Ana Isabel de la Llave Rincón

Background/Objectives: No study has investigated the effect of the catechol-O-methyltransferase (COMT) Val158Met rs4680 polymorphism in cognitive and executive performance in migraine. The current study investigated the potential influence of the Val158Met rs4680 polymorphism in cognitive performance/executive function in women with migraine. Methods: One hundred and forty women with migraine (70 chronic and 70 episodic) and 70 healthy controls completed the following neurocognitive tests (D2 Attention test and Rey–Osterrieth Complex Figure) and executive functions (subtest “Digits D/R/I” of the Wechsler Adult Intelligence Scale WAIS-IV battery for, the 5-Digit test, the Symbol Search for and the Zoo Test) for evaluating selective attention, visual perception, working memory, mental inhibition, processing speed and planning/decision making, respectively. Thus, three genotypes (Val/Val, Val/Met, and Met/Met) of the Val158Met polymorphism were identified by polymerase chain reaction. The effect of group and Val158Met genotype in neurocognitive tests and executive functions was evaluated with multivariate analysis of covariance (MANCOVA). Results: The MANCOVA revealed a significant Val158Met polymorphism* group interaction on neurocognitive performance (Wilk’s λ = 0.393, F [76,688] = 2.425, p < 0.001, n2p = 0.208, 1 − β = 0.999), not influenced by age (Wilk’s λ = 0.920, F [19,174] = 0.743, p = 0.734, n2p = 0.035, 1 − β = 0.120), educational level (Wilk’s λ = 0.875, F [19,174] = 1.024, p = 0.440, n2p = 0.047, 1 − β = 0.190) and prophylactic medication (Wilk’s λ = 0.855, F [19,174]= 1.000, p = 0.467, n2p= 0.145, 1 − β = 0.686). Post hoc analyses revealed that women with chronic migraine with the Met/Met genotype exhibited domain-specific better performance (i.e., higher selective attention, visuospatial memory) and executive functioning (i.e., working memory, planning/decision making) than those women with chronic migraine carrying Val/Val or Val/Met genotypes. Conclusions: We found an association of the Met/Met genotype with neurocognitive performance/executive functioning, particularly in women with chronic migraine since women with chronic migraine carrying the Met/Met genotype showed domain-specific better cognitive performance/executive functioning than those with the Val allele. Future studies including large sample sizes from different geographic locations are needed to better generalizability and validity of the current results.

The role of the catechol-O-methyltransferase (COMT) Val158Met rs4680 polymorphism in altered pain processing in headaches is controversial. The aim of this study was to investigate the influence of the Val158Met rs4680 polymorphism in conditioned pain modulation (CPM) in women with migraine. A case-control study including 70 women with chronic migraine, 70 with episodic migraine and 70 pain-free women was conducted. Pressure pain thresholds (PPTs) at the temporalis muscle, lateral epicondyle, and tibialis anterior were bilaterally assessed. Heat (HPT) and cold (CPT) pain thresholds at the frontalis muscle were also assessed. Subsequently, CPM was evaluated immediately after a one-minute cold-pressor test paradigm on changes obtained in PPTs, HPT and CPT. Thus, after amplifying Val158Met polymorphism by polymerase chain reaction, genotype frequencies (Val/Val, Val/Met, or Met/Met) and allele distributions were identified. The distribution of Val158Met genotypes (p = 0.097) was not significantly different among women with episodic migraine, chronic migraine and pain-free controls. The results revealed significant group*time*Val 158Met interactions for PPTs at the temporalis (Wilk’s λ = 0.917, F [4, 193] = 4.377, p = 0.002, n²p = 0.083, 1 − β = 0.930) and lateral epicondyle (Wilk’s λ = 0.892, F [4, 193] = 5.870, p < 0.001, n²p = 0.108, 1 − β = 0.982), as well as CPT (Wilk’s λ = 0.872, F [4, 193] = 7.111, p < 0.001, n²p = 0.128, 1 − β = 0.995) or HPT (Wilk’s λ = 0.921, F [4, 193] = 4.133, p = 0.003, n²p = 0.079, β − 1 = 0.914), but not for the PPT at tibialis anterior (Wilk’s λ = 0.983, F [4, 193] = 0.834, p = 0.505, n²p = 0.017, 1 − β = 0.263). Women with chronic migraine with the Met/Met genotype exhibited reduced CPM indexes for PPT, CPT, or HPT at the temporalis (trigeminal area) than those with the Val/Val genotype. This study showed that CPM deficit is higher in women with migraine with the Met/Met genotype, but this association is mostly present in the symptomatic (trigeminal) area in the chronic form of the disease. No association of the Met/Met genotype with CPM was seen in healthy controls.

Objective: To determine the influence of sensitization‐associated and neuropathic‐like symptoms and clinical features in conditioned pain modulation (CPM) activity in women with episodic or chronic migraine. Methods: A cross‐sectional study including 70 women with chronic migraine and 70 with episodic migraine was performed. Clinical migraine features (related disability, pain intensity, frequency, and duration) and pain processing variables (sensitization‐associated or neuropathic‐like symptoms) were evaluated with self‐reported outcomes. Pressure pain thresholds (PPTs) at the temporalis muscle, lateral epicondyle, and tibialis anterior were bilaterally assessed. Heat (HPT) and cold (CPT) pain thresholds at the frontalis (V1 area) muscle were also assessed. Subsequently, CPM was evaluated immediately after a 1‐min cold‐pressor test paradigm on changes obtained in PPTs, HPT, and CPT. Results: No significant group ∗ time interactions after controlling for migraine features, related disability (MIDAS, HIT‐6), sensitization‐associated (CSI), or neuropathic‐like symptoms (S‐LANSS) were found for PPTs at the temporalis muscle (Wilk’s λ = 0.996, F [1128] = 0.500, p = 0.481, n ² p = 0.004, 1 − β = 0.108), lateral epicondyle (Wilk’s λ = 0.997, F [1128] = 0.369, p = 0.545, n ² p = 0.003, 1 − β = 0.093), and tibialis anterior (Wilk’s λ = 0.999, F [1128] = 0.070, p = 0.792, n ² p = 0.001, 1 − β = 0.058) as well as CPT (Wilk’s λ = 0.991, F [1128] = 1.136, p = 0.288, n ² p = 0.009, 1 − β = 0.185) or HPT (Wilk’s λ = 0.992, F [1128] = 0.992, p = 0.315, n ² p = 0.008, 1 − β = 0.170): no significant changes in PPTs, CPTs, or HPTs were seen after the conditioned stimulus in women with either episodic or chronic migraine. No significant effect of clinical or pain processing outcomes on CPM was seen. Conclusion: This study showed similar CPM activation (lack of) in women with episodic and chronic migraine. Thus, clinical features and the presence of sensitization‐associated or neuropathic‐like symptoms did not modulate CPM activity in women with migraine.

Introduction: Migraine is featured by altered nociceptive processing and the presence of cognitive impairments. No study has previously investigated the influence of neurocognitive performance and executive functions in descending pain processing in this population. Aim: To assess the influence of neurocognitive processes and executive functions in conditioned pain modulation (CPM) activation in women with migraine. Methods: A cross-sectional case–control study including 140 women with migraine (50% chronic) and 70 control women was conducted. Clinical migraine features, neurocognitive processes (e.g., attention), and executive functions (memory, mental inhibition, speed of processing) were evaluated. Pressure pain thresholds (PPTs) were bilaterally assessed at the temporalis muscle, lateral epicondyle, and tibialis anterior muscle. Heat (HPT) and cold (CPT) pain thresholds were assessed at the frontalis (trigeminal area) muscle. Thus, CPM was evaluated with the cold pressor test paradigm by analyzing changes in mechanical/thermal stimuli after a conditioned stimulus. Results: Significant group*time interactions not associated with neurocognitive process/executive function, educational level, and employment status were found for PPTs at the temporalis muscle (Wilk’s λ = 0.588, F[2,199] = 69.756, p < 0.001, n²p = 0.412, 1 − β = 0.999), lateral epicondyle (Wilk’s λ = 0.674, F[2,200] = 48.331, p < 0.001, n²p = 0.326, 1 − β = 0.999), and tibialis anterior (Wilk’s λ = 0.751, F[2,200] = 33.110, p < 0.001, n²p= 0.249, 1 − β = 0.999): PPTs were higher after the conditioned stimulus in all points in control women (increases ranging from 11% to 17%), whereas PPTs were lower after the conditioned stimulus in women with migraine (decrease from −7.5% to −0.1%) when compared with PPTs at baseline. Changes in HPT and CPT were small and not significant, ranging from 0.1% to 0.5%. Conclusion: This study revealed that women with episodic or chronic migraine showed CPM deficits particularly against mechanical stimuli when compared with pain-free women. Neurocognitive (e.g., attention) processes or executive functions (e.g., working memory, mental inhibition) did not modulate CPM activity in women with migraine.

The aim of this study was to investigate the influence of executive functioning and cognitive performance on individual experimentally induced pain perception during distractor tasks in an asymptomatic pain-free population. A total of 59 healthy pain-free subjects (59.3% women, mean age: 46.5 ± 24.7 years) completed a battery test that assessed execution functions (cognitive flexibility, working memory, mental inhibition), attention level, and psychological aspects (anxiety/depressive levels—HADS, pain catastrophizing—PCS, pain anxiety symptoms—PASS 20, sleep quality—PSQI) before conducting two n-back distraction tasks. Pain was experimentally induced with a thermal stimulus that was able to induce moderate pain (70/100 points) and applied to the non-dominant forearm. The thermal stimulus was applied before and during both (one-back and two-back) distraction tasks. The analyses consisted of separated repeated-measures ANOVA that considered the functioning on each test (cognitive flexibility, working memory, mental inhibition, selective attention) and controlled for sociodemographic and psychological aspects by comparing the pain intensity at the baseline and during the one-back and two-back distractor tasks. All ANOVAs found a significant effect of the distraction task, which indicates that the perceived pain intensity scores were lower during the one-back and two-back tasks (p < 0.001) as compared with the baseline. No interaction effect between the distractor tasks and working memory (p = 0.546), mental inhibition (p = 0.16), cognitive flexibility (p = 0.069), or selective attention (p = 0.105) was identified. The current study found that a distraction task decreased the perceived intensity of experimentally induced pain in asymptomatic pain-free individuals and that this effect was not related to executive function or attention levels.

Knee and hip osteoarthritis are highly prevalent in the older population. Management of osteoarthritis-related pain includes conservative or surgical treatment. Although knee or hip joint replacement is associated with positive outcomes, up to 30% of patients report postoperative pain in the first two years. This study aimed to synthesize current evidence on prognostic factors for predicting postoperative pain after knee or hip replacement. An umbrella review of systematic reviews was conducted to summarize the magnitude and quality of the evidence for prognostic preoperative factors predictive of postoperative chronic pain (>6 months after surgery) in patients who had received knee or hip replacement. Searches were conducted in MEDLINE, CINAHL, PubMed, PEDro, SCOPUS, Cochrane Library, and Web of Science databases from inception up to 5 August 2022 for reviews published in the English language. A narrative synthesis, a risk of bias assessment, and an evaluation of the evidence confidence were performed. Eighteen reviews (nine on knee surgery, four on hip replacement, and seven on both hip/knee replacement) were included. From 44 potential preoperative prognostic factors, just 20 were judged as having high or moderate confidence for robust findings. Race, opioid use, preoperative function, neuropathic pain symptoms, pain catastrophizing, anxiety, other pain sites, fear of movement, social support, preoperative pain, mental health, coping strategies, central sensitization-associated symptoms, and depression had high/moderate confidence for an association with postoperative chronic pain. Some comorbidities such as heart disease, stroke, lung disease, nervous system disorders, and poor circulation had high/moderate confidence for no association with postoperative chronic pain. This review has identified multiple preoperative factors (i.e., sociodemographic, clinical, psychological, cognitive) associated with postoperative chronic pain after knee or hip replacement. These factors may be used for identifying individuals at a risk of developing postoperative chronic pain. Further research can investigate the impact of using such prognostic data on treatment decisions and patient outcomes.

Fatigue and dyspnoea are common post-COVID symptoms. The aim of this study was to apply Sankey plots and exponential bar plots for visualizing the evolution and trajectory of post-COVID fatigue and dyspnoea symptoms in a cohort of previously hospitalized COVID-19 survivors. A total of 1266 previously hospitalized patients due to COVID-19 participated in this multicentre study. They were assessed at hospital admission (T0), 8.4 months (T1), 13.2 months (T2) and 18.3 months (T3) after hospital discharge and were asked about the presence of self-reported fatigue or dyspnoea symptoms. Fatigue was defined as a self-perceived feeling of constant tiredness and/or weakness whereas dyspnoea was defined as a self-perceived feeling of shortness of breath at rest. We specifically asked for fatigue and dyspnoea that participants attributed to the infection. Clinical/hospitalization data were collected from hospital medical records. The prevalence of post-COVID fatigue was 56.94% (n = 721) at T1, 52.31% (n = 662) at T2 and 42.66% (n = 540) at T3. The prevalence of dyspnoea at rest decreased from 28.71% (n = 363) at hospital admission (T0), to 21.29% (n = 270) at T1, to 13.96% (n = 177) at T2 and 12.04% (n = 153) at T3. The Sankey plots revealed that 469 (37.08%) and 153 (12.04%) patients exhibited fatigue and dyspnoea at all follow-up periods. The recovery exponential curves show a decreased prevalence trend, showing that fatigue and dyspnoea recover the following three years after hospitalization. The regression models revealed that the female sex and experiencing the symptoms (e.g., fatigue, dyspnoea) at T1 were factors associated with the presence of post-COVID fatigue or dyspnoea at T2 and T3. The use of Sankey plots shows a fluctuating evolution of post-COVID fatigue and dyspnoea during the first two years after infection. In addition, exponential bar plots revealed a decreased prevalence of these symptoms during the first years after. The female sex is a risk factor for the development of post-COVID fatigue and dyspnoea.

Carpal tunnel syndrome (CTS) has been traditionally classified as primarily a neuropathic condition with or without pain. Precision medicine refers to an evidence-based method of grouping patients based on their susceptibility to biology, prognosis of a particular disease, or in their response to a specific treatment, and tailoring specific treatments accordingly. In 2021, the International Association for the Study of Pain (IASP) proposed a grading system for classifying patients into nociceptive, neuropathic, or nociplastic phenotypes. This position paper presents data supporting the possibility of subgrouping individuals with specific CTS related-pain into nociceptive, neuropathic, nociplastic or mixed-type phenotypes. Carpal tunnel syndrome is a neuropathic condition but can also be comorbid with a nociplastic pain condition. The presence of extra-median symptoms and the development of facilitated pain processing seem to be signs suggesting that specific CTS cases can be classified as the nociplastic pain phenotype. The clinical responses of therapeutic approaches for the management of CTS are inconclusive. Accordingly, the ability to identify the predominant pain phenotype in patients with CTS could likely be problematic for producing efficient treatment outcomes. In fact, the presence of a nociplastic or mixed-type pain phenotype would explain the lack of clinical effect of treatment interventions targeting the carpal tunnel area selectively. We propose a clinical decision tree by using the 2021 IASP classification criteria for identifying the predominant pain phenotype in people with CTS-related pain, albeit CTS being a priori a neuropathic pain condition. The identification of a nociplastic-associated condition requires a more nuanced multimodal treatment approach to achieve better treatment outcomes.