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Open-label placebos, or placebos without deception, have been found to induce analgesia, a challenging concept that need to be investigated in detail. In particular, what we need to know is the mechanism through which analgesia is induced when no deception is involved. Here we show for the first time that open-label placebo analgesia can be reversed by the opioid antagonist naloxone, as already shown for deceptive placebos. To do this, we used the tourniquet technique to induce experimental ischemic arm pain. The open-label placebo challenge started when pain scores reached 7 on a 0-10 rating scale. Whereas 59.4% of the subjects did not respond to the open-label placebo, 40.6% showed a substantial response. On the basis of the natural history control group, a placebo responder reported pain scores equal to or less than 7 after 9 min from the open-label placebo administration. In these responders, we found that a hidden injection of 10 mg naloxone could reverse placebo analgesia compared to a hidden injection of saline solution. At least two control groups showed that naloxone per se was not hyperalgesic, thus ruling out naloxone-induced hyperalgesia as a confounding variable. In light of the need to better understand open-label placebo effects, these findings represent the first experimental evidence that nondeceptive placebo analgesia may be mediated by the same mechanisms as deceptive placebo analgesia, namely, the endogenous opioid systems.
Learn More >Osteoarthritis (OA) is the most common type of degenerative arthritis and affects the entire joint, causing pain, joint inflammation, and cartilage damage. Various risk factors are implicated in causing OA, and in recent years, a lot of research and interest have been directed toward chronic low-grade inflammation in OA. Monocyte chemoattractant protein-1 (MCP-1; also called CCL2) acts through C-C chemokine receptor type 2 (CCR2) in monocytes and is a chemotactic factor of monocytes that plays an important role in the initiation of inflammation. The targeting of CCL2-CCR2 is being studied as part of various topics including the treatment of OA.
Learn More >People with chronic pain often fear and avoid movements and activities that were never paired with pain. Safe movements may be avoided if they share some semantic relationship with an actual pain-associated movement. The current study investigated whether pain-associated operant responses (movements) can become categorically associated with perceptually dissimilar responses, thus motivating avoidance of new classes of safe movements – a phenomenon known as category-based avoidance generalization. Using a robotic arm, two groups were trained to categorize arm-movements in different ways. Subsequently, the groups learned through operant conditioning, that an arm-movement from one of the categories was paired with a high probability of pain, while the others were paired with either a medium probability, and no pain (acquisition phase). Self-reported pain-related fear and pain-expectancy were collected as indices of fear learning. During a final generalization test phase, the movements categorically related to those from the acquisition phase were made available but in the absence of pain. Results showed that the generalization of outcome measures depended on the categorical connections between arm-movements, that is, the groups avoided and feared the novel generalization movement categorically related to the pain-associated acquisition movement, depending on how they had previously learned to categorize the movements. This suggests that operant pain-related avoidance can generalize to safe behaviors, which are not perceptually, but categorically, similar to a pain-associated behavior. This form of pain-related avoidance generalization is problematic because category-based relations can be extremely wide reaching and idiosyncratic. Thus, category-based generalization of operant pain-related avoidance merits further investigation.
Learn More >Black patients are less likely than White patients to receive physical therapy for musculoskeletal pain conditions. Current evidence, however, is limited to self-reported conditions and health services use. The purpose of this study was to use a large electronic health record data base to determine whether a race disparity existed in use of physical therapy within 90 days of a new musculoskeletal diagnosis.
Learn More >Painkiller administration lowers pain empathy, but whether this also reduces prosocial behavior is unknown. In this preregistered study, we investigated whether inducing analgesia through a placebo painkiller reduced effortful helping. When given the opportunity to reduce the pain of another person, individuals experiencing placebo analgesia ( = 45 adults from Austria; 21 male, 24 female) made fewer prosocial choices at the lowest helping level and exerted less physical effort when helping, compared with controls whose pain sensitivity was unaltered ( = 45; 21 male, 24 female). Self-reported empathic unpleasantness positively correlated with prosocial choices across the whole sample. While not replicating group differences in empathy, a mediation analysis revealed that the level of unpleasantness to other people's pain fully mediated the effect of placebo analgesia on prosocial choices. Given the importance of prosociality for social cohesion, these findings have broad potential implications both for individuals under the influence of painkillers and for society at large.
Learn More >The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.
Learn More >Neuropathic pain is a common chronic pain, characterized by spontaneous pain and mechanical allodynia. The incidence of neuropathic pain is on the rise due to infections, higher rates of diabetes and stroke, and increased use of chemotherapy drugs in cancer patients. At present, due to its pathophysiological process and molecular mechanism remaining unclear, there is a lack of effective treatment and prevention methods in clinical practice. Now, we use bioinformatics technology to integrate and filter hub genes that may be related to the pathogenesis of neuropathic pain, and explore their possible molecular mechanism by functional annotation and pathway enrichment analysis.
Learn More >For individuals experiencing pain, the decision to engage in clinical trials may be influenced by a number of factors including current and past care, illness severity, physical functioning, financial stress, and caregiver support. Co-occurring depression and anxiety may add to these challenges. The aim of this scoping review was to describe perspectives about clinical trial participation, including recruitment and retention among individuals with pain and pain comorbidities, including depression and/or anxiety. We searched PubMed, CINAHL, PsycINFO, and Cochrane CENTRAL databases. Study features, sample demographics, perspectives, barriers and/or motivations were collected and described. A total of 35 assessments were included in this scoping review with 24 focused on individuals with pain (24/35, 68.6%), 9 on individuals with depression and/or anxiety (9/35, 25.7%), and 2 on individuals with pain and co-occurring depression/anxiety (2/35, 5.7%). Barriers among participants with pain and those with depression included: research team's communication of information, fear of interventional risks, distrust (only among respondents with pain), too many procedures, fear of inadequate treatment, disease-life stressors and embarrassment with study procedures (more commonly reported in participants with depression). Facilitators in both groups included: altruism and supportive staff, better access to care, and the ability to have outcome feedback (more commonly among individuals with depression). Individuals with pain and depression experience challenges that affect trial recruitment and retention. Engaging individuals with pain within research planning may assist in addressing these barriers and the needs of individuals affected by pain and/or depression. PERSPECTIVE: This review highlights the need to address barriers and facilitators to participation in clinical trials, including the need for an assessment of perspectives from underserved or marginalized populations.
Learn More >Somatosensation, the detection and transduction of external and internal stimuli such as temperature or mechanical force, is vital to sustaining our bodily integrity. But still, some of the mechanisms of distinct stimuli detection and transduction are not entirely understood, especially when noxious perception turns into chronic pain. Over the past decade major progress has increased our understanding in areas such as mechanotransduction or sensory neuron classification. However, it is in particular the access to human pluripotent stem cells and the possibility of generating and studying human sensory neurons that has enriched the somatosensory research field. Based on our previous work, we describe here the generation of human stem cell-derived nociceptor-like cells. We show that by varying the differentiation strategy, we can produce different nociceptive subpopulations with different responsiveness to nociceptive stimuli such as capsaicin. Functional as well as deep sequencing analysis demonstrated that one protocol in particular allowed the generation of a mechano-nociceptive sensory neuron population, homogeneously expressing TRPV1. Accordingly, we find the cells to homogenously respond to capsaicin, to become sensitized upon inflammatory stimuli, and to respond to temperature stimulation. The efficient and homogenous generation of these neurons make them an ideal translational tool to study mechanisms of sensitization, also in the context of chronic pain.
Learn More >Fibromyalgia is a chronic condition characterized by widespread pain, as well as numerous symptoms related to central sensitization such as: fatigue, cognitive disturbances, constipation/diarrhea and sensory hypersensitivity. Furthermore, depression and anxiety are prevalent comorbidities, accompanied by emotion processing and regulation difficulties. Although fibromyalgia physiopathology is still not fully understood, neuroimaging research methods have shown brain structural and functional alterations as well as neuroinflammation abnormalities. We believe that open access to data may help fibromyalgia research advance more. Here, we present an open dataset of 33 fibromyalgia female patients and 33 paired healthy controls recruited from a Mexican population. Dataset includes demographic, clinical, behavioural and magnetic resonance imaging (MRI) data. The MRI data consists of: structural (T1- and T2- weighted) and functional (task-based and resting state) sequences. The task was an emotion processing and regulation task based on visual stimuli. The MRI data contained in the repository are unprocessed, presented in Brain Imaging Data Structure (BIDS) format and available on the OpenNeuro platform for future analysis.
Learn More >The periaqueductal gray (PAG) represents a key target of projection neurons residing in the spinal dorsal horn. In comparison to lamina I spinoparabrachial neurons, little is known about the intrinsic and synaptic properties governing the firing of spino-PAG neurons, or whether such activity is modulated by neonatal injury. Here we address this issue using ex vivo whole-cell patch clamp recordings from lamina I spino-PAG neurons in adult male and female FVB mice following hindpaw incision at postnatal day (P)3. Spino-PAG neurons were classified as high output (HO), medium output (MO) or low output (LO) based on their action potential (AP) discharge following dorsal root stimulation. The HO subgroup exhibited prevalent spontaneous burst-firing and displayed initial burst or tonic patterns of intrinsic firing, while LO neurons showed little spontaneous activity. Interestingly, the level of dorsal root-evoked firing significantly correlated with the resting potential and membrane resistance, but not with the strength of primary afferent-mediated glutamatergic drive. Neonatal incision failed to alter the pattern of monosynaptic sensory input, with the majority of spino-PAG neurons receiving direct connections from low-threshold C-fibers. Furthermore, primary afferent-evoked glutamatergic input and AP discharge in adult spino-PAG neurons were unaltered by neonatal surgical injury. Finally, Hebbian long-term potentiation at sensory synapses, which significantly increased afferent-evoked firing, was similar between P3-incised and naïve littermates. Collectively, these data suggest that the functional response of lamina I spino-PAG neurons to sensory input is largely governed by their intrinsic membrane properties and appears resistant to the persistent influence of neonatal tissue damage.
Learn More >Chronic musculoskeletal pain (CMP) is a preference-sensitive condition for which numerous treatment options are available, each with benefits and risks. Thus, patient preferences play a critical role in decision-making. This study summarized evidence from discrete choice experiments (DCEs) to quantify patient preferences for CMP treatment and identified important treatment attributes. A systematic review of DCEs on patient preferences for CMP treatment was conducted. Studies were included if they utilized DCE to determine patient preferences for CMP. A previously described methodological assessment tool was used to assess the risk of bias. The treatment attributes were summarized and sorted according to the frequency of citation and relative weight. Subgroup analyses were conducted to explore the intervention-specific attributes. A total of 15 eligible studies with 4065 participants were included. We identified "capacity to realize daily life activities", "risk of adverse events", "effectiveness in pain reduction" and "out-of-pocket cost" as important attributes. Although "treatment frequency" and "onset of treatment efficacy" were less frequently mentioned, they were also important attributes. The attribute of "risk of adverse events" was especially important for drug treatment. The "out-of-pocket cost" and "treatment location and mode" were important attributes of exercise therapy. The attributes identified in this review will inform the design of future DCE studies, facilitate the translation of measurement-based care to value-based care, and provide the rationale to promote shared decision-making and patient-centered care.
Learn More >There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (ATR) antagonism in an acute gout attack mouse model.
Learn More >Recent RCTs and meta-analyses compare the effectiveness of different types of exercise for chronic whiplash associated disorder (WAD). This study aimed to verify whether the results of these studies translate to statistically significant and clinically meaningful effects in individual participants.
Learn More >Cutaneous T-cell lymphoma (CTCL) is a chronic and progressive disease that has a major impact on quality of life (QoL).
Learn More >Botulinum toxin type A (BoNT/A) is a potent toxin, acts by cleaving synaptosome-associated-protein-25 (SNAP-25) to regulate the release of the neural transmitter and shows analgesic effect in neuropathic pain. However, the mechanisms of BoNT/A actions involved in nociceptions remain unclear. Glycine transporter 2 (GlyT2) is an isoform of glycine transporters, which plays an important role in the regulation of glycinergic neurotransmission. Inhibition of GlyTs could decrease pain sensation in neuropathic pain, the role of GlyT2 in the analgesic effect of BoNT/A has not been studied yet. In our present study, we demonstrated that the protein levels of GlyT2 and SNAP-25 were upregulated in the spinal cord after the development of chronic constriction injury (CCI)-induced neuropathic pain. Intraplantar application of BoNT/A (20 U/kg) attenuated mechanical allodynia induced by CCI and downregulated GlyT2 expression in the spinal cord. The application of BoNT/A s also decreased the expression of GlyT2 in pheochromocytoma (PC12) cells. Moreover, intrathecal application of lentivirus-mediated GlyT2 reversed the antinociceptive effect of BoNT/A in CCI rats. These findings indicate that GlyT2 contributes to the antinociceptive effect of BoNT/A and suggest a novel mechanism underlying BoNT/A's antinociception action.
Learn More >T-type Ca2+ channels play a dual role in modulating the excitability of dorsal root ganglia neurons.
A subgroup of low-threshold dorsal root ganglia (DRG) neurons discharge action potentials (APs) with an afterdepolarizing potential (ADP). The ADP is formed by T-type Ca2+ currents. It is known that T-type Ca2+ currents contribute to neuropathic pain. However, the change in ADP-firing of injured DRG neurons has not been widely studied yet. Here we applied patch clamp to record ADP-firing and T-type Ca2+ currents in intact and chronically compressed DRG (CCD) neurons and examined T-type Ca2+ channel proteins expression with western blotting. After CCD injury, the incidences of both ADP firing and non-ADP burst firing increased, and T-type Ca2+ channels contributed to both of these firing patterns. The neurons discharging large-amplitude-ADP firing were TTX-insensitive, implying that high-density T-type Ca2+ channels might cooperate with TTX-insensitive Na+ channels to reduce the AP threshold. By contrast, the neurons displaying non-ADP burst firing were TTX-sensitive, implying that low density T-type Ca2+ channels may cooperate with TTX-sensitive Na+ channels to increase AP number. In DRG neurons, T-type Ca2+ currents density varied widely, ranging between 100 pA/pF and 5 pA/pF. After injury, the proportion of DRG neurons with large T-type Ca2+ currents increased in parallel with the increase in the incidence of large-amplitude-ADP firing. And in addition to Cav3.2, Cav3.3 channels are also likely to contribute to low-threshold firing. The data revealed that T-type Ca2+ channels may play a dual role in modulating the injured neurons' high excitability through a cooperative process with Na+ channels, thereby contributing to neuropathic pain.
Learn More >The endocannabinoids 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-ethanolamine (AEA) are eicosanoids implicated in numerous physiological processes like appetite, adipogenesis, inflammatory pain and inflammation. They mediate most of their physiological effect by activating the cannabinoid (CB) receptors 1 and 2. Other than directly binding to the CB receptors, 2-AG and AEA are also metabolized by most eicosanoid biosynthetic enzymes, yielding many metabolites that are part of the oxyendocannabinoidome. Some of these metabolites have been found in vivo, have the ability to modulate specific receptors and thus potentially influence physiological processes. In this review, we discuss the biosynthesis and metabolism of 2-AG and AEA, as well as their congeners from the monoacyl-glycerol and N-acyl-ethanolamine families, with a special focus on the metabolism by oxygenases involved in arachidonic acid metabolism. We highlight the knowledge gaps in our understanding of the regulation and roles the oxyendocannabinoidome mediators.
Learn More >(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. (2) Methods: An observational cross-sectional study was conducted under CNCP outpatients with long-term prescribed opioids ( = 806), wherein 137 patients had an OUD diagnosis (cases, 64% females) and 669 did not (controls, 66% females). Socio-demographic, clinical, and pharmacological outcomes were analyzed. (3) Results: Female controls presented an older age and less intensive pain therapy but higher psychotropic prescriptions and emergency department visits compared to male controls. Meanwhile, cases demonstrated a younger age, higher work disability, double morphine equivalent daily dose, and benzodiazepine use compared with controls. Here, female cases showed an 8% greater substance use disorder (OR 2.04 [1.11-3.76]) and 24% lower tramadol use, while male cases presented a 22% higher fentanyl use (OR 2.97 [1.52-5.81]) and reported the highest number of adverse drug reactions (24%, OR 2.40 [1.12-5.16]) compared with controls. (4) Conclusions: An OUD individual risk profile was evidenced with sex-differences to take into consideration to design equal prevention programs.
Learn More >Emerging evidence indicates that regulatory T cells (Treg) intervene in the inflammatory processes that drive osteoarthritis (OA). However, whether polarized Tregs affect clinical features of the disease in the short- or long-term, and if so, what their role in OA-related pain and functional disability really is, remains elusive. Thus, the aim of the current study was to characterize the infiltration profile of Tregs in systemic (peripheral blood) and joint-derived (synovial fluid and synovial membrane) samples from patients with knee OA in relation to OA-induced symptoms. To this end, Treg infiltration (CD4CD25 CD127) was analyzed in matched samples of peripheral blood (PB), synovial fluid (SF) and synovial membrane (SM) from a total of 47 patients undergoing elective knee arthroplasty using flow cytometry. At the same time, knee pain and function were assessed and correlated with Treg proportions in different compartments (PB, SF, SM). Interestingly, matched-pair analysis revealed significantly higher Treg proportions in joint-derived samples than in PB, which was mainly attributed to the high Treg frequency in SF. Moreover, we found significant associations between infiltrating Tregs and OA-related symptoms which indicate that lower Treg proportions-especially in the SM-are related to increased pain and functional disability in knee OA. In conclusion, this study highlights the importance of local cellular inflammatory processes in OA pathology. Intra-articular Treg infiltration might play an important role not only in OA pathogenesis but also in the development of OA-related symptoms.
Learn More >Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain.
The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modification that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl in the postsynaptic neuron. As the intracellular concentration increases, the inward flow of Cl through an ionotropic GABA-A receptor is reduced, which decreases its hyperpolarizing (inhibitory) effect, a modulatory effect known as ionic plasticity. The loss of GABA-dependent inhibition enables a state of over-excitation within the spinal cord that fosters aberrant motor activity (spasticity) and chronic pain. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome. Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic benefits.
Learn More >Bone cancer pain (BCP) is one of the typical and distressing symptoms in cancer patients. Morphine is a widely used analgesic drug for BCP; however, long-term morphine administration will lead to analgesic tolerance. Our previous study indicated that spinal glial cell line-derived neurotrophic factor (GDNF) exerts analgesic effects in rats with BCP. In this study, BCP was established by inoculated Walker 256 carcinoma cells into rat tibias, while morphine tolerance (MT) was induced by intrathecally injecting morphine twice daily from the 9th to 15th postoperative day (POD) in BCP rats. The BCP rats developed mechanical and thermal hyperalgesia on POD 5 and it lasted to POD 15. The analgesic effect of morphine was decreased after repeat administration. Western blots and immunochemistry tests showed that GDNF was gradually decreased in the spinal cord after the development of MT in rats with BCP, and GDNF was colocalized with the μ opioid receptor (MOR) in the superficial laminate of the spinal cords. The overexpression of GDNF by lentivirus significantly attenuated MT, and restored the expression of MOR in the spinal cord. In summary, our results suggest that the reduction of GDNF expression participated in the development of MT in rats with BCP and could be a promising therapeutic option for BCP.
Learn More >We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals ( < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice ( < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia ( < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain.
Learn More >Many states have adopted laws that limit the amount or duration of opioid prescriptions. These limits often focus on prescriptions for acute pain, but there may be unintended consequences for those diagnosed with chronic pain, including reduced opioid prescribing without substitution of appropriate non-opioid treatments.
Learn More >The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.
Learn More >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.
Learn More >Predicting at-risk opioid use three months after ed visit for trauma: Results from the AURORA study.
Whether short-term, low-potency opioid prescriptions for acute pain lead to future at-risk opioid use remains controversial and inadequately characterized. Our objective was to measure the association between emergency department (ED) opioid analgesic exposure after a physical, trauma-related event and subsequent opioid use. We hypothesized ED opioid analgesic exposure is associated with subsequent at-risk opioid use.
Learn More >In placebo research, expectations are highlighted as one of the most influential subjective factors. While some studies have shown a relationship between expectations and pain relief, others have not. However, little is known about how methods of assessment of expectations may affect these conclusions. One of the fundamental considerations is that participants in placebo trials rate their expectations when prompted to rate them on scales in advance, but are less likely to report their prior expectations, when asked to report their experience retroactively in an unprompted manner, often expressing, for example, prior hope or wishes of recovery. This article presents previously unpublished data to elucidate and explore the concepts highlighted by individuals in a placebo analgesia trial when assessed in a prompted and unprompted manner. The data corroborates the role of expectations involved in placebo effects, particularly in placebo analgesia. Thus, the question may be a matter of and expectations contribute to placebo effects, rather than .
Learn More >Fibromyalgia-syndrome (FMS) is a complex disease characterized by chronic widespread pain and additional symptoms including depression, cognitive dysfunction ("fibro-fog") and maldigestion. Our research team examined whether FMS-related pain parameters assessed by quantitative sensory testing (QST) and psychological disturbances are accompanied by alterations of the fecal microbiome. We recruited 25 patients with FMS and 26 age- and sex-matched healthy controls. Medical background, food habits, psychopathology and quality of life were assessed through questionnaires. Stool samples were analyzed by 16S rRNA gene amplification and sequencing. QST was performed according to the protocol of the German Network for Neuropathic Pain. QST showed that both lemniscal and spinothalamic afferent pathways are altered in FMS patients relative to healthy controls and that peripheral as well as central pain sensitization processes are manifest. Psychometric assessment revealed enhanced scores of depression, anxiety and stress. In contrast, neither the composition nor the alpha- and beta-diversity of the fecal microbiome was changed in FMS patients. FMS patients segregate from healthy controls in various parameters of QST and psychopathology, but not in terms of composition and diversity of the fecal microbiome. Despite consideration of several confounding factors, we conclude that the contribution of the gut microbiome to the pathophysiology of FMS is limited.
Learn More >Visual snow syndrome is characterized by a continuous visual disturbance resembling a badly tuned analogue television and additional visual and non-visual symptoms causing significant disability. The natural course of visual snow syndrome has not hitherto been studied. In this prospective longitudinal study, 78 patients with the diagnosis of visual snow syndrome made in 2011 were re-contacted in 2019 to assess symptom evolution using a semi-structured questionnaire. Forty patients (51% of 78) were interviewed after 84 ± 5 months (mean ± SD). In all patients, symptoms had persisted. Visual snow itself was less frequently rated as the most disturbing symptom (72 versus 42%, P = 0.007), whereas a higher proportion of patients suffered primarily from entopic phenomena (2 versus 17%, P = 0.024). New treatment was commenced in 14 (35%) patients, of whom in seven, visual snow syndrome was ameliorated somewhat. Three (7%) experienced new visual migraine aura without headache, and one (2%) had new migraine headache. There were no differences in the levels of anxiety and depression measured by the Patient Health Questionnaire 8 and the Generalized Anxiety Disorder Scale 7. Thirty-eight patients (49%) were lost to follow-up. In visual snow syndrome, symptoms can persist over 8 years without spontaneous resolution, although visual snow itself might become less bothersome.
Learn More >Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study (55% and 65%, respectively) are open to pharmacogenetic testing, and most (66% and 69%, respectively) believe that genetic testing has the potential to improve their medical care. Our results further support the potential for PGx testing to inform chronic pain medication management for poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Future efforts to implement PGx testing in chronic pain management, however, must address patient concerns about genetic test result access and genetic discrimination.
Learn More >Messenger RNA (mRNA) is an emerging drug modality for protein replacement therapy. As mRNA efficiently provides protein expression in post-mitotic cells without the risk of insertional mutagenesis, direct delivery of mRNA can be applied, not only as an alternative to gene therapy, but also for various common diseases such as osteoarthritis (OA). In this study, using an mRNA-encoding interleukin-1 receptor antagonist (IL-1Ra), we attempted anti-inflammatory therapy in a rat model of the temporomandibular joint (TMJ) OA, which causes long-lasting joint pain with chronic inflammation. For the intra-articular injection of mRNA, a polyplex nanomicelle, our original polymer-based carrier, was used to offer the advantage of excellent tissue penetration with few immunogenic responses. While the protein expression was transient, a single administration of IL-1Ra mRNA provided sustained pain relief and an inhibitory effect on OA progression for 4 weeks. The mRNA-loaded nanomicelles provided the encoded protein diffusely in the disc and articular cartilage without upregulation of the expression levels of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α). This proof-of-concept study demonstrates how anti-inflammatory proteins delivered by mRNA delivery using a polyplex nanomicelle could act to alleviate OA, stimulating the development of mRNA therapeutics.
Learn More >Screening trials of spinal cord stimulation (SCS) prior to full implantation of a device are recommended by expert guidelines and international regulators. The current study sought to estimate the budget impact of a screening trial of SCS and the costs or savings of discontinuing the use of a screening trial. A budget impact analysis was performed considering a study population that reflects the size and characteristics of a patient population with neuropathic pain in England eligible for SCS. The perspective adopted was that of the NHS with a 5-year time horizon. The base case analysis indicate that a no screening trial strategy would result in cost-savings to the NHS England of £400,000-£500,000 per year. Sensitivity analyses were conducted to evaluate different scenarios. If ≥5% of the eligible neuropathic pain population received a SCS device, cost-savings would be >£2.5 million/year. In contrast, at the lowest assumed cost of a screening trial (£1,950/patient), a screening trial prior to SCS implantation would be cost-saving. The proportion of patients having an unsuccessful screening trial would have to be ≥14.4% for current practice of a screening trial to be cost-saving. The findings from this budget impact analysis support the results of a recent UK multicenter randomized controlled trial (TRIAL-STIM) of a policy for the discontinuation of compulsory SCS screening trials, namely that such a policy would result in considerable cost-savings to healthcare systems.
Learn More >The oral delivery of diclofenac sodium (DNa), a non-steroidal analgesic, anti-inflammatory drug, is associated with various gastrointestinal side effects. The aim of the research was to appraise the potential of transdermal delivery of DNa using bilosomes as a vesicular carrier (BSVC) in inflamed paw edema. DNa-BSVCs were elaborated using a thin-film hydration technique and optimized using a 3.2 multilevel categoric design with Design Expert software 10 software (Stat-Ease, Inc., Minneapolis, MI, USA). The effect of formulation variables on the physicochemical properties of BSVC, as well as the optimal formulation selection, was investigated. The BSVCs were evaluated for various parameters including entrapment efficiency (EE%), vesicle size (VS), zeta potential (ZP) and permeation studies. The optimized BSVC was characterized for in vitro release, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and incorporated into hydrogel base. The optimized DNa-BSVC gel effectiveness was assessed in vivo using carrageenan-induced paw edema animal model via cyclooxygenase 2 (COX-2), interleukin 6 (IL-6), Hemooxygenase 1 (HO-1) and nuclear factor-erythroid factor2-related factor 2 (Nfr-2) that potentiate anti-inflammatory and anti-oxidant activity coupled with histopathological investigation. The resulting vesicles presented VS from 120.4 ± 0.65 to 780.4 ± 0.99 nm, EE% from 61.7 ± 3.44 to 93.2 ± 2.21%, ZP from -23.8 ± 2.65 to -82.1 ± 12.63 mV and permeation from 582.9 ± 32.14 to 1350.2 ± 45.41 µg/cm. The optimized BSVCs were nano-scaled spherical vesicles with non-overlapped bands of their constituents in the FTIR. Optimized formulation has superior skin permeability ex vivo approximately 2.5 times greater than DNa solution. Furthermore, histological investigation discovered that the formed BSVC had no skin irritating properties. It was found that DNa-BSVC gel suppressed changes in oxidative inflammatory mediators (COX-2), IL-6 and consequently enhanced Nrf2 and HO-1 levels. Moreover, reduction of percent of paw edema by about three-folds confirmed histopathological alterations. The results revealed that the optimized DNa-BSVC could be a promising transdermal drug delivery system to boost anti-inflammatory efficacy of DNa by enhancing the skin permeation of DNa and suppressing the inflammation of rat paw edema.
Learn More >Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the μ opioid receptor (MOR) signals in ligand-free form (MOR-μ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-μ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-μ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-μ) activation to MOR-μ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-μ*, acting as potent inverse agonists. A neutral antagonist, 6β-naltrexol (6BN), binds to but does not block MOR-μ*, preventing MOR-μ activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-μ* reversal to resting-state MOR-μ. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a 'retrograde addiction modulator', 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-μ* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.
Learn More >This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1(Fig. 1).
Learn More >Recent studies have demonstrated the contribution of non-coding RNAs (ncRNAs) to neuropathic pain. However, the expression profile of ncRNAs in the trigeminal ganglion (TG) and their functional mechanism underlying trigeminal neuropathic pain are still unclear.
Learn More >Burdens related to pain, smoking/nicotine dependence, and pain-smoking comorbidity disproportionately impact Black Americans, and menthol cigarette use is overrepresented among Black adults who smoke cigarettes. Menthol may increase nicotine exposure, potentially conferring enhanced acute analgesia and driving greater dependence. Therefore, the goal of the current study was to examine associations between pain, menthol cigarette use, and nicotine dependence. Data was drawn from Black adults who were current cigarette smokers (n = 1370) at Wave 5 (2018-2019) of the Population Assessment of Tobacco and Health Study. Nicotine dependence was assessed using the Wisconsin Inventory of Smoking Dependence Motives. ANCOVA revealed that moderate/severe pain (vs. no/low pain) was associated with greater overall nicotine dependence (p < .001) and greater negative reinforcement, cognitive enhancement, and affiliative attachment smoking motives (ps < .001). Menthol smokers with moderate/severe pain also endorsed greater cigarette craving and tolerance, compared to non-menthol smokers with no/low pain (ps < .05). Findings support the notion that among Black individuals who smoke cigarettes, the presence of moderate/severe pain (vs. no/low pain) and menthol use may engender greater physical indices of nicotine dependence relative to non-menthol use. Compared to no/low pain, moderate/severe pain was associated with greater emotional attachment to smoking and greater proclivity to smoke for reducing negative affect and enhancing cognitive function. Clinical implications include the need to address the role of pain and menthol cigarette use in the assessment and treatment of nicotine dependence, particularly among Black adults. These data may help to inform evolving tobacco control policies aimed at regulating or banning menthol tobacco additives.
Learn More >There is increasing evidence that some biomarkers are implicated in migraine pathogenesis. This study looks at plasma proteome in migraine patients for potential protein biomarkers.
Learn More >Pharmaceutical opioid (PO) overdose deaths have increased in many Western countries. There are indications that those dying from a PO overdose differ from those dying from other types of overdoses. These differences might pose a challenge as the majority of current preventive measures are tailored toward those with the characteristics of "conventional" overdose deaths.
Learn More >Non-invasive, external low intensity focused ultrasound (liFUS) offers promise for treating neuropathic pain when applied to the dorsal root ganglion (DRG).
Learn More >This study aimed to investigate the mediating effects of social support on the relationship between uncertainty and quality of life (QOL) in patients with chronic low back pain (LBP).
Learn More >Fear-avoidance models of chronic pain consider excessive spreading (or overgeneralization) of pain-related avoidance toward safe activities to play a crucial role in chronic pain disability. This study (N = 96) investigated whether avoidance generalization is mitigated by positive affect induction. Pain-free, healthy participants performed an arm-reaching task during which certain movements were followed by pain, while another was not. One group then performed an exercise to induce positive affect (positive affect group), while another group performed a neutral exercise (neutral group). A third group also performed the neutral exercise, but did not learn to avoid pain during the arm-reaching task (yoked neutral group). To test generalization, we introduced novel but similar movements that were never followed by pain in all groups. Results showed no differences in generalization between the positive affect and neutral groups; however, across groups, higher increases in positive affect were associated with less generalization of avoidance, and less generalization of pain-expectancy and pain-related fear. Compared to the yoked neutral group, the neutral group showed avoidance generalization, as well as pain-expectancy and pain-related fear generalization. These results point toward the potential of positive affect interventions in attenuating maladaptive spreading of pain-related avoidance behavior to safe activities.
Learn More >This MONONOFU trial subgroup analysis evaluates the efficacy of lasmiditan across patient and migraine characteristics in Japanese patients with migraine.
Learn More >Atopic dermatitis (AD) is a common itchy inflammatory skin condition that affects many individuals. For many years, the landscape of AD treatment remained unchanged; however, there has been developing therapies that directly target the underlying immunological mechanism of AD. Janus kinase (JAK) inhibitors are small molecules that have shown anti-inflammatory and anti-itch effects in AD. Recently, abrocitinib, an oral JAK 1 inhibitor, was approved by the Food and Drug Administration for atopic dermatitis.
Learn More >Low back pain (LBP) is a major cause of physical disability in the world. The origin of this condition can be due to differents causes, with a specific cause or of unknown mechanical origin,being characterized as unspecific. In this case a physical therapy treatment approach with manual therapy is relevant, which includes the Muscle Energy Technique (MET) classified as a common conservative treatment for pathologies of the spine, mainly in LBP and disability. This study assessed the effectiveness of the muscle energy technique on nonspecific low back pain.
Learn More >Psychiatric comorbidity is common in patients with chronic pain. In peripheral neuropathic pain, particularly anxiety and mood disorders are frequently present and associated with a high level of catastrophizing. Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by pain. This study aimed to investigate the prevalence of, and factors associated with anxiety and depressive symptoms in SFN.
Learn More >This study explored a set of psychological and socio-demographic factors in childhood and adulthood associated with migraines assessed at age 42 years. Data were drawn from a large, nationally representative, prospective longitudinal study: the 1970 British Cohort Study (BCS70). In total, 5628 cohort members with data on parental social class at birth, cognitive ability (intelligence), self-esteem and locus of control at age 10 years, psychological distress and educational qualifications at age 34, and current occupation at age 42 years were examined. We assessed whether or not they regularly experienced migraines at age 42 years. Logistic regression analysis showed that childhood migraine, gender and adult psychological distress, as well as childhood locus of control (for females only), were significant and independent predictors of the prevalence of migraine in adulthood. Childhood migraine seemed to have a long-lasting effect on adult migraine, and psychological distress also appeared to detrimentally affect adult migraine over time.
Learn More >Ultrasound-guided regional techniques, including catheter-based approaches, are a subset of interventional therapies that have gained interest as an option for managing acute cancer-related pain. The authors sought to review the available published evidence and to discuss practical recommendations for expanding access to such therapies.
Learn More >Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 μmol/L) and palosetron (10 μmol/L), but not 5-HT3 receptor agonist m-CPBG (30 μmol/L) and SR 57,727 (10 μmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 μmol/L) and eptapirone (10 μmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 μmol/L) and p-MPPI (10 μmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.
Learn More >Opioids are widely prescribed for moderate to severe pain in patients with acute illness, cancer pain, and chronic noncancer pain. However, long-term opioid use can cause opioid tolerance and opioid-induced hyperalgesia (OIH), contributing to the opioid misuse and addiction crisis. Strategies to mitigate opioid tolerance and OIH are needed to reduce opioid use and its sequelae. Currently, there are few effective pharmacological strategies that reduce opioid tolerance and OIH. The intrinsic tyrosine kinase receptor B (TrkB) ligand, brain-derived neurotrophic factor (BDNF), has been shown to modulate pain. The BDNF-TrkB signaling plays a role in initiating and sustaining elevated pain sensitivity; however, increasing evidence has shown that BDNF and 7,8-dihydroxyflavone (7,8-DHF), a potent blood-brain barrier-permeable ligand to TrkB, exert neuroprotective, anti-inflammatory, and antioxidant effects that may protect against opioid tolerance and OIH. As such, TrkB signaling may be an important therapeutic avenue in opioid tolerance and OIH. Here, we review 1) the mechanisms of pain, opioid analgesia, opioid tolerance, and OIH; 2) the role of BDNF-TrkB in pain modulation; and 3) the neuroprotective effects of 7,8-DHF and their implications for opioid tolerance and OIH.
Learn More >Acquired ichthyosis (AI) is a relatively rare cutaneous entity characterized by transient, generalized scaling and pruritus in the absence of family history of ichthyosis or atopic disease. The hyperkeratosis in AI can range from the mild, white-to-brown scaling resembling that in ichthyosis vulgaris (IV) to the more prominent dark brown scaling phenotype, similar to that found in lamellar ichthyosis. The disease can wax and wane in relation to endogenous and/or exogenous factors. Histopathology of AI is similar to that found in IV. AI is usually of cosmetic concern to patients but can in some cases reflect the presence of more serious conditions, including malignancies, autoimmune diseases, or metabolic disorders. In some cases, AI can be an adverse effect of a medication or the cutaneous symptom of a toxic exposure. Other conditions, such as severe xerosis or eczema, can present with clinical findings similar to AI, making diagnosis a challenge. Furthermore, cases of AI are sporadic throughout the literature and have been documented across a wide variety of medical settings distinct from dermatology, which often contribute to misdiagnosis of this disease. Definitive management requires prompt identification and treatment of the inciting factors combined with conservative therapies, including topical emollients, keratolytics, retinoids, or corticosteroids, and in rare cases, with oral retinoids.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a serious clinical problem and challenging for oncologists. CIPN is often a persistent adverse consequence of certain chemotherapeutic agents and more cancer survivors will experience CIPN leading to chronic pain and worsening quality of life. However, the available and effective strategies for clinical treatment of CIPN are very limited. Oncologists are frequently obliged to decrease or stop neurotoxic anticancer drugs, with a possible deleterious impact on the oncological prognostic. The challenges faced by CIPN include further study on the pathological mechanism, dose threshold, incidence, risk factors and clinical characteristics of CIPN; lack of diagnostic criteria and tools of CIPN; lack of effective and standardized CIPN prevention and treatment programs. The current update of research results on these challenging issues of CIPN will provide more decision-making evidence for oncologists to diagnose and treat CIPN. Therefore, Committee of Neoplastic Supportive-Care of China Anti-Cancer Association and Cancer Clinical Chemotherapy Committee of China Anti-Cancer Association convenes some experts to summarize the recent literatures and discuss to reach the consensus about recommendations for the definition, pathophysiological mechanism, assessment, prevention, and treatment of CIPN.
Learn More >To understand the psychological and social impact of shielding on people with sickle cell disorders and their carers in the Midlands region of England. This region was badly affected during the pandemic, with the city of Birmingham having some of the highest rates of COVID-19 deaths.
Learn More >While stress plays a paramount role on the onset/exacerbation of psoriasis, via overactivation of the hypothalamic-pituitary-adrenal axis and increased release of pro-inflammatory cytokines, cutaneous inflammatory response induces, in turn, anxiety/depression symptoms, via body disfigurement and stigmatisation. The intensity of pruritus and anogenital involvement are additional risk factors for psychological comorbidity.Aims were to (1) examine the effects of intensity of pruritus and anogenital psoriasis on disease burden and psychological comorbidity and (2) identify the variables associated with the presence of clinically significant depression, anxiety, and dysmorphic concerns.
Learn More >The transient receptor potential vanilloid 1 ion channel (TRPV1) is a ligand-gated nonselective calcium-permeant cation channel involved in the detection of a wide variety of chemical and physical noxious stimuli, ranging from exogenous and endogenous ligands to noxious heat (>42 °C) and low pH (pH < 5.2). Due to its central role in pain and hyperalgesia, TRPV1 is considered a relevant therapeutic target for the development of analgesic and anti-inflammatory drugs potentially useful to relieve chronic, neuropathic, and inflammatory pain and to treat disorders such as inflammatory bowel disease. In this view, the availability of in vitro assays for the screening of novel TRPV1 modulators is highly desirable. Since TRPV1 activation leads to an increase in the intracellular calcium (Ca) levels, the use of Ca fluorescent indicators represent a valuable and sensitive tool for monitoring such intracellular changes. In this chapter, we describe methods for recording and monitoring Ca signals through the fluorescent indicators Fluo-4 acetoxymethyl (AM) and Fura-2 AM in HEK-293 cells transfected with TRPV1 or other thermoTRP channels.
Learn More >Ehlers-Danlos syndrome (EDS) represents a family of heritable connective tissue disorders with overlapping phenotypic features, frequently including joint hypermobility, tissue fragility, and skin hyperextensibility. Comorbid symptoms are common for patients with EDS and include multiple body systems marked by neurologic, cardiovascular, gastrointestinal, musculoskeletal issues, chronic pain, headaches, and anxiety and depression. The many comorbidities lead to high disease burden, which requires greater healthcare utilization.
Learn More >In 2014, the National Institute of Health Pain Consortium's research task force on research standards for chronic low back pain (CLBP) proposed a measure that could be used to stratify patients by the impact CLBP has on their lives, namely the Impact Stratification Score (ISS). This study examines the dimensionality of the ISS and support for its single total score, and evaluates its overall psychometric properties.
Learn More >The spectrum of symptoms represented by fibromyalgia syndrome (FMS) has a profound effect on daily activities and impairs the quality of life. A considerable proportion of patients with inflammatory rheumatic diseases (IRDs) fulfill the FMS criteria, which can complicate the diagnosis, treatment, and follow-ups of IRD. In addition, the coexistence of FMS may cause unnecessary laboratory and radiological assessments. Several mechanisms have been proposed that may have a role in the etiopathogenesis of FMS, one of which is autonomic dysregulation. In studies evaluating cardiac autonomic dysfunction based on heart rate variability (HRV), there has been found to be a decrease in HRV and dominance of the sympathetic nervous system. Autonomic reactivity reflects modulations of several functions to overcome the existing state and conditions. Blunted autonomic reactivity has been found in some FMS patients, which makes it difficult for these patients to respond appropriately to unexpected stress sources that occur during daily living activities. Baroreceptor signals have an inhibitory influence on the central nervous system, and these impulses cause pain suppression. From this perspective, there are studies that have suggested the involvement of diminished baroreflex sensitivity in the etiology of FMS. The risk of endothelial dysfunction and increased arterial stiffness have been shown to occur in FMS patients due to autonomic dysfunction, sympathetic nervous system dominance, chronic stress, and pain. There is also evidence linking FMS with the risk of atrial and ventricular arrhythmias. Considering all these cardiovascular autonomic dysfunctions, tests that can confirm abnormalities should be performed when suspicion arises. There is a need for specific pharmacological and non-pharmacological treatment alternatives to be identified for subgroups of patients with cardiovascular system abnormalities. Key points • The frequency of FMS accompanying inflammatory rheumatic diseases is considerable and this coexistence leads to troubles in evaluating treatment response and determining appropriate medical treatment options in inflammatory rheumatic diseases. • Various cardiovascular autonomic abnormalities have been described in FMS patients. Among these, the most emphasized are autonomic dysfunction, the disruption of the balance between the sympathetic-parasympathetic nervous systems, blunted autonomic reactivity to acute stress, changes in baroreflex sensitivity, increased arterial stiffness, and electrophysiological alterations. • Autonomic cardiovascular dysfunction may be involved in the complex etiopathogenesis of the fibromyalgia syndrome and may trigger at least some symptoms.
Learn More >The relationship between sarcopenia and pain remains unclear; thus, this study evaluated whether muscle strength is independently associated with neuropathic-like pain symptoms in patients with chronic musculoskeletal pain. A cut-off score of painDETECT ≥13 was used to indicate a possible neuropathic component. Handgrip strength was measured, and muscle mass was estimated. A total of 2599 patients, including 439 patients who reported neuropathic-like pain symptoms (16.9%), were included for analysis. Handgrip strength was significantly lower in patients experiencing neuropathic-like pain symptoms (23.23 ± 10.57 vs. 24.82 ± 10.43 kg, < 0.001), and this result was chiefly found in female patients. However, there was no difference in estimated muscle mass. Shorter duration of pain, opioid usage, pain in lower limbs, sleep disturbance, and lower handgrip strength were significantly associated with neuropathic-like pain symptoms. In patients with handgrip strength below the reference values by sex, experiencing radiating pain and at least moderate sensory symptoms by light touch and thermal stimulation were more frequently reported. In conclusion, lower handgrip strength appeared to be an independent factor associated with symptoms suggestive of neuropathic pain in this population. Interventional studies are required to determine whether improvement in muscle strength can reduce the neuropathic pain component in chronic musculoskeletal pain.
Learn More >With osteoarthritis being the most common degenerative disease in pet animals, a very broad panel of natural health products is available on the market for its management. The aim of this systematic review and meta-analysis, registered on PROSPERO (CRD42021279368), was to test for the evidence of clinical analgesia efficacy of fortified foods and nutraceuticals administered in dogs and cats affected by osteoarthritis. In four electronic bibliographic databases, 1578 publications were retrieved plus 20 additional publications from internal sources. Fifty-seven articles were included, comprising 72 trials divided into nine different categories of natural health compound. The efficacy assessment, associated to the level of quality of each trial, presented an evident clinical analgesic efficacy for omega-3-enriched diets, omega-3 supplements and cannabidiol (to a lesser degree). Our analyses showed a weak efficacy of collagen and a very marked non-effect of chondroitin-glucosamine nutraceuticals, which leads us to recommend that the latter products should no longer be recommended for pain management in canine and feline osteoarthritis.
Learn More >Lipedema is a disease with abnormally increased adipose tissue deposition and distribution. Pain sensations have been described in the clinical evaluation of lipedema, but its etiology remains poorly understood. We hypothesized that pain sensitivity measurements and ex vivo quantitation of neuronal cell body distribution in the skin would be lipedema stage-dependent, and could, thus, serve to objectively characterize neuropathic pain in lipedema. The pain was assessed by questionnaire and peripheral cutaneous mechanical sensitization (von-Frey) in lipedema ( = 27) and control ( = 23) consenting female volunteers. Dermal biopsies from ( = 11) Stages 1-3 lipedema and control ( = 10) participants were characterized for neuronal cell body and nociceptive neuropeptide calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) distribution. Stage 2 or 3 lipedema participants responded positively to von Frey sensitization in the calf and thigh, and Stage 3 participants also responded in the arm. Lipedema abdominal skin displayed reduced Tuj-1+ neuronal cell body density, compared to healthy controls, while CGRP and NGF was significantly elevated in Stage 3 lipedema tissues. Together, dermal neuronal cell body loss is consistent with hyper-sensitization in patients with lipedema. Further study of neuropathic pain in lipedema may elucidate underlying disease mechanisms and inform lipedema clinical management and treatment impact.
Learn More >Nowadays, there is evidence that relates the amount of physical activity, as well as the impact of psychological factors, to the intensity of symptoms present in patients with fibromyalgia (FM). However, there are no studies which correlate the level of association of physical activity, psychological factors and vegetative symptoms in the FM population. The study has a cross-sectional observational design with 41 participants being recruited from a private clinic and rehabilitation service. The Autonomic Symptom Profile (Compass-31) to assess vegetative symptoms, the GODIN questionnaire to evaluate the level of leisure activity, and the pain catastrophizing scale, Tampa Kinesiophobia Scale and Self-Efficacy Scale to assess psychological factors, were used. A low and significant level of association was found between pain catastrophizing (PCS) and Kinesiophobia (r = 0.398; < 0.01), as well as with catastrophizing and vegetative symptoms (r = 0.428; < 0.05). Furthermore, a low and significant level of association was also found between self-efficacy and vegetative symptoms (r = 0.397; < 0.05). No association was found between the level of daily physical activity (measured by the Godin Leisure questionnaire) and vegetative symptoms, nor with any psychological factor studied. There is an association between vegetative symptoms and psychological factors. Nevertheless, more research which takes other factors into account, such as lifestyle and nutritional, is needed.
Learn More >Osteoarthritis (OA) is a leading cause of disability, the most common form of chronic disease in the temporomandibular joint (TMJ), and the most severe disease type of temporomandibular disorders (TMD). The etiology of TMD is multifactorial, considering parafunctional habits, sleep bruxism, or sleep disturbance as common factors. Insomnia and apnea are the two most frequent forms of sleep disorders in TMD patients. Due to this, the objective of this systematic review was to highlight whether there is currently scientific evidence in the literature describing that patients with temporomandibular joint osteoarthritis (TMJ-OA) are associated with increased sleep disorders or impaired sleep quality.
Learn More >Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds – minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at ∼80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the complement of DC axons activated, and on stimulation parameters. Intrathecal administration of bicuculline shifted neural responses to low-amplitude stimulation in both the model and experiment, suggesting that analgesia is dependent on segmental GABAergic mechanisms. Our results support the hypothesis that low-frequency subperception SCS generates rapid analgesia by activating a small number of DC axons which inhibit DH neuron activity via surround inhibition.Spinal cord stimulation is an effective treatment from chronic pain, but conventional stimulation generates paresthesias, a buzzing sensation that some patients find uncomfortable. Recent studies have demonstrated substantial pain relief using low frequency spinal cord stimulation that does not generate paresthesia; however, it is unclear how this form of stimulation works. In this study, we used computational models and recordings of dorsal horn neurons and dorsal column axons to study low-frequency, low-amplitude SCS and proposed a novel mechanism of action. The mechanism of action we proposed may help design future parameter selection and drive the development of SCS as a therapy.
Learn More >To estimate the nationally representative prevalence of chronic axial pain, inflammatory back pain (IBP), axial spondyloarthritis (axSpA), and peripheral arthritis in persons diagnosed with inflammatory bowel disease (IBD).
Learn More >Loneliness increased during the COVID-19 pandemic and social distancing guidelines, potentially exacerbating negative cognitions about pain. The present study investigated the longitudinal relationship between loneliness, assessed during the early weeks of the pandemic, and pain catastrophizing, assessed after living in the pandemic for approximately 1 year, among chronic pain patients. We also examined whether severity of depressive symptoms mediated this association.
Learn More >Skin pain resulting from mechanical compression is one of the most common pains in daily life and the indispensable information for electronic skin to perceive external signals. The external mechanical stimuli are transduced into impulses and transmitted via nerve fiber, and finally, the sensation is perceived via the procession of the nerve system. However, the mathematical mechanism for pain sensation due to mechanical stimuli remains unclear. In this paper, a mathematical model for skin pain sensation under compression is established, in which the Flament solution, the revised Hodgkin-Huxley model, and the mathematical model gate control theory are considered simultaneously. The proposed model includes three parts: a mechanical model of skin compression, a model of transduction, and a model of modulation and perception. It is demonstrated that the pain sensation degree increases with the compression amplitude and decreases with deeper nociceptor location in the skin. With the help of the proposed model, the quantitative relationship between compression pain sensation and external mechanical stimuli is revealed, which has a significant benefit in promoting the design and mechanism research of electronic skin with pain perception function.
Learn More >Bone cancer pain (BCP) seriously deteriorates the life quality of patients, but its underlying mechanism is still unclear. Spinal microRNAs might contribute to the development of BCP and the role of microglial activation is controversial. In this study, we established a BCP model by injecting Walker 256 breast carcinoma cells into the tibial intramedullary cavity of rats and significant hyperalgesia was observed in the BCP rats. The lumbar spinal cords were harvested to perform RNA sequencing (RNA-seq), and 31 differentially expressed miRNAs (26 upregulated and 5 downregulated) were identified in the BCP rats. Among them, miR-155-5p was significantly upregulated in the BCP rats. Spinal microglial activation was observed during BCP development. miR-155-5p could be expressed in spinal microglia and was significantly upregulated in microglia treated with lipopolysaccharide (LPS) in vitro. Serum/glucocorticoid regulated kinase family member 3 () was predicted to be the possible downstream target of miR-155-5p and this was confirmed using a dual-luciferase reporter assay in vitro. The inhibition of miR-155-5p restored -expression-attenuated microglial activation and alleviated hyperalgesia in the BCP rats. In conclusion, spinal miR-155-5p//microglial activation might play an important role in BCP pathogenesis.
Learn More >The pathophysiological mechanism underlying migraine-associated peripheral hypersensitivity remains unclear. Acid-sensing ion channels (ASICs) and transient receptor potential ankyrin 1 (TRPA1) are known to be causative pathogenic factors of mechanical and cold allodynia, respectively. Here, we sought to investigate their involvement in cold and mechanical allodynia of the face and hindpaws, respectively, in a mouse model of repetitive nitroglycerin (NTG)-induced migraine. NTG (10 mg/kg) was administered to the mice every other day for 9 days, followed 90 min later by HC-030031 (a TRPA1 blocker) or amiloride (a non-selective ASIC blocker). Mechanical or cold sensitivity of the hindpaw and facial regions was quantified using von-Frey filaments or acetone solution, respectively. Immunohistochemistry revealed that c-Fos expression was significantly increased in the trigeminal nucleus caudalis region but not in the spinal cord. Amiloride treatment only reduced NTG-induced hindpaw mechanical allodynia, whereas HC-030031 treatment only improved facial cold allodynia. Interestingly, the number of c-Fos positive cells decreased to a similar level in each drug treatment group. These findings demonstrate that facial cold allodynia and hindpaw mechanical allodynia are differentially mediated by activation of TRPA1 and ASIC, respectively, in mice with repetitive NTG-induced hypersensitivity.
Learn More >The standard of care paradigm for migraine treatment has been based almost exclusively on approaches that grew out of the happenstance use of market pharmaceuticals. Only methysergide, which has long since been removed from use for safety concerns, the ergotamine family of drugs, and the triptans were explicitly developed with migraine and other vascular headaches in mind. While the forward and innovative thinking to utilize the broad array of agents to treat migraine served millions well, their therapeutic efficacy was often low, and adverse event profiles were troublesome in the least. Advances in biochemical and molecular biology and the application of advanced "designing drugs" methods have brought about a potentially significant shift in treatment. The gepants have efficacies similar to the triptans but without vascular safety or medication overuse concerns. Preventative gepants offer innovative approaches to prevention and efficacy that exceed even the CGRP monoclonal antibodies. Those monoclonal antibodies brought rapid and highly effective outcomes across the spectrum of migraine. They outpaced older oral medication efficacy and eliminated most adverse events while potentially improving compliance with monthly or quarterly dosing. Other serotonin receptors beyond the 5HT1B and1D receptors have been targeted for decades. They now lead us to better formulations of dihydroergotamine for efficacy, convenience, and tolerability, and a 5HT1F-specific acute treatment like the gepants opens new options for acute management. Neuromodulation goes back to the mid-1800's. Our improved understanding of applied biomedical engineering has brought forward several tantalizing devices, including the application of currents distant from the target and patient regulated. Whether these advances change the paradigm of migraine treatment and standards of care remains to be seen, and issues such as cost and patient acceptance will help mold it.
Learn More >Dry eye disease (DED) is a multifactorial disorder in which the eyes respond to minor stimuli with abnormal sensations, such as dryness, blurring, foreign body sensation, discomfort, irritation, and pain. Corneal pain, as one of DED's main symptoms, has gained recognition due to its increasing prevalence, morbidity, and the resulting social burden. The cornea is the most innervated tissue in the body, and the maintenance of corneal integrity relies on a rich density of nociceptors, such as polymodal nociceptor neurons, cold thermoreceptor neurons, and mechano-nociceptor neurons. Their sensory responses to different stimulating forces are linked to the specific expression of transient receptor potential (TRP) channels. TRP channels are a group of unique ion channels that play important roles as cellular sensors for various stimuli. These channels are nonselective cation channels with variable Ca selectivity. TRP homologs are a superfamily of 28 different members that are subdivided into 7 different subfamilies based on differences in sequence homology. Many of these subtypes are expressed in the eye on both neuronal and non-neuronal cells, where they affect various stress-induced regulatory responses essential for normal vision maintenance. This article reviews the current knowledge about the expression, function, and regulation of TRPs in ocular surface tissues. We also describe their implication in DED and ocular pain. These findings contribute to evidence suggesting that drug-targeting TRP channels may be of therapeutic benefit in the clinical setting of ocular pain.
Learn More >Heart failure (HF) is considered one of the main causes of morbidity and death among chronic diseases worldwide. Patients have increasingly reported chronic pain in long-standing heart failure as a disturbing symptom. Its unknown etiology and mechanism, in addition to its insidious progressive nature, made both the doctor and the patient not notice it until it affects the quality of life (QoL) and general health status. The primary objective of this study is to find the prevalence of pain in chronic heart failure patients and its impact on their QoL. The secondary objective is to determine the predictors of QoL in HF patients.
Learn More >To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients.
Learn More >Postoperative pain following pediatric cleft lip and palate repair provide unique challenges. As no guidelines presently exist, we sought to identify the most effective and safe perioperative pain management strategies for children undergoing primary cleft lip and palate repair.
Learn More >Neuropathic pain (NP) affects approximately 7% of the general population and is often accompanied by depressive symptoms with up to 85% of NP patients are suffering from comorbid depression (CD). The noninvasive neuromodulation technique of transcranial magnetic stimulation (TMS) is an established proven clinically effective nonpharmacological treatment for depression, and considered a highly promising option also for reducing the burden of NP by relieving pain perception and increasing patients' quality of life. In this article, we systematically review the various clinical protocols used in TMS treatments in patients suffering from NP and comorbid depression.
Learn More >In ligand bias different agonist drugs are thought to produce distinct signaling outputs when activating the same receptor. If these signaling outputs mediate therapeutic versus adverse drug effects, then agonists that selectively activate the therapeutic signaling pathway would be extremely beneficial. It has long been thought that μ-opioid receptor agonists that selectively activate G protein- over β-arrestin-dependent signaling pathways would produce effective analgesia without the adverse effects such as respiratory depression. However, more recent data indicate that most of the therapeutic and adverse effects of agonist-induced activation of the μ-opioid receptor are actually mediated by the G protein-dependent signaling pathway, and that a number of drugs described as G protein biased in fact may not be biased, but instead may be low-intrinsic-efficacy agonists. In this review we discuss the current state of the field of bias at the μ-opioid receptor and other opioid receptor subtypes. Expected final online publication date for the , Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >Pain is a personalized event or body alarm system that can limit a patient's activities and lead to negative repercussions. The commercially available conventional treatment strategies like oral, parenteral, and topical drug delivery systems for pain management are associated with side effects and poor patient compliance. The transdermal route is eminent for its painless distribution. Among transdermal drug delivery system, microneedles (MNs) are gaining attention for their application with delivery at the deeper dermal layer because it bypasses the major barrier of the skin, easily accesses the skin dermal microcirculation, prevents damage to dermal blood vessels, and can be simply inserted into the skin without utilizing any additional applicator devices. Hence, considered a promising drug delivery strategy with high patient compliance. This review highlights the recent advancements of MNs in pain management. The present work mainly emphasizes all the case studies reported from the past 10 years that utilize MNs containing therapeutics in the treatment of chronic pain-associated diseases like rheumatoid arthritis, neuropathic pain, osteoarthritis, psoriatic arthritis, and atopic dermatitis. These studies have proven the efficacious application of MNs in the management of chronic pain and inflammation. The review also covered the clinical trials, patents, and future goals of pain management by using MNs.
Learn More >The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.
Learn More >Osteoarthritis (OA) is a chronic disease with both degenerative and inflammatory characteristics, af-fecting the osteochondral unit with the involvement of cartilage, subchondral bone and periarticular tissues. OA can produce chronic pain, with neuropathic and inflammatory characteristics, leading to an increased disability. OA is secondary to many predisposing factors where the inflammatory pro-cess plays a key role. To manage OA, it would seem logical to block the factors influencing the in-flammatory process at different levels, being T lymphocytes, neutrophils, and the balance between phenotype-1 macrophages (M1, pro-inflammatory) and phenotype-2 macrophages (M2 anti-inflammatory) the managing cells. The efforts to repair and rebuild the lost cartilage as well as the attempts to implant autologous or heterologous material, with or without growth factors and the administration of drugs or the use of medical devices have failed their objective. TNF-alpha and IL-1 inhibitors can only have a transient effect on pain, intra-articular oxidized Low-Density Lipopro-teins are able to stimulate the activation of M2, while growth factors need to be better investigated. Also, intra-articular injections of mesenchymal stem cells (MSC) can inhibit the proliferation of T-lymphocytes, leading to cartilage repair and to osteophytes inhibition thanks to the release of exo-somes, nanosized particles which are the active components. Gut microbiota has a potential role in the development of OA and could be able to influence the response to therapeutic agents.
Learn More >The objective of this narrative review was to identify real-world evidence regarding the burden of migraine in Canada. We conducted a literature search in MEDLINE, Embase, and the Cochrane Database of Systematic Reviews for studies published between August 2010 and August 2020. Of the 3269 publications identified, 29 studies were included. Prevalence estimates varied widely across Canada, and mental health comorbidities were common. Individuals with migraine have a lower quality of life, detrimental impact on workforce productivity, and higher rates of health care resource utilization (HCRU), with HCRU and costs highest among those with chronic migraine. We found inconsistencies in care, including underutilization of medications such as triptans, and varied utilization of over-the-counter and prescription medications. Increased medication use was identified among those with chronic migraine, and only a small number of patients used migraine preventive medications. The burden of migraine in Canada is substantial. Reduced quality of life and workforce productivity, increased HCRU and costs, and underutilization of triptans and migraine preventive medications highlight an important need for more effective management of individuals with migraine.
Learn More >Headaches are one of the most common causes of consultation in primary care. Due to their polymorphic character and sometimes severe etiologies, it is very important to properly classify these symptoms and to look for possible associated signs of severity. It is with this objective that the international classification of headache delivered its 3rd version in 2018 with the ICHD-3. In addition, revised and validated severity criteria were also published in 2018 under the name SNNOOP10. At the same time, the concept of green flags which could allow to diagnose a primary headache without further investigations has emerged. In terms of treatment, the development of CGRP neuropeptide antagonists has allowed a major advance in the treatment of the severe forms of migraine. Finally, integrative medicine is taking on a central role.
Learn More >The so-called 4P medicine, preventive, predictive, participatory, and personalized, which places the patient at the center has influenced the latest recommendations for the management of common low back pain. The management of low back pain in the acute, subacute, and chronic phase is currently based on the profile of each patient with their risk factors, their prognosis, and the respect of their preferences, promoting an integrative approach. During the first consultation, it is important to identify factors of moderate to poor prognosis, including kinesiophobia and to search for false beliefs, through a detailed medical history. The non-pharmacological approaches are more effective and have less side effects than the medications. Reassurance and therapeutic education are the first steps in good management of common low back pain.
Learn More >Chemotherapy is widely used as a primary treatment or adjuvant therapy for cancer. Anti-microtubule agents (such as paclitaxel and docetaxel) are used for treating many types of cancer, either alone or in combination. However, their use has negative consequences that restrict the treatment's ability to continue. The principal negative effect is the so-called chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a complex ailment that depends on diversity in the mechanisms of action of the different chemotherapy drugs, which are not fully understood. In this paper, we review several neurophysiological and pathological characteristics, such as morphological changes, changes in ion channels, mitochondria and oxidative stress, cell death, changes in the immune response, and synaptic control, as well as the characteristics of neuropathic pain produced by paclitaxel.
Learn More >Centralized pain presents a complex pathology that many classic pharmacological agents for pain have not been able to sufficiently treat. To date, there are no clear guidelines for preferred treatment methods or comprehensive protocol that addresses confounding factors in this population. We sought to summarize the current field of knowledge around centrally mediated pain and to understand promising novel therapies.
Learn More >Cognitive impairments in patients with chronic pain are increasingly attracting interest in scientific research. The consequences of these cognitive impairments on coping with pain, everyday life and the driving ability are rarely included in clinical practice although half of all patients are affected. This article summarizes the current research situation and discusses possibilities of the integration in clinical and therapeutic care.
Learn More >The advent of biological disease-modifying anti-rheumatic drugs (bDMARDs) and, more recently, of Janus kinase inhibitors (JAKi) has had a major impact on the long-term outcomes of chronic inflammatory arthritis (IA). However, the persistence of pain, even in patients with a complete pharmacological control of peripheral inflammation, represents an important clinical challenge in the treatment of IA.
Learn More >Pain control in trauma is an integral part of treatment in combat casualty care. More soldiers injured on the battlefield need analgesics for pain than life-saving interventions (LSIs). Early treatment of pain improves outcomes after injury, while inadequate treatment leads to higher rates of post-traumatic stress disorder (PTSD).
Learn More >Back and low back pain have been reported as one of the leading causes of activity restriction. While degenerative changes in the spine are among the common causes of low back pain, zygapophyseal (facet) joint pain is seen as the most widely accepted cause of back pain. Standard imaging modalities may have low predictive value in detecting the source of back pain. Thanks to radionuclide bone scintigraphy, painful lesions can be distinguished from age-related changes, especially in patients with chronic low back pain. In this study, we aimed to retrospectively evaluate the clinical results of facet-induced low back pain, which was confirmed by bone scintigraphy, after facet injection treatment.
Learn More >Little is known about the nature of relationships between sleep disturbance and influencing factors in rheumatoid arthritis. The purpose of this study was to identify factors that influence sleep disturbance and to evaluate mediating effects of depression on sleep disturbance. A nonexperimental, descriptive, correlational study design was adopted. One hundred patients with rheumatoid arthritis were recruited. Inflammatory status and levels of pain, fatigue, functional disability, depression, and sleep disturbance were measured. The factors that directly influenced sleep disturbance were gender, rheumatoid arthritis duration, serum C-reactive protein level, fatigue, and depression. Depression was found to have mediating effects on the relationships between sleep disturbance and arthritis symptoms. Pain, fatigue, and depression were found to have significant direct or indirect impacts on sleep disturbance. Our findings may improve understanding of sleep disturbance and aid the development of effective nursing management strategies for patients with rheumatoid arthritis suffering from sleep disturbance.
Learn More >Neurotoxic chemotherapy has been shown to be associated with reduced corneal nerves and ocular surface discomfort. Substance P is a neuropeptide expressed by sensory nerves including those in the densely innervated cornea. It is involved in both pain signaling and the regulation of epithelial and neural health. While its levels in tear fluids have been used as a neuropathic biomarker in diabetes, investigations of tear concentrations of substance P in chemotherapy-induced peripheral neuropathy have not been explored. The current cross-sectional study assessed substance P expression in tears of patients following neurotoxic chemotherapy treatment. Patients treated with paclitaxel (n = 35) or oxaliplatin (n = 30) 3-24 months prior to assessment were recruited along with healthy controls (n = 25). Flush tear collection, in-vivo corneal confocal microscopy and neurotoxicity assessments were also conducted. Enzyme-linked immunosorbent assays were used to measure substance P concentrations in collected tears, while total protein content (TPC) was measured with the bicinchoninic acid method (BCA). General linear models were used for statistical analysis. Substance P concentration was reduced in paclitaxel-treated patients [Median (Interquartile range, IQR): 1.11 (0.20-2.24) ng/ml)] compared to the oxaliplatin group [4.28 (1.01-10.73) ng/ml, p = 0.02]. Substance P expressed as a proportion of TPC was also lower in the paclitaxel group [0.00006 (0.00001-0.00010) %] compared to the oxaliplatin group [0.00018 (0.00008-0.00040) %, p = 0.005]. Substance P concentration and its percentage in TPC were also reduced in the paclitaxel group when compared to healthy controls [4.61 (1.35-18.51) ng/ml, p = 0.02; 0.00020 (0.00006-0.00060) %, p = 0.04, respectively]. Higher cumulative dose of paclitaxel was correlated with a reduction in substance P concentrations (r = -0.40, p = 0.037), however no associations were found with corneal nerve parameters or neuropathy severity (p > 0.05). While these findings show evidence for the dysregulation of tear film substance P following paclitaxel treatment, longitudinal studies should be conducted to investigate how substance P levels in tears change during treatment.
Learn More >Despite opioid prescribing for chronic non-cancer pain (CNCP) having limited therapeutic benefits, recent evidence indicates significant increases in the prescribing of high-strength opioids for individuals with CNCP. Patients prescribed opioids for CNCP have overdose risk factors but generally have low opioid overdose awareness and low perceptions of risk related to prescribed opioids. Currently, there are few bespoke overdose prevention resources for this group.
Learn More >Pain usually receives insufficient attention by individuals due to the misconception that pain is a natural consequence of aging. For persons aged 65 and older, a disease requiring further research is fibromyalgia, characterized by chronic pain without clear pathology. Mind-body therapies like mindfulness are beneficial for this population as they affect psychological and biological aspects of pain. These therapies emphasize a nonjudgmental acceptance of thoughts and attention to the experience without attempting to resist or change them. Despite the potential benefits of mindfulness interventions for persons with fibromyalgia aged 65 and older, only few studies have examined the effects of these therapies, yielding conflicting findings. Importantly, no study has yet to be conducted exclusively on this population. This comprehensive review examined existing literature focusing on the effects of mindfulness-based interventions on the physical and mental well-being of persons with fibromyalgia aged 65 and older. It highlights the need for further research on the relationship between mindfulness, fibromyalgia, and gerontology, calling for a standard protocol of intervention.
Learn More >Rising rates of prescription opioids for chronic pain from the 1990s along with a concomitant worsening overdose crisis led to rapid evaluation and public health strategies to curb problems with prescription opioids. Guideline development, grounded in solid theory but based on limited evidence that translated into rigid and discordant policies, has contributed to controversies in pain management, worsening the treatment experience for people experiencing chronic pain and highlighting existing inequities from a system clouded with systemic racism. Newer public health approaches need to evaluate root causes and be more holistic addressing inequities as well as using trauma-informed principles.
Learn More >Health care providers are ethically obligated to provide effective management for patients suffering from chronic pain. Many patients have not had access to such management, and current bioethical principles are not sufficient to create the roadmap needed on how to improve current standard of care. Principles described in the emerging field of urban bioethics greatly enhance the toolbox available to providers regarding chronic pain management. Redefining the principles of autonomy, beneficence/nonmaleficence, and justice to agency, social justice, and solidarity is essential to having the framework needed to provide more ethical, equitable care.
Learn More >Chronic pain is a significant public health concern. Care for patients with chronic pain is complex and involves many intersecting systems, policies, and procedures. Applying systems engineering concepts to chronic pain management opens the door to addressing a wide range of performance gaps through a structured, evidence-based approach. Successful implementation of systems-based practice includes effectively incorporating interprofessional teamwork, community resources, team-based care, patient safety, hospital readmissions, use of evidence-based medicine, transitions of care, and care for the underserved, including social determinants of health into the routine delivery of health care services including pain management.
Learn More >Chronic pain syndromes include chronic low back pain, tension type and migraine headaches, fibromyalgia, and osteoarthritis. Adjunctive therapies may provide real benefit by themselves, as well as when combined with one another and more traditional treatments such as medication and physical therapy. High-quality evidence, including systematic reviews, and/or clinical practice guidelines support the use of acupuncture, acupressure, massage, and/or mindfulness-based stress reduction (MBSR) in patients with one or more of these chronic pain syndromes.
Learn More >Understanding the risks for substance use disorders (SUDs) and how to diagnose and treat is essential to the safe and effective treatment of patients with chronic noncancer pain (CNCP). Because of the common neurologic pathways underlying addiction and chronic pain and common comorbid mental health and psychosocial challenges, these conditions should be treated concurrently. Depending on setting and comfort level of the provider, primary care clinicians may have the resources to provide office-based treatment or may consider referral to specialty treatment. An awareness of the stigma facing patients with both CNCP and SUD is important to providing compassionate, patient-centered care.
Learn More >This article examines the occurrence of chronic pain across the human lifespan from pediatrics and adolescents through adulthood and concludes with geriatrics (>65). As a subset of the adolescent and adult age group, the article also explores the impact of chronic pain involving the obstetric population. Within the age groups and populations, we explore available information regarding prevalence, epidemiology, and impact of chronic pain surrounding each group as well as some of the common pain conditions and syndromes unique to a given group. While not focusing on treatment, the article reviews physiologic and other factors impacting treatment in a given group.
Learn More >Chronic pain interventions in the primary care setting can provide temporal relief and are best used as part of a comprehensive treatment plan. Interventional therapies may use steroids, local anesthetic, saline, prolotherapy, no medication at all (dry needling), acupuncture, or transcutaneous electrical nerve stimulation. These interventions may include adjuvant modalities, such as ultrasound, to improve precision and accuracy of injection. Choice of interventional therapy for chronic pain in the primary care setting is highly dependent on the clinician, location, and cause of the pain as well as a multitude of patient factors, which are discussed in this article.
Learn More >Chronic pain is a public health problem that affects millions of people; however, those with comorbid behavioral health issues are overrepresented in that number. Although pain can be caused by a variety of factors, it has traditionally been associated directly with physical pathology. We know there is variation in how patients report pain whether in the presence or absence of physical pathology; therefore, pain must be viewed as a complex issue. In this article, the authors review the relationship between pain and mental illness and discuss strategies and various modalities for addressing pain in the primary care setting.
Learn More >With benefits on pain and pain-related outcomes and low-risk profile, there has been an emphasis on nonpharmacologic management of chronic pain. Physical therapy uses exercises, manual therapies, and electrotherapy. Exercises include aerobic, strengthening, and flexibility exercises. Aquatic exercises have similar efficacy to land-based exercises. Multidisciplinary care uses a biopsychosocial approach. All are effective for pain-related outcomes. Occupational therapy focuses on ergonomics, joint protection, orthoses, and assistive devices. Limited evidence exists for taping, orthoses, assistive devices, thermotherapy, and education on pain-related outcomes. Weight loss in patients who are overweight or obese is effective for pain reduction in knee arthritis.
Learn More >Pharmacologic management of chronic pain is one component of a patient-centered care plan. Multiple classes of medications are available and can be used individually or in combination. Choice of medication is determined by the type and cause of pain, safety profile of the medication, patient values and preferences, comorbid conditions, cost, and availability. Incorporating shared decision making is critical when implementing a pharmacologic pain management regimen.
Learn More >Chronic pain is a common presenting problem in primary care offices. Primary pain disorders and chronic pain secondary to another underlying medical problem can significantly impact a patient's function and quality of life. Chronic pain is a complex diagnosis requiring individualized biomedical, psychosocial, and behavioral evaluations for each patient. Through thorough patient interview, physical examination, diagnostics, and standardized assessment tools, primary care clinicians can create a robust care plan for patients with chronic pain. Given the multifaceted nature of chronic pain, it is a diagnosis that fits into chronic disease model of care managed appropriately in the primary care setting.
Learn More >Currently available medications for chronic osteoarthritis pain are only moderately effective, and their use is limited in many patients because of serious adverse effects and contraindications. The primary surgical option for osteoarthritis is total joint replacement (TJR). The objectives of this study were to describe the treatment history of patients with osteoarthritis receiving prescription pain medications and/or intra-articular corticosteroid injections, and to estimate the incidence of TJR in these patients.
Learn More >Chronic pain is a multifaceted disorder genuinely entangled with psychic and psychosomatic symptoms, which are typically involved in the processes of chronification. The impingement syndrome of the shoulder is no exception to this rule, but several studies have shown respective peculiarities among those with pain and impingement of the shoulder. Notably, chronic pain is a lateralized experience, and, similarly, its psychosomatic correlates may be attached to the hemispheres functionally.
Learn More >Prescription opioids have been increasingly prescribed for chronic pain while the opioid-related death rates grow. Naloxone, an opioid antagonist, is increasingly recommended in these patients, yet there is limited research that investigates the intention to get naloxone. This study aimed to investigate intention toward getting naloxone in patients prescribed opioids for chronic pain and to assess the predictive utility of the theory of reasoned action (TRA) constructs in explaining intention to get naloxone.
Learn More >Chronic migraine belongs to the "chronic long-duration headaches", and it is associated to high burden and significant economic impact. Treatment for both episodic (EM) and chronic migraine (CM) is based on the management of acute attacks and their prevention. For moderate/severe attacks, pharmacological therapies are triptans, dihydroergotamine nasal sprays or injections or neuroleptics, non-steroidal anti-inflammatory drugs, and corticosteroids. Chronic migraine belongs to the "chronic long-duration headaches", and it is associated to high burden and significant economic impact. Treatment for both episodic (EM) and chronic migraine (CM) is based on the management of acute attacks and their prevention. For moderate/severe attacks, pharmacological therapies are triptans, dihydroergotamine nasal sprays or injections or neuroleptics, non-steroidal anti-inflammatory drugs, and corticosteroids. The pathophysiology of CM is characterized by an abnormal activation of the trigemino-vascular system in the meninges causing a neurogenic inflammation, which explains the use of anti-inflammatory during attacks. It seems that the objective of the preventive therapy with the botulin toxin OnaBoNT-A consists in interrupting the release of CGRP and other neuropeptides as well as the activation of C-fiber nociceptor and of the nearby A-delta fibers. The protocol for migraine treatment with OnaBoNT-A injections consists of 31-39 pericranial injection sites involving seven muscle groups bilaterally in specific areas of the head and neck, with a total dose of between 155 and 195 units, every three months. The severe adverse events reported with high doses of botulin toxin for spasticity, have not been reported for CM treated with OnabotA at the labeled dose. The established improvement with onabotulinumtoxinA treatment in CM patients had a positive impact not only in reduction monthly headache days but also in improving quality of life, with reduction in both healthcare resource utilisation (HRU) and work impairment. Aim of this review was to give an overview on the use of BoNT-A in patients with CM, giving practical advices on the clinical indications.
Learn More >Artificial Intelligence in healthcare is growing quickly in diagnostics and treatment management. Despite the quantity and variety of studies its role in clinical care is not clear. To identify the evidence gaps and characteristics of the Artificial Intelligence and Machine Learning techniques in predicting/diagnosing the pain? Pubmed/Embase were searched from the inception to October 2021 for articles without any language restrictions specifically addressing the following: the accuracy of AI in pain considering Brain Imaging, Patient-reported measures, and Electrophysiology, the ability of AI to differentiate stratify severity/types of pain, the ability of AI to predict pain and lastly the most accurate AI technique for given inputs. All the included studies were on humans. Eight hundred forty abstracts were reviewed, and 23 articles were finally included. Identified records were independently screened and relevant data was extracted. We performed conceptual synthesis by grouping the studies using available concepts of AL/ML techniques in diagnosing pain. Then we summarized the number of features/physiological measurements. Structured tabulation synthesis was used to show patterns predictions along with a narrative commentary. A total of 23 articles, published between 2015 and 2020 from 12 countries were included. Most studies were experimental in design. The most common design was cross sectional. Chronic or acute pains were predicted more often. Compared to control, the pain prediction was in the range of 57%-96% by AI techniques. Support Vector Machine and deep learning showed higher accuracy for classifying pain. From this study, it can be inferred that AI/ML can be used to differentiate healthy controls from patients. It can also facilitate categorizing them into new and different clinical subgroups. Lastly, it can predict future pain. The limitations are with respect to studies done after the search period. AL/ ML has a supportive role in pain diagnostics.
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