Chronic Pain Sensitivity Research Articles

Lifestyle factors as predictors of incident functional somatic disorder. Five-year follow-up of The DanFunD study.

To assess whether lifestyle factors, including sleep pattern, are predictors for the development of functional somatic disorder (FSD). A population-based prospective cohort of 9656 men and women aged 18-76 years was established in 2011-2015 and invited for re-examination in 2017-2020, when 5738 participated. Median follow-up period was 65 months. Participants filled in validated questionnaires on lifestyle, sleep pattern and various delimitations of FSD, which were operationalized using two different approaches: bodily distress syndrome (BDS) and functional somatic syndromes (FSS) (i.e. chronic fatigue, chronic widespread pain (CWP), irritable bowel, and multiple chemical sensitivity (MCS)). Baseline lifestyle and sleep pattern in relation to incidence of BDS and FSS (chronic fatigue, CWP, irritable bowel, MCS) was analysed by logistic regressions, adjusted for age, sex and subjective social status. Inferior sleep quality at baseline predicted both incidence of BDS and all FSS delimitations except MCS. Smoking, alcohol intake, and low physical activity, but not diet, were predictors for the development of BDS. No uniform pattern was observed for the FSS. Smoking predicted development of chronic fatigue, CWP and irritable bowel, but not MCS. Alcohol and food quality only influenced the development of chronic fatigue whereas low physical activity only influenced the development of chronic fatigue and CWP. Lifestyle factors and sleep pattern seem to be predictors for some delimitations of FSD, but the importance of the various lifestyle factors is different for the different delimitations. The study shows the importance of analysing the various FSSs separately.

Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area.

In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain. The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON). Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile). Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed. Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.

Neuronal activation patterns during self-referential pain imagination

In clinical assessments and pain therapy, patients are asked to imagine themselves in pain. However, the underlying neuronal processes remain poorly understood. Prior research has focused on empathy for pain or reported small sample sizes. Thus, the present study aimed to promote the neurobiological understanding of self-referential pain imagination. We hypothesised to find activation contrasts (pain vs. no pain) across pain-related areas and expected two of the most prominent predictors of chronic pain, pain sensitivity (PS) and locus of control (LoC), to be moderators.In an fMRI study, N = 82 participants completed a pain imagination task, in which they were asked to imagine themselves in painful and non-painful situations presented in the form of pictures and texts. After each trial, they were instructed to give painfulness ratings. As a laboratory measure of PS, electrical pain thresholds were assessed. A questionnaire was completed to measure LoC.Across presentation modes we found activity contrasts in previously pain-related regions, such as the prefrontal, supplementary motor, primary motor, somatosensory and posterior parietal cortices, and the cerebellum. We found positive associations of PS and external LoC with painfulness ratings, and a negative correlation between PS and internal LoC. Despite our hypotheses, neither PS nor internal LoC were significant predictors of the BOLD-signal contrasts.Though future studies are needed to draw further conclusions, our results provide preliminary evidence of a potential neuronal imagination-perception overlap in pain.

Photobiomodulation therapy for chronic knee pain in obese patients in pre-rehabilitation for bariatric surgery: randomised, placebo-controlled, double-blinded, clinical trial protocol

IntroductionObesity has become a worldwide public health problem and is directly linked to loss of quality of life, complications and comorbidities. One of them is chronic pain, especially in the...

Exploring the psychopathological profile of fibromyalgia: insights from the personality assessment inventory and its association with disease impact.

Fibromyalgia (FM) is a complex rheumatic disorder characterized by chronic nociplastic pain and central sensitization. Psychopathological conditions can influence FM symptoms, which worsen their condition. However, not all patients with FM have psychopathological disorders, indicating a heterogeneous population. To investigate the psychopathological profile and personality disorders in patients with FM and its relationship impact on this disease. An observational and cross-sectional comparative study was conducted with a sample of 90 women, mean age 48.7 years (SD = 8.12), from Hospital del Mar, Barcelona. The Personality Assessment Inventory (PAI) and the Fibromyalgia Impact Questionnaire (FIQ) were used for assessment. FM patients predominantly exhibited psychopathological profiles resembling affective disorders (37.7%) and Cluster C personality disorders (58.8%). The severity of FM's impact was related to affective disorder symptoms, hypervigilance, derealization, somatization, and Cluster B personality disorder (emotional instability). Different rheumatic symptoms correlated with specific psychopathological patterns. Increased somatic symptoms on the FIQ were related to an unstable and dependent personality, while heightened emotional symptoms on the FIQ were associated with avoidance, borderline traits, and passive-aggressive reactions. Recognizing psychopathological aspects is crucial for managing FM. The PAI is a valuable tool for establishing its psychopathological multidimensional profile, which predominantly shows an affective spectrum conditions and comorbid Cluster C personality disorder, exacerbating the disease's impact.

CCL2- and Notch2-mediated Central Sensitization in a Rat Chronic Pelvic Pain Model.

Chronic pelvic pain (CPP) is a common gynecological condition in women with multifactorial etiology. Some studies have revealed that patients with CPP have the same structural and functional changes in the pain matrix in the brain to patients with other types of chronic pain. However, the relationship between localized pelvic pain and changes in the structure and function of the central nervous system is still unclear. In this study, a rat model of CPP was established by pelvic nerve ligation and behavioral tests were used to validate the model. Afterwards, we compared the expression of CCL2 in CPP and control rats and observed the changes in their behavioral patterns by blocking the expression of CCL2 in the former group. In addition, we upregulated the expression of CCL2 in human microglia cells (HMC3) to further observe the effect of CCL2 on the Notch2 pathway. Our results showed that the expression of chemokine ligand 2 (CCL2) in the serum exosomes, pelvic vascular endothelial cells, and cerebrospinal fluid was higher in the CPP group than the control group (p<0.05). In HMC3 treated with recombinant CCL2 protein, a significant increase in the mRNA and protein expression of Notch2 was observed. CCL2 can activate the Notch2 signaling pathway and plays an important role in the central sensitization of chronic pelvic pain.

Direct inhibition of microglial activation by a μ receptor selective agonist alleviates inflammatory-induced pain hypersensitivity

Opioids are widely used in the treatment of moderate and severe pain. Nociceptive stimulation has been reported to potentially promote microglial activation and neuroinflammation, which also causes chronic pain sensitization. The aim of this study was to demonstrate whether the novel μ receptor agonist MEL-0614 could inhibit activated microglia directly and the associated signaling pathway. Mice were administered lipopolysaccharide and formalin to induce allodynia. Von Frey test was used to detect the anti-allodynia effect of MEL-0614 before and after LPS and formalin injection. In the spinal cord, the levels of proinflammatory cytokines and microglial activation were determined after MEL-0614 administration. BV2 and primary microglia were cultured to further explore the effect of MEL-0614 on LPS-induced microglial activation and key signaling pathways involved. MEL-0614 partially prevented and reversed allodynia induced by LPS and formalin in vivo, which was not inhibited by the μ receptor antagonist CTAP. Minocycline was effective in reversing the established allodynia. MEL-0614 also downregulated the activation of microglia and related proinflammatory cytokines in the spinal cord. Additionally, in BV2 and primary microglia, MEL-0614 inhibited the LPS-induced upregulation of proinflammatory factors, which was unaffected by CTAP. The NLR family pyrin domain containing 3 (NLRP3) related signaling pathway may be involved in the interaction between MEL-0614 and microglia. The opioid agonist MEL-0614 inhibited the activation of microglia and the subsequent upregulation of proinflammatory factors both in vivo and in vitro. Notably, this effect is partially mediated by the μ receptor.

Neural correlates of central pain sensitization in chronic low back pain: a resting-state fMRI study.

The objective of this study is to explore the neural correlates of pain sensitization in patients with chronic low back pain (cLBP). While the association between cLBP and pain sensitization has been widely reported, the underlying brain mechanism responsible for this relationship requires further investigation. Our study included 56 cLBP patients and 56 healthy controls (HC). Functional magnetic resonance imaging data were obtained, and the voxel-wise amplitude of low-frequency fluctuation (ALFF) was calculated to identify brain alterations in cLBP patients compared to HC groups. Pearson correlation coefficients were computed to explore the association between clinical data and brain alterations. Furthermore, mediation analyses were performed to investigate the path association between brain alterations and pain-related behaviors. Our findings revealed that patients with cLBP exhibited higher sensitivity, attention, and catastrophizing tendencies towards pain compared to HC. Furthermore, cLBP patients displayed significantly higher ALFF in various brain regions within the "pain matrix" and the default mode network when compared to HC. The altered precuneus ALFF was positively correlated with pain intensity (R = 0.51, P<0.001) and was negatively correlated with pain sensitivity (R = -0.43, P<0.001) in cLBP patients. Importantly, the effect of altered precuneus ALFF on pain intensity was mediated by pain threshold in these patients. Our study suggests that altered neural activity in the precuneus may contribute to pain hypersensitivity, which further exacerbating pain in cLBP patients.

Significant use of non-evidence-based therapeutics in a cohort of Australian fibromyalgia patients.

Fibromyalgia is a common condition characterised by chronic widespread musculoskeletal pain and central sensitivity features. Appropriate management requires a multidisciplinary approach prioritising non-pharmacological strategies. Evidence-based fibromyalgia medications are not always easily available, effective or tolerated. To characterise actual medication usage in Australian fibromyalgia patients. Demographic and clinical data, including medication use information, were gathered by chart review from patients attending the Monash Fibromyalgia Clinic between January 2019 and June 2022. Eligible patients were invited to complete an anonymous questionnaire between June and August 2022 to assess current therapeutic use. The questionnaire assessed fibromyalgia clinical features by using the Revised Fibromyalgia Impact Questionnaire and the 2016 modified American College of Rheumatology Fibromyalgia criteria. The chart review included 474 patients, and 108 participants completed the questionnaire. Most chart review (78.7%) and questionnaire participants (85.2%) reported using at least one medication for their fibromyalgia. 48.5% of chart review patients and 58.3% of questionnaire participants reported using at least one evidence-based medication, usually amitriptyline, duloxetine or pregabalin. However, the most common individual medications for questionnaire participants were non-steroidal anti-inflammatory drugs (48.2%), paracetamol (59.3%) and opioids (34.3%), with most opioids being typical opioids. Among questionnaire participants, 14.8% reported using cannabinoids, and 70.4% reported using at least one supplement, vitamin or herbal/naturopathic preparation. Not all medication or substance use was recorded during clinic appointments. Fibromyalgia patients engage in various pharmacotherapeutic strategies that are not always evidence-based or disclosed to their treating clinicians.

Electrophysiological evidence that TRPM3 is a candidate in latent spinal sensitization of chronic low back pain

Latent spinal sensitization is one key mechanism developing at the early stage of chronic low back pain (LBP). TRPM3-mediated calcium transients of dorsal root ganglia (DRG) neurons are considered critical presynaptic signals involved in this latent sensitization. However, postsynaptic consequences in input laminae of the spinal cord have not been addressed so far. Here, by electrophysiological recordings in acute spinal cord slices from adult rats, we show that perfusion of the TRPM3 agonist pregnenolone sulfate (PregS) induced a significant increase in the frequency but not amplitude of spontaneous postsynaptic currents in lamina I and II neurons. This frequency increase started slowly during PregS perfusion but was reversible following washout. This result is consistent with a presynaptic action of the neurosteroid PregS, indicating the presynaptic expression of functional TRPM3 in the superficial dorsal horn of adult rats. Thus, PregS-induced TRPM3 activation enhances spinal synaptic strength, implying a mediating role of TRPM3 between neuroendocrine and nociceptive signaling, which might as well exist in chronic LBP primed by chronic stress that promotes the biosynthesis of PregS.

Auricular Vagus Nerve Stimulation Improves Chronic Pain and Pain-Related Cytokine Levels: A Clinical Study

Periauricular Vagus Nerve Stimulation (pVNS) has been proven safe and effective in reducing chronic pain and related comorbidities in numerous clinical studies. This multicenter, interventional study used a non-randomized, interrupted time-series analysis to test the efficacy of an 8-week treatment protocol using the Stivax neurostimulator device. Subjects (n=33, 15 F, 18 M, age 40-77) were recruited at 3 clinic sites in California and Colorado. All subjects had long-term chronic pain and had failed other treatments. Subjects were treated with the Stivax device 3 times (2 weeks on, 1 week off). Subjective assessments of pain (Visual Analog Scale), disability (Oswestry Disability Index), depression (PHQ-9), and activity (IPAQ-E) were collected at baseline and weekly. Objective blood levels of pain-related cytokines collected at the end of weeks 2 and 8. Most subjects reported reduced pain, disability, and depression, with increased activity levels. At the end of week 8, subjects reported an average reduction in pain by 38.5% (3 subjects reported no pain), depression by 43.6% (2 subjects reported no depression), disability by 38.6% (2 subjects reported no disability), and an average 26.1% increase in activity level (5 subjects doubled their activity level). Levels of the pain-related cytokines IL-1ꞵ, IL-2, IL-3, IL-7, IL-10, IL-15, IL-17α, IL-21, TNF-α, IFN-γ, and FLT3-ligand showed improvement at week 8. pVNS is believed to “reset” central sensitization underlying chronic pain and other central sensitization syndromes, engaging the body’s pain modulation systems. Our results indicate that pVNS can clinically significantly improve chronic pain and associated morbidities without adverse effects.

Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia.

To examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain. Twelve subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: (1) chronic ocular pain; (2) presence of ocular pain over 1 week recall; and (3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4-6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4-6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed. At baseline, all subjects reported unpleasantness with light stimulation (average: 70.8 ± 32.0). Four to six weeks after BoNT-A injection, unpleasantness scores decreased (48.1 ± 33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline ("responders," n = 6), while 50% had equivalent (n = 3) or increased (n = 3) unpleasantness ("non-responders"). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not. BoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain.

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

Bone cancer pain (BCP) is excruciating for cancer patients, with limited clinical treatment options and significant side effects, due to the complex and unclear pathogenesis of bone cancer pain. Peripheral sensitization in dorsal root ganglion (DRG) neurons is a recognized cellular mechanism for bone cancer pain. The pathological mechanism of chronic pain is increasingly being affected by epigenetic mechanisms. In this study, we unbiasedly showed that the DNA hydroxymethylase ten-eleven translocation 1 (TET1) expression was significantly increased in the L4-6 DRG of BCP rats and ten-eleven translocation 2 (TET2) expression did not change significantly. Notably, TET1 inhibition by intrathecal injection of Bobcat339 (a TET1 inhibitor) effectively relieved mechanical hyperalgesia in BCP rats. Peripheral sensitization in chronic pain relies on the activation and overexpression of ion channels on neurons. Here, we demonstrated that TRPV4, one of the transient receptor potential ion channel family members, was significantly elevated in the L4-6 DRG of BCP rats. In addition, TRPV4 inhibition by intrathecal injection of HC067047 (a TRPV4 inhibitor) also significantly attenuated mechanical hyperalgesia in BCP rats. Interestingly, we found that TET1 inhibition downregulated TRPV4 expression in the L4-6 DRG of BCP rats. As a result, these findings suggested that TET1 may contribute to bone cancer pain by upregulating TRPV4 expression in the L4-6 DRG of BCP rats and that TET1 or TRPV4 may become therapeutic targets for bone cancer pain.

The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia: A Systematic Review.

Fibromyalgia (FM) is a chronic pain sensitivity syndrome characterized by diffuse musculoskeletal pain and many other systemic manifestations. Low-dose naltrexone (LDN) has been increasingly used as an off-label treatment option in FM. However, current evidence on the safety and efficacy of LDN in patients with FM is not well known. To systematically assess the current evidence on the safety and efficacy of LDN use in the treatment of FM. A comprehensive bibliographic search was conducted on EBM Reviews - Cochrane Central Register of Controlled Trials, EBM Reviews - Cochrane Database of Systematic, Embase, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions and Scopus databases in September 2022. Inclusion criteria were articles that were published in English, focusing on clinical trials involving LDN for the treatment of FM. Two reviewers independently screened and extracted the data. A qualitative analysis was used due to the high methodological heterogeneity between studies. The electronic search produced 805 articles. After applying the inclusion criteria, 9 articles (one RCT, two case reports, two case series, and four pilot trials) were selected for evaluation. LDN intervention protocols, study designs, and follow-up periods were different among the included studies. Overall, LDN was found to be effective in the symptomatic management of FM, and of the 78% of included studies that evaluated for safety, no severe adverse events were reported. Proving the efficacy and safety of low-dose naltrexone is a future possibility based on current study data, but the level of scientific evidence is limited. Future well-designed trials with large sample sizes are required.

Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain.

Pain, the primary symptom of osteoarthritis (OA), reduces both the quality and quantity of life for patients. The pathophysiology of OA pain is complex and often difficult to explain solely by radiological structural changes. One reason for this discrepancy is pain sensitization (peripheralsensitization [PS] and central sensitization [CS]) in OA. Thus, an understanding of pain sensitization is important when considering treatment strategies and development for OA pain. In recent years, pro-inflammatory cytokines, nerve growth factors (NGFs), and serotonin have been identified as causative agents that induce peripheral and central sensitization and are becoming therapeutic targets for OA pain. However, the characteristics of the clinical manifestations of pain sensitization elicited by these molecules remain unclear, and it is not well understood who among OA patients should receive the therapeutic intervention. Thus, this review summarizes evidence on the pathophysiology of peripheral and central sensitization in OA pain and the clinical features and treatment options for this condition. While the majority of the literature supports the existence of pain sensitization in chronic OA pain, clinical identification and treatment of pain sensitization in OA are still in their infancy, and future studies with good methodological quality are needed.

Relationship between physical activity and central sensitization in chronic low back pain: Insights from machine learning

Background and objectivesChronic low back pain (CLBP) is a leading cause of disability. The management guidelines for the management of CLBP often recommend optimizing physical activity (PA). Among a subsample of patients with CLBP, central sensitization (CS) is present. However, knowledge about the association between PA intensity patterns, CLBP, and CS is limited. The objective PA computed by conventional approaches (e.g. cut-points) may not be sensitive enough to explore this association. This study aimed to investigate PA intensity patterns in patients with CLBP and low or high CS (CLBP-, CLBP+, respectively) by using advanced unsupervised machine learning approach, Hidden semi-Markov model (HSMM). MethodsForty-two patients were included (23 CLBP-, 19 CLBP+). CS-related symptoms (e.g. fatigue, sensitivity to light, psychological features) were assessed by a CS Inventory. Patients wore a standard 3D-accelerometer for one week and PA was recorded. The conventional cut-points approach was used to compute the time accumulation and distribution of PA intensity levels in a day. For the two groups, two HSMMs were developed to measure the temporal organization of and transition between hidden states (PA intensity levels), based on the accelerometer vector magnitude. ResultsBased on the conventional cut-points approach, no significant differences were found between CLBP- and CLBP+ groups (p = 0.87). In contrast, HSMMs revealed significant differences between the two groups. For the 5 identified hidden states (rest, sedentary, light PA, light locomotion, and moderate-vigorous PA), the CLBP- group had a higher transition probability from rest, light PA, and moderate-vigorous PA states to the sedentary state (p < 0.001). In addition, the CBLP- group had a significantly shorter bout duration of the sedentary state (p < 0.001). The CLBP+ group exhibited longer durations of active (p < 0.001) and inactive states (p = 0.037) and had higher transition probabilities between active states (p < 0.001). ConclusionsHSMM discloses the temporal organization and transitions of PA intensity levels based on accelerometer data, yielding valuable and detailed clinical information. The results imply that patients with CLBP- and CLBP+ have different PA intensity patterns. CLBP+ patients may adopt the distress-endurance response pattern with a prolonged bout duration of activity engagement.

Gut Brain axis: The gut microbiome in peri-operative medicine.

Sir, The human body is inhabited by a multitude of bacteria, viruses, fungi, phages constituting the microbiota, and their gene pool called the microbiome which is essential for human well-being.[1] The role of gut microbiome in peri-operative medicine is recently being explored. However, most of the literature available is that of animal studies and more extensive research would be needed in humans to establish an association. The mechanism of action of gut-microbiome on various systems of the human body can be explained by the “gut-brain axis.” This is a two-way interaction between the enteric nervous system (ENS) and central nervous system (CNS) [Figure 1]. The gut microbiota secrete various metabolites and products like-short chain fatty acids (SCFA), enzymes, polysaccharides, cytokines, and neurotransmitters, which are released in to the circulation to act on the CNS. The vagus nerve also carries inputs from ENS to CNS. The brain in-turn acts on the gut through the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system.[2] Immune mediated interaction and alteration of microglial activity are other proposed mechanisms of gut-brain interaction. All these mechanisms have been proven only by preclinical animal studies.[1]Figure 1: Gut brain axis. HPA = Hypothalamic pituitary adrenal axisAnaesthetic agents-like propofol and volatile anaesthetics have been found to alter the gut microbiota composition in animal studies. Han et al. studied gut microbiota of mice after sevoflurane exposure and found that microbiome composition was reduced on day-1, 3, 7, and 14 after sevoflurane anaesthesia compared to the control group. They also noted a significant difference in fecal metabolites of the experimental and control groups.[3] Also an infusion of propofol for 3 hours in rats was found to decrease the number of certain bacterial species for 14 days.[4] Postoperative delirium (POD) and post-surgical pain (PSP) have also been attributed to the gut-microbiome by animal studies. This means, why certain patients have more POD or PSP than others can be determined by their gut-microbiome constitution and may be pre-treatment with pre-biotics, post-biotics, or fecal microbiota transplantation reduces the risk of POD and PSP in these patients. However, this association between POD/PSP and gut-microbiome has been shown mostly in animal studies and human association is yet to be established.[1] Zhang et al. compared the gut-microbiota of rats who developed POD and those who did not develop POD after abdominal surgery. The composition of microbiota was significantly different between the groups. They also conducted fecal microbiota transplantation from rats with POD to antibiotic treated rats, which then developed POD.[5] A human study has proved association of gut microbiome with chronic PSP, where Yao et al. had preoperatively collected gut-microbiome samples for 132 patients undergoing breast cancer surgery. The gut microbiota of 66 patients who developed chronic PSP (CPSP) was significantly different from those who did not develop PSP. Fecal microbiome transplantation from CPSP patients to mice led to development of hyperalgesia in these mice.[6] The gut microbiome composition has been attributed to development of opioid tolerance. Chronic opioid exposure leads to activation of opioid receptors on gut epithelium and destruction of gut mucosal barrier, allowing translocation of gut bacteria leading to an inflammatory response and pain exacerbation.[1] The gut microbiota composition influences many chronic pain conditions like fibromyalgia, headache, neuropathic, visceral, and chronic pelvic pain. The mediators of gut microbiota can alter the neuronal excitability at the dorsal root ganglia and mediate neuro inflammation leading to central sensitization and peripheral sensitization in chronic pain. Thus, targeting the gut-microbiota seems to be a promising treatment of chronic pain.[1,2] In future, gut microbiome analysis might help to screen patients at risk of postoperative cognitive dysfunction, postoperative pain, chronic pain and opioid tolerance and alteration of gut microbiota by use of prebiotics, postbiotics, dietary, and life-style changes might provide therapeutic benefit in such patients. However, this hypothesis is based majorly on animal studies and gut microbiome still needs to be explored in humans. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Neurophysiology of pain education knowledge, pain disability, patient satisfaction and central sensitization in chronic musculoskeletal pain

Chronic musculoskeletal pains are multifaceted, and Central sensitization is a potential pathophysiological mechanism underlying a group of chronic musculoskeletal pain disorders. Neurophysiology of pain education knowledge and patient satisfaction levels of chronic musculoskeletal pain subjects may contribute to central nervous system sensitization. Hence, the aim of the study was to evaluate the impact of neurophysiology of pain education knowledge and patient satisfaction levels on central sensitization in large population of patient with chronic musculoskeletal pain. The study included 200 chronic musculoskeletal pain subjects that persisted more than 3 months with average age of 43.93±13.62. A cross-sectional study used non probability sampling. Neurophysiology of pain Questionnaire (NPQ) to know the conceptualization of pain, mood rating scale(MRS) to measure patient’s mood fluctuation because of pain, pain disability scale (PDS) for evaluating patients ability to perform certain activity, central sensitization inventory(CSI) to measure nervous system sensitization and patients satisfaction scale(PSS) to understand patient’s satisfaction towards the treatment and health care provider were used. Descriptive and correlation analyses were used for analysis. The correlation analyses showed that patient disability scale negatively correlated with mood scale and positively correlated with the age, duration of the condition, impact of pain on ADL and central sensitization. And there was a positive correlation between patient satisfaction and impact of pain on ADL. The age, mood, duration of the condition and pain disability were the factors behind central sensitization in patients with chronic musculoskeletal pain. And the neuro physiology of pain knowledge had impact on pain disability and patient satisfaction.

Therapeutic effect of Baimai Ointment on peripheral sensitization of chronic inflammatory pain in mice

Chronic inflammatory pain is mainly manifested by peripheral sensitization. Baimai Ointment(BMO), a classical Tibetan medicine for external use, has good clinical efficacy in the treatment of chronic inflammatory pain, while its pharmacodynamics and mechanism for relieving peripheral sensitization remain unclear. This study established an animal model of chronic inflammatory pain induced by complete Freund's adjuvant to explore the mechanism of BMO in the treatment of chronic inflammatory pain by behavioral test, side effect assessment, network analysis, and experimental verification. The pharmacodynamics experiment showed that BMO increased the thresholds of mechanical pain sensitivity and thermal radiation pain sensitivity of chronic inflammatory pain mice in a dose-dependent manner, and had inhibitory effect on foot swelling, inflammatory mediator, and the expression of transient receptor potential vanilloid-1(TRPV1) and transient receptor potential A1(TRPA1). The results of body weight monitoring, pain sensitivity threshold detection in normal mice, rotarod performance test, and forced swimming test showed that BMO had no obvious toxic or side effect. The network analysis of 51 candidate active molecules selected according to the efficacy of BMO, content of main components, and ADME parameters showed that the inhibitory effect of BMO on chronic inflammatory pain was associated with the core regulatory elements of tumor necrosis factor(TNF) and T cell receptor signaling pathways. BMO down-regulated the protein levels of mitogen-activated protein kinase 14(MAPK14), MAPK1, and prostaglandin-endoperoxide synthase 2(PTGS2), and up-regulated the phosphorylation le-vel of glycogen synthase kinase 3 beta(GSK3 B) in the plantar tissue of mice. In conclusion, BMO can effectively relieve peripheral sensitization of chronic inflammatory pain without inducing tolerance and obvious toxic and side effects. The relevant mechanism may be related to the regulation of BMO on core regulatory elements of TNF and T cell receptor signaling pathways in surrounding tissues.

PMON68 Effect of an Amino-Acid Based Blend on Human Growth Hormone (hGH) and Fibromyalgia (FM) Symptoms

Abstract Fibromyalgia is a chronic pain sensitivity disorder that affects approximately 3-8% of the general population with symptoms that include fatigue and widespread musculoskeletal pain. Psychological and physical stressors are frequent drivers of fibromyalgia, and additional lockdown-associated stressors may worsen symptoms. Reduced production of human growth hormone (hGH) is evident in approximately 30% of individuals with fibromyalgia, which is hypothesized to contribute to common fibromyalgia symptoms. An orally administered amino acid supplement has been previously shown to improve endogenous hGH status in adults. We investigated if daily administration of the supplement would increase levels of endogenous insulin-like growth factor 1 (IGF-1), a surrogate marker of the body's hGH levels, and improve symptoms related to low-normal hGH production in a cohort of 84 individuals being treated for fibromyalgia. This is the full-cohort analysis of an open-label, single-arm study that investigated the effects of 24 weeks of daily oral administration of the supplement in individuals with low-normal hGH production. The primary endpoint was the change from baseline to endpoint (Week 24) in serum IGF-1. Additional endpoints included the change in body weight, clinical symptoms (assessed with the Revised Fibromyalgia Impact Questionnaire [FIQR], range 0-100, and Perceived Stress Scale [PSS], range 0-40), fasting cardiometabolic markers, tolerability, and safety. Participants continued to receive standard care. The study enrolled 84 fibromyalgia patients with low-normal age-adjusted IGF-1 serum levels. High mean±SD baseline FIQR and PSS scores of 76±16 and 32±5, respectively, indicated poor to moderate symptom management with standard care. All individuals completed 24 weeks of treatment. Serum IGF-1 levels increased with a Week 24 mean±SE change of 28.4±3.0 ng/mL (paired t-test p&amp;lt;0.001). Body weight was reduced with a Week 24 mean±SE change of -5.5±0.3 kg (p&amp;lt;0.001). The change from baseline in FIQR and PSS scores were -29.1±1.1 and -20.0±0.8, respectively (both p&amp;lt;0.001), indicating a substantial improvement. Statistically significant improvements from baseline were also observed for systolic and diastolic blood pressure, HbA1c, LDL and HDL cholesterol, and triglycerides (all p&amp;lt;0.001). The supplement was well tolerated; no adverse events were reported. Sustained augmentation of IGF-1 with the supplement may represent a unique method of improving clinical symptoms of fibromyalgia in individuals with low-normal hGH production. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.