The polymorphism Val158Met in the COMT gene: disrupted dopamine system in fibromyalgia patients?

ABSTRACT: The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). The concurrent impact of Val158Met genotypes and FM comorbid disorders (depression and sleep impairment) on FM risk were tested. In addition, the genotypic distribution of FM patients in relation to pain intensity was evaluated. The G allele (Val) resulted in being more represented in the FM group (57.8%) compared with the control group (48.8%; P = 0.037). Logistic regression highlighted that having the G/G (Val/Val) homozygous genotype was associated with 2 times higher risk of having FM compared with the A/A (Met/Met) carriers ( P = 0.038), whereas depression and sleep impairment increased FM risk by 12 and 8 times, respectively ( P < 0.001). However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment.

Is Antiviral Treatment with Remdesivir at the Acute Phase of SARS-CoV-2 Infection Effective for Decreasing the Risk of Long-Lasting Post-COVID Symptoms?

The aim of this study was to investigate the effects of administrating Remdesivir at the acute COVID-19 phase on developing post-COVID symptoms in previously hospitalized COVID-19 survivors by controlling factors such as age, sex, body mass index, and vaccination status. A case-control study was performed. Hospitalized COVID-19 survivors who had received intravenous Remdesivir during the acute phase (n = 216) were matched by age, sex, body mass index, and vaccination status with survivors who did not receive antiviral treatment (n = 216). Participants were asked to self-report the presence of any post-COVID symptom (defined as a symptom that started no later than three months after infection) and whether the symptom persisted at the time of study (mean: 18.4, SD: 0.8 months). Anxiety levels (HADS-A), depressive symptoms (HADS-D), sleep quality (PSQI), and severity/disability (FIC) were also compared. The multivariate analysis revealed that administration of Remdesivir at the acute COVID-19 phase was a protective factor for long-term COVID development (OR0.401, 95%CI 0.256-0.628) and specifically for the following post-COVID symptoms: fatigue (OR0.399, 95%CI 0.270-0.590), pain (OR0.368, 95% CI 0.248-0.548), dyspnea at rest (OR0.580, 95%CI 0.361-0.933), concentration loss (OR0.368, 95%CI 0.151-0.901), memory loss (OR0.399, 95%CI 0.270-0.590), hair loss (OR0.103, 95%CI 0.052-0.207), and skin rashes (OR0.037, 95%CI 0.005-0.278). This study supports the potential protective role of intravenous administration of Remdesivir during the COVID-19 acute phase for long-lasting post-COVID symptoms in previously hospitalized COVID-19 survivors.

Presence of SARS-CoV-2 RNA in COVID-19 survivors with post-COVID symptoms 2 years after hospitalization: The VIPER study.

The SARS-CoV-2 VIrus PERsistence (VIPER) study investigated the presence of long-lasting SARS-CoV-2 RNA in plasma, stool, urine, and nasopharyngeal samples in COVID-19 survivors. The presence of SARS-CoV-2 RNA reverse transcription polymerase chain reactions (RT-PCR) were analyzed within plasma, stool, urine, and nasopharyngeal swab samples in COVID-19 survivors with post-COVID symptoms and a comparison group of COVID-19 survivors without post-COVID symptoms matched by age, sex, body mass index and vaccination status. Participants self-reported the presence of any post-COVID symptom (defined as a symptom that started no later than 3 months after the initial infection). Fifty-seven (57.9% women, age: 51.1, standard deviation [SD]: 10.4 years) previously hospitalized COVID-19 survivors with post-COVID symptoms and 55 (56.4% women, age: 50.0, SD: 12.8 years) matched individuals who had a past SARS-CoV-2 infection without post-COVID symptoms were evaluated 27 (SD 7.5) and 26 (SD 8.7) months after hospital discharge, respectively. The presence of SARS-CoV-2 RNA was identified in three nasopharyngeal samples of patients with post-COVID symptoms (5.2%) but not in plasma, stool, or urine samples. Thus, SARS-CoV-2 RNA was not identified in any sample of survivors without post-COVID symptoms. The most prevalent post-COVID symptoms consisted of fatigue (93%), dyspnea, and pain (both, 87.7%). This study did not find SARS-CoV-2 RNA in plasma, stool, or urine samples, 2 years after the infection. A prevalence of 5.2% of SARS-CoV-2 RNA in nasopharyngeal samples, suggesting a potential active or recent reinfection, was found in patients with post-COVID symptoms. These results do not support the association between SARS-CoV-2 RNA in plasma, stool, urine, or nasopharyngeal swab samples and post-COVID symptomatology in the recruited population.

Prevalence and Risk Factors of Multitype Post-COVID Pain in a Cohort of Previously Hospitalized COVID-19 Survivors: A Danish Cross-Sectional Survey.

This population-based study investigated the prevalence of de novo, multitype, post-coronavirus disease (COVID) pain and its associated risk factors in previously hospitalized coronavirus disease 2019 (COVID-19) survivors. The nationwide, cross-sectional study included a cohort of Danish residents previously hospitalized due to severe acute respiratory syndrome coronavirus-2 infection between March 2020 and December 2021. Demographic data, preexisting medical comorbidities, previous pain-related symptoms, medication use for pain management, pain intensity (4-point scale), and development of de novo, multitype, post-COVID pain were collected by a self-reported survey distributed via e-Boks (a secured national digital mail system used in Denmark to provide public information to residents). The sample comprised 4,712 previously hospitalized COVID-19 survivors (48.6% women, mean age: 60.1 ± 15.6 years). At the time of the study (21 ± 6 months after hospitalization), 18.0% (847) reported the presence of de novo, multitype, post-COVID pain, and 38.6% of any pain. A multivariate analysis revealed that female sex (Odds Ratio (OR) 1.711, 95% Confidence Interval (CI) 1.444-2.023), higher body mass index (OR 1.032, 95% CI 1.019-1.045), intensive care unit admission (OR 1.597, 95% CI 1.324-1.926), previous history of whiplash (OR 2.471, 95% CI 1.004-6.081), anxiety (OR 3.626, 95% CI 1.335-9.708), and younger age (OR .982, 95% CI .976-.987) were factors associated with development of de novo, multitype, post-COVID pain. High income (OR .635, 95% CI .494-.817) and high educational level (OR .774, 95% CI .609-.984) were protective factors. In conclusion, multitype pain as a de novo post-COVID symptom was present in 18.0% of previously hospitalized COVID-19 survivors more than 1 year after hospital discharge and as such can be considered as adding to the global burden of chronic pain. PERSPECTIVE: The study investigates the prevalence of de novo, multitype, post-COVID pain in previously hospitalized COVID-19 survivors. This article presents potential risk factors associated with developing new pain symptoms. The results will contribute to understanding the possibility of predicting postinfectious pain from COVID-19 for future analysis.

A potential link between inflammatory profiles, clinical pain, pain catastrophizing and long-term outcomes after total knee arthroplasty surgery.

BACKGROUND: Chronic postoperative pain after total knee replacement (TKR) is a major clinical problem. It is still unclear if specific inflammatory mediators are associated with long-term postoperative pain complications. The current exploratory study aimed to (1) evaluate a multiplex of inflammatory mediators 5 years after TKR surgery in patients with different degrees of postoperative pain intensities and (2) study any association of the markers with clinical pain intensity, cognitive and functional outcomes. METHODS: Plasma samples were collected 5 years after TKR surgery from 76 knee patients (43 females; 33 males) and analysed for 44 inflammatory markers. Pain (using visual analogue scale, VAS), the pain catastrophizing scale (PCS) and the Oxford knee score (OKS) were evaluated. Patients were categorized as high or low groups based on VAS, PCS and OKS scores. Associations between inflammatory markers, VAS, PCS and OKS were analysed and the marker expressions were compared between groups. RESULTS: Pearson's correlations found 12 biomarkers associated with VAS (p < 0.05), 4 biomarkers with PCS and 3 biomarkers with OKS (p < 0.05). Four markers were altered in patients suffering from high compared to low chronic postoperative pain, three markers were altered in high compared to low catastrophizers and three markers were altered in patients with poor functional scores (p < 0.05). CONCLUSIONS: The present exploratory study suggests that low-grade inflammation might be present in a subset of patients with high pain, high catastrophizing and low function 5 years after TKR. These exploratory results provide insights into some of the long-term postoperative complications after TKR surgery. SIGNIFICANCE STATEMENT: This exploratory study evaluated a subset of inflammatory markers and the association to clinical pain intensity, knee function and pain catastrophizing in patients 5 years after total knee replacement surgery. Our results provide insights into the understanding of the underlying mechanisms that may drive the long experience of pain after TKR surgery.

Inflammatory Polymorphisms (IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252) Are Not Associated with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors.

The aim of this study was to identify the association between four selected inflammatory polymorphisms with the development of long-term post-COVID symptoms in subjects who had been hospitalized due to SARS-CoV-2 infection during the first wave of the pandemic. These polymorphisms were selected as they are associated with severe COVID-19 disease and cytokine storm, so they could be important to prognoses post-COVID. A total of 408 (48.5% female, age: 58.5 ± 14.0 years) previously hospitalized COVID-19 survivors participated. The three potential genotypes of the following four single-nucleotide polymorphisms, IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252, were obtained from non-stimulated saliva samples of the participants. The participants were asked to self-report the presence of any post-COVID symptoms (defined as symptoms that had started no later than one month after SARS-CoV-2 acute infection) and whether the symptoms persisted at the time of the study. At the time of the study (mean: 15.6, SD: 5.6 months after discharge), 89.4% of patients reported at least one post-COVID symptom (mean number of symptoms: 3.0; SD: 1.7). Fatigue (69.3%), pain (40.9%), and memory loss (27.2%) were the most prevalent post-COVID symptoms in the total sample. Overall, no differences in the post-COVID symptoms depending on the IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252 genotypes were seen. The four SNPs assessed, albeit having been previously associated with inflammation and COVID-19 severity, did not cause a predisposition to the development of post-COVID symptoms in the previously hospitalized COVID-19 survivors.

Inflammatory biomarkers in patients with painful knee osteoarthritis: exploring the potential link to chronic postoperative pain after total knee arthroplasty-a secondary analysis.

ABSTRACT: Total knee arthroplasty (TKA) is the end-stage treatment of knee osteoarthritis (OA), and approximately 20% of patients experience chronic postoperative pain. Studies indicate that inflammatory biomarkers might be associated with pain in OA and potentially linked to the development of chronic postoperative pain after TKA. This study aimed to (1) evaluate preoperative serum levels of inflammatory biomarkers in patients with OA and healthy control subjects, (2) investigate preoperative differences of inflammatory biomarker profiles in subgroups of patients, and (3) compare subgroups of patients with and without postoperative pain 12 months after surgery. Serum samples from patients with OA scheduled for TKA (n = 127) and healthy participants (n = 39) were analyzed. Patients completed the Knee-injury-and-Osteoarthritis-Outcome-Score (KOOS) questionnaire and rated their clinical pain intensity using a visual analog scale (VAS) before and 12 months after TKA. Hierarchical cluster analysis and Orthogonal Partial Least Squares Discriminant Analysis were used to compare groups (patients vs control subjects) and to identify subgroups of patients in relation to postoperative outcomes. Difference in preoperative and postoperative VAS and KOOS scores were compared across subgroups. Twelve inflammatory markers were differentially expressed in patients when compared with control subjects. Cluster analysis identified 2 subgroups of patients with 23 proteins being significantly different ( P < 0.01). The 12-months postoperative VAS and KOOS scores were significantly different between subgroups of patients ( P < 0.05). This study identified differences in specific inflammatory biomarker profiles when comparing patients with OA and control subjects. Cluster analysis identified 2 subgroups of patients with OA, with one subgroup demonstrating comparatively worse 12-month postoperative pain intensity and function scores.

Prevalence and Risk Factors of De Novo Widespread Post-COVID Pain in Nonhospitalized COVID-19 Survivors: A Nationwide Exploratory Population-Based Survey.

This survey investigated the prevalence of de novo widespread musculoskeletal post-COVID pain and risk factors for its development in nonhospitalized COVID-19 survivors. A nationwide exploratory cross-sectional study was conducted, including a cohort of 593,741 Danish residents who had suffered from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from March 2020 to December 2021. A questionnaire was distributed to the Danish population via the digital mail system (e-Boks). Self-reported demographic data, previous medical comorbidities (diagnosed), socioeconomic data, time of infection, prior chronic pain conditions (diagnosed), development of de novo widespread pain after infection, pain medication, and pain intensity information were collected. Responders consisted of 130,443 nonhospitalized participants (58.2% women; mean age: 50.2 years). At a mean of 14.4 (standard deviation 6.0) months after infection, 6,875 (5.3%) patients reported the presence of de novo widespread musculoskeletal post-COVID pain. Almost 75% of the patients reported a moderate to severe intensity of the pain. In conclusion, de novo widespread post-COVID pain was present in 5.3% of nonhospitalized COVID-19 survivors 1 year after infection (14.4 ± 6.0 months). Older age, female sex, higher BMI, and history of migraine, whiplash, stress, type-2 diabetes, neurological disorders, and lower socioeconomic status were risk factors associated with the development of de novo widespread post-COVID pain in nonhospitalized patients. As de novo widespread pain is considered a sign of sensitization, this group will require specialized pain management attention. PERSPECTIVE: This article presents de novo widespread post-COVID pain prevalence in a cohort of 130,443 citizens infected with COVID-19. The study identifies potential risk factors associated with the development of these new pain symptoms. The results may increase focus on this patient group and potentially help identify predictors for postinfection pain development.

Long COVID or Post-COVID-19 Condition: Past, Present and Future Research Directions.

The presence of symptoms after an acute SARS-CoV-2 infection (long-COVID) has become a worldwide healthcare emergency but remains underestimated and undertreated due to a lack of recognition of the condition and knowledge of the underlying mechanisms. In fact, the prevalence of post-COVID symptoms ranges from 50% during the first months after the infection up to 20% two-years after. This perspective review aimed to map the existing literature on post-COVID symptoms and to identify gaps in the literature to guide the global effort toward an improved understanding of long-COVID and suggest future research directions. There is a plethora of symptomatology that can be due to COVID-19; however, today, there is no clear classification and definition of this condition, termed long-COVID or post-COVID-19 condition. The heterogeneity in the symptomatology has led to the presence of groups/clusters of patients, which could exhibit different risk factors and different mechanisms. Viral persistence, long-lasting inflammation, immune dysregulation, autoimmune reactions, reactivation of latent infections, endothelial dysfunction and alteration in gut microbiota have been proposed as potential mechanisms explaining the complexity of long-COVID. In such an equation, viral biology (e.g., re-infections, SARS-CoV-2 variants), host biology (e.g., genetics, epigenetics) and external factors (e.g., vaccination) should be also considered. These various factors will be discussed in the current perspective review and future directions suggested.

COVID-19 and musculoskeletal pain: an overview of the current knowledge.

The Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has provoked billions of infections worldwide. Several meta-analyses have observed that up to 50% of individuals who had survived to a SARS-CoV-2 acute infection suffer from post-COVID symptoms lasting for weeks or months and up to one year after infection. The prevalence of post-COVID pain ranges between 10% to 20% when assessed with other overall post-COVID symptoms and can reach up to 50% to 60% when investigated specifically. The most common musculoskeletal manifestations of post-COVID-19 condition include fatigue, myalgia, arthralgia or back pain. Despite pain of musculoskeletal origin is one of the most prevalent post-COVID pain symptoms, the exact pathophysiological mechanisms of musculoskeletal post-COVID pain are not completely understood. Studies have reported the complexity of post-COVID pain including immune, biological, and psychological factors, and more recently, they have suggested that genetic and epigenetic factors may also play a potential role, highlighting the need for further investigation into these mechanisms. Its management is still controversial, as no specific guideline for treating musculoskeletal post-COVID pain has been proposed with only general consideration about the relevance of multidisciplinary and multimodal treatment approaches. In this paper we will highlight the clinical features, the mechanism, and the management possibilities of musculoskeletal post-COVID pain.

Apolipoprotein E (ApoE) ε4 Genotype (ApoE rs429358-ApoE rs7412 Polymorphisms) Is Not Associated with Long COVID Symptoms in Previously Hospitalized COVID-19 Survivors.

The role of genetics as a predisposing factor related to an increased risk of developing long COVID symptomatology is under debate. The aim of the current secondary analysis was to identify the association between the Apolipoprotein E (ApoE) gene, a gene affecting cholesterol metabolism and previously associated with a higher risk of SARS-CoV-2 infection and COVID-19 severity, and the development of long COVID in a cohort of individuals who had been hospitalized by SARS-CoV-2 infection. Unstimulated whole saliva samples were collected from 287 previously hospitalized COVID-19 survivors. Three genotypes of the ApoE gene (ApoE ε2, ε3, ε4) were obtained based on the combination of ApoE rs429358 and ApoE rs7412 polymorphisms. Participants were asked to self-report the presence of any post-COVID symptom in a face-to-face interview at 17.8 ± 5.2 months after hospital discharge and medical records were obtained. Each participant reported 3.0 (1.9) post-COVID symptoms. Overall, no significant differences in long COVID symptoms were observed depending on the ApoE genotype (ApoE ε2, ApoE ε3, ApoE ε4). The presence of the ApoE ε4 genotype, albeit associated with a higher risk of SARS-CoV-2 infection and COVID-19 severity, did not appear to predispose for the presence of long COVID in our cohort of previously hospitalized COVID-19 survivors.

Precision management of post-COVID pain: An evidence and clinical-based approach.

Background Pain after a SARS-CoV-2 acute infection (post-COVID pain) is becoming a new healthcare emergency but remains underestimated and most likely undertreated due to a lack of recognition of the phenomenon and knowledge of the underlying pain mechanisms. Evidence supporting any particular treatment approach for the management of post-COVID pain is lacking. Large variability in the patient response to any standard pain treatments is clinically observed, which has led to calls for a personalized, tailored approach to treating patients with chronic post-COVID pain (i.e. 'precision pain medicine'). Applying the global concerted action towards precision medicine to post-COVID pain could help guide clinical decision-making and aid in more effective treatments. Methods The current position paper discusses factors to be considered by clinicians for managing post-COVID pain ranging from identification of the pain phenotype to genetic consideration. Results The ability of clinicians to phenotype post-COVID pain into nociceptive, neuropathic, nociplastic or mixed type is suggested as the first step to better planification of a treatment programme. Further, the consideration of other factors, such as gender, comorbidities, treatments received at the acute phase of infection for onset-associated COVID-19 symptoms, factors during hospitalization or the presence of emotional disturbances should be implemented into a treatment programme. Conclusions Accordingly, considering these factors, management of post-COVID pain should include multimodal pharmacological and non-pharmacological modalities targeting emotional/cognitive aspects (i.e. psychological and/or coping strategies), central sensitization-associated mechanisms (i.e. pain neuroscience education), exercise programmes as well as lifestyle interventions (e.g. nutritional support and sleep management). SIGNIFICANCE: This position paper presents an evidence-based clinical reasoning approach for precision management of post-COVID pain.

The temporal expression of circulating microRNAs after acute experimental pain in humans.

BACKGROUND: MicroRNAs (miRNAs) can modulate several biological systems, including the pain system. This study aimed to evaluate the temporal expression of circulating miRNAs in the plasma of healthy volunteers as a marker for epigenetic changes before and after an acute, experimental, pain provocation by intramuscular hypertonic saline injection. METHODS: Twenty volunteers were randomly allocated into two groups and received either hypertonic (pain) or isotonic (control) saline injection in the first dorsal interosseous muscle of their dominant hand. Pain intensity was continuously recorded for 20 minutes after injection on a VAS scale from 0 to 100 (0 indicates no pain and 100 the worst imaginable pain). Blood samples were taken at baseline, 30 minutes, 3 hours, and 24 hours post-injection, and plasma was separated. MiRNA extracts were used for RNA sequencing with the Illumina NextSeq platform. MiRNA transcripts were compared between the pain and the no-pain, control group at every time point. Significant differences were considered when folds were >2 and the False Discovery Rate was p < 0.05. RESULTS: After 30 minutes, 4 miRNAs were significantly altered in the pain group compared to controls, which increased to 24 after 3 hours and to 42 after 24 hours from baseline (p < 0.0001). Two miRNAs were consistently upregulated throughout the experiment. Enrichment analysis showed significant miRNAs involved in brain perception of pain, brain signalling and response to stimuli. CONCLUSIONS: This exploratory study is the first to report on the temporal expression of circulating miRNAs after an acute, human experimental muscle pain model. SIGNIFICANCE: This exploratory study evaluated the temporal profile of circulating miRNAs in the plasma of healthy subjects after acute experimental pain. Several miRNAs were altered in subjects at the times of follow-up after the acute pain model when compared to controls. MiRNAs previously associated with pain processes were altered in the pain group. Our results, by showing the fast and prolonged modifications of miRNA elicited by the acute experimental pain model, add new perspectives to the topic of epigenetics and pain.

Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors.

The aim of the study was to identify the association between four selected COVID-19 polymorphisms of ACE2 and TMPRSS2 receptors genes with the presence of long-COVID symptomatology in COVID-19 survivors. These genes were selected as they associate with the entry of the SARS-CoV-2 virus into the cells, so polymorphisms could be important for the prognoses of long-COVID symptoms. Two hundred and ninety-three (n = 293, 49.5% female, mean age: 55.6 ± 12.9 years) individuals who had been previously hospitalized due to COVID-19 were included. Three potential genotypes of the following single nucleotide polymorphisms (SNPs) were obtained from non-stimulated saliva samples of participants: ACE2 (rs2285666), ACE2 (rs2074192), TMPRSS2 (rs12329760), TMPRSS2 (rs2070788). Participants were asked to self-report the presence of any post-COVID defined as a symptom that started no later than one month after SARS-CoV-2 acute infection and whether the symptom persisted at the time of the study. At the time of the study (mean: 17.8, SD: 5.2 months after hospital discharge), 87.7% patients reported at least one symptom. Fatigue (62.8%), pain (39.9%) or memory loss (32.1%) were the most prevalent post-COVID symptoms. Overall, no differences in long-COVID symptoms were dependent on ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760, or TMPRSS2 rs2070788 genotypes. The four SNPs assessed, albeit previously associated with COVID-19 severity, do not predispose for developing long-COVID symptoms in people who were previously hospitalized due to COVID-19 during the first wave of the pandemic.

Post-COVID Pain Is Not Associated with Inflammatory Polymorphisms in People Who Had Been Hospitalized by COVID-19.

Our aim was to assess the association between four inflammatory polymorphisms with the development of post-COVID pain and to associate these polymorphisms with the clinical pain phenotype in individuals who had been hospitalized by COVID-19. Three potential genotypes of IL-6 (rs1800796), IL-10 (rs1800896), TNF-α (rs1800629), and IFITM3 (rs12252) single nucleotide polymorphisms (SNPs) were obtained from no-stimulated saliva samples from 293 (49.5% female, mean age: 55.6 ± 12.9 years) previously hospitalized COVID-19 survivors by polymerase chain reactions. Pain phenotyping consisted of the evaluation of pain features, sensitization-associated symptoms, anxiety levels, depressive levels, sleep quality, catastrophizing, and kinesiophobia levels in patients with post-COVID pain. Analyses were conducted to associate clinical features with genotypes. One hundred and seventeen (39.9%) patients experienced post-COVID pain 17.8 ± 5.2 months after hospital discharge. No significant differences in the distribution of the genotype variants of any SNPs were identified between COVID-19 survivors with and without post-COVID pain (all, p > 0.47). Similarly, the clinical pain phenotype was not significantly different between patients with and without post-COVID pain since no differences in any variable were observed for any SNPs. In conclusion, four SNPs associated with inflammatory and immune responses did not appear to be associated with post-COVID pain in previously hospitalized COVID-19 survivors. Further, neither of the SNPs were involved in the phenotyping features of post-COVID pain.

The link between epigenetics, pain sensitivity and chronic pain.

Increasing evidence suggests an association between gene expression and clinical pain. Epigenetic modifications are the main modulators of gene expression or protein translation in response to environmental stimuli and pathophysiological conditions. Preclinical and clinical studies indicate that epigenetic modifications could also impact the development of pain, the transition from acute to chronic pain, and the maintenance hereof.

Are Pain Polymorphisms Associated with the Risk and Phenotype of Post-COVID Pain in Previously Hospitalized COVID-19 Survivors?

Objective: To investigate the association of different, selected pain polymorphisms with the presence of de novo long-COVID pain symptoms and to analyze the association between these polymorphisms with clinical, sensory-related, cognitive and psychological variables in COVID-19 survivors. Methods: Two hundred and ninety-three (n = 293, 49.5% female, mean age: 55.6 ± 12.9 years) previously hospitalized COVID-19 survivors participated. Three genotypes of the following single nucleotide polymorphisms (SNPs) were obtained from non-stimulated saliva: OPRM1 (rs1799971), COMT (rs4680), BDNF (rs6265), and HTR1B (rs6296) by polymerase chain reactions in all participants. Further, clinical (intensity/duration of pain), sensory-related (sensitization-associated symptoms, neuropathic pain features), psychological (anxiety or depressive levels, sleep quality), and cognitive (catastrophizing, kinesiophobia) variables were collected in those COVID-19 survivors suffering from post-COVID pain. Analyses were carried out to associate clinical features with genotype. Results: Participants were assessed 17.8 ± 5.2 months after hospitalization. One hundred and seventeen (39.9%) experienced post-COVID pain (particularly of musculoskeletal origin). The distributions of the genotype variants of any SNP were not significantly different between COVID-19 survivors with and without long-term post-COVID pain (all, p > 0.178). No differences in sensitization-associated symptoms, neuropathic pain features, catastrophizing, kinesiophobia levels, anxiety and depressive levels or sleep quality according to the genotype variant in any SNPs were found. No effect of gender was identified. Conclusion: The four SNPs generally associated with pain did not appear to predispose to the development of de novo long-COVID pain symptoms in previously hospitalized COVID-19 survivors. The SNPs were not involved in the phenotypic features of post-COVID pain either.

Effects of Salicornia-Based Skin Cream Application on Healthy Humans' Experimental Model of Pain and Itching.

Halophyte plants are salt-tolerant and are acclimated for growth in saline soils such as along coastal areas. Among the halophytes, the Salicornia species have been used as both folk medicine and functional food for many years due to their high levels of bioactive compounds with supposed anti-inflammatory and antioxidative effects. However, the properties of Salicornia bioactive extracts on pain and itching still remain unclear. In this study, 30 healthy volunteers were randomized to treatments with 10% Salicornia-based cream or placebo cream for 24 or 48 h. On day 0, and 24 or 48 h post cream application, cold/heat detection and pain thresholds, mechanical pain thresholds and sensitivity, trans-epidermal water loss, histamine- and cowhage-evoked itch, and micro-vascular reactivity (neurogenic inflammation) were assessed to evaluate the analgesic, anti-pruritogenic and vasomotor effects. Skin permeability was reduced in the Salicornia-treated area for 48 h compared with 24 h application (p-value < 0.05). After 48 h of application, a decrease in mechanical-evoked itching (hyperkinesis) compared with 24 h treatment (p-value < 0.05) and increased warm detection and heat pain thresholds (p-value < 0.05) was found. Histamine-induced neurogenic inflammation showed a significant reduction in the cream-treated areas after 48 h compared with 24 h (p-value < 0.05). The results of this study indicate the overall inhibitory effect of Salicornia on hyperkinesis (mechanically evoked itch), the analgesic effect on thermal sensation, and modulation of the skin barrier architecture. Further studies are needed for the assessment of the long-term effects.

Circulating long non-coding RNA signature in knee osteoarthritis patients with postoperative pain one-year after total knee replacement.

OBJECTIVES: The incidence of chronic postoperative pain after total knee replacement (TKR) is approx. 20%, and hence preoperative risk factors are important to identify. Recent studies have indicated that preoperative inflammatory markers might hold prognostic information for the development of chronic postoperative pain. Long non-coding RNA (lncRNA) regulates the expression of genes related to e.g. inflammatory processes. The current study aimed to investigate the preoperative lncRNA signature as possible preoperative predictive markers for chronic postoperative pain following TKR. METHODS: Serum samples, collected preoperatively from 20 knee osteoarthritis (KOA) patients, were analyzed for 84 validated circulatory lncRNA. Pain intensity was assessed using a visual analog scale (VAS) before and one-year after TKR. Differences for the lncRNA expression were analyzed between patients with chronic postoperative pain (VAS≥3) and those with a normal postoperative recovery (VAS<3). RESULTS: LncRNA Myeloid Zinc Finger 1 Antisense RNA 1 (MZF1-AS1) (fold change -3.99; p-value: 0.038) (shown to be involved neuropathic pain) Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (fold change -3.39; p-value: 0.044) (shown to be involved neuropathic pain); Patched 1 pseudogene (LOC100287846) (fold change -6.99; p-value: 0.029) (unknown in pain) were down-regulated preoperatively in the group with chronic postoperative pain compared to the group normal postoperative pain recovery. CONCLUSIONS: These findings suggest, that TKR patients with chronic postoperative pain present preoperative downregulations of three specific lncRNA detectable at the systemic level. The presented study might give new insights into the complexity of chronic postoperative pain development and show how non-coding RNA plays a role in the underlying molecular mechanisms of pain.