Background and purpose
Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL‐N), whereas the impact of upper limb neuropathy (UL‐N) on hand ...functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL‐N and its functional and psychosocial consequences in type 2 diabetes.
Methods
Individuals with type 2 diabetes (n = 141) and an age‐ and sex‐matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status.
Results
The prevalence of UL‐N was 30.5% in patients with diabetes and that of LL‐N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL‐N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL‐N had reduced estimates of psychosocial health including health‐related QoL compared to control subjects and patients without UL‐N. UL‐N correlated with the severity of LL‐N, but not with duration of diabetes, glycemia, age, or sex.
Conclusions
This study points to a substantial prevalence of UL‐N in type 2 diabetes. The sensory phenotype of patients with UL‐N was similar to LL‐N and was characterized by loss of sensory function. Our study demonstrated an association of UL‐N with impaired manual dexterity and reduced health‐related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes.
One night of total sleep deprivation results in generalized hyperalgesia and mood changes. TSD emerges a translational surrogate pain model for studies on the relationship between 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±4.1year; 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.
As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to ...estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.
Background
Thermo‐test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device (“Q‐Sense”) was introduced, which is less expensive ...but has reduced cooling capacity (20°C). We assessed the reliability/validity of the “Q‐Sense” by comparing it with the Thermal Sensory Analyzer (TSA).
Methods
Using a phantom‐skin model, the physical characteristics of both devices were compared. The clinical performance was assessed in a multicentre study by performing Quantitative Sensory Testing (QST) in 121 healthy volunteers and 83 diabetic patients (Eudra‐Med‐No. CIV‐12‐05‐006501).
Results
Both device types showed ~40% slower temperature ramps for heating/cooling than nominal data. Cold/warm detection thresholds (CDT, WDT) and heat pain thresholds (HPT) of healthy subjects did not differ between device types. Cold pain thresholds (CPT) were biased for Q‐Sense by a floor effect (p < .001). According to intraclass correlation coefficients (ICC), agreement between TSA and Q‐Sense was good/excellent for CDT (ICC = 0.894) and WDT (ICC = 0.898), moderate for HPT (ICC = 0.525) and poor for CPT (ICC = 0.305). In diabetic patients, the sensitivity of Q‐Sense to detect cold hypoesthesia was reduced in males >60 years. Moderate correlations between thermal detection thresholds and morphological data from skin biopsies (n = 51) were similar for both devices.
Conclusions
Physical characteristics of both thermo‐test devices are similarly limited by the poor temperature conduction of the skin. The Q‐Sense is useful for thermal detection thresholds but of limited use for pain thresholds. For full clinical use, the lower cut‐off temperature should be set to ≤18°C.
Significance
High purchase costs prevent a widespread use of thermo‐test devices for diagnosing small fibre neuropathy. The air‐cooled “Q‐Sense” could be a lower cost alternative, but its technical/clinical performance needs to be assessed because of its restricted cut‐off for cooling (20°C). This study provides critical information on the physical characteristics and the clinical validity/reliability of the Q‐Sense compared to the “Thermal Sensory Analyzer” (TSA). We recommend lowering the cut‐off value of the Q‐Sense to ≤18°C for its full clinical use.
Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury ...(SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18-63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, non-disabled controls (NDC); age 19-63 were included. The percentage of individuals with SCI responding to stimuli (70-77%;
< 0.001), their response rates (16-21%;
< 0.05) and their reflex magnitude (
< 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b
≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher's exact
< 0.05; Eta-coefficient
< 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.
Background and Aims
Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no ...study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers.
Methods
QST data of 1,252 patients (669 female, 583 male) with PNI (n = 342), PNP (n = 571) or CRPS (n = 339), and average pain intensity reports from previously published studies were included. Absolute and z‐values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects.
Results
Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p < .05). However, after z‐transformation these differences disappeared except for PPT in CRPS (p = .001).
Discussion
Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes.
Significance
Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance.
Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide ...(CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified.
1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2)) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2) and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect.
We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2) (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Disturbed sleep is known to substantially aggravate both the pain condition and the affective state of pain patients. The neurobiological mechanisms underlying these adverse effects are unknown. ...Oxytocin (OT), being largely involved in social and emotional behavior, is considered to also play a modulatory role in nociception. We hypothesized a pathophysiological role of OT for the hyperalgesic and anxiogenic effects of sleep loss. An established human model of one night of total sleep deprivation (TSD) was used to test this hypothesis. Twenty young healthy students (
= 10 male and
= 10 female) were investigated in a balanced cross-over design, contrasting TSD with a night of habitual sleep (HS). All females took monophasic oral contraceptives (OC) and were investigated during their 'pill-free' phase. Plasma OT concentrations were correlated with (1) pain thresholds, (2) descending pain inhibition, and (3) state-anxiety scores. Compared to the HS condition, the plasma OT concentration was significantly increased in sleep deprived females (
= 0.02) but not males (
= 0.69). TSD resulted in pain hypersensitivity to noxious cold (
= 0.05), noxious heat (
= 0.023), and pricking stimuli (
= 0.013) and significantly increased state-anxiety (
= 0.021). While, independent of sex, lower heat pain thresholds correlated with higher plasma OT (
= 0.036), no such associations were found for cold/mechanical pain. In sleep-deprived females, higher plasma OT showed a mild (but insignificant) association with lower pain inhibition (
= 0.093). We found a positive correlation between anxiety-scores and OT (
= 0.021), which was enhanced when respecting "sex" (
= 0.008) and "sleep" (
= 0.001) in a hierarchical regression analysis. Altogether, our study revealed a complex and partially sex-dependent correlation between plasma OT and TSD-induced changes of experimental pain and anxiety. The minor role of OT for TSD-induced changes of evoked pain, and its major involvement in anxiety, argues against a specific role of OT for linking the adverse effects of TSD on pain sensitivity and anxiety with each other. Future investigations are needed in order to dissect out the effect of OC on the sex-dependent effects of TSD observed in our study.
Background
The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate ...the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two
in vivo
models of migraine.
Methods
Male Sprague–Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene
c-fos
was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery.
Results
Inflammatory up-regulation of
c-fos
in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ-38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner.
Conclusion
Our results describe two TRPV1 antagonists that are effective in two
in vivo
models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine.