Non-invasive neurostimulation of the brain or of nerve/muscles/spinal roots, alone or in combination with conventional therapy, represents a fertile ground to develop more efficient approaches for pain management in CRPS.Background Slow stroking touch is generally perceived as pleasant and reduces thermal pain. However, the tactile stimuli applied tend to be short-lasting and typically applied to the forearm. This study aimed to compare the effects of a long-lasting brushing stimulus applied to the facial region and the forearm on pressure pain thresholds (PPTs) taken on the hand. Outcome measurements were touch satiety and concurrent mechanical pain thresholds of the hand. Methods A total of 24 participants were recruited and randomized to receive continuous stroking, utilizing a robotic stimulator, at C-tactile (CT) favorable (3 cm/s) and non-favorable (30 cm/s) velocities applied to the right face or forearm. Ratings of touch pleasantness and unpleasantness and PPTs from the hypothenar muscle of the right hand were collected at the start of stroking and once per minute for 5 min. Results A reduction in PPTs (increased pain sensitivity) was observed over time (P less then 0.001). However, the increase in pain sensitivity was less prominent when the face was stroked compared to the forearm (P = 0.001). Continuous stroking resulted in a significant interaction between region and time (P = 0.008) on pleasantness ratings, with a decline in ratings observed over time for the forearm, but not on the face. Unpleasantness ratings were generally low. Conclusion We observed touch satiety for 5 min of continuous robotic brushing on the forearm confirming previous studies. However, we did not observe any touch satiety for brushing the face. Mechanical pain sensitivity, measured in the hand, increased over the 5-min period but less so when paired with brushing on the face than with brushing on the forearm. The differential effects of brushing on the face and forearm on touch satiety and pain modulation may be by the differences in the emotional relevance and neuronal pathways involved.Background Prescribing practice of pain medication is changing in the Netherlands; opioids are used more often instead of nonsteroidal anti-inflammatory drugs (NSAIDs), therefore we aimed to compare the use of pain medication with Slovenia which has stringent prescribing rules for strong opioids. Methods We conducted a cohort study into national prescription databases of the Netherlands and Slovenia covering pharmacy claims between January 1, 2013 and December 31, 2019. In the analysis about 17 million Dutch and 2 million Slovenian residents were included. Findings The use of opioids and NSAIDs was higher in Slovenia than in the Netherlands. More frequent use of opioids in Slovenia could be almost entirely explained by weak opioids (about 6% of the population), whereas they were prescribed 50% less frequently in the Netherlands. The opioid use has increased by about 20% in the Netherlands (4.85 and 6.00% of the population in 2013 and 2018, respectively), and the majority of this increase could be explained by strong opioids (4.05% in 2018), specifically, by oxycodone whose use increased by more than 2-fold between 2013 and 2019. In comparison, oxycodone was seldomly used in Slovenia (about 0.3% of the population received a prescription in a year). Interpretation When medication use is controlled by stringent prescribing rules, like for strong opioids in Slovenia, the use is lower as compared to when such rules do not exist.As pain consists of both sensory and affective components, its management by pharmaceutical agents remains difficult. Alternative forms of neuromodulation, such as electrical stimulation, have been studied in recent years as potential pain treatment options. Although electrical stimulation of the brain has shown promise, more research into stimulation frequency and targets is required to support its clinical applications. Here, we studied the effect that stimulation frequency has on pain modulation in the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) in acute pain models in rats. We found that low-frequency stimulation in the prelimbic region of the PFC (PL-PFC) provides reduction of sensory and affective pain components. Meanwhile, high-frequency stimulation of the ACC, a region involved in processing pain affect, reduces pain aversive behaviors. Our results demonstrate that frequency-dependent neuromodulation of the PFC or ACC has the potential for pain modulation.In recent years, preclinical pain research has failed to develop genuinely new analgesics for clinical use. This fact is reflected by a high number of patients, limited drug efficacy accompanied by side effects, and a long-term opioid intake. Two main aspects have been addressed, which hinder translation the use of non-relevant pain models and a mismatch between pain-related outcomes in preclinical and clinical studies. Conversely, disease-specific pain models that mirror more closely the clinical situation and multidimensional behavioral outcome measures that objectively and reproducibly assess relevant pain-related symptoms in a preclinical setting could improve translation. Mechanistically, a matter of debate is the role of Ly6G+ neutrophil granulocytes (NGs) for pain. NGs are essential to eliminate pathogens and promote the wound healing process. For this purpose, there is a need to release various pro- and anti-inflammatory mediators, some of which could ameliorate or enhance pain. However, the contributrt a novel assessment to detect NEP in mice after unilateral injuries using a more unbiased approach. Additionally, we are capable of detecting an antalgic gait for both pain entities with unique trajectories. The different trajectories between MEP and other pain modalities suggest that the underlying mechanisms differ. We further conclude that NGs play a subordinate role in pain-related behaviors in incisional and inflammatory pain.Assessment of cancer rehabilitation outcome measures is integral for patient assessment, symptom screening, and advancing scientific research. In the broad field of cancer rehabilitation, outcome measures can cross-cut across many different branches of oncologic care including clinician-reported, patient-reported, and objective measures. Specific outcome measures that apply to cancer rehabilitation include those pertinent to pain, function, quality of life, fatigue, and cognition. These outcome measures, when used in cancer rehabilitation, can be utilized to evaluate the effectiveness of an intervention and to triage to the appropriate supportive care service. This review article summarizes some of the commonly used outcome measures that can be applied in the cancer rehabilitation setting to support scholarly work and patient care.Background Pain captures attention and interferes with competing tasks demanding cognitive effort. Brief mindfulness interventions involving both conceptual learning and meditation exercises have been shown to improve attention and reduce pain sensitivity, and could potentially reduce pain interference. This study assesses the effect of a 5-day mindfulness intervention (20 min/day) on the interference produced by thermal pain on working memory performance using a 2-back task. Methods Healthy participants were randomized into three groups exposed to mindfulness meditation training (n = 15), an active educational control intervention comprising only conceptual information on mindfulness (n = 15), or no intervention (n = 15). The two active interventions were administered in a dual-blind fashion and outcomes were assessed by research personnel blind to this allocation. Evaluation sessions were conducted before and after the interventions to assess the effect of pain on 2-back performance (pain interference). Impt mindfulness produced some unexpected benefits. Although the generalization of experimental findings to clinical pain conditions may be premature, these results highlight the importance of distinguishing the contribution of mindfulness education and meditation training in future studies. Understanding the effects of mindfulness training on pain regulation and management must take into consideration the multiple factors underlying this complex intervention.We conducted an analytic review of the clinical scientific literature bearing on the use of opioids for treatment of chronic non-cancer pain in the United States. There is substantial, albeit not definitive, scientific evidence of the effectiveness of opioids in treating pain and of high variability in opioid dose requirements and side effects. The estimated risk of death from opioid treatment involving doses above 100 MMED is ~0.25%/year. Multiple large studies refute the concept that short-term use of opioids to treat acute pain predisposes to development of opioid use disorder. The prevalence of opioid use disorder associated with prescription opioids is likely less then 3%. Morbidity, mortality, and financial costs of inadequate treatment of the 18 million Americans with moderate to severe chronic pain are high. Because of the absence of comparative effectiveness studies, there are no scientific grounds for considering alternative non-pharmacologic treatments as an adequate substitute for opioid therapy but these treatments might serve to augment opioid therapy, thereby reducing dosage. There are reasons to question the ostensible risks of co-prescription of opioids and benzodiazepines. As the causes of the opioid crisis have come into focus, it has become clear that the crisis resides predominantly in the streets and that efforts to curtail it by constraining opioid treatment in the clinic are unlikely to succeed.Objective This study offers direction for interaction between physical therapists and patients about cancer-related pain during physical training. The study may increase awareness of rehabilitation strategies for cancer-related pain during and after cancer treatment. Methods Qualitative study, evaluating results of two qualitative studies. Data has been collected using semi-structured interviews, in which topics were discussed with patients and physical therapists. Respondents were adult patients with cancer in the Northern Netherlands with moderate to severe pain who followed physical training with a (oncologic) physical therapist. The physical therapists were respondents specialized in oncology and working with patients with cancer in a primary care setting in in the Netherlands. Data were analyzed using thematic analysis. Results Eighteen patients and fifteen physical therapists were interviewed. Data was categorized in statements regarding „patients’ needs”, „patients’ experiences” and „clinical reasoningent are used. It is recommended that physical therapists who give physical training take the initiative to repeatedly discuss pain.Oxaliplatin, which is widely used in treating cancers such as colorectal cancer, frequently causes peripheral neuropathy. It not only significantly reduces the patient’s quality of life due to physical distress but may also result in a change or discontinuation of cancer treatment. Oxaliplatin-induced peripheral neuropathy (OIPN) is classified as acute or chronic depending on the onset time of side effects; however, the prevention and treatment of OIPN has not been established. As these peripheral neuropathies are side effects that occur due to treatment, the administration of effective prophylaxis can effectively prevent their onset. Although transient relief of symptoms such as pain and numbness enable the continuation of cancer treatment, it may result in the worsening of peripheral neuropathy. Thus, understanding the pathological mechanisms of OIPN and finding better preventative measures are important. This review focuses on animal models to address these issues, clarifies the pathological mechanisms of OIPN, and summarizes various approaches to solving OIPN, including targets for preventing OIPN.Purpose Transcranial Direct Current Stimulation (tDCS) is an intervention that seems to be an ideal tool to enhance the effects of rehabilitation therapies given it facilitates generation of plasticity in the stimulated brain area. In stroke this strategy has been highly utilized; however, the results have been mixed. In this trial we have evaluated the analgesic and functional effects of Transcranial Direct Current Stimulation (tDCS) combined with physiotherapy in stroke survivors with shoulder pain. Methods Twenty-six stroke surviving adults with shoulder pain received 10 sessions of passive mobilization and performed upper limb exercises using a cycle ergometer, combined with active or sham tDCS. The intensity of pain in the hemiplegic shoulder was measured using the Visual Analog Scale (VAS); secondary outcomes were the level of motor impairment, handgrip strength, range of motion, motor function of the upper limbs, and quality of life (QOL) assessed before and after 10 sessions and 1 month after the end of the treatment. Results A clinically important pain reduction (3 points) was found in both groups and was maintained at follow-up; there was no significant difference between groups (p = 0.3). Similarly, the shoulder range of motion improved, motor function and quality of life improved showed no significant differences between groups. One result that needs to be underscored is that both groups had a significant effect size toward improvement in all of these outcomes. Conclusions We discuss in this study that tDCS is not a useful combination strategy when the physical therapy has a large effect by itself and we also review other negative trials of combined therapy under this framework of ceiling effect of the main physical therapy. Trial registry Trial registration Brazilian Registry of Clinical Trials, RBR-8F5MNY (http//www.ensaiosclinicos.gov.br/rg/RBR-8f5mny/). Registered on June 2, 2017. Beginning of the recruitment of the volunteers august, 2017.Injuries to the nervous system can result in a debilitating neuropathic pain state that is often resistant to treatment with available analgesics, which are commonly associated with several side-effects. Growing pre-clinical and clinical evidence over the last two decades indicates that immune cell-mediated mechanisms both in the periphery and in the Central Nervous System (CNS) play significant roles in the establishment and maintenance of neuropathic pain. Specifically, following peripheral nerve injury, microglia, which are CNS resident immune cells, respond to the activity of the first pain synapse in the dorsal horn of spinal cord and also to neuronal activity in higher centres in the brain. This microglial response leads to the production and release of several proinflammatory mediators which contribute to neuronal sensitisation under neuropathic pain states. In this review, we collect evidence demonstrating the critical role played by the Fractalkine/CX3CR1 signalling pathway in neuron-to-microglia communication in neuropathic pain states and explore how strategies that include components of this pathway offer opportunities for innovative targets for neuropathic pain.Background Little is known regarding the clinical impact of treatment and treatment duration of probiotic VSL#3 on gut and microbiome function in irritable bowel syndrome (IBS). As part of a safety trial, we assessed the effect of VSL#3 treatment duration on abdominal pain, stooling, gut permeability, microbiome composition and function. Methods Adults with IBS were randomized into an open label trial to receive the probiotic VSL#3 for 4 or 8 weeks. Adverse events, abdominal pain, and stooling patterns were recorded daily. Gut permeability, fecal bile acid levels, and microbiome composition were profiled at baseline and after treatment. Results Fifteen subjects completed the trial (4-week n = 8; 8-week n = 7). Number of pain episodes decreased in both groups (P = 0.049 and P = 0.034; 4- vs. 8-week, respectively). Probiotic organisms contained in VSL#3 were detected in feces by whole shotgun metagenomic sequencing analysis and relative abundances of Streptococcus thermophilus, Bifidobacterium animalis, Lactobacillus plantarum, and Lactobacillus casei subsp. paraccasei correlated significantly with improved abdominal pain symptoms and colonic permeability at study completion. Although abdominal pain correlated significantly with the detection of probiotic species at study completion, a composite view of gut microbiome structure showed no changes in community diversity or composition after VSL#3 treatment. Conclusions Probiotic organisms identified in stool correlated significantly with improvement in colonic permeability and clinical symptoms, prompting future studies to investigate the mechanistic role of VSL#3 and colonic permeability in IBS pathophysiology in a larger randomized controlled trial. Clinical Trial Registration http://www.clinicaltrials.gov, Identifier NCT00971711.Sixteen million people suffer with chronic low back pain and related healthcare expenditures can be as high as $USD 635 billion. Current pain treatments help a significant number of acute pain patients, allowing them to obtain various treatments and then „exit the market for pain services” quickly. However, chronic patients remain in pain and need multiple, varying treatments over time. Often, a single pain provider does not oversee their care. Here, we analyze the current pain market and suggest ways to establish a new treatment paradigm. We posit that more cost effective treatment and better pain relief can be achieved with multi-disciplinary care with a provider team overseeing care.Chronic migraine is a disabling neurological disorder that imposes a considerable burden on individual and socioeconomic outcomes. Chronic migraine is defined as headaches occurring on at least 15 days per month with at least eight of these fulfilling the criteria for migraine. Chronic migraine typically evolves from episodic migraine as a result of increasing attack frequency and/or several other risk factors that have been implicated with migraine chronification. Despite this evolution, chronic migraine likely develops into its own distinct clinical entity, with unique features and pathophysiology separating it from episodic migraine. Furthermore, chronic migraine is characterized with higher disability and incidence of comorbidities in comparison to episodic migraine. While existing migraine studies primarily focus on episodic migraine, less is known about chronic migraine pathophysiology. Mounting evidence on aberrant alterations suggest that pronounced functional and structural brain changes, central sensitization and neuroinflammation may underlie chronic migraine mechanisms. Current treatment options for chronic migraine include risk factor modification, acute and prophylactic therapies, evidence-based treatments such as onabotulinumtoxinA, topiramate and newly approved calcitonin gene-related peptide or receptor targeted monoclonal antibodies. Unfortunately, treatments are still predominantly ineffective in aborting migraine attacks and decreasing intensity and frequency, and poor adherence and compliance with preventative medications remains a significant challenge. Novel emerging chronic migraine treatments such as neuromodulation offer promising therapeutic approaches that warrant further investigation. The aim of this narrative review is to provide an update of current knowledge and perspectives regarding chronic migraine background, pathophysiology, current and emerging treatment options with the intention of facilitating future research into this debilitating and largely indeterminant disorder.Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly heterogeneous chronic and debilitating condition which effects millions of women and men in the United States. While primarily defined by urinary symptoms and pain perceived to be emanating from the bladder, IC/BPS patients frequently have co-occurring conditions and symptoms, many of which affect diverse body systems related to autonomic nervous system function. The impact on the autonomic system appears to stem from increased sympathetic innervation of the urinary tract, along with increased systemic sympathetic tone and decreased parasympathetic tone. Concurrent with these findings is evidence for destruction of peripheral sympathetic innervation to the sweat glands which may relate to small fiber polyneuropathy. It is unknown to what degree the wider alterations in autonomic function are also related to destruction/alterations in the small fibers carrying autonomic innervation. This potential nexus is an important point of investigation to better understand the unclarified pathophysiology of interstitial cystitis/bladder pain syndrome, the numerous co-occurring symptoms and syndromes, and for the identification of novel targeted therapeutic strategies.In the urinary bladder, mechanosensitive ion channels (MSCs) underlie the transduction of bladder stretch into sensory signals that are relayed to the PNS and CNS. PIEZO1 is a recently identified MSC that is Ca2+ permeable and is widely expressed throughout the lower urinary tract. Recent research indicates that PIEZO1 is activated by mechanical stretch or by pharmacological agonism via Yoda1. Aberrant activation of PIEZO1 has been suggested to play a role in clinical bladder pathologies like partial bladder outlet obstruction and interstitial cystitis/bladder pain syndrome (IC/BPS). In the present study, we show that intravesical instillation of Yoda1 in female Wistar rats leads to increased voiding frequency for up to 16 hours after administration compared to vehicle treatment. In a cyclophosphamide (CYP) model of cystitis, we found that the gene expression of several candidate MSCs (Trpv1, Trpv4, Piezo1, and Piezo2) were all upregulated in the urothelium and detrusor following chronic CYP-induced cystitis, but not acute CYP-induced cystitis. Functionally with this model, we show that Ca2+ activity is increased in urothelial cells following PIEZO1 activation via Yoda1 in acute and intermediate CYP treatment, but not in naïve (no CYP) nor chronic CYP treatment. Lastly, we show that activation of PIEZO1 may contribute to pathological bladder dysfunction through the downregulation of several tight junction genes in the urothelium including claudin-1, claudin-8, and zona occludens-1. Together, these data suggest that PIEZO1 activation plays a role in dysfunctional voiding behavior and may be a future, clinical target for the treatment of pathologies like IC/BPS.Introduction Migraine is a chronic neurological disease that is the primary cause of years lived with disability in people under the age of 50. Remote electrical neuromodulation (REN) is a novel drug-free acute treatment of migraine, that is FDA cleared for episodic and chronic migraine. As a prescribed digital therapeutic, REN enables large-scale post-marketing research, thus providing real-world information on the use of the intervention in a wide range of populations, environments, and situations. Methods The REN device (®Nerivio) includes a secured, personal migraine diary, which patients can use to record their symptoms before treatment and 2 h post-treatment. Real-world data on REN treatments were collected via the app from patients across the United States who used Nerivio between October 1st, 2019, and May 24th, 2021. Data analysis focused on four metrics 1. Per-treatment patterns of REN use as a standalone treatment vs. in combination with medications. 2. Per-user intra-individual efficacy across mulatment option for acute treatment of migraine in real-world settings, both as a standalone replacement of pharmaceuticals, as well as an adjunct to medications.Background Peritoneal carcinomatosis often results in alterations in intestinal peristalsis and recurrent abdominal pain. Pain management in these patients is often unsatisfactory. This study aimed to investigate whether endothelin-1 (EDN1) was involved in pain mediation in peritoneal carcinomatosis, and thus whether the EDN1 pathway could be a new therapeutic target for peritoneal carcinomatosis-associated pain. Methods EDN1 plasma levels and abdominal pain severity were assessed in patients with abdominal tumors, with or without peritoneal carcinomatosis, and in healthy donors. The effects of EDN1 on the visceromotor response to colorectal distension, and on colonic contractions were then examined in mice, and the mechanism of action of EDN1 was then investigated by measuring the impact of EDN1 exposure on calcium mobilization in cultured neurons. Inhibition studies were also performed to determine if the effects of EDN1 exposure could be reversed by EDN1-specific receptor antagonists. Results A positive correlation between EDN1 plasma levels and abdominal pain was identified in patients with peritoneal carcinomatosis. EDN1 exposure increased visceral sensitivity and the amplitude of colonic contractions in mice and induced calcium mobilization by direct binding to its receptors on sensory neurons. The effects of EDN1 were inhibited by antagonists of the EDN1 receptors. Conclusions This preliminary study, using data from patients with peritoneal carcinomatosis combined with data from experiments performed in mice, suggests that EDN1 may play a key role mediating pain in peritoneal carcinomatosis. Our findings suggest that antagonists of the EDN1 receptors might be beneficial in the management of pain in patients with peritoneal carcinomatosis.Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic stavide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.Pediatric chronic orofacial pain (OFP) is an umbrella term which refers to pain associated with the hard and soft tissues of the head, face, and neck lasting >3 months in patients younger than 18 years of age. Common chronic pediatric OFP diagnoses include temporomandibular disorder, headaches, and neuropathic pain. Chronic OFP can adversely affect youth’s daily functioning and development in many areas of well-being, and may be associated with emotional stress, depression, functional avoidance, and poor sleep, among other negative outcomes. In this mini-review, we will discuss common psychological comorbidities and familial factors that often accompany chronic pediatric OFP conditions. We will also discuss traditional management approaches for pediatric orofacial pain including education, occlusal appliances, and psychological treatments such as relaxation, mindfulness-based interventions, and cognitive-behavioral treatments. Finally, we highlight avenues for future research, as a better understanding of chronic OFP comorbidities in childhood has the potential to prevent long-term pain-related disability in adulthood.Glial cells play an essential role in maintaining the proper functioning of the nervous system. They are more abundant than neurons in most neural tissues and provide metabolic and catabolic regulation, maintaining the homeostatic balance at the synapse. Chronic pain is generated and sustained by the disruption of glia-mediated processes in the central nervous system resulting in unbalanced neuron-glial interactions. Animal models of neuropathic pain have been used to demonstrate that changes in immune and neuroinflammatory processes occur in the course of pain chronification. Spinal cord stimulation (SCS) is an electrical neuromodulation therapy proven safe and effective for treating intractable chronic pain. Traditional SCS therapies were developed based on the gate control theory of pain and rely on stimulating large Aβ neurons to induce paresthesia in the painful dermatome intended to mask nociceptive input carried out by small sensory neurons. A paradigm shift was introduced with SCS treatments that do n while modulating them toward expression levels of healthy animals. The ability of DTMP to modulate key genes and proteins involved in glia-mediated processes affected by pain toward levels found in uninjured animals demonstrates a shift in the neuron-glial environment promoting analgesia.Approximately 100 million adults in the United States have chronic pain, though only a subset utilizes the vast majority of healthcare resources. Multidisciplinary care has been shown to improve outcomes in a variety of clinical conditions. There is concern that multidisciplinary care of chronic pain patients may overwhelm existing resources and increase healthcare utilization due to the volume of patients and the complexity of care. We report our findings on the use of multidisciplinary conferences (MDC) to facilitate care for the most complex patients seen at our tertiary center. Thirty-two of nearly 2,000 patients seen per year were discussed at the MDC, making up the top 2% of complex patients in our practice. We evaluated patients’ numeric rating score (NRS) of pain, medication use, hospitalizations, emergency department visits, and visits to pain specialists prior to their enrollment in MDC and 1 year later. Matched samples were compared using Wilcoxon’s signed rank test. Patients’ NRS scores significantly decreased from 7.64 to 5.54 after inclusion in MDC (p less then 0.001). A significant decrease in clinic visits (p less then 0.001) and healthcare utilization (p less then 0.05) was also observed. Opioid and non-opioid prescriptions did not change significantly (p = 0.43). 83% of providers agreed that MDC improved patient care. While previous studies have shown the effect of multi-disciplinary care, we show notable improvements with a team established around a once-a-month MDC.Introduction Effective clinical care for chronic pain requires accurate, comprehensive, meaningful pain assessment. This study investigated healthcare providers’ perspectives on seven pain measurement indices for capturing pain intensity. Methods Semi-structured telephone interviews were conducted with a purposeful sample from four US regions of 20 healthcare providers who treat patients with chronic pain. The qualitative interview guide included open-ended questions to address perspectives on pain measurement, and included quantitative ratings of the importance of seven indices [average pain, worst pain, least pain, time in no/low pain, time in high pain, fluctuating pain, unpredictable pain]. Qualitative interview data were read, coded and analyzed for themes and final interpretation. Standard quantitative methods were used to analyze index importance ratings. Results Despite concerns regarding 10-point visual analog and numeric rating scales, almost all providers used them. Providers most commonly asked about average pain, although they expressed misgivings about patient reporting and the index’s informational value. Some supplemented average with worst and least pain, and most believed pain intensity is best understood within the context of patient functioning. Worst pain received the highest mean importance rating (7.60), average pain the second lowest rating (5.65), and unpredictable pain the lowest rating (5.20). Discussion Assessing average pain intensity obviates obtaining clinical insight into daily contextual factors relating to pain and functioning. Pain index use, together with timing, functionality and disability, may be most effective for understanding the meaning to patients of high pain, how pain affects their life, how life affects their pain, and how pain changes and responds to treatment.Introduction Clumsiness has been described as a symptom associated with neck pain and injury. However, the actuality of this symptom in clinical practice is unclear. The aim of this investigation was to collect definitions and frequency of reports of clumsiness in clinical studies of neck pain/injury, identify objective measures of clumsiness and investigate the association between the neck and objective measures of clumsiness. Methods Six electronic databases were systematically searched, records identified and assessed including a risk of bias. Heterogeneity in designs of studies prevented pooling of data, so qualitative analysis was undertaken. Results Eighteen studies were retrieved and assessed; the overall quality of evidence was moderate to high. Eight were prospective cross-sectional studies comparing upper limb sensorimotor task performance and ten were case series involving a healthy cohort only. Clumsiness was defined as a deficit in coordination or impairment of upper limb kinesthesia. All but one of 18 studies found a deterioration in performing upper limb kinesthetic tasks including a healthy cohort where participants were exposed to a natural neck intervention that required the neck to function toward extreme limits. Conclusion Alterations in neck sensory input occurring as a result of requiring the neck to operate near the end of its functional range in healthy people and in patients with neck pain/injury are associated with reductions in acuity of upper limb kinesthetic sense and deterioration in sensorimotor performance. Understanding the association between the neck and decreased accuracy of upper limb kinesthetic tasks provide pathways for treatment and rehabilitation strategies in managing clumsiness.Background Bone cancer pain (BCP) significantly affects patient quality of life, results in great bodily and emotional pain, and creates difficulties in follow-up treatment and normal life. Transient receptor potential ankyrin 1 (TRPA1) is an essential transduction ion channel related to neuropathic and inflammatory pain. However, the role of TRPA1 in BCP remains poorly understood. This study aimed to explore the relationship between TRPA1 and BCP. Methods A BCP model was induced by Walker256 cells to the left tibia. The sham group was induced by normal saline to the left tibia. Thereafter, pain behaviors and TRPA1 expression between the BCP group and the sham group were observed on the 14th day of modeling. The TRPA1 antagonist A967079 (10 mg/kg) was injected via tail vein. TRPA1 antisense oligodeoxynucleotide (AS-ODN, 5 nmol/10 μl) and missense oligodeoxynucleotide (MS-ODN, 5 nmol/10 μl) were intrathecally delivered via a mini-osmotic pump for 5 consecutive days to assess the effect of TRPA1 on BCP. Behavio allodynia and thermal hyperalgesia in a rat BCP model.Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are excellent analgesics, but recent clinical evidence suggests that these drugs might worsen disease severity in Crohn’s disease patients, limiting their clinical utility for treating Inflammatory Bowel Disease (IBD). One indicator of change in well-being from conditions such as IBD is behavioral depression and disruption to activities of daily living. Preclinical measures of behavioral depression can provide an indicator of changes in quality of life and subsequent modification by candidate analgesics. In mice, nesting is an adaptive unconditioned behavior that is susceptible to disruption by noxious stimuli, and some types of pain related nesting depression are responsive to opioid and NSAID analgesics. Here we show that a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) model of experimental colitis depresses nesting behavior in mice, and we evaluated effects of morphine, an opioid, and ketoprofen, a NSAID, on TNBS-induced nesting depression. In Swiss Webster mice, TNBS significantly reduced nesting that peaked on Day 3 and recovered in a time-dependent manner with complete recovery by Day 7. In the absence of colonic inflammation, daily treatment with morphine (1-10 mg/kg) did not decrease nesting except at 10mg/kg/day. However, in TNBS-treated mice 3.2 mg/kg/day morphine significantly exacerbated TNBS-induced nesting depression and delayed recovery. While 3.2 mg/kg/day morphine alone did not alter locomotor activity and TNBS-induced depression of locomotion recovered, the combination of TNBS and 3.2 mg/kg/day morphine significantly attenuated locomotion and prevented recovery. Daily treatment with 3.2 or 10 mg/kg ketoprofen in TNBS-treated mice did not prevent depression of nesting. These data suggest that opioid analgesics but not NSAIDS worsen colonic inflammation-induced behavioral depression. Furthermore, these findings highlight the importance of evaluating analgesic effects in models of colonic inflammation induced depression of behavior.Objectives Functional Abdominal Pain (FAP) and Irritable Bowel Syndrome (IBS) are common recurrent abdominal pain diagnoses with the hallmark, lack of inflammation. To identify a biological signature for IBS/FAP in the colon, this study used genetic profiling to uncover gene expression changes associated with IBS/FAP and abdominal pain. Methods Patients (8 to 17 years) newly diagnosed with IBS or FAP were enrolled in the study. At diagnostic colonoscopy, three rectal biopsies were collected, and gene expression analysis was performed using a Qiagen PCR Array. Relative fold difference in gene expression for 84 pain-associated genes was calculated using the 2-ΔΔ Cq method compared with pain-free controls. Factors affecting pain burden (Pain Burden Interview; PBI) were analyzed, including age, sex, rectal inflammation, and gene expression. Data were analyzed using multiple stepwise linear regression and 2-tailed t tests (P ≤ 0.05). Results Of the 22 total patients in the study, 19 were diagnosed with either IBS-Constipation (frequency of 5.26%), IBS-Diarrhea (47.37%), IBS-Mixed (10.53%), or FAP (36.84%). IBS/FAP patients reported significantly higher pain burden at the time of diagnosis compared to pain-free controls (p less then 0.001), as well as significantly higher abdominal pain (p = 0.01). Of the 84 genes, expression of GRIN1 (p = 0.02), MAPK3 (p = 0.04), P2X4 (p = 0.04), and PTGES3 (p = 0.02) were all significantly associated with PBI score. Discussion Abdominal pain associated with IBS/FAP in pediatric patients may be linked to the expression of GRIN1, MAPK3, P2X4, and PTGES3, pointing to potential novel therapeutic targets for management of recurring abdominal pain.There is strong evidence that psychosocial variables, including pain catastrophizing, influence parental and child ratings of pain, pain expression, and long-term outcomes among children with chronic pain. The role of these factors among children who have communication deficits due to cerebral palsy (CP) and other intellectual and developmental disabilities is currently unclear. In this study, parental pain catastrophizing was assessed before intrathecal baclofen (ITB) pump implantation for spasticity management in 40 children and adolescents with CP, aged 4 to 24 years. Pain was assessed before and after surgery with two methods a parent-reported pain interference scale, and behavioral pain signs during a standardized range of motion exam. Linear mixed models with clinical/demographic factors and scores from the Pain Catastrophizing Scale for Parents (PCS-P), and child spoken language ability as predictors and the pain variables as the outcomes were implemented. On average, both pain outcomes improved after surgery. Only child spoken language ability predicted change in behavioral reactivity scores, with children with phrase speech showing an increase in reactivity at follow-up compared to pre-surgery levels, on average. A significant interaction between PCS-P scores and spoken language ability on change in pain interference scores over time showed that dyads with children with phrase speech whose parents reported high PCS-P scores reported the least improvement in pain interference at follow-up. Due to the preliminary nature of the study, future work is needed to investigate the parental behaviors that mediate the relationships between parental catastrophizing and pain outcomes in this population.Objective Complex regional pain syndrome (CRPS) is a common pain condition characterized by the changes in the brain that are not yet addressed by conventional treatment regimens. Repetitive peripheral magnetic stimulation (rPMS) of muscles is painless and non-invasive and can influence these changes (the induction of brain plasticity) to reduce pain and improve motricity. In patients with CRPS, this open-label pilot study tested rPMS after-effects on the pain intensity and sensorimotor control of the upper limb along with the excitability changes of the primary motor cortex (M1). Methods Eight patients with CRPS were enrolled in a single-session program. Patients were tested at pre- and post-rPMS over the flexor digitorum superficialis (FDS) muscle. The clinical outcomes were pain intensity, proprioception, active range of motion (ROM), and grip strength. M1 excitability was tested using the single- and paired-pulse transcranial magnetic stimulation (TMS) of M1. Results In our small sample study, rPMS reduced instant and week pain, improved proprioception and ROM, and reduced the hemispheric imbalance of several TMS outcomes. The more M1 contralateral to the CRPS side was hyperactivated at baseline, the more pain was reduced. Discussion This open-label pilot study provided promising findings for the use of rPMS in CRPS with a focus on M1 plastic changes. Future randomized, placebo-controlled clinical trials should confirm the existence of a causal relationship between the TMS outcomes and post-rPMS decrease of pain. This will favor the development of personalized treatments of peripheral non-invasive neurostimulation in CRPS.Opioid are the most powerful analgesics ever but their use is still limited by deleterious side effects such as tolerance, dependence, and respiratory depression that could eventually lead to a fatal overdose. The opioid crisis, mainly occurring in north America, stimulates research on finding new opioid ligands with reduced side effects. Among them, biased ligands are likely the most promising compounds. We will review some of the latest discovered biased opioid ligands and see if they were able to fulfill these expectations.Most adolescents identify their best friend as their main source of social support. Adolescents with chronic pain (ACP) report the loss of friendships due to pain. Friendships protect against loneliness and depression, yet adolescents with pain experience increased levels of loneliness and depression compared to peers. This longitudinal study examines the friendship stability of dyads that included an adolescent with chronic pain compared to non-pain friendship dyads as well as the factors contributing to a friendship breakup. Eighty-three participants from 61 same-sex friendship dyads across 3 sites participated in a 1-year follow-up survey designed to capture friendship features, indices of social-emotional well-being, pain characteristics, and friendship stability. Chi-square, repeated measures ANOVA, and logistic regression were used to analyze the data. Dyads that included an ACP experienced higher rates of friendship breakup. The shorter length of friendship and having chronic pain predicted a friendship breakup at time 2. ACP continues to experience worse scores on indices of social-emotional well-being that are not predicted with a friendship breakup. Understanding what contributes to positive long-term friendships for those with pain may inform strategies to maintain and improve friendships for those with pain and who experience social challenges.When a patient presents to a health provider, the course of the disorder is composed of three effects natural effects, specific effects, and contextual effects. Part of the contextual effect is due to the relationship between the healer and the patient. Social healing appears to be present in eusocial species and particularly well-developed in humans. Evidence for the importance of the relationship in healing is found in placebo studies, including placebo analgesics, medicine, and psychotherapy. Although the theory for how the relationship is therapeutic is not well-developed, four possible mechanisms are discussed. The implications for health care and the treatment of pain are discussed.Background The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of renal complications. Resolution of renal adverse effects after NSAID administration has been observed after short-term use. Thus, the present study aimed to investigate a series of patients with chronic musculoskeletal pain who underwent long-term NSAID administration followed by switching to tramadol hydrochloride/acetaminophen (TA) combination tablets to study the impact of NSAID-induced renal adverse effects. Methods This was a longitudinal retrospective study of 99 patients with chronic musculoskeletal pain. The patients were administrated with NSAIDs daily during the first 12 months, followed by daily TA combination tablets for 12 months. Estimated glomerular filtration rate (eGFR) and serum levels of aspartate aminotransferase and alanine transaminase were measured at baseline, after NSAID administration and after TA administration. Results eGFR was significantly reduced after 12-month NSAID administration (median, from 84.0 to 72.8 ml/min/1.73 m2), and the reduction was not shown after the subsequent 12-month TA administration (median, 71.5 ml/min/1.73 m2). Reduction in eGFR was less in patients who received celecoxib (median, -1.8 ml/min/1.73 m2) during the first 12 months. There was no significant difference in aspartate aminotransferase and alanine transaminase in each period. Conclusions Thus, patients receiving NSAIDs for 12 months displayed both reversible and irreversible reduction of eGFR upon cessation of NSAIDs and switching to TA. Our data highlight the potential safety benefit of utilizing multimodal analgesic therapies to minimize the chronic administration of NSAIDs.Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p less then 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p less then 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRPvWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects.the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.Background Anterior knee pain is a common complaint amongst adolescents, which can both be persistent, and in some cases, disabling. This study investigated a series of potential risk factors potentially linked to the onset of anterior knee pain. Methods Questionnaires were distributed amongst 367 10-15 years-olds enrolled in the local school board. These surveys included questions on sex, age, sport participation, and history of anterior knee pain verified by a physician. Bivariate correlations and a binomial logistic regression were conducted. Overall rate of AKP in the population studied was 7.4%. The results indicated that past history of knee pain, age, and increased sports participation significantly correlated with increased risk of AKP. AKP was significantly more common in females than males. While sex, height, age, overall sport participation, participation in specific sports, and history of knee injury all contributed to the binomial model.