using well established tests for nearly all aspects of somatosensation. This protocol encompasses thermal as well as mechanical testing procedures. Our rationale was to test for patterns of sensory loss (small and large nerve fiber functions) or gain (hyperalgesia, allodynia, hyperpathia), and to assess both cutaneous and deep pain sensitivity. The practicality of the QST protocol was tested in 18 healthy subjects, 21-58 years, half of them female. All subjects were tested bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for the presence of paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64-Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus-response-functions for pinprick and dynamic mechanical allodynia (pain to light touch), and pain summation (wind-up ratio) using repetitive pinprick stimulation. The full protocol took 27+/-2.3 min per test area. The majority of QST parameters were normally distributed only after logarithmic transformation (secondary normalization) except for the frequency of paradoxical heat sensations, cold and heat pain thresholds, and for vibration detection thresholds. Thresholds were usually lowest over face, followed by hand, and then foot. Only thermal pain thresholds, wind-up ratio and vibration detection thresholds were not significantly dependent on the body region. There was no significant right-to-left difference for any of the QST parameters; left-to-right correlation coefficients ranged between 0.78 and 0.97, thus explaining between 61% and 94% of the variance. This study has shown that a complete somatosensory profile of one affected area and one unaffected control area, which will be necessary to characterize patients with a variety of diseases, can be obtained within 1 h. Case examples of selected patients illustrate the value of z-transformed QST data for an easy survey of individual symptom profiles.     

Effect of conditioned pain modulation on trigeminal somatosensory function evaluated by quantitative sensory testing

The aim of the study was to systematically investigate the effect of craniofacially evoked conditioned pain modulation on somatosensory function using a quantitative sensory testing (QST) protocol applied to the trigeminal area in healthy humans. Pressure pain evoked by a mechanical compressive device was applied as conditioning stimulus (CS) in the craniofacial region, with a pain intensity of 5 on a visual analogue scale (VAS: 0–10 cm) (painful session) or with VAS score of 0 (control session). A full QST battery of 13 parameters was performed as test stimuli on the dominant-side cheek. The individual QST data from 11 men and 12 women were transformed into z scores, and the QST data and z scores were tested using analyses of variance. Analyses of variance of pressure pain threshold (PPT) data (log-transformed values and z scores) indicated significant session (P ? .003) and time (P < .001) effects with a session–time interaction (P < .001), but no main effect of sex (P ? .053, effect size ? .166). The session–time interaction showed that the PPTs in the painful session were associated with significantly higher log-transformed PPT values and significantly lower z scores compared with the control session at the time point during CS (hypoalgesia) (P < .001). No other QST parameters were significantly modulated by the CS. Sex differences were not detected in this study; a larger sample size may be needed to further explore this possibility. However, the findings indicate that when extensive QST protocols are applied, PPT may be the most sensitive measure to detect endogenous pain inhibitory mechanisms.     

Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P < .05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P < .05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P < .05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P < .05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders.     

Deep brain stimulation of the subthalamic nucleus improves temperature sensation in patients with Parkinson's disease

Patients with Parkinson’s disease (PD) reportedly show deficits in sensory processing in addition to motor symptoms. However, little is known about the effects of bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) on temperature sensation as measured by quantitative sensory testing (QST). This study was designed to quantitatively evaluate the effects of STN-DBS on temperature sensation and pain in PD patients. We conducted a QST study comparing the effects of STN-DBS on cold sense thresholds (CSTs) and warm sense thresholds (WSTs) as well as on cold-induced and heat-induced pain thresholds (CPT and HPT) in 17 PD patients and 14 healthy control subjects. The CSTs and WSTs of patients were significantly smaller during the DBS-on mode when compared with the DBS-off mode (P < .001), whereas the CSTs and WSTs of patients in the DBS-off mode were significantly greater than those of healthy control subjects (P < .02). The CPTs and HPTs in PD patients were significantly larger on the more affected side than on the less affected side (P < .02). Because elevations in thermal sense and pain thresholds of QST are reportedly almost compatible with decreases in sensation, our findings confirm that temperature sensations may be disturbed in PD patients when compared with healthy persons and that STN-DBS can be used to improve temperature sensation in these patients. The mechanisms underlying our findings are not well understood, but improvement in temperature sensation appears to be a sign of modulation of disease-related brain network abnormalities.     

Altered experimental pain perception after cerebellar infarction

Animal studies have suggested that the cerebellum, in addition to its motor functions, also has a role in pain processing and modulation, possibly because of its extensive connections with the prefrontal cortex and with brainstem regions involved in descending pain control. Consistently, human imaging studies have shown cerebellar activation in response to painful stimulation. However, it is presently not clear whether cerebellar lesions affect pain perception in humans. In the present study, we used experimental pain testing to compare acute pain perception and endogenous pain inhibition in 30 patients 1 to 11 years after cerebellar infarction and in 30 sex- and age-matched healthy control subjects. Compared to controls, patients exhibited a significantly increased pain perception in response to acute heat stimuli (44°C–48°C, average pain intensity rating for patients 3.4 ± 2.8 and for controls 1.5 ± 1.7 [on a numeric rating scale of 0–10], P < .01) and to repeated 256 mN pinprick stimuli (1.3 ± 1.9 vs 0.6 ± 1.0 [0–10], P < .05). Heat hyperalgesia in patients was more pronounced on the body side ipsilateral to the infarction. In addition, patients showed reduced offset analgesia (change in pain intensity rating: 0.0% ± 15.8% vs −16.9% ± 36.3%, P < .05) and reduced placebo analgesia (change in pain intensity rating: −1.0 ± 1.1 vs −1.8 ± 1.3 [0–10], P < .05) compared to controls. In contrast, heat and pressure pain thresholds were not significantly different between groups. These results show that, after cerebellar infarction, patients perceive heat and repeated mechanical stimuli as more painful than do healthy control subjects and have deficient activation of endogenous pain inhibitory mechanisms (offset and placebo analgesia). This suggests that the cerebellum has a previously underestimated role in human pain perception and modulation.     

Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: Clinical evidence of enhanced pain sensitivity after surgical injury

Staged bilateral total knee arthroplasty (TKA) may provide an ideal clinical model for the study of central sensitization. In staged TKA, hyperalgesia may be induced as a result of repeated surgical injury possibly via central sensitization, which can decrease functional outcomes. Therefore, we hypothesized that in staged bilateral TKA, patients would have greater pain in the second operated knee than in the first. Thirty patients undergoing staged bilateral TKA at a 1-week interval were enrolled. Postoperative pain, which was reported on the basis of a visual analog scale (VAS; primary outcome) at rest and at maximum knee flexion, and the amount of patient-controlled analgesic (i.v. fentanyl) and rescue analgesic (i.v. ketoprofen; secondary outcomes) administered during the 48 h after the operation, were compared between the first and second TKA. VAS scores at rest and at maximum knee flexion were greater on the second operated knee (P < .001 and P < .01, respectively). The cumulative amounts of patient-controlled analgesic and the rescue analgesic were greater in the second than in the first TKA (P < .001 and P < .05, respectively). Patients undergoing staged bilateral TKA experience greater postoperative pain in the second operated knee than the first. This suggests extension of hyperalgesia beyond the initially injured site to remote regions after surgical injury, in which central sensitization may be involved. Therapeutic approaches to reduce such hyperalgesia induced in the course of staged operations are required.     

Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P < 0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.     

Modality-Specific Nociceptor Sensitization Following UV-B Irradiation of Human Skin

Ultraviolet-B (UV-B) irradiation is a well-established inflammatory pain model inducing mechanical and thermal hyperalgesia, presumably mediated by released mediators that sensitize sensory nerve endings. Here, we used additional electrical stimulation to investigate axonal hyperexcitability. The lower leg of 13 volunteers was irradiated with 3-fold the minimum erythema UV-B dose and sensitization was recorded at days 1, 3, 7, and 14. Maximum heat pain (47°C, 5 seconds) developed at day 1 (visual analog scale [VAS: 0–100]; 59), was reduced at day 3 (VAS 43, P < .002), and was back to normal at day 7 (VAS 18). Mechanical impact pain (8 m/s), pinprick (150 mN), and pressure (100 kPa) hyperalgesia were maximum throughout days 1 to 3 (VAS 16, 8, and 12, respectively, P < .001) and back to normal at day 7. Suprathreshold transcutaneous electrical stimuli (1.5-fold pain threshold) were delivered in trains of 10 pulses at frequencies of 5 to 100 Hz. Electrical pain thresholds (determined at 2 Hz) decreased significantly (P < .002) and suprathreshold electrical pain increased by about 70% at days 1 to 3 after irradiation (VAS 36, P < .002). Electrical hyperalgesia did not correlate with mechanical sensitization but with reduced heat pain threshold and increased tonic heat pain (r = ?.46 and .53; P < .05 and < .01), indicating that axonal hyperexcitability might contribute to heat hyperalgesia. Released inflammatory mediators (eg, prostaglandins) might sensitize both heat transducer molecules and axonal ion channels and receptors, which would explain the simultaneous development and close correlation between heat hyperalgesia and axonal hyperexcitability.PerspectiveLocal inflammation by UV-B irradiation sensitizes not only sensory endings, but also axons. Increased axonal excitability could contribute to inflammatory hyperalgesia by facilitating spike generation and increasing peak discharge frequencies of nociceptors. Thus, axonal channels and receptors crucial for this sensitization need to be identified to provide new therapeutic targets.     

Foot placement in a body reference frame during walking and its relationship to hemiparetic walking performance

Background

Foot placement during walking is closely linked to the body position, yet it is typically quantified relative to the other foot. The purpose of this study was to quantify foot placement patterns relative to body post-stroke and investigate its relationship to hemiparetic walking performance.

Methods

Thirty-nine participants with hemiparesis walked on a split-belt treadmill at their self-selected speeds and 20 healthy participants walked at matched slow speeds. Anterior–posterior and medial–lateral foot placements (foot center-of-mass) relative to body (pelvis center-of-mass) quantified stepping in body reference frame. Walking performance was quantified using step length asymmetry ratio, percent of paretic propulsion and paretic weight support.

Findings

Participants with hemiparesis placed their paretic foot further anterior than posterior during walking compared to controls walking at matched slow speeds (P < .05). Participants also placed their paretic foot further lateral relative to pelvis than non-paretic (P < .05). Anterior–posterior asymmetry correlated with step length asymmetry and percent paretic propulsion but some persons revealed differing asymmetry patterns in the translating reference frame. Lateral foot placement asymmetry correlated with paretic weight support (r = .596; P < .001), whereas step widths showed no relation to paretic weight support.

Interpretation

Post-stroke gait is asymmetric when quantifying foot placement in a body reference frame and this asymmetry related to the hemiparetic walking performance and explained motor control mechanisms beyond those explained by step lengths and step widths alone. We suggest that biomechanical analyses quantifying stepping performance in impaired populations should investigate foot placement in a body reference frame.     

The effects of mexiletine,desipramine and fluoxetine in rat models involving central sensitization

Drugs that are clinically effective (mexiletine and desipramine) or ineffective (fluoxetine) in the treatment of human neuropathic pain were evaluated for efficacy in rat models involving central sensitization (i.e., formalin model and the L5/L6 spinal nerve ligation model of neuropathic pain) using tests that differ in stimulus modality: noxious chemical stimulus (formalin model) as well as noxious (pin prick) and innocuous mechanical stimuli (application of von Frey filaments). Mexiletine (10–100 mg/kg, s.c.) significantly (P<0.05) attenuated hyperalgesia in formalin-treated (60 mg/kg and 100 mg/kg) and neuropathic rats (100 mg/kg) as well as tactile allodynia in neuropathic rats (100 mg/kg). Desipramine (1–100 mg/kg, s.c.), on the other hand, reduced hyperalgesia significantly (P<0.05) in formalin-treated (3, 10, 30 and 100 mg/kg) and neuropathic rats (10 mg/kg and 100 mg/kg), but did not reduce tactile allodynia in the neuropathic rats. Fluoxetine (3–30 mg/kg, s.c.) did not inhibit either hyperalgesia or allodynia in any of the tests employed. Fluoxetine, which is relatively ineffective in reducing neuropathic pain in humans, was also ineffective in reducing hyperalgesia and allodynia associated with central sensitization in rats. Thus, drugs which are effective in reducing human neuropathic pain consistently attenuated hyperalgesia in formalin-treated or neuropathic rats. Desipramine also distinguished mechanical hyperalgesia from tactile allodynia in rats rendered neuropathic by spinal nerve ligation. These data are consistent with the hypothesis that the neuronal mechanisms underlying these two manifestations of neuropathic pain are different     

Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord

Cervical facet joint injury induces persistent pain and central sensitization. Preventing the peripheral neuronal signals that initiate sensitization attenuates neuropathic pain. Yet, there is no clear relationship among facet joint afferent activity, development of central sensitization, and pain, which may be hindering effective treatments for this pain syndrome. This study investigates how afferent activity from the injured cervical facet joint affects induction of behavioral sensitivity and central sensitization. Intra-articular bupivacaine was administered to transiently suppress afferent activity immediately or 4 days after facet injury. Mechanical hyperalgesia was monitored after injury, and spinal neuronal hyperexcitability and spinal expression of proteins that promote neuronal excitability were measured on day 7. Facet injury with saline vehicle treatment induced significant mechanical hyperalgesia (P < .027), dorsal horn neuronal hyperexcitability (P < .026), upregulation of pERK1/2, pNR1, mGluR5, GLAST, and GFAP, and downregulation of GLT1 (P < .032). However, intra-articular bupivacaine immediately after injury significantly attenuated hyperalgesia (P < .0001), neuronal hyperexcitability (P < .004), and dysregulation of excitatory signaling proteins (P < .049). In contrast, intra-articular bupivacaine at day 4 had no effect on these outcomes. Silencing afferent activity during the development of neuronal hyperexcitability (4 hours, 8 hours, 1 day) attenuated hyperalgesia and neuronal hyperexcitability (P < .045) only for the treatment given 4 hours after injury. This study suggests that early afferent activity from the injured facet induces development of spinal sensitization via spinal excitatory glutamatergic signaling. Peripheral intervention blocking afferent activity is effective only over a short period of time early after injury and before spinal modifications develop, and is independent of modulating spinal glial activation.     

Pain and somatosensory findings in patients 3 years after total hip arthroplasty

Background: Chronic hip pain after total hip arthroplasty (THA) is a significant problem, but the aetiology remains unclear. Aims: To determine sensory function in patients with chronic hip pain 3 years after THA. Patients without hip pain after THA served as controls. Methods: Eighteen patients with chronic hip pain and 18 controls without chronic hip pain were recruited from a previous questionnaire study about hip pain after total hip arthroplasty. All participants answered questions about pain and mental vulnerability and underwent clinical examination followed by quantitative sensory testing (brush‐evoked allodynia, pinprick hyperalgesia, mechanical and thermal thresholds). Results: Brush‐evoked allodynia was present in 4 patients with hip pain (P=0.1) and pinprick hyperalgesia (P=0.02) was more frequent in patients with chronic hip pain. Mechanical and thermal thresholds were similar in patients and controls. Patients with chronic hip pain had higher scores on the mental vulnerability scale (P<0.001). Chronic hip pain was significantly associated with low back pain (P=0.002). Conclusions: We found signs of hypersensitivity on the operated side, which was more prominent in patients with pain. Pain referred from the back or deeper structures in the hip seems to play a role for the pain in subgroups of patients. In addition, chronic hip pain was associated with mental vulnerability.