Evaluating the association of TRPA1 gene polymorphisms with pain sensitivity: a protocol for an adaptive recall by genotype study

Background Pain is a complex polygenic trait whose common genetic underpinnings are relatively ill-defined due in part to challenges in measuring pain as a phenotype. Pain sensitivity can be quantified, but this is difficult to perform at the scale required for genome wide association studies (GWAS). Existing GWAS of pain have identified surprisingly few loci involved in nociceptor function which contrasts strongly with rare monogenic pain states. This suggests a lack of resolution with current techniques. We propose an adaptive methodology within a recall-by-genotype (RbG) framework using detailed phenotyping to screen minor alleles in a candidate ‘nociceptor’ gene in an attempt to estimate their genetic contribution to pain. Methods/design Participants of the Avon Longitudinal Study of Parents and Children will be recalled on the basis of genotype at five common non-synonomous SNPs in the ‘nociceptor’ gene transient receptor potential ankylin 1 (TRPA1). Those homozygous for the common alleles at each of the five SNPs will represent a control group. Individuals homozygous for the minor alleles will then be recruited in a series of three sequential test groups. The outcome of a pre-planned early assessment (interim) of the current test group will determine whether to continue recruitment or switch to the next test group. Pain sensitivity will be assessed using quantitative sensory testing (QST) before and after topical application of 10% cinnamaldehyde (a TRPA1 agonist). Discussion The design of this adaptive RbG study offers efficiency in the assessment of associations between genetic variation at TRPA1 and detailed pain phenotypes. The possibility to change the test group in response to preliminary data increases the likelihood to observe smaller effect sizes relative to a conventional multi-armed design, as well as reducing futile testing of participants where an effect is unlikely to be observed. This specific adaptive RbG design aims to uncover the influence of common TRPA1 variants on pain sensation but can be applied to any hypothesis-led genotype study where costly and time intensive investigation is required and / or where there is large uncertainty around the expected effect size. Trial registration: ISRCTN, ISRCTN16294731. Retrospectively registered 25th November 2021.

Dispositional and situational personal features and acute post-collision head and neck pain: Double mediation of pain catastrophizing and pain sensitivity

Pain variability can be partially attributed to psycho-cognitive features involved in its processing. However, accumulating research suggests that simple linear correlation between situational and dispositional factors may not be sufficiently explanatory, with some positing a role for mediating influences. In addition, acute pain processing studies generally focus on a post-operative model with less attention provided to post-traumatic injury. As such, this study aimed to investigate a more comprehensive pain processing model that included direct and indirect associations between acute pain intensity in the head and neck, pain catastrophizing (using pain catastrophizing scale (PCS)), and pain sensitivity (using the pain sensitivity questionnaire (PSQ)), among 239 patients with post-motor vehicle collision pain. The effect of personality traits (using Ten Items Personality Inventory (TIPI)) and emotional status (using Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS)) on that model was examined as well. To this end, three Structural Equation Modeling (SEM) analyses were conducted. Overall, the data had good fit to all the models, with only PSQ found to have a direct correlation with acute pain intensity. The SEM analyses conversely revealed several mediations. Specifically, that: first, PSQ fully mediated the relationship between PCS and pain intensity; second, PCS and PSQ together fully mediated the relationship between conscientiousness (personality trait) and pain intensity; and finally, emotional status had direct and indirect links with PSQ and pain intensity. In conclusion, these models suggest that during the acute post-collision phase, pain sensitivity intermediates between emotional states and personality traits, partially via elevated pain catastrophizing thoughts.

CHARACTERISTICS OF PERIPHERAL NERVOUS SYSTEM IN PATIENTS WITH PSORIASIS

Psoriasis is a chronic non-infectious inflammatory dermatosis characterized by excessive proliferation of epithelial cells, impaired differentiation, often involving the musculoskeletal system. Materials and Methods. The authors examined 60 patients with psoriasis, 39 men and 21 women, aged from 21 to 69 (the average subject age was 46.3±13.94). All patients underwent a standard dermatological and neurological examination. Motor function was assessed according to knee jerk, elbow jerk and Achilles jerk. Pain sensitivity was established after pricking the thumb dorsum with a special blunt-end needle. Nonparametric methods were used for statistical analysis. The Mann-Whitney U-test was used to check the differences between independent groups of patients. The distribution of characteristic was assessed using a probability calculator. Differences were statistically significant at 95 % probability (p<0.05). Results. Mild psoriasis was found in 8 patients (13.3 %), moderate-to-severe psoriasis – in 14 patients (23 %) (PASI=11–30), severe psoriasis – in 38 patients (63.7 %) (PASI>30). Type I psoriasis was detected in 32 patients (53.2 %), type II – in 28 patients (46.8 %). Dysfunctions of the peripheral nervous system were found in 30 patients (50 %). In 12 subjects (20 %) symmetrical sensory and motor disturbances were observed in the distal parts of all four limbs. In 9 patients (15 %) symmetrical decrease in knee and Achilles jerks was observed. Symmetrical decrease in tactile and temperature sensitivity in the distal parts of the lower extremities was noted in 9 patients with psoriasis (15 %). Conclusion. Distal symmetric sensorimotor polyneuropathy is common in patients with psoriasis. Severe psoriasis is accompanied by distal symmetric sensorimotor polyneuropathy. Key words: psoriasis, comorbidity, demyelination, polyneuropathy. Псориаз – это хронический неинфекционный воспалительный дерматоз, характеризующийся избыточной пролиферацией эпителиоцитов, нарушением их дифференциации, нередко вовлекающий в процесс опорно-двигательный аппарат. Материалы и методы. Обследовано 60 больных псориазом, из них 39 мужчин и 21 женщина в возрасте от 21 до 69 лет (средний возраст обследуемых 46,3±13,94 года). Всем больным проводился стандартный дерматологический и неврологический осмотр. Двигательная функция исследовалась с помощью оценки коленного, локтевого и ахиллова рефлексов. Болевая чувствительность устанавливалась после укола тыльной поверхности большого пальца специальной иглой с притупленным концом. Для статистического анализа использовались непараметрические методы. Для проверки отличий между независимыми группами больных применялся Mann – Whitney U-test. Распределение признака оценивалось с помощью вероятностного калькулятора. Статистические значимыми считались отличия при уровне вероятности более 95 % (p<0,05). Результаты. Легкая степень псориаза установлена у 8 (13,3 %) больных, умеренно тяжелый псориаз – у 14 (23 %) пациентов (индекс PASI 11–30 баллов), тяжелая форма псориаза – у 38 (63,7 %) больных (индекс PASI более 30 баллов). Псориаз I типа определялся у 32 (53,2 %) больных, II типа – у 28 (46,8 %). У 30 (50 %) больных обнаружены нарушения функции периферической нервной системы. У 12 (20 %) чел. наблюдались симметричные сенсорные и двигательные нарушения в дистальных отделах всех четырех конечностей. У 9 (15 %) чел. отмечалось симметричное снижение коленного и ахиллова рефлексов. Девять (15 %) больных псориазом имели симметричное снижение тактильной и температурной чувствительности в дистальных отделах нижних конечностей. Выводы. У больных псориазом часто встречается дистальная симметричная сенсорно-моторная полинейропатия. Тяжелое течение псориаза сопровождается дистальной симметричной сенсорно-моторной полинейропатией. Ключевые слова: псориаз, коморбидность, демиелинизация, полинейропатия.

Validation and Cross-Cultural Adaptation of the Spanish Version of the Pain Sensitivity Questionnaire (PSQ-S)

Experimental pain testing requires specific equipment and may be uncomfortable for patients. The Pain Sensitivity Questionnaire (PSQ) was developed to assess pain sensitivity, based on the pain intensity ratings (range: 0–10) of painful situations that occur in daily life. The main objective of this study was to carry out a cross-cultural adaptation and validation of the Spanish version of the PSQ (PSQ-S). A total of 354 subjects (296 healthy and 58 chronic pain patients) filled in the PSQ-S. A subgroup of 116 subjects performed experimental pain testing, including two modalities (cold and pressure), with different measures: pain intensity rating, pressure pain threshold, and tolerance. The validation results showed two factors: PSQ-S-moderate and PSQ-S-minor and, for the total scale and the two factors, an excellent internal consistency (Cronbach’s alpha coefficient > 0.9) and a substantial reliability (Intraclass Correlation Coefficient > 0.8). We obtained strong correlations with all the experimental pain rating parameters, catastrophizing, and depression variables, as well as moderate correlations with anxiety, central sensibilization, and impact on the quality of life. Chronic pain patients received elevated PSQ-S scores compared to healthy controls, and three cut-off values (PSQ-S-total = 7.00, PSQ-S-moderate = 7.57, and PSQ-S-minor = 6.29) based on ROC curve analyses were shown to be able to discriminate between healthy adults and adults with chronic pain. Therefore, PSQ-S may be a simple alternative to experimental pain procedures for clinical and experimental pain research.

Clinical Evaluation of a New Electronic Periodontal Probe: A Randomized Controlled Clinical Trial

Precise measurements of periodontal parameters (such as pocket depths: PPD, gingival margins: GM) are important for diagnosis of periodontal disease and its treatment. Most examiners use manual millimeter-scaled probes, dependent on adequate pressure and correct readouts. Electronic probes aim to objectify and facilitate the diagnostic process. This randomized controlled trial compared measurements of a standard manual (MP) with those of an electronic pressure-sensitive periodontal probe (EP) and its influence on patients’ acceptance and practicability. In 20 patients (2436 measuring points) PPD and GM were measured either with MP or EP by professionals with different levels of experience: dentist (10 patients), 7th and 10th semester dental students (5 patients each). Time needed was measured in minutes and patients’ subjective pain was evaluated by visual analogue scale. Differences were analyzed using the generalized estimating equations approach (GEE) and paired Wilcoxon tests. Mean PPD varied with ΔPPD 0.38 mm between both probes, which was significant (p < 0.001), but GM did not (ΔREC 0.07 mm, p = 0.197). There was a statistically significant correlation of both probes (Spearman’s rho correlation coefficient GM: 0.674, PPD: 0.685). Differences can be considered robust (no deviation in either direction). The comparison of time needed and pain sensitivity did not result in statistically significant differences (p > 0.05).

Influence of Catechol-O-Methyltransferase Gene Polymorphism on the Correlation between Alexithymia and Hypervigilance to Pain

The psychological characteristic of having difficulty expressing emotions, known as alexithymia, is associated with hypervigilance to pain and is considered one of the risk factors for chronic pain. The correlation between alexithymia and hypervigilance to pain can be observed even in healthy individuals. However, the factors influencing this correlation remain unknown. We explored the dopamine system, which is known to be involved in emotion and pain. The dopamine-degrading enzyme catechol-O-methyltransferase (COMT) has a genetic polymorphism known to influence dopamine metabolism in the prefrontal cortex. COMT polymorphism reportedly affects various aspects of pain and increases pain sensitivity in Met allele carriers. Therefore, we investigated whether the correlation between alexithymia and hypervigilance to pain is influenced by COMT polymorphism in healthy individuals. The results revealed a significant positive correlation between the “difficulty describing feelings” of the 20-item Toronto Alexithymia Scale and the “attention to changes in pain” of the pain vigilance and awareness questionnaire in COMT Met carriers but not in Val/Val individuals. This finding suggests that the correlation between alexithymia and hypervigilance to pain is influenced by COMT polymorphism.