No pain no gain:Exploration and validation of experimental pain models in human healthy volunteers for applications in drug development and implications of quantitative sensory testing in neuropathic pain patients

Pijnbehandeling blijft een belangrijke uitdaging voor de huidige medische wetenschappen. Er wordt geschat dat de prevalentie van chronische pijn op kan lopen tot 35%. Dat betekent dat een op de drie mensen een periode met chronische pijn heeft in zijn leven. Deze last voor onze samenleving benadrukt het belang van de ontwikkeling van effectieve pijnbehandelingen. We hebben onderzocht of Kwantitatieve Sensorische Testen (KST) voor acute pijn en neuropathische pijn de betrouwbaarheid van effectiviteitsstudies in gezonde vrijwilligers en patiënten kan verbeteren. Tevens was het doel om een robuust capsaicine model voor neuropathische pijn te ontwikkelen dat betrouwbare hyperalgesie en allodynia zou induceren. Onze resultaten laten zien dat de pijngrens voor hitte, de pijngrens voor druk en de ‘cold pressor’ test de meest betrouwbare maten zijn om effectiviteit van pijnstillers voor acute pijn te testen. In het algemeen ondersteunt de hoge test-hertest-betrouwbaarheid in onze studies het gebruik van KST voor het testen van pijnstillers en kan het de ‘assay-sensitivity’ van klinische studies verbeteren. Onze KST database heeft aangetoond dat menig patiënt met chronische pijn niet alleen een verstoorde sensorische verwerking heeft aan de pijnlijke pathologische lichaamshelft maar ook aan de contralaterale (niet-pijnlijke) kant. Het ‘Heat Capsaicin Warmth (HCW) model voor neuropathische pijn met continue pijn door capsaicine gecombineerd met warmte, is een goede methode om allodynie te bewerkstelligen, een belangrijk symptoom van neuropathische pijn. In het algemeen dragen de resultaten van onze studies bij aan de selectie van de juiste pijn testen en modellen en de verbetering van klinische studies voor pijnbehandelingen

Somatosensory Profiles but Not Numbers of Somatosensory Abnormalities of Neuropathic Pain Patients Correspond with Neuropathic Pain Grading

Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as ‘definite’, ‘probable’, ‘possible’ and ‘unlikely’ neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of abnormalities would be present in patients with ‘probable’ and ‘definite’ grades. To test this hypothesis, we investigated the presence of somatosensory abnormalities by means of Quantitative Sensory Testing (QST) in patients with a clinical diagnosis of neuropathic pain and correlated the number of sensory abnormalities and sensory profiles to the different grades. Of patients who were clinically diagnosed with neuropathic pain, only 60% were graded as ‘definite’ or ‘probable’, while 40% were graded as ‘possible’ or ‘unlikely’ neuropathic pain. Apparently, there is a mismatch between a clinical neuropathic pain diagnosis and neuropathic pain grading. Contrary to the expectation, patients with ‘probable’ and ‘definite’ grades did not have a greater number of abnormalities. Instead, similar numbers of somatosensory abnormalities were identified for each grade. The profiles of sensory signs in ‘definite’ and ‘probable’ neuropathic pain were not significantly different, but different from the ‘unlikely’ grade. This latter difference could be attributed to differences in the prevalence of patients with a mixture of sensory gain and loss and with sensory loss only. The grading system allows a separation of neuropathic and non-neuropathic pain based on profiles but not on the total number of sensory abnormalities. Our findings indicate that patient selection based on grading of neuropathic pain may provide advantages in selecting homogenous groups for clinical research

Bilateral Sensory Abnormalities in Patients with Unilateral Neuropathic Pain; A Quantitative Sensory Testing (QST) Study

In patients who experience unilateral chronic pain, abnormal sensory perception at the non-painful side has been reported. Contralateral sensory changes in these patients have been given little attention, possibly because they are regarded as clinically irrelevant. Still, bilateral sensory changes in these patients could become clinically relevant if they challenge the correct identification of their sensory dysfunction in terms of hyperalgesia and allodynia. Therefore, we have used the standardized quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS) to investigate somatosensory function at the painful side and the corresponding non-painful side in unilateral neuropathic pain patients using gender- and age-matched healthy volunteers as a reference cohort. Sensory abnormalities were observed across all QST parameters at the painful side, but also, to a lesser extent, at the contralateral, non-painful side. Similar relative distributions regarding sensory loss/gain for non-nociceptive and nociceptive stimuli were found for both sides. Once a sensory abnormality for a QST parameter at the affected side was observed, the prevalence of an abnormality for the same parameter at the non-affected side was as high as 57% (for Pressure Pain Threshold). Our results show that bilateral sensory dysfunction in patients with unilateral neuropathic pain is more rule than exception. Therefore, this phenomenon should be taken into account for appropriate diagnostic evaluation in clinical practice. This is particularly true for mechanical stimuli where the 95% Confidence Interval for the prevalence of sensory abnormalities at the non-painful side ranges between 33% and 50%

Factors associated with health status and exacerbations in COPD maintenance therapy with dry powder inhalers

Funding Information: J.K. reports grants, personal fees and non-financial support from AstraZeneca, GSK and Boehringer Ingelheim; grants and personal fees from Chiesi Pharmaceuticals and TEVA; grants from Mundipharma; personal fees from MSD and COVIS Pharma; and also holds 72.5% of shares in the General Practitioners Research Institute. H.W. has received grants from Boehringer Ingelheim, which is the financial and scientific partner of GPRI for the submitted study, and from AstraZeneca, Novartis and Chiesi for scientific projects in the area of COPD/asthma. S.B.-A. has received grants from TEVA, and personal fees from TEVA, Boehringer Ingelheim, AstraZeneca, GSK, Sanofi and Mylan. J.C.d.S. reports or personal fees from AstraZeneca, Bial, Boehringer Ingelheim, GSK, Medinfar, Mundipharma and Sanofi. B.C. received honorarium from GSK and Sanofi. J.v.C., L.D., I.v.G.-P., I.v.d.H., Y.J., M.K., B.M., K.S., N.S., M.H., B.M. and M.T.L. were employed by General Practitioners Research Institute (GPRI) at the time of the study. In the past three years (2019–2021), GPRI conducted investigator- and sponsor-initiated research funded by non-commercial organizations, academic institutes, and pharmaceutical companies (including AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, Novartis, and Teva). R.D. has received grants and personal fees from TEVA, Boehringer Ingelheim, AstraZeneca, GSK, Chiesi, Focus Care, and Glenmark. R.G. has received personal fees from AstraZeneca, GSK and Chiesi. E.D. holds 27.5% of shares in the General Practitioners Research Institute. M.G.P. receives grants from AstraZeneca, GSK and Boehringer Ingelheim. A.G. and A.d.l.H. are employees of Boehringer Ingelheim. F.L. received grants and personal fees from GSK, personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini International, Novartis, Orion, and Trudell International, outside the submitted work. T.M. is an Assoicate Editor at npj Primary Care Respiratory Medicine. J.M. received grants from Boehringer Ingelheim, during the conduct of the study; and grants from AstraZeneca, Chiesi, Novartis, and GSK, outside the submitted work. D.P. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Theravance and Zentiva (Sanofi Generics); grants from the British Lung Foundation, Respiratory Effectiveness Group, UK National Health Service, and AKL Research and Development Ltd; personal fees from Cipla, GlaxoSmithKline, Kyorin, Merck, Mundipharma, Airway Vista Secretariat, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, and WebMD Global LLC; non-financial support from Efficacy and Mechanism Evaluation programme and Health Technology Assessment; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); and 5% shareholding in Timestamp, which develops adherence monitoring technology. M.R.-R. receives grants and personal fees from AstraZeneca and GSK; and personal fees from Boehringer Ingelheim, Chiesi, Menarini, Mundipharma, Novartis, Pfizer, TEVA and BIAL. I.T. reports grants and personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Menarini, Novartis, Chiesi and Elpen. O.U. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Edmond Pharma, Chiesi and GSK; grants from Edmond Pharma; and personal fees from Napp, Mundipharma, Sandoz, Takeda, Cipla, COVIS, Novartis, Mereobiopharma, Orion, and Menarini. S.B.-A. and T.M. are Associate Editors at npj Primary Care Respiratory Medicine, and I.T. is Editor in Chief. These authors were not involved in the journal’s review of, or decisions related to, this manuscript.Peer reviewedPublisher PD

Dynamic crossmodal links revealed by steady-state responses in auditory-visual divided attention

Frequency tagging has been often used to study intramodal attention but not intermodal attention. We used EEG and simultaneous frequency tagging of auditory and visual sources to study intermodal focused and divided attention in detection and discrimination performance. Divided-attention costs were smaller, but still significant, in detection than in discrimination. The auditory steady-state response (SSR) showed no effects of attention at frontocentral locations, but did so at occipital locations where it was evident only when attention was divided between audition and vision. Similarly, the visual SSR at occipital locations was substantially enhanced when attention was divided across modalities. Both effects were equally present in detection and discrimination. We suggest that both effects reflect a common cause: An attention-dependent influence of auditory information processing on early cortical stages of visual information processing, mediated by enhanced effective connectivity between the two modalities under conditions of divided attention. (C) 2009 Elsevier B.V. All rights reserved

Z-score profiles at the affected side and contralateral side in neuropathic pain patients.

<p>Sensory abnormalities (Z score <−1.96 or >1.96) for each Quantitative Sensory Testing (QST) parameter at the affected side (left) and contralateral side (right) in 81 neuropathic pain patients. Grey area indicates parameters within the normal range (−1.96</p

Overview of sensory abnormalities in QST.

<p>Patient numbers with sensory abnormalities at the affected (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037524#pone-0037524-t002" target="_blank">Table 2A</a>, top) and contralateral side (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037524#pone-0037524-t002" target="_blank">Table 2B</a>, bottom). Sensory abnormalities were defined as Z score <−.96 or >1.96 corresponding with 95% of values obtained from healthy volunteers. Shown are direction (n of sensory gain/n of sensory loss) and overall abnormalities in percent (% of sensory abnormality) for each Quantitative Sensory Testing (QST) parameters in 81 chronic pain patients. QST parameter: Cold Pain Threshold (CPT), Heat Pain Threshold (HPT), Warm Detection Threshold (WDT), Wind Up Ratio (WUR), Cold Detection Threshold (CDT), Thermal Sensory Limen (TSL), Paradoxical Heat Sensation (PHS), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), Mechanical Detection Threshold (MDT), Vibration Disappearance Threshold (VDT), Pressure Pain Threshold (PPT) and Dynamic Mechanical Allodynia (DMA). Wilson estimates with upper and lower bound of the 95% CI for each QST parameter (* p<0.05).</p

Quantitative Sensory Testing (QST) abnormalities at the affected and contralateral side in neuropathic pain patients.

<p>Quantitative Sensory Testing (QST) Z-score abnormalities in % at the affected (left) and contralateral side (right) in 81 neuropathic pain patients. Sensory abnormalities were defined as Z score < −1.96 or >1.96 corresponding with 95% of values obtained from healthy volunteers. QST parameter are ordered as sensory parameters: Cold Detection Threshold (CDT), Warm Detection Threshold (WDT), Thermal Sensory Limen (TSL), Mechanical Detection Threshold (MDT), Vibration Disappearance Threshold (VDT), Paradoxical Heat Sensation (PHS), Dynamic Mechanical Allodynia (DMA) and nociceptive parameters: Cold Pain Threshold (CPT), Heat Pain Threshold (HPT), Pressure Pain Threshold (PPT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS) and Wind Up Ratio (WUR). Z-scores with positive sensory signs (gain of sensory function) plotted rightwards and negative sensory signs (loss of sensory function) plotted leftwards. Absence of DMA is normal and therefore no negative sign possible.</p

Patient characteristics.

<p>Demographic patient overview; Patient ID, gender and age are indicated. Patient’s rating of ongoing pain prior to Quantitative Sensory Testing (QST) using a Numeric Rating scale (NRS) indicating “0” as “no pain” and “100” as the ‘‘most intense pain imaginable’’. Involved nerve indicates nerves (N.) or innervations area of nerves affected in relation to the cause of pain. Number of QST abnormalities refers to parameter exceeding CI 95% of z-scores (<−1.96 or >1.96) of values obtained from healthy volunteers for the affected (A.) and contralateral (C.) side of patients.</p

Diagnostic consequence of using either the contralateral side or normative data from healthy volunteers.

<p>The interpretation of sensory function and its clinical manifestation at the affected side using the contralateral side or reference values from healthy volunteers. The observation at the affected side and contralateral side indicate the sensory response for a Quantitative Sensory Testing (QST) parameter in patients. Clinical results using the contralateral side as reference or healthy volunteers as reference indicate sensory interpretation for the affected side. ‘0’ indicate normal sensory function, ‘+’ indicate sensory gain such as hyperalgesia/allodynia, ‘−’ indicate sensory loss such as hypoesthesia, ‘++’ or ‘− −’ indicate overestimation of sensory gain or sensory loss, respectively.</p