Stress-free blood sampling in minipigs: A novel method for assessing 24-h cortisol profiles and drug effects on diurnal and ultradian rhythms.

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.

Pleasantness and unpleasantness in somatosensory investigation.

BACKGROUND: Qualitative sensory testing (QualST) is a simple, standardised, chairside method for evaluating somatosensory function; however, testing focuses on detection of cold, touch and pain with no recognition of perceptions of pleasantness and unpleasantness. OBJECTIVES: The study aimed to utilise the stimuli in QualST, with the addition of a soft brush, to investigate stimulus-evoked perceptions of pleasantness and unpleasantness on the facial skin and if any side-to-side differences. Additional aims were to determine the inter- and intra-rater reliability using the modified QualST protocol and in the side-to-side differences. METHODS: Thirty healthy adult female participants underwent three sessions of sensitivity testing as per the modified QualST protocol. Stimuli were applied bilaterally to the facial skin, and participants provided separate yes/no responses for presence of stimulus-evoked pleasantness, unpleasantness and/or differences between sides. RESULTS: The stimuli were able to evoke sensations of pleasantness and unpleasantness with little differences in responses between the Q-tip and goat hair brush for the perceptions. Side-to-side differences in evoked perceptions were observed and greatest, when evaluating for pinprick-evoked unpleasantness (range between sessions = 18-19 participants). Acceptable percentage (≥90%) and excellent Cohen's Kappa (≥0.762) inter- and intra-rater agreements were identified for one or more positive responses for each stimulus modality and the targeted perception. CONCLUSION: The modified QualST protocol provides a simple, reproducible method for the investigation of perceptions of pleasantness and unpleasantness, with readily accessible instrumentation to dental professionals and allowing for a more holistic approach in somatosensory testing.

Are orofacial pain and xerostomia associated with differences in diet, sensory perception, appetite and enjoyment of eating?-An explorative study.

BACKGROUND: Orofacial function is believed to influence an individual's diet. knowledge on appetite and enjoyment of eating in orofacially impaired individuals is scarce. OBJECTIVE: We aimed to explore potential associations between impaired orofacial function, that is, orofacial pain, jaw function limitation and xerostomia, respectively, and diet, appetite, taste perception, as well as the enjoyment of eating. METHODS: An online questionnaire was shared among Aarhus University's dental patients and through social media. A convenience sample of 351 individuals responded (97 men, 254 women, aged 18-86 years). Participants were divided into groups with and without orofacial pain or xerostomia based on responses. Questions about food intake, appetite, meal-related well-being and oral/general health were included. Data were analysed using Mann Whitney U tests, Spearman's correlation, Chi-square tests, and t-tests. RESULTS: Participants with (n = 123) and without (n = 228) orofacial pain differed significantly regarding age, perceived oral/general health, frequency of consumption of for example cooked vegetables and raw whole fruit, perception of sourness, chewiness, and nausea/pain when eating (p ≤ .031). Participants with (n = 101) and without (n = 250) xerostomia differed significantly regarding perceived oral/general health, intake of prepared fruit, alcohol, ice cream/mousse/pudding, general appetite, intake of breakfast and liquid snacks, nausea/pain when eating, taste and chewiness of food (p ≤ .038). CONCLUSION: Diet, appetite, taste and sensory perception, as well as enjoyment of eating of individuals reporting orofacial pain and/or xerostomia differed slightly to that of individuals free of such symptoms. However, due to the explorative nature of this study, the results should be interpreted with caution pending further research on potential long-term effects on nutritional status and well-being.

Clinical features of chronic primary pain in individuals presenting painful temporomandibular disorder and comorbidities.

BACKGROUND: The diagnosis of chronic primary pain (CPP), according to the recently released International Classification of Disease (ICD-11) criteria, refers to conditions with complex aetiologies. CPP is characterized by specific clinical features such as generalized sensory hypersensitivity and widespread pain, and is associated with functional disability and emotional distress. OBJECTIVE: This study investigated clinical features of CPP in individuals with painful temporomandibular disorders (TMD) and comorbidities (fibromyalgia, migraine and/or tension-type headache). METHODS: This cross-sectional study was conducted with a sample of 129 individuals. Painful TMD, fibromyalgia and primary headaches were evaluated based on well-established international criteria. Generalized sensory hypersensitivity was assessed using psychophysical tests. Symptoms of anxiety and depression were assessed by the Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9. The Central Sensitization Inventory was applied to assess central sensitization-related symptoms and the Pittsburg Sleep Quality Index to evaluate the quality of sleep. The presence of widespread pain was assessed using a body map. The sample was stratified into three groups: control (n = 25), TMD-painful TMD only (n = 35) and TMD + Cm-painful TMD and comorbidities (n = 69). Statistical analysis was performed using one-way ANOVA, chi-squared test and ANCOVA, considering gender as a covariate (α = .05). RESULTS: Compared to controls, individuals presenting painful TMD and comorbidities showed lower pressure pain thresholds in all evaluated areas (p ≤ .012) and a higher number of painful areas in the body (p = .001). They presented more symptoms of anxiety (p = .040) and depression (p = .018), and a higher score in the Central Sensitization Inventory (p ≤ .006) than the other groups. CONCLUSION: Individuals with painful TMD and comorbidities presented more clinical features of CPP compared to those affected by TMD only.

Constructing the brief diagnostic criteria for temporomandibular disorders (bDC/TMD) for field testing.

BACKGROUND: Despite advances in temporomandibular disorders' (TMDs) diagnosis, the diagnostic process continues to be problematic in non-specialist settings. OBJECTIVE: To complete a Delphi process to shorten the Diagnostic Criteria for TMD (DC/TMD) to a brief DC/TMD (bDC/TMD) for expedient clinical diagnosis and initial management. METHODS: An international Delphi panel was created with 23 clinicians representing major specialities, general dentistry and related fields. The process comprised a full day workshop, seven virtual meetings, six rounds of electronic discussion and finally an open consultation at a virtual international symposium. RESULTS: Within the physical axis (Axis 1), the self-report Symptom Questionnaire of the DC/TMD did not require shortening from 14 items for the bDC/TMD. The compulsory use of the TMD pain screener was removed reducing the total number of Axis 1 items by 18%. The DC/TMD Axis 1 10-section examination protocol (25 movements, up to 12 sets of bilateral palpations) was reduced to four sections in the bDC/TMD protocol involving three movements and three sets of palpations. Axis I then resulted in two groups of diagnoses: painful TMD (inclusive of secondary headache), and common joint-related TMD with functional implications. The psychosocial axis (Axis 2) was shortened to an ultra-brief 11 item assessment. CONCLUSION: The bDC/TMD represents a substantially reduced and likely expedited method to establish (grouping) diagnoses in TMDs. This may provide greater utility for settings requiring less granular diagnoses for the implementation of initial treatment, for example non-specialist general dental practice.

Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

BACKGROUND: Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. CONCLUSION: In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

Impact of postoperative intravenous iron therapy on postoperative infections in older patients with severe anaemia after hip fracture surgery.

BACKGROUND: Anaemia is common following hip fracture in ortho-geriatric patients and is associated with postoperative infections.. This study investigated whether intravenous iron supplements reduced the rate of postoperative infections within 30 days postoperatively in older adults after hip fracture surgery. METHODS: This observational study included 198 ortho-geriatric patients July 2018-May 2020. In May 2019 a local guideline was implemented and recommended II therapy on the 3rd postoperative day if haemoglobin concentration was < 6.5 mmol/L after hip fracture surgery. RESULTS: The patients were divided into four treatment groups: blood transfusion (n = 44), IV iron (n = 69), blood transfusion + IV iron (n = 35) and no treatment (n = 50). The number of patients who had an infection within 30 days was similar in the two time periods (38.8% before vs. 38.9% after systematic I.V. iron supplementation, P = 1.00) and no significant difference according to risk of infection was found between treatment groups. CONCLUSION: This study documents no effect of intravenous iron supplements on postoperative infections in older adults after hip fracture surgery. TRIAL REGISTRATION: The study was registered with the Danish Data Protection Authority (2008-58-0028) the 2th of September 2019.

Nocebo response in dentistry: A systematic review and meta-analysis of adverse events in analgesic trials of third molar removal.

BACKGROUND: The nocebo response refers to the phenomenon where non-specific factors, including negative verbal suggestion and treatment expectations, cause adverse events (AE) following a placebo treatment. Non-specific factors are also likely to influence AE occurrence following administration of active pharmacological treatments. OBJECTIVE: This meta-analysis aimed to estimate the nocebo response in dentistry by assessing the AEs prevalence in placebo- and active arms of randomised controlled trials (RCTs) assessing analgesic treatment following third molar (M3) surgery. METHODS: A systematic search was performed in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials. Eligible studies had to report the number of patients experiencing at least one drug-related AE (patients with AE ≥ 1) separately for the active and placebo arms. The proportion of patients with AE ≥ 1 and drug-related dropouts were pooled, and risk differences (RDs) between patients in the placebo- and active arm were calculated. RESULTS: In 50 independent RCTs of 47 identified articles, the pooled rates of patients with AE ≥ 1 were 22.8% in the placebo arm and 20.6% in the active arm. The pooled rates of drug-related dropout were 0.24% in the placebo arm and 0.08% in the active arm. There were no significant RDs in patients with AE ≥ 1 and drug-related dropouts. CONCLUSION: These results show that patients in the placebo arm reported AEs to the same extent as patients receiving active treatment, suggesting that most AEs in analgesic medication following M3 surgery may be attributed to the nocebo phenomenon.

Role of dairy proteins in the reduction of capsaicin-induced oral burning pain.

Capsaicin-induced burning sensation in the oral mucosa can be relieved by skimmed and whole milk. The mechanism behind this effect, however, is unknown. This study aimed to asses the role of milk proteins in reducing capsaicin-induced oral burning sensation. 24 healthy participants were included in this single-blinded cross-over study consisting of four sessions. In each sessions, mucosal burning sensation was evoked by having the participants dip their tongues in a cup containing 0.1% capsaicin gel for a total of 8 min. The perceived levels of unpleasantness and burning intensity were scored on two different numerical rating scales. After capsaicin exposure, the participants rinsed their mouth for 10 s with a different solution in each session (3.5% casein, 3.5% whey, 3.5% lactose (non-protein control) and skimmed milk (active/positive control)). Mechanical (64, 128 and 256 mN pinprick) and thermal (5, 40, 45 and 50 ̊C) sensitivity of the tongue was measured using semi-quantative sensory testing at baseline, immediately after capsaicin exposure and when the scores for unpleasantness and burning intensity reached the minimum value of 0. Thermographic images of the tongue were taken at the same time-points. Overall, no statistically significant difference in unpleasantness and burning intensity was found between the four sessions (P ≥ 0.070). Explorative pair-wise comparisons, however, showed slight short-term reduction in unpleasantness and burning intensity when comparing the casein solution with the lactose solution (P ≤ 0.020). Scores for burning intensity and unpleasantness varied over time (P ≤ 0.001). Statistically significant changes in heat and mechanical sensitivity was observed between time-points (P < 0.001) but not sessions (P ≥ 0.410). An increased sensitivity towards heat and a decreased sensitivity towards mechanical stimuli was observed after capsaicin exposure compared with baseline (P < 0.001). Similarly, changes in thermographic temperature of the tongue was observed between time-points (P < 0.001), but not sessions (P ≥ 0.827). An increased maximum, minimum and average temperature of the tongue was observed immediately after capsaicin exposure compared with baseline (P < 0.001). In conclusion, short-term rinsing with room temperature milk proteins did not robustly alter capsaicin-induced oral burning sensation, unpleasantness, somatosensory changes or tongue temperature compared with control. Further studies exploring the effects of increased rinsing time and concentrations are needed in the future.

What is the nocebo effect and does it apply to dentistry?-A narrative review.

BACKGROUND: Evidence for the nocebo effect, a phenomenon characterised by suboptimal treatment efficacy, worsening of symptoms, or the occurrence of adverse events caused by an individual's negative treatment expectations, is growing across a multitude of medical fields. However, little attention has been paid to patients' negative expectations and the nocebo effect within dentistry. AIM: This review summarises essential evidence of the nocebo phenomenon especially in relation to pain and drug administration. Subsequently, an overview of the current evidence of the nocebo phenomenon in the dental field is presented. METHODS: A PubMed search was performed using keywords related to "nocebo," "placebo," "expectations," and "dentistry." In addition to the articles selected from the search, placebo/nocebo researchers and dental researchers added important references from their respective fields. RESULTS: Although research on the nocebo effect in dentistry is limited, available current evidence suggests that the factors, which is related to the nocebo effect are likely to play a role in dental practice. CONCLUSION: Preliminary evidence from the review warrants further investigation into the nocebo effect in dentistry. Finally, based on the general knowledge of the nocebo effect, the review indicates fruitful arrays of research into the nocebo effect in dentistry.

A conceptual model of oro-facial health with an emphasis on function.

The individual inclination to lead an autonomous life until death is associated with requirements that may be of physiological, psychosocial and environmental nature. We aim to describe a conceptual oro-facial health model with an emphasis on oro-facial function, taking the domains of quality of life and patient-centred values into account. In the context of oro-facial function, the requirements of life are met when the oro-facial system is in a fit state. 'Fitness of the oro-facial system, that is oro-facial health, is a state that is characterised by an absence of, or positive coping with physical disease, mental disease, pain and negative environmental and social factors. It will allow natural oro-facial functions such as sensing, tasting, touching, biting, chewing, swallowing, speaking, yawning, kissing and facial expression'. In the presented conceptual model of oro-facial health, it is postulated that each individual has present and future potentials related to biological prerequisites and resources that are developed by an individual through the course of life. These potentials form the oro-facial functional capacity. When the individual potentials together do not meet the requirements of life anymore, dysfunction and disease result. The oro-facial system is subject to physiological ageing processes, which will inevitably lead to a decrease in the oro-facial functional capacity. Furthermore, comorbid medical conditions might hamper oro-facial function and, alongside with the ageing process, may lead to a state of oral hypofunction. Currently, there is a lack of widespread, validated, easy-to-use instruments that help to distinguish between states of oro-facial fitness as opposed to oral hypofunction. Clearly, research is needed to establish adequate, validated instruments alongside with functional rehabilitation procedures.

Painful and non-painful symptoms evoked by experimental bracing and thrusting of the mandible in healthy individuals.

BACKGROUND: Bruxism may involve bracing and thrusting of the mandible, in addition to clenching or grinding of the teeth. It is unclear how bracing and thrusting may contribute to potential musculoskeletal symptoms associated with bruxism. OBJECTIVE: To examine the effect of experimental bracing and thrusting of the mandible on the development of musculoskeletal symptoms in healthy volunteers. METHODS: Thirty healthy volunteers performed six trials of 5 min of repeated bracing and thrusting of the mandible. Bracing involved forcefully maintaining maximum protruded position (5 s with 1 s rest in between), whereas thrusting involved forcefully moving the mandible in a forward direction and back (1 Hz). The participants rated pain, unpleasantness, soreness, fatigue, tension, stiffness, stress and headache on 10-cm visual analogue scales (VAS) before, immediately and 24 h after the tasks. Pain drawings were obtained and maximum voluntary protrusive force (MVPF) was determined before and after the tasks. The outcome parameters for each task were compared between the time points. RESULTS: There was a significant increase in the VAS scores (2-4/10) of pain, unpleasantness, soreness, fatigue, tension, stiffness and stress immediately following the tasks compared to baseline and 24 h after the tasks (p < .008). Pain was frequently reported in masseter muscles. MVPF values were significantly higher immediately (p < .001) and 24 h after thrusting (p < .001) and bracing (p = .012) tasks compared to the baseline. CONCLUSIONS: Experimental bracing and thrusting of the mandible evoked transient, mild-to-moderate levels of muscle pain, fatigue, tension and stiffness and increased unpleasantness and stress scores in healthy volunteers.

Association between intravenous iron therapy and short-term mortality risk in older patients undergoing hip fracture surgery: an observational study.

BACKGROUND: Anemia is common among ortho-geriatric hip fracture patients and is associated with prolonged recovery and increased postoperative mortality rate. Intravenous iron seems to increase hemoglobin recovery and reduce the mortality rate in patients undergoing orthopedic surgeries. This study investigated the association between short-term mortality risk and intravenous iron therapy in older patients undergoing hip fracture surgery. METHODS: This observational study included 210 patients undergoing hip fracture surgery from July 2018 to May 2020. These 210 patients were alive and had a hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day. In May 2019, a local intravenous iron therapy protocol was implemented and recommended intravenous iron (Monofer©) if hemoglobin on the 3rd postoperative day was ≤ 6.5 mmol/L. According to the treatment of postoperative anemia between the 1st and 3rd day post-surgery, the patients were divided into four groups: no treatment (n=52), blood transfusion (n=38), IV Monofer (n=80), and blood transfusion and IV Monofer (n=40). Primary outcome was 30-day mortality post-surgery. The secondary outcome was the impact on hemoglobin level 14-30 days postoperatively. Multivariable Cox regression was used to estimate the 30-day mortality standardized for covariates. RESULTS: Of 210 patients, 17 (8.1%) died within 30 days after surgery. There was a significantly lower mortality among the patients who received IV Monofer compared to those who received no treatment (HR 0.17, 95% CI [0.03-0.93], P = 0.041). Among the 86 patients with available hemoglobin measurements within 14 to 30 days post-surgery, there was no significant difference in hemoglobin level between the various treatment groups (mean 6.6 mmol/L, P = 0.1165). CONCLUSION: IV Monofer on the 3rd postoperative day in older hip fracture patients seemed to reduce 30-day mortality compared with no treatment. No significant differences in hemoglobin levels between 14 and 30 days post-surgery across treatment groups were found, although this was assessed in a subset of patients with available hemoglobin levels warranting further study.

Lack of correlation between central sensitization inventory and psychophysical measures of central sensitization in individuals with painful temporomandibular disorder.

OBJECTIVE: To assess the correlation between the Central Sensitization Inventory (CSI) scores and the results of psychophysical tests and psychosocial questionnaires according to the presence of painful temporomandibular disorder (TMD). DESIGN: It was a cross-sectional study involving 146 participants, aged 20-65 years. Painful TMD was classified using the Research Diagnostic Criteria for Temporomandibular Disorders. CSI was applied to assess "central sensitization-related symptoms", as has been suggested. Wind-up ratio, pressure pain threshold and conditioned pain modulation were used as psychophysical tests to evaluate signs and symptoms of central sensitization. Psychosocial factors were assessed by the presence of non-specific physical symptoms, depressive and anxiety symptoms. The sample was divided into two groups: Control (n = 31); Painful TMD (n = 115). Descriptive statistics characterized the sample. Correlation analysis were performed using Pearson's and Spearman's correlation coefficients (α = 5%). RESULTS: Of the total sample, 78.8 % presented painful TMD, and the mean (standard deviation) age was 37.4 (±11.5) years. Anxiety symptoms (p = 0.028) and non-specific physical symptoms (p < 0.001) were more frequent in the painful TMD group than in controls. Painful TMD patients presented higher scores of the CSI (p < 0.001) and lower pressure pain thresholds (p ≤ 0.020) compared to controls. CSI scores were significantly correlated with psychosocial measures (p < 0.001) but not with psychophysical tests (p ≥ 0.089). CONCLUSION: The CSI scores did not correlate with psychophysical measures of central sensitization but were positively correlated with the results of psychosocial questionnaires.

Robotic Stroking on the Face and Forearm: Touch Satiety and Effects on Mechanical Pain.

Background: Slow stroking touch is generally perceived as pleasant and reduces thermal pain. However, the tactile stimuli applied tend to be short-lasting and typically applied to the forearm. This study aimed to compare the effects of a long-lasting brushing stimulus applied to the facial region and the forearm on pressure pain thresholds (PPTs) taken on the hand. Outcome measurements were touch satiety and concurrent mechanical pain thresholds of the hand. Methods: A total of 24 participants were recruited and randomized to receive continuous stroking, utilizing a robotic stimulator, at C-tactile (CT) favorable (3 cm/s) and non-favorable (30 cm/s) velocities applied to the right face or forearm. Ratings of touch pleasantness and unpleasantness and PPTs from the hypothenar muscle of the right hand were collected at the start of stroking and once per minute for 5 min. Results: A reduction in PPTs (increased pain sensitivity) was observed over time (P < 0.001). However, the increase in pain sensitivity was less prominent when the face was stroked compared to the forearm (P = 0.001). Continuous stroking resulted in a significant interaction between region and time (P = 0.008) on pleasantness ratings, with a decline in ratings observed over time for the forearm, but not on the face. Unpleasantness ratings were generally low. Conclusion: We observed touch satiety for 5 min of continuous robotic brushing on the forearm confirming previous studies. However, we did not observe any touch satiety for brushing the face. Mechanical pain sensitivity, measured in the hand, increased over the 5-min period but less so when paired with brushing on the face than with brushing on the forearm. The differential effects of brushing on the face and forearm on touch satiety and pain modulation may be by the differences in the emotional relevance and neuronal pathways involved.

Defining pleasant touch stimuli: a systematic review and meta-analysis.

Pleasantness is generally overlooked when investigating tactile functions. Addition of a pleasant stimulus could allow for a more complete characterisation of somatosensory function. The aims of this review were to systematically assess the methodologies used to elicit a pleasant sensation, measured via psychophysical techniques, and to perform a meta-analysis to measure the effect of brush stroking velocity on touch pleasantness. Eighteen studies were included in the systematic review, with five studies included in the meta-analysis. The review found that factors such as texture, velocity, force, and the duration of continuous stroking influence tactile evoked pleasantness. Specifically, using a soft material and stroking at a velocity of 3 cm/s with light force is generally considered as particularly pleasant. The meta-analysis showed that a brush stroking velocity of 30 cm/s was rated as less pleasant than 3 cm/s, on the forearm. The present study collates the factors that are most likely to provide a stimulus to elicit a pleasant sensation. The results should be important for studies requiring a well-defined pleasant stimulus including neurosensory assessment protocols, allowing for a more complete multimodality assessment of somatosensory function.

New International Classification of Orofacial Pain: What Is in It For Endodontists?

Pain is a common symptom in endodontic conditions, but differential diagnostic procedures are often needed to exclude other pain origins. Thus, general dentists and endodontists need to be aware of alternative painful orofacial conditions and be able to identify them. The new International Classification of Orofacial Pain (ICOP) is the first comprehensive classification that uniquely deals with orofacial pain. The ICOP is a hierarchical classification modeled on the International Classification of Headache Disorders and covers pain in dentoalveolar and anatomically related tissues, muscle pain, temporomandibular joint pain, neuropathic pain affecting cranial nerves, pain resembling primary headaches, and idiopathic pain in the orofacial region. A description of each condition is given, and structured diagnostic criteria for each condition are proposed based on research data when available. This narrative review aims (1) to give an overview and brief explanation of the ICOP system, (2) to describe and give examples of how it can be of use to general dentists and endodontists with special attention to differential diagnosis of tooth pain, and (3) to highlight how endodontic research can contribute to validation and improvement of the classification. A comparison to other classification and diagnostic systems is also included.

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

Orofacial quantitative sensory testing: Current evidence and future perspectives.

BACKGROUND AND OBJECTIVE: Orofacial quantitative sensory testing (QST) is an increasingly valuable psychophysical tool for evaluating neurosensory disorders of the orofacial region. Here, we aimed to evaluate the current evidence regarding this testing method and to discuss its future clinical potential. DATA TREATMENT: We conducted a literature search in Medline, Embase and Scopus for English-language articles published between 1990 and 2019. The utilized search terms included QST, quantitative, sensory testing and neurosensory, which were combined using the AND operator with the terms facial, orofacial, trigeminal, intraoral and oral. RESULTS: Our findings highlighted many methods for conducting QST-including method of levels, method of limits and mapping. Potential stimuli also vary, and can include mechanical or thermal stimulation, vibration or pinprick stimuli. Orofacial QST may be helpful in revealing disease pathways and can be used for patient stratification to validate the use of neurosensory profile-specific treatment options. QST is reportedly reliable in longitudinal studies and is thus a candidate for measuring changes over time. One disadvantage of QST is the substantial time required; however, further methodological refinements and the combination of partial aspects of the full QST battery with other tests and imaging methods should result in improvement. CONCLUSIONS: Overall, orofacial QST is a reliable testing method for diagnosing pathological neurosensory conditions and assessing normal neurosensory function. Despite the remaining challenges that hinder the use of QST for everyday clinical decisions and clinical trials, we expect that future improvements will allow its implementation in routine practice.

Reliability of orofacial quantitative sensory testing for pleasantness and unpleasantness.

BACKGROUND: Quantitative sensory testing protocols for perceptions of pleasantness and unpleasantness based on the German Research Network on Neuropathic Pain protocol were recently introduced. However, there are no reliability studies yet published. AIM: To evaluate the intra-examiner (test-retest) and inter-examiner reliability for orofacial pleasantness and unpleasantness quantitative sensory testing protocols. METHODS: Sixteen healthy participants from Aarhus University (11 women and five men, mean age 24, range 21-26 years) contributed. Two examiners were trained in performing the entire quantitative sensory testing protocols for pleasantness and unpleasantness, which included the additional dynamic tactile stimulation test using a goat-hair brush. Each participant underwent examination of both protocols by each examiner (inter-examiner reliability) on day 1. They returned at least 8 days following the testing to be re-examined by one examiner (intra-examiner reliability). All testing was performed on the skin of the right mandibular mental region. The intraclass correlation (ICC) was used to determine reliability. RESULTS: For the protocol investigating pleasantness, the majority of parameters had good to excellent intra-examiner (11/14: Intraclass correlation 0.67-0.87) and inter-examiner (13/14: Intraclass correlation 0.62-0.96) reliabilities. Similarly, the protocol investigating unpleasantness had good to excellent intra-examiner (intraclass correlation 0.63-0.99) and inter-examiner (intraclass correlation 0.65-0.98) reliabilities for most (13/15) of the parameters. CONCLUSION: Intra and inter-examiner reliabilities in the majority of quantitative sensory testing parameters (apart from the summation ratio) investigating pleasantness and unpleasantness are acceptable when assessing somatosensory function of the orofacial region.Trial registration: NA.