OBJECTIVES:Focal spinal cord lesions occur across a variety of neurological diseases including non-traumatic cervical myelopathies which can lead to neuropathic pain. Currently, the degree to which signs and symptoms of neuropathic pain correlate with functional impairments and/or anatomical deficits remains unclear. This study aimed to identify structural and functional determinants associated with neuropathic pain in individuals with focal spinal lesions. METHODS:Individuals fulfilling the diagnostic criteria of neuropathic pain were identified among individuals with cervical myelopathy presenting with focal spinal lesions. Lesion volume and the extent of structural damage affecting the spinothalamic tract, dorsal columns, dorsal horn, and ventral horn were evaluated with tract-specific MRI of the cervical spinal cord. Quantitative sensory testing (QST) (i.e., thermal/mechanical thresholds) was performed at the most affected skin area. Additionally, contact heat-evoked potentials (CHEPs) were acquired following stimulation at the most affected skin area to objectively assess the functional integrity of the spinothalamic tract. RESULTS:MRI-derived structural damage was similar for individuals with (n=8) and without (n=8) neuropathic pain in all regions of interest (p>0.05). Mechanical hyperalgesia upon QST was observed in both groups. However, functional preservation of the spinothalamic system, measured by CHEPs, was present in 87 % of individuals with neuropathic pain, compared to 38 % of pain-free individuals (p=0.039). CONCLUSIONS:These observations suggest that segmental hyperexcitability resulting from structural spinal cord damage, in combination with residual sparing of spinothalamic afferents, may represent a key pathophysiological constellation contributing to central neuropathic pain following focal spinal lesions.

BACKGROUND:Conditioned pain modulation (CPM) is a set of psychophysical paradigms that is increasingly used clinically to evaluate descending pain modulation pathways. Impairment is common in chronic pain, suggesting CPM may serve as a mechanistic indicator. However, the lack of protocol standardization and reference data prevents clinical use in individual patients. METHODS:We compared two CPM protocols with different conditioning stimulus intensities, test stimulus types, and interaction timing. We assessed CPM effect size, test-retest reliability and sensitivity to detect loss of descending inhibition. RESULTS:Conditioning with 0°C water led to stronger inhibition of pressure pain threshold (PPT) than conditioning with 7°C water (Cohen's d = 0.52), when tested immediately after conditioning. When tested during conditioning, effects of 7°C water immersion on heat pain sensitivity had similar magnitude (D = 0.53) and test-retest reliability (ICC = 0.77) as those on PPT (D = 0.54, ICC = 0.73). For all outcomes assessed, 95% confidence intervals (CI) of CPM effect included some facilitation instead of inhibition. The maximum degree of facilitation compatible with normal CPM (upper cutoff of CI) indicates potential sensitivity to detect individual abnormality. This was most favourable for PPT assessed after conditioning with 0°C water (decrease by more than 75 kPa or 14% of baseline PPT). CONCLUSIONS:In conclusion, testing during conditioning stimulation yields medium to large effect sizes and good test-retest reliability. PPT testing immediately after ice water immersion has the narrowest 95% CI and hence offers the potential to generalize CPM assessments beyond group-level differences and compare inhibition among individuals in clinical practice. SIGNIFICANCE STATEMENT:Indicating the main aspects where this work adds significantly to existing knowledge in the field, and if appropriate to clinical practice. Simultaneous CPM protocols exhibit large effect sizes but are confounded by divided attention. We recommend a sequential protocol and provide model reference data for abnormal facilitation.

Complex Regional Pain Syndrome (CRPS) exhibits persistent disproportionate limb pain and hyperalgesia associated with neuroinflammatory and autonomic changes, typically after inciting limb injury. However, little is known about the progression of somatosensory changes over time. We reviewed cross-sectional studies employing standardised Quantitative Sensory Testing (QST) in accordance with the DFNS comprehensive somatosensory test protocol, stratified for CRPS duration. This study was registered with PROSPERO ID CRD42020216485. Reporting follows PRISMA guidelines. Databases searched were PubMed, Cochrane Library, Google Scholar, EMBASE, Web of Science and Scopus. Studies of adult patients with CRPS and QST according to the DFNS protocol were included. 1415 articles were screened and 23 studies meeting the inclusion criteria were included in quantitative analysis and narrative synthesis. Analysis was stratified by CRPS duration into an early (≤ 6 months), intermediate (6-12 months) and late (> 12 months) time window. Across all studies encompassing 2059 CRPS patients all somatosensory parameters deviated significantly from healthy subject profiles (all P < 0.001). All non-nociceptive detection parameters displayed a significant loss of sensitivity, while all nociceptive parameters as well as thermal and mechanical dysesthesias, i.e., paradoxical heat sensation and allodynia displayed a significant gain of sensitivity. Pressure pain threshold (PPT) showed the most drastic sensory gain with a large effect size (> 2 SD; Hedges' g = 0.9) equivalent to more than half of CRPS patients exhibiting abnormal pressure hyperalgesia. Moreover, PPT significantly increased progressively with increasing CRPS duration (from 1.7 to 2.2 and 2.8 SD above normal). In late CRPS (> 12 months), additionally contralateral, mirror image test site sensory loss (P < 0.001) and pressure hyperalgesia (P < 0.001) became evident. Stratification for magnitude of pain did only modestly predict relevant differences in somatosensory profiles. Quantitative analysis of 23 cross-sectional QST studies in CRPS demonstrates pressure hyperalgesia as the signature CRPS sensory abnormality, distinguishing CRPS from neuropathic pain conditions. Further, pressure hyperalgesia exhibits a peculiar dramatic step progression between 4-12 months, without equivalent in other parameters. In late CRPS, somatosensory profiles become significantly abnormal at contralateral areas indicating loss of regionality. These findings have important implications for the classification of CRPS as a chronic primary pain condition, for understanding challenges to rehabilitative interventions, and for condition-subtyping. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All human data used in this study were previously published in peer-reviewed biomedical journals. All studies included had obtained the necessary patient consent as well as the necessary approval from Ethics Committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Chronic pain represents the defining and quality-of-life limiting feature in patients with cancer pain (CP) or chronic non-cancer pain (CNCP) and is often treated with opioids. Over time, opioid use is frequently accompanied by necessity of an increasing dose due to pharmacological tolerance and progress of the underlying diseases. The potential side effects were found to correlate with accelerating doses. More recently, the opioid crisis in the United States has drawn attention to the adverse effects and toxicities. Until today it is unclear what high-dose opioid therapy is and guidelines are inconsistent regarding an evidence-based threshold. This systematic review and meta-analysis aim to determine a threshold for high-dose opioid therapy. A systematic literature search was conducted in 4 databases from earliest publication available until May 2025. Studies were eligible if participants with CP or CNCP were able to self-titrate their opioid dosage to reach a sufficient pain relief. 4305 records were screened. Nineteen included studies with a total of 3111 participants investigating eight different opioids were included. The studies were assessed for risk of bias. Results were synthesised as oral morphine equivalents (OMEs). The meta-analysis found a weighted mean of 74.7 mg OME per day and the 97.5

Transcutaneous high-frequency electrical stimulation (HFS) elicits pain and produces prolonged mechanical pinprick hypersensitivity. This study investigated whether acute stress, induced by the Mannheim Multicomponent Stress Test (MMST), elevates HFS-related pain and pinprick hypersensitivity in healthy women. Two between-subject experiments were conducted. In experiment 1 (N = 66), the MMST or a control task was applied before HFS to assess whether stress enhances pain during HFS and contributes to subsequent pinprick hypersensitivity. In experiment 2 (N = 60), stress was induced 20 minutes after HFS to evaluate its effect on already established pinprick hypersensitivity. Unlike the control task, the MMST significantly increased subjective stress in both experiments. In experiment 1, the average pain ratings across all 5 HFS trains did not differ significantly between groups. However, exploratory analysis showed that pain ratings for the first HFS train were 10 points higher (on a 0-100 scale) in the MMST group, although this effect diminished over subsequent trains. Pinprick hypersensitivity developed similarly in both groups, suggesting that stress before HFS may elevate HFS pain but does not influence the development of hypersensitivity. In experiment 2, pinprick hypersensitivity significantly increased after the MMST compared to the control task, although the absolute effect size was relatively small (5 points on a 0-100 scale). Collectively, these findings indicate that acute stress before HFS may elevate HFS pain without influencing the development of subsequent pinprick hypersensitivity. Conversely, when acute stress is induced after HFS, when pinprick hypersensitivity has already been established, it increases hypersensitivity.

Mechanisms of pancreatic pain are insufficiently understood, and quantitative sensory testing (QST) may help to identify the underlying mechanisms. Accordingly, this study assessed comprehensive somatosensory profiles encompassing nociceptive and nonnociceptive parameters in 70 patients with distinct pancreatic diseases, namely acute (n = 23), chronic (n = 20), or autoimmune pancreatitis (n = 10) and pancreatic cancer (n = 17) and compared it with 30 healthy control subjects by standardized QST (protocol of the German research network on neuropathic pain). Patients with pancreatic diseases presented significant somatosensory deficits in all thermal and tactile detection and pain thresholds in the pancreatic viscerotome (Th10), when compared with a remote control area (dermatome C5) or reference data of matched healthy controls ( P < 0.05- P < 0.0001). Unaltered vibration detection emphasizes the strictly regional character of losses. Loss of sensitivity paralleled the occurrence of paradoxical heat sensation (Th10 vs C5; P < 0.05), an indicator of thermal integration deficit. Punctate hyperalgesia or pain to light touch, the hallmark signs of spinal central sensitization were mostly absent and pain summation remained unchanged ( P > 0.05). Stratification of patients revealed that somatosensory deficits were significantly more pronounced in acute compared with chronic pancreatitis (eg, cold and warm detection thresholds: −2.19 ± 1.42 vs −1.10 ± 1.23 and −1.30 ± 1.68 vs −0.11 ± 1.80 z-values; P < 0.05 each). Notably, blunt pressure hyperalgesia, the only somatosensory parameter exhibiting significant gain compared with the patients' remote C5 segment, was a frequent finding only in acute, but not in chronic pancreatitis. The somatosensory phenotype of patients with distinct pancreatic disorders was characterized by a wide array of sensory losses being most severe in acute pancreatitis.

Bedeutung der Klassifizierung für die Praxis und damit auch für die Patienten*innen – eine kritische Würdigung

BACKGROUND:Endometriosis is a chronic, inflammatory disease with considerable symptom load in affected female patients. Cyclic pain (associated with menstruation) dominates in most patients, but few patients suffer from persistent non-cyclic pain. This study aims to investigate whether the somatosensory profile in endometriosis differs from healthy controls or between cyclic and non-cyclic subtypes. Moreover, we aimed at potential identifiers of peripheral or central nervous sensitization underpinnings of endometriosis in the QST profile. METHODS:The standardised investigation protocol for quantitative sensory testing (QST) of the German research network of neuropathic pain was used to find possible differences compared to healthy controls or between cyclic and non-cyclic subtypes of endometriosis potentially providing hints for altered peripheral and central nociceptive processing. RESULTS:Endometriosis patients showed significant hyperalgesia to cold and blunt pressure in the affected body area (non-cyclic>cyclic, all p < 0.05), but not pinprick hyperalgesia, dynamic mechanical allodynia or facilitated pain summation (all p > 0.30). Exaggerated pressure hyperalgesia was most pronounced, regionally restricted and present in every patient (p << 0.0001). Higher thermal and tactile detection thresholds indicated non-nociceptive somatosensory loss, which differed only marginally between subgroups. Thermal loss and hyperalgesia to cold, heat and blunt pressure were also identified to a lesser extent in a remote test site (hand dorsum). CONCLUSIONS:Endometriosis patients exhibited a pattern of somatosensory changes that is consistent with peripheral rather than central sensitization. Primary afferent sensitization facilitating spinal transmission of convergent input from the affected and suprapubic referred pain area is the most likely mechanism of hyperalgesia in endometriosis. SIGNIFICANCE STATEMENT:Pain and hyperalgesia are amongst the most burdensome features in endometriosis. This QST case-control study in endometriosis patients identifies massive pressure hyperalgesia as the most significant somatosensory alteration in the viscerotome of the lower abdomen, which is easily accessible for testing in patients. This finding highlights the role of peripheral sensitization as the dominant mechanism of endometriosis-related hyperalgesia, which has major implications for future treatment, which may target prevention of peripheral sensitization by suppression of NGF or TRPV1 receptors.

Der Artikel zeigt die Bedeutung von und das Ringen um Klarheit bei der Einordnung und Benennung der vielfältigen Ursachen und Erscheinungsformen des Schmerzes. Es werden die Kategorien des nozizeptiven, des neuropathischen und des noziplastischen Schmerzes beschrieben.

Die „International Association for the Study of Pain“ (IASP) führte im Jahr 2016 als mechanistische dritte Schmerzkategorie den „Noziplastischen Schmerz“ ein. Die IASP-Definition erklärt Noziplastizität als veränderte Nozizeption in Folge einer Modulation der Reizverarbeitung ohne den Nachweis einer Gewebe- oder Nervenschädigung. Die begriffliche Unschärfe und Breite der Definition sowie ihre unklare Verknüpfung mit neurophysiologischen Mechanismen eröffnen damit potenziell einen weiteren Weg der Stigmatisierung der Patient*innen.

ABSTRACT:Pain sensitivity of healthy subjects in the cold-pressor (CP) test was proposed to be dichotomously distributed and to represent a pain sensitivity trait. Still, it has not been systematically explored which factors influence this pain sensitivity readout. The aim of this study was to distinguish potential contributions of local tissue-related factors such as perfusion and thermoregulation or gain settings in nociceptive systems. Cold-pressor-sensitive and CP-insensitive students screened from a medical student laboratory course were recruited for a CP retest with additional cardiovascular and bilateral local vascular monitoring. In addition, comprehensive quantitative sensory testing according to Deutscher Forschungsverbund Neuropathischer Schmerz standards and a sustained pinch test were performed. Cold pressor was reproducible across sessions (Cohen kappa 0.61 ± 0.14, P < 0.005). At 30 seconds in ice water, CP-sensitive subjects exhibited not only more pain (78.6 ± 26.3 vs 29.5 ± 17.5, P < 0.0001) but also significantly stronger increases in mean arterial blood pressure (12.6 ± 9.3 vs 5.6 ± 8.1 mm Hg, P < 0.05) and heart rate (15.0 ± 8.2 vs 7.1 ± 6.2 bpm, P < 0.005), and lower baroreflex sensitivity, but not local or vasoconstrictor reflex-mediated microcirculatory responses. Cold-pressor-sensitive subjects exhibited significantly lower pain thresholds also for cold, heat, and blunt pressure, and enhanced pain summation, but no significant differences in Aδ-nociceptor-mediated punctate mechanical pain. In conclusion, differences in nociceptive signal processing drove systemic cardiovascular responses. Baroreceptor activation suppressed pain and cardiovascular responses more efficiently in CP-insensitive subjects. Cold-pressor sensitivity generalized to a pain trait of C-fiber-mediated nociceptive channels, which was independent of local thermal and vascular changes in the ice-water-exposed hand. Thus, the C-fiber pain trait reflects gain setting of the nociceptive system.

Die ,,International Association for the Study of Pain" (IASP) f & uuml;hrte im Jahr 2016 als mechanistische dritte Schmerzkategorie den ,,Noziplastischen Schmerz" ein. Die IASP-Definition erkl & auml;rt Noziplastizit & auml;t als ver & auml;nderte Nozizeption in Folge einer Modulation der Reizverarbeitung ohne den Nachweis einer Gewebe- oder Nervensch & auml;digung . Die begriffliche Unsch & auml;rfe und Breite der Definition sowie ihre unklare Verkn & uuml;pfung mit neurophysiologischen Mechanismen er & ouml;ffnen damit potenziell einen weiteren Weg der Stigmatisierung der Patient*innen.

Noziplastische Schmerzen sind eine dritte mechanistische Schmerzkategorie. Anders als bei nozizeptiven oder neuropathischen Schmerzen findet sich weder eine Gewebeschädigung, noch eine Läsion im somatosensorischen Nervensystem. Die IASP-Definition erklärt die Pathophysiologie als veränderte Nozizeption infolge einer Modulation der Reizverarbeitung. Die Breite der Definition und ihre nur entfernte Verknüpfung mit neurophysiologischen Mechanismen machen sie allerdings potentiell zum Sammelbecken unspezifischer und unklarer Befunde.

Department of Neurophysiology, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany *Corresponding author. Address: Neurophysiology, Mannheim Center for Translational Neurosciences, Heidelberg University, Ludolf-Krehl-Str. 13-17, Mannheim 68167, Germany. Tel.: +49 621 383 71400; fax: +49 621 383 71401; E-mail address: [email protected] (R.-D. Treede). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Acute low back pain can be experimentally induced by injections of hypertonic saline into deep tissues of the back, such as fascia and muscle. The current study investigated the dose-dependency of peak-pain and spatial extent of concomitant radiating pain following 50, 200 and 800 μL bolus injections of hypertonic saline (5.8%) into the thoracolumbar fascia and multifidus muscle, since data on dose-dependency is lacking in humans. Sixteen healthy subjects rated (11 female, 5 male; 23.3 ± 3.1 years, mean ± SD) intensity and spatial extent of pain. Injections into the fascia resulted in significantly higher peak-pain (+86%, p < 0.001), longer pain durations (p < 0.05), and larger pain areas (+65%, p < 0.02) and were less variable than intramuscular injections. Peak-pain ratings and pain areas were 2–3-fold higher/larger for 200 μL vs. 50 μL. In contrast, peak pain increased only marginally at 800 μL by additional 20%, while pain areas did not increase further at all in both, fascia and muscle. Thus, higher injection volumes did also not compensate the lower sensitivity of muscle. Peak-pain ratings and pain areas correlated between fascia and muscle (r = 0.530, p < 0.001 and r = 0.337, p < 0.02, respectively). Peak-pain ratings and pain areas correlated overall (r = 0.490, p < 0.0001), but a weak correlation remained when the impact of between-tissue differences and different injection volumes were singled out (partial r = 0.261, p < 0.01). This study shows dose-dependent pain responses of deep tissues where an injection volume of 200 μL of hypertonic saline is deemed an adequate stimulus for tissue differentiation. We suggest that pain radiation is not simply an effect of increased peripheral input but may afford an individual disposition for the pain radiation response. Substantially higher pain-sensitivity and wider pain areas support fascia as an important contributor to non-specific low back pain.

Abstract Background Surviving breast cancer does not necessarily mean complete recovery to a premorbid state of health. Among the multiple psychological and somatic symptoms that reduce the quality of life of breast cancer survivors, persistent pain after breast cancer treatment (PPBCT) with a prevalence of 15–65% is probably the most invalidating. Once chronic, PPBCT is difficult to treat and requires an individualized multidisciplinary approach. In the past decades, several somatic and psychological risk factors for PPBCT have been identified. Studies aiming to prevent PPBCT by reducing perioperative pain intensity have not yet shown a significant reduction of PPBCT prevalence. Only few studies have been performed to modify psychological distress around breast cancer surgery. The AMAZONE study aims to investigate the effect of online cognitive behavioral therapy (e-CBT) on the prevalence of PPBCT. Methods The AMAZONE study is a multicenter randomized controlled trial, with an additional control arm. Patients (n=138) scheduled for unilateral breast cancer surgery scoring high for surgical or cancer-related fears, general anxiety or pain catastrophizing are randomized to receive either five sessions of e-CBT or online education consisting of information about surgery and a healthy lifestyle (EDU). The first session is scheduled before surgery. In addition to the online sessions, patients have three online appointments with a psychotherapist. Patients with low anxiety or catastrophizing scores (n=322) receive treatment as usual (TAU, additional control arm). Primary endpoint is PPBCT prevalence 6 months after surgery. Secondary endpoints are PPBCT intensity, the intensity of acute postoperative pain during the first week after surgery, cessation of postoperative opioid use, PPBCT prevalence at 12 months, pain interference, the sensitivity of the nociceptive and non-nociceptive somatosensory system as measured by quantitative sensory testing (QST), the efficiency of endogenous pain modulation assessed by conditioned pain modulation (CPM) and quality of life, anxiety, depression, catastrophizing, and fear of recurrence until 12 months post-surgery. Discussion With perioperative e-CBT targeting preoperative anxiety and pain catastrophizing, we expect to reduce the prevalence and intensity of PPBCT. By means of QST and CPM, we aim to unravel underlying pathophysiological mechanisms. The online application facilitates accessibility and feasibility in a for breast cancer patients emotionally and physically burdened time period. Trial registration NTR NL9132 , registered December 16 2020.

We had previously shown that a "blunt blade" stimulator can mimic the noninjurious strain phase of incisional pain, but not its sustained duration. Here, we tested whether acute sensitization of the skin with topical capsaicin can add the sustained phase to this noninvasive surrogate model of intraoperative pain. Altogether, 110 healthy volunteers (55 male and 55 female; 26 ± 5 years) participated in several experiments using the "blunt blade" (0.25 × 4 mm) on normal skin (n = 36) and on skin pretreated by a high-concentration capsaicin patch (8%, Qutenza; n = 36). These data were compared with an experimental incision (n = 40) using quantitative and qualitative pain ratings by numerical rating scale and SES Pain Perception Scale descriptors. Capsaicin sensitization increased blade-induced pain magnitude and duration significantly (both P < 0.05), but it failed to fully match the sustained duration of incisional pain. In normal skin, the SES pattern of pain qualities elicited by the blade matched incision in pain magnitude and pattern of pain descriptors. In capsaicin-treated skin, the blade acquired a significant facilitation only of the perceived heat pain component (P < 0.001), but not of mechanical pain components. Thus, capsaicin morphed the descriptor pattern of the blade to become more capsaicin-like, which is probably explained best by peripheral sensitization of the TRPV1 receptor. Quantitative sensory testing in capsaicin-sensitized skin revealed hyperalgesia to heat and pressure stimuli, and loss of cold and cold pain sensitivity. These findings support our hypothesis that the blade models the early tissue-strain-related mechanical pain phase of surgical incisions.

The new IASP diagnostic criteria for complex regional pain syndrome (CRPS) (aka “the Budapest Criteria”3; Table 1) have improved the diagnostic specificity for CRPS while maintaining good sensitivity. Internationally, these criteria are now in common use. The IASP CRPS Special Interest Group convened a workshop of CRPS experts in Valencia/Spain in September 2019 to review perceived ambiguities in the diagnostic text and issues identified in applying these criteria in both the research and clinical contexts. After this review, workshop attendees discussed and reached a consensus regarding adaptations to the diagnostic taxonomy text. This process resulted in pragmatic updates to CRPS assessment instructions and the associated text in the IASP taxonomy. The wording of the diagnostic criteria themselves was not altered so as to avoid invalidating the criteria. Table 1 - New IASP diagnostic criteria for complex regional pain syndrome (“Budapest criteria”2) (A–D must apply). A. The patient has continuing pain which is disproportionate to any inciting eventB. The patient reports at least one symptom in 3 or more of the categoriesC. The patient displays at least one sign in 2 or more of the categoriesD. No other diagnosis can better explain the signs and symptoms □□□□ Category Symptom (the patient reports a problem) Sign (you can see or feel a problem on examination) 1 “Sensory” Allodynia (to light touch/brush stoke and/or temperature sensation and/or deep somatic pressure and/or joint movement), and/or hyperalgesia (to pinprick) Reported hyperesthesia also qualifies as a symptom□ □ 2 “Vasomotor” Temperature asymmetry and/or skin colour changes and/or skin colour asymmetry □ □ 3 “Sudomotor/oedema” Oedema and/or sweating changes and/or sweating asymmetry □ □ 4 “Motor/trophic” Decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair/nail/skin) □ □ Adapted from https://www.rcplondon.ac.uk/guidelines-policy/complex-regional-pain-syndrome-adults with permission. The results of this meeting were also used as a justification to update the new ICD-11 text regarding CRPS and its diagnosis. This focus on incorporating changes into the ICD-11 was triggered by the current absence of plans to further update the existing CRPS IASP taxonomy. A consensus proposal was sent to WHO for amending ICD-11 CRPS-related text.5 WHO has already accepted some adaptations (marked with # below). Here, we summarise all the proposed changes. The proposed wording of all new text for CRPS in the ICD-11 development version is attached in the web appendix (Online appendix, available at http://links.lww.com/PAIN/B358). Changes concern 3 areas: (a) diagnostic parenting under ICD-11, (b) CRPS subtypes, and (c) the diagnostic procedure. (a) Diagnostic parenting under ICD-11: The current first parent classification of CRPS in the ICD-11 is “focal or segmental autonomic disorder” (ICD-11 BD8A). We consider this classification to be a mistake based on the historic misunderstanding of CRPS as primarily an autonomic disorder. The past 3 decades of CRPS experimental and clinical research clearly demonstrate that this is not the case. We therefore have proposed that the correct parent is “chronic primary pain.” This proposal is also supported by the American Autonomic Society. (b) CRPS subtypes: (i) CRPS II as defined in the IASP criteria is associated with discrete peripheral nerve damage as indicated by neurological examination, electrodiagnostic testing, or other quasi-objective testing. We now clarify that the diagnostic signs of CRPS II must extend beyond any identified injured nerve territory. Nerve lesion itself may cause separate CRPS-concomitant symptoms and signs, including neuropathic pain, paraesthesias, numbness, and autonomic dysfunction restricted to the injured nerve territory. CRPS II should therefore not be classed as a neuropathic pain condition in accordance with current criteria #.4 Diagnostic signs of CRPS I (without discrete nerve damage) and II are identical. The clinical relevance and implications of subgrouping CRPS into these 2 subtypes remain unclear at present.# (ii) We have introduced a third CRPS subtype and have also modified the description of the current diagnostic label CRPS Not Otherwise Specified (NOS) to minimise any confusion with using this latter term. Patients previously documented as having fully met CRPS criteria (either CRPS I or CRPS II, Table 1) but who currently display CRPS features insufficient to fully meet the diagnostic criteria should be classified into the new CRPS subtype, “CRPS with Remission of Some Features.” These patients should not be classified as having CRPS NOS. Notably, a reduction in the number of CRPS diagnostic signs and symptoms does not necessarily constitute an improvement in the lived experience of CRPS; these patients may not have improved pain nor are they usually free of all CRPS-related signs and symptoms. CRPS with Remission of Some Features is a third formal subtype of CRPS, which by necessity overlaps with either CRPS I or II. At what point CRPS changes from being an ongoing condition potentially requiring continued clinical management (ie, CRPS with Remission of Some Features) to being considered resolved is a topic that will need to be addressed in future research. (iii) The term “CRPS-NOS” in the current IASP criteria has been retained exclusively for application to patients who have never been documented to fulfil the new IASP CRPS criteria (Table 1). That is, they now display some but not all features of CRPS required for formal diagnosis, and no other diagnosis better explains the clinical features. (iv) Warm/cold CRPS and early/persistent CRPS are overlapping presentations that are clinically observed. The group did not consider there to be sufficient evidence yet to create formal CRPS subgroups according to these features. However, there was consensus that research and clinical reports should include this information when describing individual patients, study inclusion criteria, or research participants (clinical experience and research suggest that a substantial proportion of individuals who develop acute CRPS improve or resolve, with a smaller subgroup that fails to substantially improve even with standard care. This transition of CRPS to a more prolonged and difficult to manage condition seems to occur during the first 12-18 months after onset, although there is no widely accepted demarcation point for this distinction. The word “persistent” is used here as a descriptive term for this subgroup of prolonged and intractable CRPS. Use of the alternative term “chronic” is preferred by some CRPS experts. However, we note that the term “chronic” is also broadly used across all pain conditions to refer to pain lasting more than 3 months after tissue injury to distinguish it from “acute” pain. To avoid incorrect implications of the word ‘chronic’ to be understood as a >3 months' pain duration in patients with CRPS, the word “persistent” is used to refer to such prolonged CRPS. For clarity, ‘persistent’ does not necessarily indicate the condition will persist indefinitely—a minority of patients with persistent CRPS will naturally improve).# (c) The diagnostic procedure ICD-11 includes additional text to clarify diagnostic terms and procedures. The purpose of that text, pragmatic clarification of the diagnostic process, bears resemblance to that of the IASP taxonomy and associated text (https://www.iasp-pain.org/files/Content/ContentFolders/Publications2/ClassificationofChronicPain/Part_II-A.pdf), which is not currently being updated. This ICD-11 supplemental text has now been updated for CRPS. The following key points are now all implemented (except viii): (i) All patients should be asked systematically about all symptoms listed in the criteria at each formal diagnostic evaluation, even if they have not previously reported certain symptoms. This is recommended because CRPS signs and symptoms are clinically observed to fluctuate over time.# (ii) Clarification of the terms “asymmetry” and “changes” as used in the current IASP CRPS criteria (Table 1): For unilateral CRPS, assess asymmetry by comparing the affected side to the unaffected side. For (much rarer) bilateral and symmetrical CRPS, assess changes in the affected limbs relative to an unaffected limb in the patient or to the limbs of a typical healthy individual. Asymmetry is based on clinical judgment only, rather than any prespecified criteria.# (iii) For evaluating possible spreading of CRPS beyond a single limb, the full diagnostic criteria must be applied to each limb individually. True spreading of CRPS is defined as CRPS that meets full new IASP/ICD-11 diagnostic criteria (Table 1) for multiple limbs—extension of pain alone to other limbs, which is not unusual, in the absence of other CRPS features is not formally considered to be spreading CRPS.# (iv) Hyperalgesia (note that other definitions of hyperalgesia and allodynia exist for use in other chronic pain conditions)4 is a clinical observation in which a painful stimulus evokes more pain than it normally would. The group recommended standard testing for hyperalgesia by comparing the response to a single pinprick applied in the center of the most affected region to the response to an identical pinprick at the corresponding location on the unaffected limb, or an equivalent control site in the case of bilateral CRPS. The test is positive if reported pain is more intense or lasts longer on the affected limb.# (v) Allodynia is a clinical observation in which pain is evoked by a stimulus that is not normally painful. Stimuli used in clinical allodynia assessment can include light touch, vibration, cool or warm temperature, deep tissue or joint pressure in the affected area, or joint movement. Only one of these is required to confirm whether allodynia is present or absent. Suggested clinical assessment procedures are now outlined as below in the revised text: “allodynia to light touch as tested by light manual touch (or brush); allodynia to tissue pressure as assessed by pressure applied to a joint or other tissue using the evaluator's finger with just enough pressure to make the fingernail bed of the evaluator blanch (turn white) (equating to a pressure of below 100g/cm2, and a load of no more than 500 g; this is substantially less than the pressure recommended for the examination of tender points [4 kg/cm2]),6 allodynia to vibration as assessed using a graded tuning fork over bony prominence on the affected limb; allodynia to cool or warm temperature.”# (vi) Temperature asymmetry is assessed in the affected area and compared with the corresponding area on the contralateral extremity, or a suitable control site in the case of bilateral CRPS. Such asymmetry should be obvious to the touch of the dorsum of the hand of the examiner.# (vii) Obvious color asymmetry of a regional nature (ie, hand, foot, knee, or larger region). Please specify the nature of the color changes, eg, red, blue, pale, or mottled.# (viii) A rare limitation of the CRPS diagnostic criteria is noted: In some cases, an objective CRPS diagnostic sign such as color or temperature asymmetry may be observed by the examiner without the patient reporting the corresponding subjective symptom. This may occur, for example, because the patient cannot feel a temperature change, or a color change is difficult to see (this similarly applies to swelling). This situation may result in a patient's diagnostic symptom-category count dropping below the threshold of 3 required for formal diagnosis, despite the patient objectively displaying sufficient clinical features for diagnosis. In these instances, because of the statistical methods on which the IASP criteria were developed and validated, the obvious common-sense approach that ‘signs override symptoms’ (ie, a sign automatically generates a tick also as a symptom) cannot automatically apply. A related challenge arises also where a patient has impaired vision and is therefore unable to ascertain objective color changes; in these rare cases, a pragmatic solution must be found in which common sense prevails. It is hoped that the modified ICD-11 text clarifies important pragmatic aspects of CRPS assessment and diagnosis, and that it will enhance usability of these criteria in both clinical and research settings. All changes and clarifications marked with a # above have already been incorporated into the ICD-11 CRPS text and should be applied in the CRPS diagnostic process immediately. Future research should (1) clarify whether CRPS type 1 and 2 are indeed separate entities or are better merged; (2) assess whether introduction of further subgroups such as warm-cold and early-persistent CRPS is useful (eg, for predicting treatment responses); (3) ascertain the utility of biomarkers for supporting the clinical CRPS diagnosis1; and (4) define “resolved CRPS.” Conflict of interest statement The authors have no conflicts of interest to declare. Appendix A. Supplemental digital content Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/B358. Supplemental video content A video abstract associated with this article can be found at http://links.lww.com/PAIN/B329.