Rolf-Detlef Treede’s research while affiliated with Central Institute of Mental Health and other places

Background Conditioned pain modulation (CPM) is considered a human proxy for descending inhibitory pain pathways. However, there is wide variation in the CPM response described in the literature and ongoing debate about its utility. Methods Here we explored CPM in women with ( n = 59) and without ( n = 26) chronic pelvic pain (CPP), aiming to determine the magnitude of effect and factors influencing variability in the CPM response. Results Using a pressure pain threshold test stimulus and ischaemic pressure cuff conditioning stimulus (CS), we found no significant difference in the mean CPM effect between CPP and control participants. Using a robust statistical method (+/−2 standard error of measurement) to further investigate CPM, there was no significant difference in the proportion exhibiting inhibition between controls and CPP participants ( X ² = 0.003, p = 0.96). Notably, only 23.1% of our healthy controls demonstrated a “true” CPM effect ( n = 4 inhibitory, n = 2 facilitatory). Despite a rich data set, we were unable to identify any single questionnaire, clinical or psychophysical covariate correlating with the CPM effect. Conclusions Despite using one of the recommended CPM paradigms we were only able to demonstrate “true” CPM in 23.1% of control participants. Thus, the absence of differences between women with and without chronic pelvic pain must be interpreted with caution. Future studies using different CPM paradigms or larger sample sizes may find different results. Although CPM in chronic pain populations is of major theoretical mechanistic interest, the lack of an established assessment standard led us to question its added value in current clinical research.

High-frequency electrical stimulation (HFS) of the skin using a multi-pin electrode activating epidermal nociceptors is used to explore spinal central sensitization in humans. Most previous studies applied HFS to the volar forearm. To prepare for clinical applications in which HFS could be applied to different body sites, this study compared the secondary hyperalgesia induced by stimulation of the foot dorsum vs. the forearm in 32 healthy volunteers. HFS consisted in five 1-s trains of 100 Hz pulses (inter-train interval: 10 s; intensity: 20x detection threshold) delivered via a novel electrode optimized for stimulation of different body sites (ten 0.25 mm pins in a 5-mm circle). Pinprick sensitivity was assessed before HFS and 30–240 minutes after HFS, at the treated site and the corresponding contralateral site. The area of hyperalgesia was quantified. HFS to the foot induced a significant increase in pinprick sensitivity of the surrounding skin, similar in magnitude to the increase at the forearm, and decaying similarly over time (half-lives 150 vs. 221 min). The radius of secondary hyperalgesia was smaller at the foot (22 mm) compared to the forearm (38 mm, p < 0.001), and decreased more rapidly over time (53 vs. 87 min, p < 0.01). Our results show that strength of HFS-induced secondary hyperalgesia can be used as indicator of spinal central sensitization across body sites, and thereby profile patients with localized or regional pain conditions. The size of the area of hyperalgesia may depend on innervation density and peripheral receptive field sizes.

Since clinical features of chronic muscle pain originating from the low back and limbs are different (higher prevalence and broader/duller sensation of low back muscle pain than limb muscle pain), spinal and/or supraspinal projection of nociceptive information could differ between the two muscles. We tested this hypothesis using c-Fos immunohistochemistry combined with retrograde-labeling of dorsal horn (DH) neurons projecting to ventrolateral periaqueductal grey (vlPAG) or ventral posterolateral nucleus of the thalamus (VPL) by fluorogold (FG) injections into the vlPAG or VPL. C-Fos expression in the DH was induced by injecting 5% formalin into the multifidus (MF, low back) or gastrocnemius-soleus (GS, limb) muscle. A double-labeled DH neuron showing both c-Fos-immunoreactive nucleus and retrogradely transported FG in the cytoplasm was considered as a nociceptive projection neuron. Consistent with DH somatotopy for proximal vs. distal cutaneous inputs, DH neurons with MF input were located in the most lateral area of laminae I − II (segments Th12 − L5), while those with GS input were located in the middle area of laminae I − II (L3 − L5). DH neurons projecting to the vlPAG were located in superficial DH, while those projecting to VPL were located in deep DH. Supraspinal projection derived from more spinal segments for MF input than for GS input. These data suggest that nociceptive input from low back muscles is integrated more in craniocaudal direction than for limb muscles, and that these signals are then forwarded to both PAG and thalamus and contribute to the different nature of muscle pain arising from the low back and limbs.

Objective After over 25 years of developing clinical practice guidelines, the Association of the Scientific Medical Societies in Germany (AWMF) held a symposium to discuss the following topics in order to improve the way evidence is implemented in the delivery of care: expansion of the data pool for guideline development, the regulatory policy framework for this expansion, the transfer of clinical practice guideline statements to medical practice, the associated opportunities and risks resulting from the European legislation. Methods The AWMF held its Berlin Forum on 27 April 2022 where experts from scientific medical societies and national institutions in the healthcare sector reported their experiences and perceptions on the topics mentioned. Three writing groups compiled the key statements from these contributions to and discussions made at the Berlin Forum into a position paper. Results The AWMF recommends the following: – The creation of a digital infrastructure that serves the quality assurance of clinical practice guidelines and makes their content available at the bedside and during consultations – An increase in the number of industry-independent clinical trials on prevention, diagnostics and therapy with medicinal products, medical devices or other procedures – The funding of registry structures to generate point-of-care healthcare data – The reduction of excessive bureaucratic hurdles at both the national and EU level Conclusions By making concrete recommendations in this position paper, the AWMF maps out the steps required to improve the translation of evidence to the delivery of clinical care.

Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across laboratories. In this white paper, we report on a consensus meeting attended by neuropathic pain experts, designed to accelerate protocol alignment and harmonization of studies involving relevant peripheral tissues. The meeting was held in London in March 2024 and attended by 28 networking partners, including industry and patient representatives. We achieved consensus on minimal recommended phenotyping, harmonised wet laboratory protocols, statistical design, reporting, and data sharing. Here, we also share a variety of relevant standard operating procedures as supplementary protocols. We envision that our recommendations will help unify human tissue research in the field and accelerate our understanding of how abnormal interactions between sensory neurons and their local peripheral environment contribute towards neuropathic pain.

The concept “nociplastic pain” has been developed for patients with features of nociceptive system sensitization that are not explained as nociceptive or neuropathic. Here, we tested how well the recently published grading system differentiates between chronic primary and secondary pain conditions. We recruited patients with fibromyalgia (FMS, n = 41), complex regional pain syndrome (CRPS, n = 11), osteoarthritis (OA, n = 21), or peripheral nerve injury (PNI, n = 8). We used clinical history, pain drawings, quantitative sensory testing (QST), and questionnaires to classify their pains as possibly or probably “nociplastic.” All patients with chronic primary pain exhibited widespread/regional pain not explainable by either nociceptive or neuropathic mechanisms. Widespread pain occurred in 12 patients with OA but was identified as nociceptive in 11 of 12. Regional pain occurred in 4 patients with PNI but was identified as neuropathic in 3 of 4. At this step, the grading system had 100% sensitivity and 93% specificity. Clinical evidence for pain hypersensitivity by QST, and history of hypersensitivity and mental comorbidities did not differentiate between chronic primary pain (QST: 36/52 = 69%, history: 43/52 = 83%) and secondary pain conditions (QST: 20/29 = 69%, history: 24/29 83%). Based on these data, specificity remained excellent (93%), but sensitivity dropped substantially (60%) due to lacking evidence for pain hypersensitivity in many patients with FMS. This low sensitivity suggests that the published grading system is not suitable for screening purposes. We suggest structural and content modifications to improve sensitivity, including placement of patient history before clinical examination and addition of a high tender point count as evidence for widespread pain hypersensitivity.

The 11th revision of the International Classification of Diseases and Related Health Problems (ICD-11) aims at improving the lives of persons with the lived experience of chronic pain by providing clearly defined and clinically useful diagnoses that can reduce stigma, facilitate communication, and improve access to pain management, among others. The aim of this study was to assess the perspective of people with chronic pain on these diagnoses. An international web-based survey was distributed among persons with the lived experience of chronic pain. After having seen an information video, participants rated the diagnoses on 8 endorsement scales (eg, diagnostic fit, stigma) that ranged from −5 to +5 with 0 representing the neutral point of no expected change. Overall ratings and differences between participants with chronic primary pain (CPP) and chronic secondary pain (CSP) were analyzed. N = 690 participants were included in the data analysis. The ratings on all endorsement scales were significantly higher than the neutral point of 0. The highest ratings were obtained for “openness” (2.95 ± 1.93) and “overall opinion” (1.87 ± 1.98). Participants with CPP and CSP did not differ in their ratings; however, those with CSP indicated an improved diagnostic fit of the new diagnoses, whereas participants with CPP rated the diagnostic fit of the new diagnoses similar to the fit of their current diagnoses. These results show that persons with the lived experience of chronic pain accept and endorse the new diagnoses. This endorsement is an important indicator of the diagnoses' clinical utility and can contribute to implementation and advocacy.