Priming of central- and peripheral mechanisms with heat and cutaneous capsaicin facilitates secondary hyperalgesia to high frequency electrical stimulation

Heat/capsaicin sensitization and electrical high frequency stimulation (HFS) are well known model of secondary hyperalgesia, a phenomenon related to chronic pain conditions. This study investigated whether priming with heat/capsaicin would facilitate hyperalgesia to HFS in healthy subjects. Heat/capsaicin priming consisted of a 45 °C heat stimulation for 5 min followed by a topical capsaicin patch (4x4 cm) for 30 minutes on the volar forearm of 20 subjects. HFS (100 Hz, 5 times 1s, minimum 1.5 mA) was subsequently delivered through a transcutaneous pin electrode approximately 1.5 cm proximal to the heat/capsaicin application. Two sessions were applied in a crossover design; traditional HFS (HFS) and heat/capsaicin sensitization followed by HFS (HFS+HEAT/CAPS). Heat pain threshold (HPT), mechanical pain sensitivity (MPS) and superficial blood perfusion were assessed at baseline, after capsaicin removal, and up to 40 min after HFS. MPS was assessed with pinprick stimulation (128 mN and 256 mN) in the area adjacent to both HFS and heat/capsaicin, distal but adjacent to heat/capsaicin and in a distal control area. HPT was assessed in the area of heat/capsaicin. Higher sensitivity to 128 mN pinprick stimulation (difference from baseline and control area) was observed in the HFS+HEAT/CAPS session than in the HFS session 20 and 30 minutes after HFS. Furthermore, sensitivity was increased after HFS+HEAT/CAPS compared to after heat/capsaicin in the area adjacent to both paradigms, but not in the area distal to heat/capsaicin. Results indicate that heat/capsaicin causes priming of the central- and peripheral nervous system, which facilitates secondary mechanical hyperalgesia to HFS.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study

Background Headache affects 90–99% of the population. Based on the question “Do you think that you never ever in your whole life have had a headache?” 4% of the population say that they have never experienced a headache. The rarity of never having had a headache suggests that distinct biological and environmental factors may be at play. We hypothesized that people who have never experienced a headache had a lower general pain sensitivity than controls. Methods We included 99 male participants, 47 headache free participants and 52 controls, in an observer blinded nested case-control study. We investigated cold pain threshold and heat pain threshold using a standardized quantitative sensory testing protocol, pericranial tenderness with total tenderness score and pain tolerance with the cold pressor test. Differences between the two groups were assessed with the unpaired Student’s t-test or Mann-Whitney U test as appropriate. Results There was no difference in age, weight or mean arterial pressure between headache free participants and controls. We found no difference in pain detection threshold, pericranial tenderness or pain tolerance between headache free participants and controls. Conclusion Our study clearly shows that freedom from headache is not caused by a lower general pain sensitivity. The results support the hypothesis that headache is caused by specific mechanisms, which are present in the primary headache disorders, rather than by a decreased general sensitivity to painful stimuli. Trial registration Registered at ClinicalTrials.gov (NCT04217616), 3rd January 2020, retrospectively registered.

Lack of Effects of the Presence of a Dog on Pain Perception in Healthy Participants—A Randomized Controlled Trial

Animal-assisted interventions (AAIs) have been shown to be effective in the treatment of pain. Studies suggest that relationships with animals can have comparable qualities to relationships with humans and that this enables animals to provide social support. Further, the presence of an animal can strengthen the therapeutic alliance between patients and treatment providers. This suggests that the analgesic effects of AAI might be mediated by social support from an animal or by strengthening the alliance between the patient and the treatment provider. To test these assumptions, we examined the effects of the presence of a dog on experimentally induced pain in a pain assessment and a pain therapy context. Hundred thirty-two healthy participants were randomly assigned to the conditions “pain,” “pain + dog,” “pain + placebo,” or “pain + placebo + dog.” We collected baseline and posttreatment measurements of heat-pain tolerance and the heat-pain threshold and of the corresponding subjective ratings of heat-pain intensity and unpleasantness as well as of participants' perceptions of the study investigator. The primary outcome was heat-pain tolerance. The presence of the dog did not influence the primary outcome (“pain” vs. “pain + dog”: difference = 0.04, CI = −0.66 to 0.74, p = 0.905; “pain + placebo” vs. “pain + placebo + dog”: difference = 0.43, CI = −0.02 to 0.88, p = 0.059). Participants did also not perceive the study investigator to be more trustworthy in the presence of the dog (“pain” vs. “pain + dog”: difference = 0.10, CI = −0.67 to 0.87, p = 0.796; “pain + placebo” vs. “pain + placebo + dog”: difference = 0.11, CI = −0.43 to 0.64, p = 0.695). The results indicate that the mere presence of a dog does not contribute to pain reduction and that the analgesic effects of AAI that previous studies have found is not replicated in our study as AAI did not increase perceived social support and had no effect on the alliance between the participant and the treatment provider. We assume that the animal most likely needs to be an integrated and plausible part of the treatment rationale so that participants are able to form a treatment-response expectation toward AAI.Clinical Trial Registration: This study was preregistered as a clinical trial on www.clinicaltrials.gov (Identifier: NCT0389814).

Altered Neurotransmitter Ratio in the Prefrontal Cortex is Associated with Pain in Fibromyalgia Syndrome

The central mechanisms underlying fibromyalgia syndrome (FMS) remain undetermined. The dorsolateral prefrontal cortex (DLPFC) is particularly relevant to FMS because it is implicated in cognitive, affective, and top-down pain regulation. Imbalances in excitatory (Glutamate) and inhibitory (Gamma aminobutyric acid; GABA) neurochemicals may play a critical role in the pathophysiology of the condition and more generally in homeostatic function within cortical circuits. Although the balance of excitation and inhibition are intrinsically linked no investigations to date have investigated the E/I ratio in FMS. Thus, the primary objective of this study was to determine whether the E/I ratio in the DLPFC is altered in participants with FMS compared to healthy controls using magnetic resonance spectroscopy. Additionally, we examined the relationship between E/I ratio and pain metrics. We hypothesized that the E/I ratio within the DLPFC would be altered in participants with FMS compared to controls and, secondly, that E/I ratio would be associated with both clinical pain and thermal pain sensitivity. The Brief Pain Inventory (BPI) self-assessment was used to evaluate pain severity and impact on physical functioning and acute pain sensitivity was determined via quantitative sensory testing to define thermal (heat) pain threshold and tolerance. Our results revealed an elevation in the E/I ratio in FMS compared to controls. A positive relationship between E/I ratio and thermal pain sensitivity measures was identified in the FMS cohort. Collapsing across groups, there was a positive relationship between E/I ratio and BPI score. These findings suggest that dysfunction in the balance between excitation and inhibition within cognitive brain circuitry may play a role in pain processing in FMS.

Effect of virtual reality hypnosis on pain threshold, neurophysiological and autonomic biomarkers in healthy volunteers: a prospective randomized cross-over study. (Preprint)

BACKGROUND Virtual reality hypnosis (VRH) is a promising tool to reduce pain. However, VRH benefits on pain perception and on the physiological expression of pain still require further investigation. OBJECTIVE In this study, we characterized the effects of VRH on heat pain threshold in adult healthy volunteers and simultaneously monitored several physiological and autonomic functions. METHODS 60 healthy volunteers were prospectively included to receive nociceptive stimulations. The first series of thermal stimuli consisted of 20 stimulations at 60°C (duration: 500 ms) to trigger contact heat evoked potentials (CHEPs). The second series of thermal stimuli consisted of temperature ramps (1°C/sec) to determine the thermal pain thresholds of the participants. Electrocardiogram, electrodermal conduction, respiration rate as well as the analgesia nociception index were also recorded throughout the experiment. RESULTS Data from 58 participants were analysed. There was a significant increase in pain threshold in VRH compared to NoVRH (p<0.001, Wilcoxon matched-pairs signed ranks). No significant effect of VRH on CHEPs and heart rate parameters was observed. Compared to control, VRH subjects display a clear reduction in their autonomic sympathetic tone as seen by the low number of non-specific skin conductance peak responses (p = 0.0007, 2-way ANOVA) and the analgesia nociception index increase (p = 0.0005; paired t-test). CONCLUSIONS The results obtained in this study support the idea that VRH administration to healthy volunteers is effective at increasing heat pain thresholds and impacts autonomic functions. As a non-pharmacological intervention, VRH has beneficial action on acute experimental heat pain. This beneficial action will now need to be evaluated for the treatment of other types of pain including chronic pain.

A cross-sectional analysis of persistent low back pain, using correlations between lumbar stiffness, pressure pain threshold, and heat pain threshold

Introduction Little is known about the underlying biomechanical cause of low back pain (LBP). Recently, technological advances have made it possible to quantify biomechanical and neurophysiological measurements, potentially relevant factors in understanding LBP etiology. However, few studies have explored the relation between these factors. This study aims to quantify the correlation between biomechanical and neurophysiological outcomes in non-specific LBP and examine whether these correlations differ when considered regionally vs. segmentally. Methods This is a secondary cross-sectional analysis of 132 participants with persistent non-specific LBP. Biomechanical data included spinal stiffness (global stiffness) measured by a rolling indenter. Neurophysiological data included pain sensitivity (pressure pain threshold and heat pain threshold) measured by a pressure algometer and a thermode. Correlations were tested using Pearson’s product-moment correlation or Spearman’s rank correlation as appropriate. The association between these outcomes and the segmental level was tested using ANOVA with post-hoc Tukey corrected comparisons. Results A moderate positive correlation was found between spinal stiffness and pressure pain threshold, i.e., high degrees of stiffness were associated with high pressure pain thresholds. The correlation between spinal stiffness and heat pain threshold was poor and not statistically significant. Aside from a statistically significant minor association between the lower and the upper lumbar segments and stiffness, no other segmental relation was shown. Conclusions The moderate correlation between spinal stiffness and mechanical pain sensitivity was the opposite of expected, meaning higher degrees of stiffness was associated with higher pressure pain thresholds. No clinically relevant segmental association existed.

Low mechano-afferent fibers reduce thermal pain but not pain intensity in CRPS

Background Human hairy (not glabrous skin) is equipped with a subgroup of C-fibers, the C-tactile (CT) fibers. Those do not mediate pain but affective aspects of touch. CT-fiber-activation reduces experimental pain if they are intact. In this pilot study we investigated pain modulating capacities of CT-afferents in CRPS. Methods 10 CRPS-patients (mean age 33 years, SEM 3.3) and 11 healthy controls (mean age 43.2 years, SEM 3.9) participated. CT-targeted-touch (brush stroking, velocity: 3 cm/s) was applied on hairy and glabrous skin on the affected and contralateral limb. Patients rated pleasantness of CT-targeted-touch (anchors: 1 “not pleasant”—4 “very pleasant”) twice daily on 10 days. Pain intensity (NRS: 0 “no pain” – 10 “worst pain imaginable”) was assessed before, 0, 30, 60 and 120 min after each CT-stimulation. To assess sensory changes, quantitative-sensory-testing was performed at the beginning and the end of the trial period. Results CT-targeted-touch was felt more pleasant on the healthy compared to the affected limb on hairy (p < 0.001) and glabrous skin (p 0.002), independent of allodynia. In contrast to healthy controls patients felt no difference between stimulating glabrous and hairy skin on the affected limb. Thermal pain thresholds increased after CT-stimulation on the affected limb (cold-pain-threshold: p 0.016; heat-pain-threshold: p 0.033). Conclusions CT-stimulation normalizes thermal pain thresholds but has no effect on the overall pain in CRPS. Therefore, pain modulating properties of CT-fibers might be too weak to alter chronic pain in CRPS. Moreover, CT-fibers appear to lose their ability to mediate pleasant aspects of touch in CRPS.

The Relationship Between Plasma BDNF and Pain in Older Adults With Knee Osteoarthritis

Osteoarthritis (OA) is the most prevalent cause of chronic pain and disability in people aged ≥45 years, with the knee being the most affected joint. Neurotrophic factors like brain-derived neurotrophic factor (BDNF), which promotes neurogenesis and neuroplasticity, have been shown to significantly affect chronic pain. This study aimed to investigate the relationship between resting plasma BDNF levels and clinical pain and quantitative sensory testing measures in older adults with knee OA pain. For this secondary analysis, a previously reported dataset was used comprised of older adults with knee OA who underwent quantitative sensory testing. A comprehensive generalized linear model (GLM) was built to understand the relationships between BDNF and important covariates, followed by the elastic net (EN) method for variable selection. GLM was then performed to regress BDNF levels against only the variables selected by EN. The mean age of the sample was 60.4 years ( SD = 9.1). Approximately half of the participants were female (53%). Plasma BDNF levels were positively associated with heat pain threshold and the numeric rating scale of pain. Future mechanistic studies are needed to replicate and extend these findings to advance our knowledge of the underlying mechanisms of BDNF in knee OA and other chronic pain conditions.