Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system.

ABSTRACT: Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients.

The association of self-reported symptoms of central sensitization and sleep disturbances in neuropathic pain.

Introduction: Patients with neuropathic pain (NP) report a higher impairment of quality of life and sleep than patients with chronic pain without neuropathic characteristics. These include somatosensory peculiarities like allodynia, a surrogate marker for central sensitization. Objectives: This study aimed to investigate the relation between symptoms of central sensitization and sleep disturbances in patients with NP. Methods: Within this cross-sectional study, data sets of 3339 patients with chronic NP syndromes (painful diabetic polyneuropathy, n = 543; postherpetic neuralgia, n = 1480) or complex regional pain syndromes (CRPS, n = 1316) were analyzed. Neuropathic pain symptoms were assessed with the painDETECT questionnaire (PD-Q), depression with the Patient Health Questionnaire-9, and sleep impairment with items of the Medical Outcomes Study Sleep Scale in 4 subscales. The association of demographic/clinical data, somatosensory phenotype, depression, and pain intensity with sleep impairment was assessed by unadjusted Spearman correlation analyses and multivariable regression analyses. Results: Sleep impairment was observed in all pain aetiologies although with some significant differences in the single sleep items. The intensity of the individual PD-Q items differed to some extent between the 3 pain entities, whereas the PD-Q sum score was similar. Thermal hyperalgesia and burning assessed by the PD-Q were significantly associated with sleep disturbance, adequacy, and quantity but not with sleep somnolence. Only depression and self-reported allodynia had a significant relation to all 4 sleep elements. Conclusion: Beside depression, allodynia as a surrogate marker hints to a possible impact of central sensitization on the sleep disruption of patients with NP.

Chronic Pain and the Endocannabinoid System: Smart Lipids - A Novel Therapeutic Option?

The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).

[Tapentadol versus classical WHO-III opioids for chronic back pain. Health services research study based on representative data from health insurance funds]. / Tapentadol versus klassische WHO-III-Opioide bei chronischen Rückenschmerzen : Versorgungsforschungsstudie auf Basis repräsentativer Krankenkassendaten.

BACKGROUND/OBJECTIVE: In clinical trials, tapentadol prolonged release (PR) showed a more favourable gastrointestinal tolerability profile compared to other strong opioids in the treatment of pain. The present analysis compared tapentadol PR and classical WHO-III PR opioids in routine clinical practice. METHOD: Retrospective cohort study (matched pair approach) using anonymised health insurance data of patients with chronic low back pain who were prescribed strong opioids following pretreatment with WHO-I/II analgesics. Data were analysed from the date of first prescription in 2015 over a maximum period of two years. The primary analysis parameter was the prescription of laxatives. RESULTS: Data of 227 patients per cohort could be included in the analysis. Significantly fewer tapentadol PR than WHO-III PR patients were prescribed laxatives (20.3% vs. 37%; p < 0.0001). In addition, laxative dosages were significantly lower in the tapentadol PR cohort (26.4 vs. 82.5 defined daily doses; p < 0.0001). A significant difference in laxative prescription was also observed under long-term treatment (tapentadol PR patients 27.7% vs. WHO-III PR patients 50%; p = 0.0029). CONCLUSION: Routine clinical practice indirectly confirmed the more favourable gastrointestinal tolerability of tapentadol PR in the treatment of chronic pain which had previously been demonstrated in clinical trials and non-interventional studies.

Longitudinal resting-state electroencephalography in patients with chronic pain undergoing interdisciplinary multimodal pain therapy.

ABSTRACT: Chronic pain is a major healthcare issue posing a large burden on individuals and society. Converging lines of evidence indicate that chronic pain is associated with substantial changes of brain structure and function. However, it remains unclear which neuronal measures relate to changes of clinical parameters over time and could thus monitor chronic pain and treatment responses. We therefore performed a longitudinal study in which we assessed clinical characteristics and resting-state electroencephalography data of 41 patients with chronic pain before and 6 months after interdisciplinary multimodal pain therapy. We specifically assessed electroencephalography measures that have previously been shown to differ between patients with chronic pain and healthy people. These included the dominant peak frequency; the amplitudes of neuronal oscillations at theta, alpha, beta, and gamma frequencies; as well as graph theory-based measures of brain network organization. The results show that pain intensity, pain-related disability, and depression were significantly improved after interdisciplinary multimodal pain therapy. Bayesian hypothesis testing indicated that these clinical changes were not related to changes of the dominant peak frequency or amplitudes of oscillations at any frequency band. Clinical changes were, however, associated with an increase in global network efficiency at theta frequencies. Thus, changes in chronic pain might be reflected by global network changes in the theta band. These longitudinal insights further the understanding of the brain mechanisms of chronic pain. Beyond, they might help to identify biomarkers for the monitoring of chronic pain.

Cannabis-Based Medicines and Medical Cannabis in the Treatment of Nociplastic Pain.

Nociplastic pain is defined as pain due to sensitization of the nervous system, without a sufficient underlying anatomical abnormality to explain the severity of pain. Nociplastic pain may be manifest in various organ systems, is often perceived as being more widespread rather than localized and is commonly associated with central nervous system symptoms of fatigue, difficulties with cognition and sleep, and other somatic symptoms; all features that contribute to considerable suffering. Exemplified by fibromyalgia, nociplastic conditions also include chronic visceral pain, chronic headaches and facial pain, and chronic musculoskeletal pain. It has been theorized that dysfunction of the endocannabinoid system may contribute to persistent pain in these conditions. As traditional treatments for chronic pain in general and nociplastic pain in particular are imperfect, there is a need to identify other treatment options. Cannabis-based medicines and medical cannabis (MC) may hold promise and have been actively promoted by the media and advocacy. The medical community must be knowledgeable of the current evidence in this regard to be able to competently advise patients. This review will briefly explain the understanding of nociplastic pain, examine the evidence for the effect of cannabinoids in these conditions, and provide simplified guidance for healthcare providers who may consider prescribing cannabinoids for these conditions.

Dynamics of brain function in patients with chronic pain assessed by microstate analysis of resting-state electroencephalography.

ABSTRACT: Chronic pain is a highly prevalent and severely disabling disease that is associated with substantial changes of brain function. Such changes have mostly been observed when analyzing static measures of resting-state brain activity. However, brain activity varies over time, and it is increasingly recognized that the temporal dynamics of brain activity provide behaviorally relevant information in different neuropsychiatric disorders. Here, we therefore investigated whether the temporal dynamics of brain function are altered in chronic pain. To this end, we applied microstate analysis to eyes-open and eyes-closed resting-state electroencephalography data of 101 patients suffering from chronic pain and 88 age- and sex-matched healthy controls. Microstate analysis describes electroencephalography activity as a sequence of a limited number of topographies termed microstates that remain stable for tens of milliseconds. Our results revealed that sequences of 5 microstates, labelled with the letters A to E, consistently described resting-state brain activity in both groups in the eyes-closed condition. Bayesian analysis of the temporal characteristics of microstates revealed that microstate D has a less predominant role in patients than in controls. As microstate D has previously been related to attentional networks and functions, these abnormalities might relate to dysfunctional attentional processes in chronic pain. Subgroup analyses replicated microstate D changes in patients with chronic back pain, while patients with chronic widespread pain did not show microstates alterations. Together, these findings add to the understanding of the pathophysiology of chronic pain and point to changes of brain dynamics specific to certain types of chronic pain.

Pregabalin for neuropathic pain in primary care settings: recommendations for dosing and titration.

Pregabalin is one of the first-line treatments approved for the management of neuropathic pain (NeP). While many patients benefit from treatment with pregabalin, they are often treated with suboptimal doses, possibly due to unfamiliarity around prescribing the drug and/or side effects that can occur with up-titration. This narrative review discusses key aspects of initiating, titrating, and managing patients prescribed pregabalin therapy, and addresses concerns around driving and the potential for abuse, as well as when to seek specialist opinion. To ensure that patients derive maximum therapeutic benefit from the drug, we suggest a 'low and slow' dosing approach to limit common side effects and optimize tolerability alongside patients' expectations. When requiring titration to higher doses, we recommend initiating 'asymmetric dosing,' with the larger dose in the evening. Fully engaging patients in order for them to understand the expected timeline for efficacy and side effects (including their resolution), can also help determine the optimal titration tempo for each individual patient. The 'low and slow' approach also recognizes that patients with NeP are heterogeneous in terms of their optimal therapeutic dose of pregabalin. Hence, it is recommended that general practitioners closely monitor patients and up-titrate according to pain relief and side effects to limit suboptimal dosing or premature discontinuation.

The serotonin receptor 2A (HTR2A) rs6313 variant is associated with higher ongoing pain and signs of central sensitization in neuropathic pain patients.

BACKGROUND: The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. METHODS: At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.-1438G > A (rs6311) and c.102C > T (rs6313). Genotype-related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. RESULTS: There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (-0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p < .001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. -0.34 ± 0.23 p = .002; MPS, +0.66 ± 0.17 vs. -0.09 ± 0.23, p = .009) and ongoing pain was increased by 30%. CONCLUSIONS: The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. SIGNIFICANCE: This article presents new insights into serotonin receptor 2A-mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism-based therapies.

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.

Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients.

Chronic pain is a major health care issue characterized by ongoing pain and a variety of sensory, cognitive, and affective abnormalities. The neural basis of chronic pain is still not completely understood. Previous work has implicated prefrontal brain areas in chronic pain. Furthermore, prefrontal neuronal oscillations at gamma frequencies (60-90 Hz) have been shown to reflect the perceived intensity of longer lasting experimental pain in healthy human participants. In contrast, noxious stimulus intensity has been related to alpha (8-13 Hz) and beta (14-29 Hz) oscillations in sensorimotor areas. However, it is not fully understood how the intensity of ongoing pain as the key symptom of chronic pain is represented in the human brain. Here, we asked 31 chronic back pain patients to continuously rate their ongoing pain while simultaneously recording electroencephalography (EEG). Time-frequency analyses revealed a positive association between ongoing pain intensity and prefrontal beta and gamma oscillations. No association was found between pain and alpha or beta oscillations in sensorimotor areas. These findings indicate that ongoing pain as the key symptom of chronic pain is reflected by neuronal oscillations implicated in the subjective perception of longer lasting pain rather than by neuronal oscillations related to the processing of objective nociceptive input. The findings, thus, support a dissociation of pain intensity from nociceptive processing in chronic back pain patients. Furthermore, although possible confounds by muscle activity have to be taken into account, they might be useful for defining a neurophysiological marker of ongoing pain in the human brain.

Fronto-Insular Connectivity during Pain Distraction Is Impaired in Patients with Somatoform Pain.

BACKGROUND AND PURPOSE: Somatoform pain disorder is characterized by chronic pain and various psychological symptoms including increased attention to mental and physical processes. Given that the medial prefrontal cortex (mPFC) of the default mode network (DMN) and the anterior insula of the salience network are critically involved in intrinsic and attentional processes, we investigated the involvement of these networks during the distraction from physical pain in somatoform pain patients. METHODS: During painful and nonpainful heat stimulation, attentional distraction from physical processes was modulated with a Stroop task. Thirteen patients were investigated with functional magnetic resonance imaging (fMRI) and compared to 13 controls. Main outcomes were spatial maps of coherent fMRI activity based on independent component analysis and functional connectivity (FC) resulting from psychophysiological interaction analysis. RESULTS: Behavioral pain intensity ratings were reduced during the distraction task in both groups. At brain level, we found deviant network activities in the DMN (particularly in the mPFC) and in the salience network (bilaterally in the anterior insula) in patients. During pain stimulation, Stroop-induced distraction decreased the FC between the mPFC and anterior insula in controls but not in patients. CONCLUSIONS: Modulating the FC between the mPFC and the insula may be highly relevant for shifting the attention away from external stimuli, including nociceptive input. The observed alterations in somatoform pain patients may foster new strategies in cognitive behavioral training tools for these patients.

Pathophysiological mechanisms of neuropathic pain: comparison of sensory phenotypes in patients and human surrogate pain models.

As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.

Sensory symptom profiles differ between trigeminal and thoracolumbar postherpetic neuralgia.

INTRODUCTION: Animal experimental evidence suggests that mechanisms of pain generation and response to treatment differ between neuropathic pain in the cephalic and the extracephalic innervation territories. OBJECTIVES: The objective of the study was to examine whether in humans an identical peripheral painful neuropathy is associated with different pain qualities and sensory abnormalities in the face as compared with the thoracic region. METHODS: We retrospectively analysed epidemiological and clinical data of 639 patients with postherpetic neuralgia (PHN) in the face and at the trunk who were collected within a cross-sectional cohort survey and compared the respective sensory symptom profiles captured with the painDETECT questionnaire. RESULTS: Two hundred twenty-four patients suffered from trigeminal PHN and 415 from thoracolumbar PHN. There were no significant differences in sex-ratio, age, body mass index, and pain duration. Patients with trigeminal PHN were more often severely depressed. Anxiety and sleep scores were not different. The average pain intensity was slightly higher in thoracolumbar PHN than trigeminal PHN (visual analogue scale 5.0 vs 4.6). Postherpetic neuralgia in the thoracolumbar region showed significantly more intense burning sensations, allodynia, painful attacks, and significantly less prickling and numbness than PHN in the face. CONCLUSIONS: The differences in sensory symptom profiles between facial PHN and truncal PHN might be associated with different pathophysiological mechanisms and different treatment response. Drugs that primarily act on sensitization processes in the peripheral nociceptive system may work better in thoracolumbar PHN than in trigeminal PHN. If new medications are tested in patients with PHN, it would therefore be of interest to include an analysis of the treatment results in regard to subgroups based on the localisation of pain in patients with PHN.

Motor Responses to Noxious Stimuli Shape Pain Perception in Chronic Pain Patients.

Pain serves vital protective functions, which crucially depend on appropriate motor responses to noxious stimuli. Such responses not only depend on but can themselves shape the perception of pain. In chronic pain, perception is often decoupled from noxious stimuli and motor responses are no longer protective, which suggests that the relationships between noxious stimuli, pain perception, and behavior might be changed. We here performed a simple experiment to quantitatively assess the relationships between noxious stimuli, perception and behavior in 22 chronic pain patients and 22 age-matched healthy human participants. Brief noxious and tactile stimuli were applied to the participants' hands and participants performed speeded motor responses and provided perceptual ratings of the stimuli. Multi-level moderated mediation analyses assessed the relationships between stimulus intensity, perceptual ratings and reaction times for both stimulus types. The results revealed a significantly stronger involvement of motor responses in the translation of noxious stimuli into perception than in the translation of tactile stimuli into perception. This significant influence of motor responses on pain perception was found for both chronic pain patients and healthy participants. Thus, stimulus-perception-behavior relationships appear to be at least partially preserved in chronic pain patients and motor-related as well as behavioral interventions might harness these functional relationships to modulate pain perception.

Association of clinical headache features with stroke location: An MRI voxel-based symptom lesion mapping study.

Background We have recently shown that the presence of headache in ischemic stroke is associated with lesions of the insular cortex. The aim of this post-hoc subgroup analysis was to investigate the association of specific headache features with stroke location in patients with acute ischemic stroke. Methods In this observational study, patients (mean age: 61.5, 58% males) with ischemic stroke and acute headache (n = 49) were investigated. Infarcts were manually outlined on 3D diffusion weighted magnetic resonance imaging (MRI) scans and transformed into standard stereotaxic space; lesions of the left hemisphere were mirrored in the x-axis to allow a voxel-wise group analysis of all patients. We analyzed the association of lesion location and the following phenotypical characteristics by voxel-based symptom lesion mapping: Headache intensity, different qualities of headache (pulsating, tension-type like and stabbing), and the presence of nausea, of cranial autonomic symptoms and of light or noise sensitivity. Results Headache intensity was associated with lesions of the posterior insula, the operculum and the cerebellum. "Pulsating" headache occurred with widespread cortical and subcortical strokes. The presence of "tension-like" and "stabbing" headache was not related to specific lesion patterns. Nausea was associated with lesions in the posterior circulation territory. Cranial-autonomic symptoms were related to lesions of the parietal lobe, the somatosensory cortex (SI) and the middle temporal cortex. The presence of noise sensitivity was associated with cerebellar lesions, whereas light sensitivity was not related to specific lesions in our sample. Conclusion Headache phenotype in ischemic stroke appears to be related to specific ischemic lesion patterns.

Treatment of Low Back Pain with a Digital Multidisciplinary Pain Treatment App: Short-Term Results.

BACKGROUND: Even though modern concepts of disease management of unspecific low back pain (LBP) postulate active participation of patients, this strategy is difficult to adapt unless multidisciplinary pain therapy is applied. Recently, mobile health solutions have proven to be effective aides to foster self-management of many diseases. OBJECTIVE: The objective of this paper was to report on the retrospective short-term results of a digital multidisciplinary pain app for the treatment of LBP. METHODS: Kaia is a mobile app that digitalizes multidisciplinary pain treatment and is in the market as a medical product class I. For the current study, the data of anonymized Kaia users was retrospectively analyzed. User data were evaluated for 12 weeks regarding duration of use and effect on in-app user reported pain levels, using the numerical rating scale (NRS), depending on whether LBP was classified as acute, subacute, or chronic back pain according to current guidelines. RESULTS: Data of 180 users were available. The mean age of the users was 33.9 years (SD 10.9). Pain levels decreased from baseline NRS 4.8 to 3.75 for all users at the end of the observation period. Users who completed 4, 8, or 12 weeks showed an even more pronounced decrease in pain level NRS (baseline 4.9 [SD 1.7] versus 3.6 [SD 1.5] at 4 weeks; baseline 4.7 [SD 1.8] versus 3.2 [SD [2.0] at 8 weeks; baseline 4.6 [SD 2.2] versus 2.6 [SD 2.0] at 12 weeks). In addition, subgroup analysis of acute, subacute, or chronic classification revealed no significant main effect of group (P>.30) on the reduction of pain. Conclusions: This retrospective study showed that in a pre-selected population of app users, an app digitalizing multidisciplinary rehabilitation for the self-management of LBP reduced user-reported pain levels significantly. The observed effect size was clinically relevant. Ongoing prospective randomized controlled trials (RCTs) will adjust for potential bias and selection effects. CONCLUSIONS: This retrospective study showed that in a pre-selected population of app users, an app digitalizing multidisciplinary rehabilitation for the self-management of LBP reduced user-reported pain levels significantly. The observed effect size was clinically relevant. Ongoing prospective RCTs will adjust for potential bias and selection effects.

Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations.

In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5.

Symptom profiles in the painDETECT Questionnaire in patients with peripheral neuropathic pain stratified according to sensory loss in quantitative sensory testing.

The painDETECT Questionnaire (PDQ) is commonly used as a screening tool to discriminate between neuropathic pain (NP) and nociceptive pain, based on the self-report of symptoms, including pain qualities, numbness, and pain to touch, cold, or heat. However, there are minimal data about whether the PDQ is differentially sensitive to different sensory phenotypes in NP. The aim of the study was to analyze whether the overall PDQ score or its items reflect phenotypes of sensory loss in NP as determined by quantitative sensory testing. An exploratory analysis in the Innovative Medicines Initiative Europain and Neuropain database was performed. Data records of 336 patients identified with NP were grouped into sensory profiles characterized by (1) no loss of sensation, (2) loss of thermal sensation, (3) loss of mechanical sensation, and (4) loss of thermal and mechanical sensation. painDETECT Questionnaire profiles were analyzed in a 2-factor analysis of variance. Patients with loss of thermal sensation (2 and 4) significantly more often reported pain evoked by light touch, and patients with loss of mechanical sensation (3 and 4) significantly more often reported numbness and significantly less often burning sensations and pain evoked by light touch. Although the PDQ was not designed to assess sensory loss, single items reflect thermal and/or mechanical sensory loss at group level, but because of substantial variability, the PDQ does not allow for individual allocation of patients into sensory profiles. It will be useful to develop screening tools according to the current definition of NP.