INTRODUCTION:Chronic pain is a major public health issue due to limited treatment efficacy. Within the IMI-PainCare project, we aimed to identify spinal biomarkers reflecting nociceptive processing and responsive to analgesics. Standardization and pharmacological validation are key for advancing analgesic development and improving care. METHODS:In a multi-center, randomized, double-blind, placebo-controlled crossover trial in healthy subjects, we assessed single doses of tapentadol (primary endpoint), lacosamide, and pregabalin (secondary endpoints) on two spinal biomarkers: RIII flexion reflex area and N13 somatosensory evoked potentials (N13-SEP), after hyperalgesia induction via high-frequency stimulation (HFS). Exploratory analyses included RIII reflex threshold and pain ratings. RESULTS:Twenty-four participants were enrolled. Tapentadol and pregabalin reduced the RIII flexion reflex area on the HFS sensitized side, 60 min after drug, compared to placebo, but the predetermined level of significance (p = 0.025) was not reached. No drug affected N13-SEP amplitude. All drugs significantly increased RIII threshold vs. placebo. Tapentadol and pregabalin also reduced RIII pain ratings. CONCLUSIONS:Although primary and secondary endpoints were not met, tapentadol and pregabalin reduced the RIII flexion reflex area with medium, non-significant effect sizes. Exploratory analysis showed all drugs significantly increased the RIII threshold in HFS-induced hyperalgesic condition. N13-SEP amplitudes remained unchanged, questioning its reliability as a spinal biomarker. SIGNIFICANCE:Our findings support the RIII threshold as an objective spinal biomarker to assess antihyperalgesic drug effect. This study informs future choices of biomarkers, optimal timing, and analysis strategies in analgesic research.

The International classification of diseases and related health problems, 11th revision (ICD-11) includes an organized system of linked biomedical concepts and hierarchical coding tables called linearizations, of which the most important is the ICD-11 for Mortality and Morbidity Statistics. A publicly accessible web-based platform supports the dynamic maintenance of ICD-11 content, including proposals for modifications, based on scientific evidence and clinical relevance. This paper describes how proposals submitted through the platform are reviewed by the ICD-11 Medical and Scientific Advisory Committee. We analysed World Health Organization data on proposals to modify ICD-11 entities submitted between 2021 and 2025, according to proposal source, subject area, proposal type, time to decision and outcome. The advisory committee reviewed 256 proposals concerning 92% (24/26) of ICD-11 chapters. Proposals were submitted by international bodies, individual practitioners, patient advocacy groups and scholarly societies, with similar acceptance rates across groups. The most common proposal type was the addition of an entry, which had an acceptance rate 65% (81/125); followed by the deletion of an obsolete entity, which had an acceptance rate of 77% (44/57). The mean time to decision was 13.8 months. Overall, 69% (176/256) of proposals were recommended for adoption. These findings indicate that the advisory committee's review process is functioning adequately, with reasonable acceptance rates following scientific scrutiny. Outreach should be considered to encourage submissions in chapters with few updates between 2021 and 2025. Turnaround time may improve with the expansion of the advisory committee's membership and clearer guidance on proposal quality.

INTRODUCTION:Chronic pain is a significant and debilitating symptom observed in individuals with post-COVID condition (PCC), yet the underlying mechanisms remain poorly understood. This study aimed to investigate whether changes in psychophysical indicators of myofascial pain perception and modulation are present in individuals with PCC compared to symptom-free healthy controls (HC), and whether these changes correlate with the severity of clinical symptoms. METHODS:The study involved 84 individuals with PCC and 50 HC, assessing pain detection and tolerance thresholds (PDT and PTT), spatial and temporal summation of pain (SSP and TSP), and conditioned pain modulation (CPM) using phasic cuff pressure on the legs. RESULTS:Results indicated that individuals with PCC exhibited lower PDT and PPT (PDT: d = -0.557, p = 0.0022; PTT: d = -0.575, p = 0.0016), increased TSP (d = 0.424, p = 0.02) and decreased SSPPTT (d = -0.532, p = 0.0038) compared to HC CPM effects (CPMPDT: p = 0.058; CPMPTT: p = 0.43) did not differ significantly between groups but post hoc analysis revealed a significantly higher proportion of inhibitory responders among HC. Subgroup analyses highlighted that these effects were particularly pronounced in participants that reported chronic pain among their PCC symptoms, as well as those with more severe PCC symptomatology. CONCLUSION:The findings suggest that individuals with PCC demonstrate altered myofascial pain perception, indicative of central sensitization. These results underscore the need for further research into targeted therapeutic strategies for managing chronic pain in PCC. SIGNIFICANCE STATEMENT:Individuals with post-COVID condition (PCC) often experience persistent pain. Using quantitative sensory testing of deep tissue pain, we found that individuals with PCC had lower pain detection and tolerance thresholds, stronger spatial and temporal summation, and a higher proportion of facilitatory conditioned pain modulation compared to healthy controls. This pattern is consistent with nociplastic pain, suggesting altered central pain processing in PCC. Understanding these mechanisms is essential for developing targeted treatments of chronic pain in this growing patient population.

Research question:Germany's longstanding separation of healthcare sectors - most prominently between outpatient and inpatient care - creates risks of fragmented service delivery, disrupted information flows, and ultimately suboptimal outcomes for patients. This position paper examines how cross-sectoral and integrated strategies can effectively mitigate or overcome this fragmentation. Methods:During a Berlin Forum of the Association of the Scientific Medical Societies in Germany (AWMF) (6 December 2024), experts presented best-practice models and discussed legal, structural, financial, and regional dimensions of integrated care. The insights from these discussions were synthesized into AWMF's recommendations. Results:Integrated care represents a critical lever for improving the efficiency and quality of the German healthcare system. Promising examples exist across surgical, medical, psychiatric, and regionalized care settings. Key recommendations address the following topics: harmonized financing and remuneration system, regional population-based healthcare networks, interoperable information exchange across healthcare sectors, shared decision-making on care options. Health services research - and especially implementation research - plays an indispensable role in guiding and evaluating these reforms. The AWMF further emphasizes the need for integrated education and postgraduate training, particularly within structured residency networks, and offers AWMF as an important interdisciplinary and interprofessional platform for promoting cross-sectoral care. Conclusions:Broad implementation of integrated care, combined with robust and evidence-based monitoring of implementation, is essential for meeting the challenges posed by demographic change and increasing demands on healthcare delivery.

INTRODUCTION:Chronic primary low back pain (cpLBP) is a global health concern with poorly understood pathomechanisms, potentially involving spinal sensitization. The capsaicin receptor TRPV1 plays a crucial role in sensitization across pain models. This study employed a rat model of cpLBP induced by two nerve growth factor (NGF) injections into lumbar muscles to explore TRPV1's roles in NGF-induced spinal sensitization. MATERIAL AND METHODS:Male wildtype (WT) and TRPV1-/- rats of both sexes (N = 10 each) underwent behavioural tests post NGF and vehicle injections. Tests included low back pressure pain thresholds (PPT), paw withdrawal thresholds (PWT), heat pain thresholds (HPT), and exploratory behaviour. Spinal TRPV1 expression after NGF injections was assessed in WT rats. RESULTS:WT rats displayed latent local mechanical hypersensitivity after a single NGF injection, turning into manifest after the second, with presynaptic TRPV1 upregulation. TRPV1-/- rats showed pronounced local mechanical hypersensitivity after a single NGF injection, increasing after the second NGF injection. Repeated NGF injections led to anxiety-like behaviour and delayed remote mechanical hypersensitivity in both genotypes. DISCUSSION:TRPV1 is upregulated during manifest sensitization but is not essential for developing local or remote mechanical hypersensitivity. TRPV1-/- rats lacked early remission after a single NGF injection, suggesting TRPV1 may be involved in homeostatic maintenance rather than induction of spinal sensitization. SIGNIFICANCE STATEMENT:TRPV1 contributes to NGF-induced sensitization but is not required for its development. These findings put TRPV1's potential as a therapeutic target for hyperalgesia into perspective and suggest a potential regulatory role in pain homeostasis.

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.

Research question: Germany’s longstanding separation of healthcare sectors – most prominently between outpatient and inpatient care – creates risks of fragmented service delivery, disrupted information flows, and ultimately suboptimal outcomes for patients. This position paper examines how cross-sectoral and integrated strategies can effectively mitigate or overcome this fragmentation. Methods: During a Berlin Forum of the Association of the Scientific Medical Societies in Germany (AWMF) (6 December 2024), experts presented best-practice models and discussed legal, structural, financial, and regional dimensions of integrated care. The insights from these discussions were synthesized into AWMF's recommendations. Results: Integrated care represents a critical lever for improving the efficiency and quality of the German healthcare system. Promising examples exist across surgical, medical, psychiatric, and regionalized care settings. Key recommendations address the following topics: harmonized financing and remuneration system, regional population-based healthcare networks, interoperable information exchange across healthcare sectors, shared decision-making on care options. Health services research – and especially implementation research – plays an indispensable role in guiding and evaluating these reforms. The AWMF further emphasizes the need for integrated education and postgraduate training, particularly within structured residency networks, and offers AWMF as an important interdisciplinary and interprofessional platform for promoting cross-sectoral care. Conclusions: Broad implementation of integrated care, combined with robust and evidence-based monitoring of implementation, is essential for meeting the challenges posed by demographic change and increasing demands on healthcare delivery.

Using neuroimaging to understand the mechanisms of pain is an important task. But we must understand that the gold standard of measuring pain will always be the self-report.

Abstract:We explore bladder sensitivity profiles in females with chronic pelvic pain, using a non-invasive bladder sensitivity paradigm. We aim to determine how profiles differ between groups defined by symptoms; groups defined by diagnoses; and understanding how bladder sensitivity relates to clinical symptoms. A previously developed non-invasive bladder sensitivity paradigm will be used, which assesses pain and urgency ratings during physiological bladder filling, time to reach descriptive sensations, and volume voided at the paradigm end. Our cohort comprised individuals with (pain + bladder) and without (pain only) overt bladder symptoms and pain-free/bladder-symptom-free controls; within both pain groups were participants with and without endometriosis. In addition, questionnaires were completed, which included bladder- and bowel-related symptoms. Participants with pain + bladder symptoms had significantly greater pain intensity scores throughout the paradigm compared with controls. When looking at underlying diagnoses, the only significant difference between those with bladder symptoms, with and without endometriosis, was in the volume voided at the end of the paradigm. We found correlations between pain ratings during the paradigm and gastrointestinal symptom scores from questionnaires. We found that the paradigm can distinguish between those with overt bladder symptoms and controls. It also appears to potentially identify a group of individuals with 'silent' bladder symptoms. It is currently unclear whether those with 'silent' symptoms go on to develop overt symptoms. Overall, our study highlights the need to explore bladder sensitivity in individuals with any form of chronic pelvic pain, as comorbidity is common and 'silent' symptoms are not well understood. Lay summary:This study explored bladder sensitivity in people with chronic pelvic pain, with and without bladder symptoms, compared with a control group of people without pain. We wanted to explore pain and urgency when people drank water and how this differed in people with different symptoms and diagnoses. We asked people to drink 20 fl oz of water and give ratings of pain and urgency throughout, as well as when they felt certain sensations. We found differences between those with overt bladder symptoms and the control group, with those with overt bladder symptoms experiencing greater pain. We did not find differences between different diagnoses (e.g. those with and without endometriosis) in pain or urgency ratings. This study highlights the need to explore bladder sensitivity in individuals with any form of chronic pelvic pain.

BACKGROUND:The underlying pathophysiological mechanisms of complex regional pain syndrome (CRPS) have been under debate in recent years. Previous studies identified mechanistic CRPS subtypes, which were characterised as 'cold' and 'warm' or peripheral and central phenotypes. Our aim was to examine CRPS patients through comprehensive somatosensory testing and identify potential subgroups using unbiased statistics. Thus, our approach differs fundamentally from previous top-down approaches which stratified along predefined pathophysiological mechanisms. METHODS:In total, 604 patients (age: 51.9 [SD 13.4] yr, female: 436, disease duration: 1.6 [SD 2.9] yr) with CRPS (type I: n=520; type II: n=84) underwent Quantitative Sensory Testing according to the DFNS protocol (German Research Network on Neuropathic Pain). We assessed 13 parameters, including thermal and mechanical detection and pain thresholds, indicating one distinct sensory profile for each participant. We conducted a hypothesis-free cluster analysis in a training set (A, n=380), which was re-evaluated in a validation set (B, n=224) to account for possible overfitting of the data and a comparison towards human pain surrogate models. RESULTS:We identified three sensory phenotypes in the training set, which were confirmed in the validation set. The largest group showed pronounced hypersensitivity towards cold and heat pain (n=382), a second group showed loss of thermal and mechanical sensation (n=200), and a third, small, but consistent, group exhibited strong allodynia and mechanical hyperalgesia (n=22). CONCLUSION:A novel bottom-up approach can stratify CRPS based on sensory phenotypes, adding to a mechanistic understanding through a comparative analysis of human pain surrogate models.

Background/AimPersistent idiopathic facial pain (PIFP) is a rare condition with a lifetime prevalence of approximately 0.03%. It is characterized by persistent daily facial pain without identifiable cause and presents diagnostic and therapeutic challenges due to unknown pathophysiology, symptom overlap with other painful disorders, and limited evidence-based treatments. The aim of this Delphi study was to establish international consensus-derived guidelines for the management of patients with PIFP.MethodsA three-round Delphi study was conducted with 16 international pain experts, each with ≥10 years of clinical experience in pain management and extensive peer-reviewed publications. The first round involved open-ended questions, and the qualitative data were analyzed using systematic text condensation, resulting in a quantitative questionnaire with 42 statements. Subsequent rounds employed Likert-scale responses to these statements. Consensus was defined as ≥80% agreement or disagreement. In addition, if 11-12 (68-75 percent) out of the 16 experts agreed or disagreed, consensus was not reached, but a majority was considered to have a particular opinion.ResultsConsensus was reached in 35 out of the 42 statements (83%), emphasizing multidisciplinary collaboration and avoidance of invasive procedures in the treatment of PIFP. In an additional three statements (7%) a majority of the experts agreed with each other. In four statements (10%), no consensus or majority was reached. Pharmacological treatments, including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids, may be considered; however, opioids should generally be avoided in the treatment of PIFP. Patient education and behavioral therapies are important interventions, and the most important measure of therapeutic success is improved quality of lifeConclusionThe present Delphi study has established internationally derived consensus guidelines and recommendations for the evaluation and comprehensive management of patients with PIFP. This is a first step in gathering knowledge for future evidence-based guidelines and more specific treatment recommendations. These international expert consensus guidelines recommend a multi- or interdisciplinary approach in managing PIFP, avoiding invasive interventions and prioritizing patient-centered outcomes.

INTRODUCTION:Non-suicidal self-injury (NSSI) is found in over 70% of patients with Borderline Personality Disorder (BPD). The most common method is cutting, which is often used to reduce high levels of aversive tension under stress. Recent studies have shown that pain during injury is a major factor reducing this stress. This report focuses on the question, whether the stress relieving effect of a sharp pain stimulus is different, when the patient herself is inflicting the stimulus on the forearm. METHODS:86 patients with BPD participated in this study. Stress was induced with a personalized script, followed by a non-invasive pain stimulus with a blunt blade, either self-inflicted or inflicted by the experimenter. Subjective (arousal, urge for NSSI, pain intensity) and objective (heart rate) parameters were measured to evaluate stress and pain. Group differences were analysed using hierarchical linear modelling. RESULTS:Pain intensity, arousal and the urge for NSSI were similar under both conditions. The initial decrease in heart rate following the pain stimulus was significantly larger when the stimulus was applied by the experimenter and was delayed by a few minutes in the self-inflicted condition. CONCLUSIONS:In this experimental setting, the perspective of pain application (self vs. other) had no differential influence on either NSSI, pain intensity, or stress level. The stronger initial decrease in heart rate in the other-inflicted group during the stimulus may be due to the lack of active physical involvement in the procedure, which could have delayed the decrease of heart rate in the self-inflicted group.

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.

Exposure to noxious stimuli induces secondary hyperalgesia (SH), likely due to long-term potentiation (LTP) in the dorsal horn or "central sensitization." Previous studies have suggested that repeated exposure to a sensitizing stimulus may promote a persistent form of potentiation. We tested this hypothesis by characterizing the time course and spatial spread of SH induced by repeated exposures to high-frequency electrical stimulation (HFS) in healthy volunteers. Separate groups of 16 participants received either a single session of 5 or 10 HFS trains ("HFS 1x5" and "HFS 1x10" groups) or 2 sessions of 5 HFS trains separated by 1 hour and applied to the same forearm ("HFS 2x5" group) or the contralateral forearm ("HFS 2x5 bilateral" group). HFS trains consisted of 1 second of 100-Hz stimulation (×20 detection threshold). The magnitude and spread of SH were assessed using pinprick stimulation at nine time points up to 24 hours post-HFS. Temporal decay of HFS-induced increase in pinprick sensitivity was significantly slower in the HFS 2x5 versus the HFS 1x5 and HFS 1x10 groups (half-life: 438 vs. 255 vs. 247 min). In contrast, the time course of hyperalgesia area was similar in the HFS 2x5 and HFS 1x5 groups (451 and 470 min) but decayed more rapidly in the HFS 1x10 group (92 min). In the HFS 2x5 bilateral group, preexposure to HFS on one forearm did not affect contralateral hyperalgesia magnitude or half-life but slightly increased its spatial extent. These findings suggest that repeated exposure to noxious stimulation favors the induction of a longer-lasting form of central sensitization.NEW & NOTEWORTHY This study shows in healthy human volunteers that two sessions of high-frequency electrical stimulation of the skin (HFS) separated by 1 hour induce longer-lasting secondary hyperalgesia as compared to a single session matched in terms of the number of HFS pulses. This finding suggests that repeated exposures to noxious stimulation can favor the induction of a longer-lasting form of central sensitization.

Chronic primary low back pain (cpLBP) is a leading contributor to years lived with disability. Early-life stress is a major risk factor predisposing to cpLBP later in life upon minor injuries. We investigated sex differences in the involvement of microglia in the pathophysiology of early-life stress effects on pain responses to a secondary stimulus in adulthood. During adolescence, male and female Wistar Han rats underwent repeated restraint stress for 12 consecutive days, while controls were handled. In adulthood, acute LBP was induced by NGF or saline injections into the lumbar multifidus muscle. Subsequently, the animals were sacrificed and perfused for spinal cord extraction. A total of 3516 microglia cells were classified into three functional states (surveillant, primed, activated) using partition around medoids clustering and UMAP dimensionality reduction methods for eight 3-dimensional morphological features obtained from MATLAB 3DMorph. Across all conditions, the proportion of surveillant microglia was significantly higher in females than in males (p < 0.0001, d = 1.85), while males had more primed (p < 0.0001, d = 1.56) and activated (p < 0.01, d = 1.87) microglia. Priming by stress led to an increase in activated microglia after NGF injection (p < 0.05, d = 0.63), more distinct in males (p < 0.05, d = 0.82) than in females (p > 0.05, d = 0.43). Additive effect of stress and NGF caused a shift towards primed state in males (p > 0.05, d = 0.62), but not in females. In conclusion, stress was confirmed to play a critical role in priming microglia and predisposing to cpLBP. Sex differences previously shown for neuropathic pain were found to be also relevant in this more frequent musculoskeletal pain condition.

Chronic pain and depression are leading causes of disability, frequently co-occurring and exacerbating each other. This cross-sectional study investigated putative transdiagnostic processes of affective dysregulation in fibromyalgia (FMS) and major depressive disorder (MDD) using psychometric questionnaires (Beck Depression Inventory-II, Hospital Anxiety and Depression Scale, Cognitive Emotion Regulation Questionnaire, Perceived Stress Scale, Widespread Pain Index, Somatic Symptom Disorder B Criteria Scale 12), ecological momentary assessments, and real-time functional magnetic resonance imaging amygdala neurofeedback during an emotion regulation task. We compared clinical symptoms, stress sensitivity, and emotion regulation in patients with FMS (N = 46) and MDD (N = 48) with healthy controls (N = 34). Patients with fibromyalgia syndrome and major depressive disorder reported similar psychopathological and affective dysregulation profiles, and they exhibited more psychopathology and emotion regulation deficits than healthy controls (HC). Differences between MDD and FMS were limited to pain-specific pathology in FMS (pain spread and frequency P < 0.001, intensity P < 0.05) and more rumination (P < 0.05) and self-blame (P < 0.01) in MDD. Momentary stress predicted higher subsequent pain and worse affective states across groups, with FMS and MDD exhibiting stronger stress responses (all P's < 0.05). Directly after neurofeedback training, FMS and MDD were less able to downregulate left amygdala activity than HC (P = 0.039) compared to baseline performance, and this brain marker predicted daily life psychopathology (negative affect, anxiety, and rumination, all P's < 0.05). Patients with fibromyalgia syndrome additionally exhibited unique deficits in right amygdala regulation (P = 0.004). Our findings highlight transdiagnostic affective dysregulation patterns in FMS and MDD, specific differences in emotion regulation strategies, and a potential neuronal marker of a shift towards right amygdala sensitization during affective processing in FMS.

ABSTRACT:The high failure rate in translating novel analgesics into the clinic has highlighted the need for more translatable biomarkers of analgesic target engagement. The N13 component of spinal somatosensory evoked potential (SEP) has been proposed as a biomarker of spinal nociceptive processing in humans, but it is not known whether this can be back translated into rodents. Tapentadol, lacosamide, and pregabalin were used as pharmacological probes to assess the sensitivity of spinal SEPs to drug action. In anaesthetised, naïve rats (n = 44), a multielectrode silicon probe was inserted into the L4 spinal cord to record SEPs from the dorsal horn after electrical stimulation of the sciatic nerve. At baseline, the N1 component (rodent equivalent of the human N13) had an amplitude of 1.33 ± 0.07 mV at a latency of 4.6 ± 0.2 milliseconds after low-intensity stimulation (average 0.32 mA), with an intensity-dependent amplitude increase into the noxious range (0.4-3.2 mA). The N1 amplitude was significantly reduced by 10 mg/kg tapentadol (40.2 ± 12.5% vs vehicle 96.2 ± 8.0%) and 30 mg/kg lacosamide (46.3 ± 20.9% lacosamide vs vehicle 115 ± 5.9%) at 60 minutes after intraperitoneal administration. Tapentadol also reduced the N1 amplitude in the noxious range. Lacosamide increased the stimulus current required to evoke the half maximal N1 response (EC50), without reducing the maximum N1 amplitude in the noxious range. Pregabalin (at any dose up to 30 mg/kg) did not modulate the N1 amplitude. These results show that the spinal N1 is differentially modulated in a way that reflects distinct mechanisms of analgesic action consistent with it being a translatable biomarker of target engagement.

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 (X2 = 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.