Search

Background: Pain is the leading cause of disability and reduced quality of life worldwide. Despite the increasing burden for patients and healthcare systems, pain research remains underfunded and under focused. Having stakeholders identify and prioritize areas that need urgent attention in the field will help focus funding topics, reduce 'research waste', improve the effectiveness of pain research and therapy and promote the uptake of research evidence. In this study, the European Pain Federation (EFIC) developed a Pain Research Strategy for Europe., Methods: The study used multiple methods, including literature searches, multidisciplinary expert debate, a survey and a final consensus meeting. The cross-sectional survey was conducted among 628 European pain researchers, clinicians, educators and industry professionals to obtain the rating and hierarchy of pain research priorities. The final consensus meeting involved a multidisciplinary expert panel including people with lived experience from 23 countries. The survey results guided discussions where top priorities were agreed., Results: Content analysis identified nine survey themes, of which five emerged as top priorities: (i) understand the pathophysiology of pain; (ii) understand and address comorbidities; (iii) critically assess current therapies; (iv) develop new treatments; and (v) explore the biopsychosocial impacts of pain. Physical, psychological and social approaches were prioritized at the same level as pharmacological treatments. The top priorities were endorsed by a multidisciplinary expert panel. The panel emphasized the importance of also clearly communicating the concepts of prediction, prevention self-management and personalized pain management in the final strategy., Conclusions: The content of the final top research priorities' list reflects a holistic approach to pain management. The equal importance given to physical, psychological and social aspects alongside pharmacological treatments highlights the importance of a comprehensive biopsychosocial-orientated research strategy. The expert panel's endorsement of five top priorities, coupled with an emphasis on communicating the concepts of prediction, prevention, self-management and personalized pain management, provides a clear direction for future basic, translational and clinical research., Significance: EFIC has developed a Pain Research Strategy for Europe that identifies pain research areas deserving the most focus and financial support. Implementation and wide dissemination of this Strategy is vital to increase the conduct of urgent pain projects, pain research funding and the implementation of research findings into practice, to ultimately decrease the personal, societal and financial burden of pain., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, β1, and β2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased β1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and β band oscillations and may have relevance for pain therapies., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Sensitized pain mechanisms are often reported in musculoskeletal pain conditions, but population-based paediatric studies are lacking. We assessed whether adolescents with musculoskeletal pain history had evidence of increased responsiveness to experimental pressure stimuli., Methods: Data were from 1496 adolescents of the Generation XXI birth cohort. Pain history was collected using the Luebeck Pain Questionnaire (self-reported at 13, parent-reported at 7 and 10 years). Two case definitions for musculoskeletal pain were considered: (1) cross-sectional-musculoskeletal pain lasting more than 3 months at age 13 and (2) longitudinal-musculoskeletal pain at age 13 with musculoskeletal pain reports at ages 7 and/or 10. Lower limb cuff pressure algometry was used to assess pain detection and tolerance thresholds, conditioned pain modulation effects (CPM, changes in thresholds in the presence on painful conditioning) and temporal summation of pain effects (TSP, changes in pain intensity to 10 phasic painful cuff stimulations)., Results: Adolescents with musculoskeletal pain at age 13 plus a history of pain in previous evaluations (longitudinal definition) had lower pain tolerance thresholds compared to the remaining sample (40.2 v. 49.0 kPa, p = 0.02), but showed no differences in pain detection threshold, CPM effect and TSP effect. Pain sensitivity, CPM effects and TSP effects were not significantly different when the current pain only case definition (cross-sectional) was used., Conclusions: Adolescents with current musculoskeletal pain who had a history of pain since childhood had lower tolerance to cuff stimulation. This may suggest long-standing musculoskeletal pain since childhood may contribute to sensitisation, rather than the presence of current pain only., Significance: Repeated musculoskeletal pain up to age 13 years may contribute to higher pain sensitivity (particularly lowered pressure pain tolerance) in the general adolescent population. This does not seem to be the case when reported pain experiences are recent or when the outcomes are temporal pain summation or CPM. In this community-based paediatric sample, the vast majority showed no sign of altered pain processing, but a small fraction may reveal some pain sensitization at 13 years of age., (© 2023 European Pain Federation - EFIC®.)

Background: Alterations in the default mode network (DMN) connectivity across pain stages suggest a possible DMN involvement in the transition to persistent pain., Aim: This study examined whether pain-free DMN connectivity at lower alpha oscillations (8-10 Hz) accounts for a unique variation in experimental peak pain intensity beyond the contribution of factors known to influence pain intensity., Methods: Pain-free DMN connectivity was measured with electroencephalography prior to 1 h of capsaicin-evoked pain using a topical capsaicin patch on the right forearm. Pain intensity was assessed on a (0-10) numerical rating scale and the association between peak pain intensity and baseline measurements was examined using hierarchical multiple regression in 52 healthy volunteers (26 women). The baseline measurements consisted of catastrophizing (helplessness, rumination, magnification), vigilance, depression, negative and positive affect, sex, age, sleep, fatigue, thermal and mechanical pain thresholds and DMN connectivity (medial prefrontal cortex [mPFC]-posterior cingulate cortex [PCC], mPFC-right angular gyrus [rAG], mPFC-left Angular gyrus [lAG], rAG-mPFC and rAG-PCC)., Results: Pain-free DMN connectivity increased the explained variance in peak pain intensity beyond the contribution of other factors (ΔR 2  = 0.10, p = 0.003), with the final model explaining 66% of the variation (R 2  = 0.66, ANOVA: p < 0.001). In this model, negative affect (β = 0.51, p < 0.001), helplessness (β = 0.49, p = 0.007), pain-free mPFC-lAG connectivity (β = 0.36, p = 0.003) and depression (β = -0.39, p = 0.009) correlated significantly with peak pain intensity. Interestingly, negative affect and depression, albeit both being negative mood indices, showed opposing relationships with peak pain intensity., Conclusions: This work suggests that pain-free mPFC-lAG connectivity (at lower alpha) may contribute to individual variations in pain-related vulnerability., Significance: These findings could potentially lead the way for investigations in which DMN connectivity is used in identifying individuals more likely to develop chronic pain., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: Prolonged and repeated sensorimotor training is a crucial driver for promoting use-dependent plasticity, but also a main risk factor for developing musculoskeletal pain syndromes, yet the neural underpinnings that link repetitive movements to abnormal pain processing are unknown., Methods: Twenty healthy musicians, one of the best in vivo models to study use-dependent plasticity, and 20 healthy non-musicians were recruited. Perceptual thresholds, reaction times (RTs) and event-related potentials (ERPs) were recorded using nociceptive intra-epidermal and non-nociceptive transcutaneous electrical stimulation., Results: In response to comparable stimulus intensities, musicians compared to non-musicians showed larger non-nociceptive N140 (associated with higher activation of regions within the salience network), higher nociceptive N200 ERPs (associated with higher activation of regions within the sensorimotor network) and faster RTs to both stimuli. Non-musicians showed larger non-nociceptive P200 ERP. Notably, a similar P200 component prominently emerged during nociceptive stimulation in non-musicians. Across participants, larger N140 and N200 ERPs were associated with RTs, whereas the amount of daily practice in musicians explained non-nociceptive P200 and nociceptive P300 ERPs., Conclusions: These novel findings indicate that the mechanisms by which extensive sensorimotor training promotes use-dependent plasticity in multisensory neural structures may also shape the neural signatures of nociceptive processing in healthy individuals., Significance: Repetitive sensorimotor training may increase the responsiveness of nociceptive evoked potentials. These novel data highlight the importance of repetitive sensorimotor practice as a contributing factor to the interindividual variability of nociceptive-related potentials., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: The use of high-definition transcranial direct current stimulation (HD-tDCS) has shown analgesic effects in some chronic pain patients, but limited anti-nociceptive effects in healthy asymptomatic subjects., Methods: This double-blinded sham-controlled study assessed the effects of HD-tDCS applied on three consecutive days on central pain mechanisms in healthy participants with (N = 40) and without (N = 40) prolonged experimental pain induced by intramuscular injection of nerve growth factor into the right hand on Day 1. Participants were randomly assigned to Sham-tDCS (N = 20 with pain, N = 20 without) or Active-tDCS (N = 20 with pain, N = 20 without) targeting simultaneously the primary motor cortex and dorsolateral prefrontal cortex for 20 min with 2 mA stimulation intensity. Central pain mechanisms were assessed by cuff algometry on the legs measuring pressure pain sensitivity, temporal summation of pain (TSP) and conditioned pain modulation (CPM), at baseline and after HD-tDCS on Day 2 and Day 3. Based on subject's assessment of received HD-tDCS (sham or active), they were effectively blinded., Results: Compared with Sham-tDCS, Active-tDCS did not significantly reduce the average NGF-induced pain intensity. Tonic pain-induced temporal summation at Day 2 and Day 3 was significantly lower in the NGF-pain group under Active-tDCS compared to the pain group with Sham-tDCS (p ≤ 0.05). No significant differences were found in the cuff pressure pain detection/tolerance thresholds or CPM effect across the 3 days of HD-tDCS in any of the four groups., Conclusion: HD-tDCS reduced the facilitation of TSP caused by tonic pain suggesting that efficacy of HD-tDCS might depend on the presence of sensitized central pain mechanisms., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: A subset of osteoarthritis patients will experience chronic postoperative pain after total knee arthroplasty (TKA), but the source of pain is unclear. The aim of this exploratory study was to assess patients with and without postoperative pain after TKA using magnetic resonance imaging (MRI), quantitative sensory testing (QST), clinical assessment of pain and assessments of catastrophizing thoughts., Methods: Forty-six patients completed the 6-month postoperative assessment. MRI findings were scored according to the MRI Osteoarthritis Knee Score recommendation for Hoffa synovitis, effusion size and bone marrow lesions. QST included assessment of pressure pain thresholds (PPTs), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Pain catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). Clinical pain assessment was conducted using a visual analogue scale (VAS, 0-10 cm), and groups of moderate-to-severe (VAS > 3) and none-to-mild postoperative pain (VAS ≤ 3) were identified., Results: Patients with moderate-to-severe postoperative pain (N = 15) demonstrated higher grades of Hoffa synovitis (p < 0.001) and effusion size (p < 0.001), lower PPTs (p = 0.039), higher TSP (p = 0.001) and lower CPM (p = 0.014) when compared with patients with none-to-mild postoperative pain (N = 31). No significant difference was found in PCS scores between the two groups. Multiple linear regression models found synovitis (p = 0.036), effusion size (p = 0.003), TSP (p = 0.013) and PCS (p < 0.001) as independent parameters contributing to the postoperative pain intensity., Conclusion: These exploratory findings could indicate that chronic postoperative pain after TKA is a combination of joint-related synovitis and effusion, sensitization of central pain mechanisms and potentially pain catastrophizing thoughts, but larger studies are needed to confirm this., Significance: The end-stage treatment of knee osteoarthritis is total knee arthroplasty. Some patients experience chronic postoperative pain after total knee arthroplasty, but the mechanism for chronic postoperative pain is widely unknown. The current study indicates that higher levels postoperative of synovitis and effusion, higher temporal summation of pain and higher pain catastrophizing scores could be associated with higher chronic postoperative pain., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: Endogenous pain inhibitory mechanisms are known to reduce pain intensity, but whether they influence the size and distribution of pain referral is unclear. This study aimed to determine if referred pain is reduced by applying a remote, conditioning painful stimulus., Methods: Twenty-four healthy men participated in this randomized, crossover study with a control and conditioning session. Referred pain was induced from the infraspinatus muscle (dominant side) by a painful pressure for 60 s. When applying pressure, the intensity was adjusted to a local pain intensity of 7/10 on a numerical rating scale. In the conditioning session, tonic painful pressure was simultaneously applied to the non-dominant leg during induction of referred pain. The area of referred pain was drawn onto a digital body chart and size extracted for data analysis., Results: For the total group and in a subgroup with distinct patterns of referred pain (n = 15/24), the pain area perceived in the back and front+back was smaller during the conditioning compared with the control (p < 0.05). No significant difference was found between sessions in a subgroup only demonstrating local pain (n = 9/24)., Conclusions: Engaging the descending noxious inhibitory control reduced the size of pain areas predominately when distinct pain referral was present. Assuming a conditioning effect of descending inhibitory control acting on dorsal horn neurons, these findings may indicate that mechanisms underlying pain referral can be modulated by endogenous control. The findings may indicate that referred pain may be a useful proxy to evaluate sensitivity of central pain mechanisms as previously suggested., Significance: The current results indicate a link between endogenous inhibition and pain referral. Descending inhibitory control effects on pain referral support a spinal mechanism involved in pain referral. Future studies should investigate whether the spatial characteristics of referred pain (e.g. size, frequency of affected body regions and distribution away from the primary nociceptive stimulus) can useful to evaluate the efficiency of endogenous pain modulation., (© 2021 European Pain Federation - EFIC®.)

Background: Antinociceptive effects of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) have been extensively studied in the past years. However, M1 does not work in isolation, but it rather interacts within a network, the so-called resting-state motor network., Objective: To explore the anti-nociceptive effects of a new multifocal tDCS approach administered to regions linked to the resting state motor network (network-tDCS) compared to sham tDCS., Methods: Healthy individuals were included in this randomized, parallel and double-blinded study comprising two consecutive interventions with 24-hr interval of either active (n = 19) or sham (n = 19) network-tDCS. Prolonged pain was induced by application of topical capsaicin on the dorsum of the hand during a 24-hr period. Assessments of corticomotor excitability (transcranial magnetic stimulation), pain ratings (numerical rating scale, NRS), skin pain sensitivity on the arm (heat and mechanical), temporal summation of pain (TSP) and conditioned pain modulation (CPM) were performed at baseline (Day1-baseline), after 25 min of capsaicin application and before the first tDCS session (Day1-post-cap), and after the second tDCS session (Day2)., Results: Comparing Day2 to Day1-baseline measures, there was reduced corticomotor excitability (p < .05) and impaired CPM-effect (p < .05) after sham but not after active network-tDCS. Pain NRS ratings increased at Day2 compared to Day1-post-cap (p < .01) in both groups whereas no significant changes were found in pain sensitivity and TSP., Conclusions: Present findings demonstrate that tDCS applied over regions linked to the resting state motor network reverts the inhibition of corticomotor excitability and CPM impairment both provoked by prolonged experimental pain for 24 hr., Significance: These findings highlight that the stimulation of the resting state motor network with multifocal tDCS may represent a potential cortical target to treat chronic pain, particularly in patients exhibiting maladaptive corticomotor excitability and impaired conditioned pain modulation effects., (© 2021 European Pain Federation - EFIC®.)

Objectives: Exercise therapy is recommended for low back pain (LBP) although the immediate effects on pain are highly variable. In 96 individuals with LBP this cross-sectional study explored (a) the magnitude of exercise-induced hypoalgesia (EIH) and (b) measures of pain sensitivity and clinical pain manifestations in individuals reporting a clinical relevant increase in back pain during physical activity compared with individuals reporting low or no increase in back pain during physical activity., Methods: Cuff algometry was performed at baseline on the leg to assess pressure pain threshold (cPPT), tolerance (cPTT) and temporal summation of pain (cTSP). Manual PPTs were assessed on the back and leg before and after a 6-min walk test (6MWT). Back pain was scored on a numerical rating scale (NRS) after each minute of walking. The EIH-effect was estimated as the increase in PPTs after the walk exercise., Results: Twenty-seven individuals reported an increase of ≥2/10 in pain NRS scores during walking and compared with the individuals with <2/10 NRS scores: cPPT and EIH-effects were lower whereas cTSP, pain intensity and disability were increased (p < 0.03). Baseline NRS scores, EIH and pain thresholds were associated with the likelihood of an increase of ≥2/10 in back pain intensity during walking (p < 0.05)., Conclusions: Pain flares in response to physical activity in individuals with LBP seem to be linked with baseline pain sensitivity and pain intensity, and impair the beneficial EIH. Such information may better inform when individuals with LBP will have a beneficial effect of physical activity., Significance: Pain flares in response to physical activity in individuals with LBP seem to be linked with baseline pain sensitivity and pain intensity, and impair the beneficial exercise-induced hypoalgesia. Such information may better inform when individuals with LBP will have a beneficial effect of physical activity., (© 2021 European Pain Federation - EFIC®.)

For decades, basic research on the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need. In this opinion paper bringing together pain researchers from very different disciplines, the opportunities and challenges of translational pain research are discussed. The many factors that may prevent the successful translation of bench observations into useful and effective clinical applications are reviewed, including interspecies differences, limited validity of currently available preclinical disease models of pain, and limitations of currently used methods to assess nociception and pain in non-human and human models of pain. Many paths are explored to address these issues, including the backward translation of observations made in patients and human volunteers into new disease models that are more clinically relevant, improved generalization by taking into account age and sex differences, and the integration of psychobiology into translational pain research. Finally, it is argued that preclinical and clinical stages of developing new treatments for pain can be improved by better preclinical models of pathological pain conditions alongside revised methods to assess treatment-induced effects on nociception in human and non-human animals. Significance: For decades, basic research of the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: Diffuse noxious inhibitory controls (DNIC) as measured in rat and conditioned pain modulation (CPM), the supposed psychophysical paradigm of DNIC measured in humans, are unique manifestations of an endogenous descending modulatory pathway that is activated by the application of a noxious conditioning stimulus. The predictive value of the human CPM processing is crucial when deliberating the translational worth of the two phenomena., Methods: For CPM or DNIC measurement, test and conditioning stimuli were delivered using a computer-controlled cuff algometry system or manual inflation of neonate blood pressure cuffs, respectively. In humans (n = 20), cuff pain intensity (for pain detection and pain tolerance thresholds) was measured using an electronic visual analogue scale. In isoflurane-anaesthetized naïve rats, nociception was measured by recording deep dorsal horn wide dynamic range (WDR) neuronal firing rates (n = 7) using in vivo electrophysiology., Results: A painful cuff-pressure conditioning stimulus on the leg increased pain detection and pain tolerance thresholds recorded by cuff stimulation on the contralateral leg in humans by 32% ± 3% and 24% ± 2% (mean ± SEM) of baseline responses, respectively (p < .001). This finding was back-translated by revealing that a comparable cuff-pressure conditioning stimulus (40 kPa) on the hind paw inhibited the responses of WDR neurons to noxious contralateral cuff test stimulation to 42% ± 9% of the baseline neuronal response (p = .003)., Conclusions: These data substantiate that the noxious cuff pressure paradigm activates the descending pain modulatory system in rodent (DNIC) and man (CPM), respectively. Future back and forward translational studies using cuff pressure algometry may reveal novel mechanisms in varied chronic pain states., Significance: This study provides novel evidence that a comparable noxious cuff pressure paradigm activates a unique form of endogenous inhibitory control in healthy rat and man. This has important implications for the forward translation of bench and experimental pain research findings to the clinical domain. If translatable mechanisms underlying dysfunctional endogenous inhibitory descending pathway expression (previously evidenced in painful states in rat and man) were revealed using cuff pressure algometry, the identification of new analgesic targets could be expedited., (© 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation EFIC ®.)