There is initial evidence of microstructural abnormalities in the fibre-tract pathways of the cerebellum and cerebrum of individuals diagnosed with Type I Chiari malformation. However, it is unclear whether abnormal white matter architecture and macro-level morphological deviations that have been observed in Chiari translate to differences in functional connectivity. Furthermore, common symptoms of Chiari include pain and cognitive deficits, but the relationship between these symptoms and functional connectivity has not been explored in this population. Eighteen Type I Chiari patients and 18 age-, sex- and education-matched controls underwent resting-state functional MRI to measure functional connectivity. Participants also completed a neuropsychological battery and completed self-report measures of chronic pain. Group differences in functional connectivity were identified. Subsequently, pathways of significant difference were re-analyzed after controlling for the effects of attention performance and self-reported chronic pain. Chiari patients exhibited functional hypoconnectivity between areas of the cerebellum and cerebrum. Controlling for attention eliminated all deficits with the exception of that from the posterior cerebellar pathway. Similarly, controlling for pain also eliminated deficits except for those from the posterior cerebellar pathway and vermis VII. Patterns of Chiari hyperconnectivity were also found between regions of the cerebellum and cerebrum in Chiari patients. Hyperconnectivity in all regions was eliminated after controlling for attention except between left lobule VIII and the left postcentral gyrus and between vermis IX and the precuneus. Similarly, hyperconnectivity was eliminated after controlling for pain except between the default mode network and globus pallidus, left lobule VIII and the left postcentral gyrus, and Vermis IX and the precuneus. Evidence of both hyper- and hypoconnectivity were identified in Chiari, which is posited to support the hypothesis that the effect of increased pain in Chiari draws on neural resources, requiring an upregulation in inhibitory control mechanisms and resulting in cognitive dysfunction. Areas of hypoconnectivity in Chiari patients also suggest disruption in functional pathways, and potential mechanisms are discussed. Resting-state fMRI imaging was conducted on a group of Type I Chiari malformation patients and age- and education-matched controls. Analyses yielded patterns of relative hypo- and hyperconnectivity, associations between differences in functional connectivity and self-reported chronic pain, and relationships between differences in functional connectivity and attentional capacity.  First, CMI-related differences in functional connectivity, as indexed by resting-state fMRI (rs-fMRI), are assessed using a case–control design. Second, the relationship between functional connectivity differences and symptom severity is examined by re-analyzing pathways of significant difference after covarying for cognitive performance and self-reported pain. To date, there have been two prior studies that have correlated CMI symptoms with neuroimaging indices associated with neural microarchitecture.,,,,,,,There is accumulating evidence that cognitive dysfunction is a common symptom of CMI.It has also been demonstrated that the experience of chronic pain can divert cognitive resources away from the task at hand, causing a reduction in performance.Using DTI, Kumar et al.However, it remains unclear whether (i) CMI is associated with differences in functional connectivity between fibre tracts of the cerebellum and cerebrum,Eighteen CMI patients and 18 controls matched for age, sex and education participated in this study. CMI patients were diagnosed by either MGL or SV based upon radiological evidence and symptom profile and were recruited during presurgical consultation. Healthy controls were recruited from the Akron and Cleveland community. No participants reported using opioids for pain management. Participants were compensated $100 for their time and were permitted a copy of their scanned images.Participants completed MRI scans and a neuropsychological assessment, typically within one week. This study was approved by local institutional review boards of the University of Akron and the Cleveland Clinic, and written informed consent was provided by all participants. Imaging for all CMI patients occurred prior to undergoing surgery and after undergoing presurgical consultation. The RBANS was administered prior to surgery for 16 CMI patients and following surgery for two CMI patients. For the two who were assessed post-surgery, assessment was conducted approximately three months later to avoid post-surgery complications and surgery-related pain. Outlier analysis and visual inspection of the data from these two participants indicated that their data did not meaningfully differ from that of the 16 patients. Thus, results were interpreted for the full sample of 18 CMI patients and their matched controls.Participants completed the short-form McGill Pain Questionnaire as a self-report measure of chronic pain, consisting of 15 questions where subjects are asked to rate their pain on a Likert-type scale (0 = none to 5 = worst possible). The Chiari Symptom Profile (CSP) was also administered to participants. The CSP is comprised of 57 items on a 0–4 scale used to assess aspects of Chiari Malformation and treatment outcomes, where higher scores indicate greater disability.The RBANS has been used to assess cognitive status for a variety of acquired, progressive neurological and neuropsychiatric conditions.Imaging was performed on a 3 tesla Siemens Prisma with a standard 20 channel head-neck array  at the Cleveland Clinic. For the rs-fMRI protocol, participants were instructed to lie still with eyes closed during the blood oxygenation level-dependent (BOLD) scan .www.nitrc.org/projects/conn, RRID: SCR_009550) with statistical parametric mapping 12  in MATLAB (R2019b). For this study, functional connectivity differences were examined using the following seeds: (i) the frontoparietal pathway, given prior literature demonstrating a deficit in self-focused attention in CMI patients,,Seed-based correlational analyses were performed to evaluate group-differences in resting-state blood oxygenation level-dependent activation using the Functional Connectivity (CONN) toolbox  artefact detection tool (ART) outlier detection was used to identify outlier and tissue confounds, which were added to the model as first level covariates and were subsequently removed using linear-regression and bandpass-filtering (0.01–0.1). Through the CONN toolbox, severe imaging artefacts were identified in one CMI patient’s images, rendering their data unusable.First-level seed-to-voxel analysis was computed using general linear model, which computes the correlation from a seed ROI with all other brain voxels for each seed within each individual. Seeds were selected from the list of pre-defined ROIs within CONN, and included the frontoparietal pathway, PPC, PCP, Crus I, lobule III, lobule VIII, Vermis I and II, Vermis VII, and Vermis IX. Three factors drove the selection of these seeds. First, the anterior cingulate cortex has been associated with pain processing—and a central goal of this study was to determine whether CMI was associated with the functional connectivity involving this region. Second, given the apparent attention deficits in CMI,P < 0.05 and cluster-level extent threshold  correction to maintain an alpha of <0.05. Second-level analyses controlling for attention and pain scores were conducted to examine differences between-group statistical parametric maps. FDR was controlled for in the group comparisons using a voxel-level height threshold of The data that support the findings of this study are available from the corresponding author, upon reasonable request.MCMI = 32.5 years, Mcontrol = 37.3 years) and years of education . CSP outcomes indicated that CMI patients presented with typical symptomology. As reported previously,P < 0.003). Additionally, attention performance was correlated with chronic pain across all participants, r(33) = −0.42, P = 0.002, but not separately within each group  = −5.95, P < 0.001, and left parahippocampal gyrus, t(33) = −5.95, P < .001. Additionally, there was a pattern of hyperconnectivity for patients compared to controls between Crus I and the left superior frontal gyrus (SFG), t(33) = −5.33, P < .001. Hyperconnectivity in patients was also found between cerebellar lobule VIII with part of the left postcentral gyrus, t(33) = −6.2, P < 0.001, and Vermis IX and the precuneus, t(33) = −4.74, P < 0.001  = 4.94, P < .001. Within the cerebellum, there was hypoconnectivity between the left lobule III and the left inferior frontal gyrus, t(33) = 5.29, P < 0.001, and the right Crus II, t(33) = 5.20, P < .001. Further hypoconnectivity was observed between Vermis I/II and the left SFG, t(33) = 5.08, P < 0.001 and between Vermis VII and the right lingual gyrus (LG), t(33) = 5.32, P < 0.001  = −5.86, P < 0.001, as well as between Vermis IX and the precuneus, t(32) = −4.21, P < .001. Additionally, the pattern of hypoconnectivity between the PCP and right supramarginal gyrus remained significant after controlling for attention performance, t(32) = 4.50, P < .001. All other patterns of hypoconnectivity were no longer significant after controlling for attention scores. Results for group differences in patterns of activation after controlling for RBANS attention scores are summarized in To determine whether differences in functional connectivity could be associated with CMI-related deficits in attention performance, RBANS attention scores were added to the general linear model model as a covariate. With attention scores added to the model, CMI patients no longer exhibited a pattern of hyperconnectivity between the PCC and both the left parahippocampal gyrus and left globus pallidus, and between the Crus I and left SFG. However, hyperconnectivity between left Lobule VIII and the left postcentral gyrus remained significant, t(32) = −5.43, P < .001. CMI patients also still displayed relative hyperconnectivity between Vermis IX and the precuneus, t(32) = −4.71, P < .001. Finally, patterns of hypoconnectivity remained significant after controlling for pain between the PCP and right supramarginal gyrus, t(32) = 4.66, P < 0.001, as well as Vermis VII and the right LG, t(32) = 5.32, P < .001. No other patterns of hypoconnectivity were apparent after controlling for pain , thereby likely leading to deficits in these functions. Implications of these findings are discussed below.,,,,Beginning with the finding of CMI relative hyperconnectivity in the PCC, it is important to note the role of the posterior cingulate as a central hub for the default mode network. Disruption of default mode dynamics have been identified in chronic pain patients.,There was also evidence of relative hypoconnectivity between the PCC and the left parahippocampal gyrus, left lobule III and the left inferior frontal gyrus and right Crus 2, Vermis I/II and the left SFG, and Vermis VII and the right LG in the CMI patients. Many of these differences were eliminated once covarying for pain and attention, suggesting a relationship between the hypoconnectivity of these pathways, cognitive dysfunction, and pain. However, other relationships, including those relationships involving Vermis VII and the PCP, remained. These results are consistent with Schmahmann’s hypothesis of tissue damage in the cerebellum in CMI resulting in functional connectivity deficits.,It was also found that CMI patients had relative hyperconnectivity between left lobule VIII and a large cluster comprised of the left postcentral gyrus. Similar to the anterior lobes of the cerebellum (i.e. lobules I–V), lobule VIII is associated with sensorimotor function.,Among the several novel findings in this study, the functional connectivity differences involving the cerebellar vermis are particularly interesting. The vermis, while traditionally associated with regulation of posture and movement, has also been shown to be associated with feelings of pain and anxiety, and disruptions to the cerebro-cerebellar connections from the vermis have been shown to be associated with emotional dysfunction.,,Connectivity between Vermis I/II and the left SFG was also reduced in patients compared to controls, but this pattern was eliminated after controlling for both attention and pain separately. The role of the Vermis I/II is not entirely understood, although there is some agreement that the anterior region of the cerebellum (lobules I–V) tend to play a larger role in motoric function than cognitive function, meanwhile the posterior region (lobules VI–X) are more involved in cognitive processes.a priori, limiting findings to the selected seeds of interest.a priori constraints. However, the independent component analysis approach is unable to provide insight into network-to-network communication and relies on a pre-specified number of components such that a network could be broken into subnetworks and not accurately reflected as a singular component.,Although this study largely establishes the literature on resting-state functional connectivity differences in CMI, it is not without limitation. First, given the relatively small sample size, the design of this study is limited in its ability to infer directional correlations between self-reported pain values and patterns of rs-fMRI activation. Second, although we emphasized a matched case–control design, our CMI sample had relatively high levels of education, which may not reflect that of the entire CMI population. Finally, the use of seed-based analyses requires that these seeds be selected The goal of this study was to determine whether there were functional connectivity differences between CMI patients and healthy controls as have been shown for structural connectivity.https://www.conquerchiari.org) for contributing funding to this study. The authors thank the Conquer Chiari Foundation (The authors report no competing interests.


Background: Fibromyalgia, a complex disorder that affects 1% to 5% of the population, presents as widespread chronic musculoskeletal pain without physical or laboratory signs of any specific pathologic process. The mechanism, while still being explored, suggests central sensitization and disordered pain regulation at the spinal cord and supraspinal levels, with a resulting imbalance between excitation and inhibition that may alter central nervous system nociceptive processing. Nociceptive hypersensitivity results from activity of the N-methyl-D-aspartate receptor (NMDAR)–mediated glutamatergic synaptic transmission in the spinal cord and brain. Because ketamine, an NMDAR antagonist, may reduce induction of synaptic plasticity and maintenance of chronic pain states, the study of its use in intravenous form to treat fibromyalgia has increased.Methods: We conducted a literature search with the objectives of examining the effect of intravenous ketamine administration on pain relief, identifying side effects, and highlighting the need for clinical studies to evaluate ketamine infusion treatment protocols for patients with fibromyalgia. We used the keywords “fibromyalgia,” “chronic pain,” “ketamine,” “intravenous,” and “infusion” and found 7 publications that included 118 patients with fibromyalgia who met inclusion criteria.Results: Clinical studies revealed a short-term reduction—only for a few hours after the infusions—in self-reported pain intensity with single, low-dose, intravenous ketamine infusions, likely attributable to nociception-dependent central sensitization in fibromyalgia via NMDAR blockade. Case studies suggest that increases in the total dose of ketamine and longer, more frequent infusions may be associated with more effective pain relief and longer-lasting analgesia. Another neurotransmitter release may be contributing to this outcome.Conclusion: This systematic review suggests a dose response, indicating potential efficacy of intravenous ketamine in the treatment of fibromyalgia. Most patients also experience fatigue, memory problems, sleep disturbance, depression, and anxiety.2 Similar to other chronic pain disorders, prevalence rates of fibromyalgia are higher in females than in males.3 The underlying mechanisms for the continued pain in fibromyalgia are still being explored. A substantial amount of research evidence supports that a low threshold to pain is caused by central sensitization and disordered pain regulation at the spinal cord and supraspinal levels.5 Increased reactivity of pain-processing cells in the spinal cord or brain evokes hyperexcitability of pain pathways combined with decreased activity of inhibitory pathways.6 Thus, the imbalance between the amount of excitation and inhibition results in alterations of central nervous system (CNS) nociceptive processing.Fibromyalgia is a complex disorder that affects 1% to 5% of the population and can occur at any age.7 As such, low-level non-noxious stimuli are perceived as pain because of the increased sensitivity of deep spinal cord neurons that transmit sensory information and amplified trafficking of pain signals. At the supraspinal level, chronic pain is associated with the changes of sensory regions in the brain responsible for nociceptive processing. Specific brain structures that display greater activation include the secondary somatosensory cortex, insula, and anterior cingulate cortex.9 Functional neuroimaging studies in patients with fibromyalgia compared to normal individuals showed higher brain activation in the thalamus, primary and secondary somatosensory cortices, insula, and cingulate cortex with pressure, heat, or nociceptive stimuli.13 Patients with fibromyalgia also showed impairment of the descending inhibitory pain pathways that resulted in decreased activation in the anterior cingulate cortex and thalamus, as well as a significant imbalance in connectivity within the pain network during rest.14An important mechanism at the spinal cord level is the interaction between the peripheral mechanoreceptors and the deep spinal cord neurons. The evidence shows that in chronic pain conditions, peripheral sensory neurons and axons show synaptic remodeling in the spinal dorsal horn, resulting in nociceptive hypersensitivity that is dependent on the activity of the N-methyl-D-aspartate receptor (NMDAR).16 Further, clinical treatment that simultaneously increases serotonin and norepinephrine levels has been successful in restoring descending inhibitory activity in fibromyalgia.2 Altered dopaminergic and GABAergic neurotransmission may also contribute to the augmented central processing of pain in patients with fibromyalgia.17 Brain imaging in patients with fibromyalgia has shown elevated glutamate levels in pain-related brain regions such as the posterior cingulate gyrus, posterior insula, ventrolateral prefrontal cortex, and amygdala.18 Patients with fibromyalgia also show increased glutamate and glycine in cerebrospinal fluid.19 When patients are treated with pregabalin, elevated glutamate levels in the insula and functional connectivity between the default mode network and insula decrease with both clinical and experimental pain.18The greater activation of some regions and the inhibition of others likely result in changes in the neurotransmitter levels in the brain. A decrease in serotonergic and noradrenergic activities of the inhibitory monoaminergic pain control pathways has been proposed as one of the mechanisms in underlying chronic pain.20 Gene research suggests that fibromyalgia is potentially associated with polymorphisms in the serotoninergic, dopaminergic, and catecholaminergic systems, predisposing an individual to an insufficient analgesic response.21 Two potential susceptibility candidate genes are the serotonin transporter gene (SLC64A4) and the transient receptor potential vanilloid channel 2 gene (TRPV2) on chromosome 17p11.2–q11.2.20 Polymorphism of SLC64A4 and TRPV2 has been linked to endogenous pain modulation in patients with fibromyalgia.22 Two additional genes are the myelin transcription factor 1 like gene (MYT1L), responsible for neuronal differentiation and cognitive ability, and the neurexin 3 gene (NRXN3), a receptor in the nervous system and a cell adhesion molecule.23 However, no single nucleotide polymorphism has achieved the genome-wide significant threshold.The pathogenesis of fibromyalgia appears to have a strong genetic component. A genome-wide linkage study confirmed a potential inheritance mechanism by showing a 13.6-fold increased risk of developing the syndrome in first-degree relatives.7 Consequently, NMDAR antagonists such as ketamine may be used to reduce the excessive nociceptive input and central pain sensitization. In clinical practice, ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexanone] is primarily used for anesthesia and perioperative analgesia. Ketamine acts as a noncompetitive inhibitor that binds an intrachannel NMDAR site, resulting in decreased channel opening time.24 In clinical use, the S (+) stereoisomer of ketamine is the most potent form of NMDAR antagonist.24 Because ketamine blockade of NMDARs has the potential to reduce the induction of synaptic plasticity in central and peripheral neurons and prevent functional changes responsible for the maintenance of chronic pain states, ketamine's use for chronic pain management has increased since 1995.25 Ketamine also interacts with other receptors and channels in the CNS, including monoaminergic receptors, opioid receptors, nicotinic and muscarinic acetylcholine receptors, and voltage-sensitive sodium signaling.26 Ketamine binds with high affinity to dopamine D2 receptors. Suppression of the normal activity of dopamine-releasing neurons within the limbic system is hypothesized to contribute to pain in fibromyalgia.27 Because dopamine plays a dominant role in natural analgesia, potentiation of dopamine signaling may contribute to ketamine's analgesia. The potential of ketamine to enhance endogenous antinociceptive systems results in potentiation of the descending serotoninergic inhibition pathways.28 Further, ketamine may also reduce substance P receptor–mediated pain and restore altered brain-derived neurotrophic factor (BDNF) expression.25 Ketamine also has an anti-inflammatory effect, modulating the production of different proinflammatory mediators that are implicated in the pathogenesis of fibromyalgia.29 Therefore, in addition to ketamine's effect on NMDAR, functional changes in neuroplasticity in chronic pain may relate to multiple neuronal pathways that are implicated in fibromyalgia pain physiology.The NMDAR mediates the excitatory glutamatergic synaptic transmission in the spinal cord and brain that is strongly implicated in the amplification of pain signals and central sensitization in fibromyalgia.30 Besides having analgesic properties, ketamine is an effective treatment for severe major depressive disorder, a condition that has a high prevalence in patients with fibromyalgia.32 Based on ketamine's robust antidepressant effect, the US Food and Drug Administration approved a nasal spray formulation in March 2019 for the management of treatment-resistant depression.33Because the same neurotransmitters that control pain also regulate sleep, cognition, energy, and emotional networks in the brain, these functions/neural networks may improve in patients with fibromyalgia.The evidence of ketamine's effectiveness in fibromyalgia is evolving. The objectives of this review were to examine the effect of intravenous (IV) ketamine administration on pain relief, to identify side effects, and to highlight the need for clinical studies to evaluate ketamine infusion treatment protocols for patients with fibromyalgia.We conducted a literature search on ketamine for the treatment of fibromyalgia in PubMed using the following search keywords: “fibromyalgia,” “chronic pain,” “ketamine,” “intravenous,” and “infusion.” We limited the search to human subjects, English language, and articles with full text available. We searched the bibliographic sections of all manuscripts for additional relevant citations. Both prospective and retrospective studies were included, as well as smaller studies and case reports.40 A total of 118 patients with fibromyalgia, 106 of whom were treated with ketamine, were included in this systematic review, and data were subjected to qualitative analysis. As summarized in the Although ketamine is used in the management of a number of chronic pain disorders, few studies have evaluated the use of IV ketamine in patients with fibromyalgia. We identified 106 potential articles. Once the duplicate records were removed, we screened the remaining 92 publications and excluded an additional 71 records because the publications primarily focused on other chronic pain syndromes treated with ketamine. Of the 21 full-text articles we assessed, we excluded 10 articles because they did not include patients with a confirmed diagnosis of fibromyalgia and 4 articles because they involved modes of ketamine administration other than IV. The 7 reviewed publications included 4 randomized controlled trials with IV ketamine involving 82 patients , 1 prospective trial (34 patients) that did not include a placebo control, and 2 case studies (1 patient each) with IV administration .34-40 A 34 A significant reduction (>50%) was seen in pain intensity scores measured by the visual analog scale (VAS) at the end of the infusion (P<0.05) and after 20 to 80 minutes in ketamine-treated patients vs placebo . In the majority of ketamine-exposed patients, pain alleviation lasted 2 to 7 days. Patients treated with ketamine also reported a significant decrease in tenderness (P<0.02), increased muscle endurance (P<0.02), decreased pain threshold (P<0.02), and pain tolerance at tender points and control points .34In a double-blind, placebo-controlled study by Sörensen et al, 11 female patients with fibromyalgia received a single dose of ketamine infusion (0.3 mg/kg) or placebo  in a crossover design.35 Patients who responded to ketamine showed sustained improvements in pain threshold and pain tolerance for up to 120 minutes relative to placebo and had significantly improved Fibromyalgia Impact Questionnaire (FIQ) scores.Sörensen et al further tested pain response in 18 patients with fibromyalgia in a randomized, double-blind, crossover study with IV administration of ketamine (0.3 mg/kg), lidocaine, morphine, and saline.36 In the first part of the study, patients who showed >50% pain decrease on 2 consecutive VAS assessments were identified as ketamine responders. Of the 17 responders, 15 were exposed to the effect of either placebo or 0.3 mg/kg ketamine in the second part of the study that assessed a central mechanism of muscular nociceptive activity such as muscle pain and temporal summation. When local pain and referred pain were induced by intramuscular infusion of hypertonic saline, patients experienced a progressive reduction of VAS scores with 30-minute ketamine infusions (P<0.05), showing attenuation of muscular hyperalgesia and muscle pain at rest. The pain intensity area also showed significant reduction relative to placebo (P<0.02). Ketamine infusion also resulted in a decrease of temporal summation after cutaneous and muscular electrical stimulation in comparison to placebo.36Another randomized, double-blind, crossover study by Graven-Nielsen et al in 29 patients with fibromyalgia investigated IV ketamine at the 0.3 mg/kg dose.37 The initial VAS and FIQ scores were assessed 2.5 hours after infusion and weekly for 8 weeks. Similar to the findings of other studies, Noppers et al found that ketamine caused a significant initial pain reduction (P<0.01 vs baseline). Although ketamine infusion resulted in a significantly higher number of responders in comparison to midazolam (P<0.05), no significant difference in treatment effect on fibromyalgia pain and experimental heat pain was found 2.5 hours after the infusion or during the 8-week follow-up between the ketamine- and midazolam-treated patients.37Noppers et al examined the robustness of response to a single infusion of S-ketamine at 0.5 mg/kg to an infusion of 5 mg midazolam (active placebo group) in 24 patients with fibromyalgia in a double-blind, placebo-controlled study.37These 4 double-blind, prospective, randomized controlled trials, which tested low doses of ketamine between 0.3 and 0.5 mg/kg administered for 10 to 30 minutes, showed significant reductions of pain during and at the end of the ketamine infusion. Although sustained pain decreases with ketamine relative to placebo were observed by Sörensen and colleagues for up to 2 hours, the study by Noppers and colleagues did not show a prolonged effect of ketamine action.38The study by Cohen et al in 34 patients with fibromyalgia with low-dose ketamine infusion (0.1 mg/kg) followed by oral dextromethorphan treatment showed a VAS reduction of >50% in 18 patients and a significant correlation between pain relief with ketamine and dextromethorphan, but no long-term benefit from the 1-time ketamine infusion was observed.37 was similar to the less-potent racemic ketamine in terms of the duration of the clinically useful benefit. Results from this review of low-dose ketamine infusion studies suggest that the duration of infusion is the primary factor associated with clinically meaningful, short-term analgesia and can be linked to the pharmacokinetics of ketamine.In these earlier studies, the S-ketamine formulation used by Noppers et al39 The patient was simultaneously treated with diazepam and midazolam to relieve anxiety and promote sedation, as well as ondansetron to control nausea, a common side effect associated with ketamine administration. In another case study by Hanna et al, a patient with fibromyalgia and rheumatoid arthritis received 10 consecutive ketamine infusions with escalating ketamine doses from 428 mg to 1,063 mg.40 The patient's pain score gradually decreased during treatment and remained at 80% improvement from the preketamine levels, with booster ketamine infusions administered approximately every 3 months. Taken together, these 2 cases suggest that higher doses and longer, repeated ketamine infusions have the potential to achieve sustained analgesia in patients with fibromyalgia.In contrast to these initial studies, recent case studies (2016 and 2018) with IV ketamine for pain treatment of patients with fibromyalgia used higher doses of ketamine and greater frequency and duration of administration. Hanna and Smith administered IV ketamine to a patient with fibromyalgia over 4 hours at doses escalating from 200 mg to 800 mg for 5 days, with a booster of 800 mg 2 weeks later; the result was long-lasting remission from chronic pain and improved quality of life.Unpleasant mild to moderate psychomimetic side effects were reported with low total doses of ketamine in the above studies. Other common ketamine-related adverse outcomes included nausea, dizziness, confusion, and drowsiness. These side effects were short lasting and resolved within approximately 30 minutes after infusions. On the other hand, the higher doses of ketamine used in the 2 case studies were well tolerated, and no unexpected adverse effects were observed, including hepatotoxicity.15 As summarized in the In patients with fibromyalgia, central sensitization is demonstrated as pain hypersensitivity, specifically diffuse allodynia and pressure hyperalgesia.Although studies comparing the effectiveness of higher doses of ketamine administered more frequently for longer periods are lacking, the 2 case studies provide a potential direction for future clinical research. The infusion protocols from the case studies suggest that increases in the total dose of ketamine administered, longer duration of infusions, and more frequent infusions are required to produce a higher degree of pain relief and possibly longer-lasting analgesia. Because the scientific evidence supports a major role for central sensitization in the generation of the symptoms of fibromyalgia, prolonged ketamine infusions and higher total doses are more likely to induce NMDAR blockade and activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), resulting in the release of other neurotransmitters, leading to synaptogenesis and changes in neuroplasticity. Based on preliminary clinical data, patients with fibromyalgia may be able to achieve a longer-term analgesic effect with prolonged and repetitive IV ketamine infusion regimens.41 However, serious side effects that require close monitoring may occur, particularly with higher doses and prolonged ketamine infusions. Ketamine action on a number of receptors, such as NMDAR, acetylcholine, histamine, opioid, and monoamine, may be associated with psychomimetic, gastrointestinal, and cardiovascular adverse consequences; therefore, the need for controlled, multiple-dose studies is necessary.41The literature about ketamine infusion for other pain conditions shows that patients experience transient psychomimetic side effects such as dysphoria and sedation, regardless of infusion duration or total dose infused.42 The mechanism of action of ketamine as an antidepressant includes direct synaptic or extrasynaptic NMDAR inhibition, AMPAR activation, glutamate surge with enhanced glutamatergic firing, and synaptogenesis, resulting in the reversal of the negative effects of depression.44 Major depressive disorder is characterized by synaptic downregulation in the prefrontal cortex and hippocampus. Functional magnetic resonance imaging in treatment-resistant depression supports normalization of prefrontal dysconnectivity with ketamine.44 Ketamine's antidepressant actions on synaptic plasticity also include enhanced release and translation of BDNF.45 Published evidence also points to similarities in neuroendocrine changes, psychological symptoms, and physical symptoms between fibromyalgia and major depression, although the underlying construct between the 2 conditions is not known.46 In addition to the role of NMDAR in the pathophysiology of chronic pain and depression, NMDAR is important for learning and memory that are often affected in patients with both conditions. These mechanisms—direct synaptic or extrasynaptic NMDAR inhibition, AMPAR activation, glutamate surge with enhanced glutamatergic firing, synaptogenesis, and neuroplasticity—of ketamine action may also account for enhanced neurocognitive function that is associated with the improvement in depressive symptoms with ketamine.Clinical evidence shows that the pharmacodynamic actions of ketamine that induce rapid and sustained antidepressant actions overlap with those seen with ketamine administration for fibromyalgia.The ability of ketamine to modulate NMDAR, glutaminergic signaling, BDNF, descending inhibition, and inflammation and thereby result in a reduction of central sensitization may provide a comprehensive approach for the management of patients with fibromyalgia. Overall, ketamine has the potential to provide an alternative avenue for managing diverse CNS alterations that contribute to the symptoms of fibromyalgia.The growing body of literature suggests that ketamine infusions impact a number of aspects of pain pathology in fibromyalgia. Large prospective, placebo-controlled clinical trials with different infusion protocols and long-term follow-up periods are needed to determine the effectiveness, dose response, and safety of ketamine infusion as a therapeutic modality for fibromyalgia.


Inhaled methoxyflurane, newly licensed in Europe for acute trauma pain in adults, has limited evidence of effectiveness in the pre-hospital setting. We aimed to investigate the clinical effectiveness and costs of methoxyflurane delivered when administered by ambulance staff compared with usual analgesic practice (UAP) for adults with trauma.® or parenteral analgesics. Verbal numerical pain scores (VNPS) were gathered over time in adults with moderate to severe trauma pain attended by ambulance staff trained in administering and supplied with methoxyflurane. Comparator VNPS were obtained from database records of UAP in similar patients. Clinical efficacy was tested using an Ordered Probit panel regression model of pain intensity linked by observational rules to VNPS. Scenario analyses were used to compare durations under analgesia spent in severe pain, and costs.A non-randomised control group design was used to compare methoxyflurane versus Entonox® 44.4 (39.5–49.3); 25.8 (24.5–27.1) versus IV paracetamol 40.7 (34.6–46.9); 25.7 (24.4–27.0) versus IV morphine sulfate 41.9 (38.9–44.8). Scenario analyses of time spent in severe pain (VNPS on administration just scoring 10 reducing to a score of 7) were significantly less for methoxyflurane : 7.6 mins (95%CI 6.5–8.7) versus Entonox® 24.6 (20.1–29.0); 6.7 (5.6–7.7) versus IV paracetamol 23.0 (17.9–28.0); 6.9 (5.9–7.9) versus IV morphine sulfate 14.9 (13.3–16.6). Costing scenarios compared single-dose use of methoxyflurane versus Entonox® and versus parenteral analgesics (80–20% weighted episode mix of morphine sulfate and paracetamol). In both scenarios, the benefits of methoxyflurane were achieved at higher cost: the additional cost per treated patient was £8.77 versus Entonox® and £9.69 versus parenteral analgesics. The BNF list price for one vial containing a 3 mL dose of methoxyflurane for vaporisation in a Penthrox® inhaler is £17.89 per pack.Over the 12-month evaluation period, 96 trained paramedics and technicians prepared 510 doses of methoxyflurane for administration to a grand total of 483 patients. Thirty-two patients reported side effects, 19 of whom discontinued early. Thirteen patients, 10 aged over 75 years, were nonadherent to instructions given on inhaler use. Modelling results included demonstration of statistically significant clinical effectiveness of methoxyflurane over each comparator . Methoxyflurane’s time to achieve maximum pain relief was significantly faster : 25.7 mins (95%CI 24.4–27.0) versus Entonox® or parenteral drugs. Methoxyflurane provides a useful addition to pre-hospital analgesia.Methoxyflurane administered by ambulance clinicians reduced moderate or severe pain due to trauma in adults more rapidly compared to Entonox


Conclusions: Intraperitoneal adhesions are most common in women after pelvic surgery and with chronic ailments. The best results for sensitivity, specificity, positive predictive value, and negative predictive value in the diagnosis of endometriosis are found in women with irregular menstruations during which the pain increases. Laparoscopy still remains the primary diagnostic and therapeutic method for these women.Background: Chronic pelvic pain affects approximately 15% of reproductive age women. It is mainly caused by adhesions (20–40%). Despite CPP being the main symptom of endometriosis, the disease is confirmed by laparoscopy only in 12–18% of cases. The aim of this study was to evaluate the results of laparoscopy in women with CCP and to assess the sensitivity and specificity of elements of an interview and clinical examination. Materials and methods: The study included 148 women with CPP. Each patient underwent laparoscopy. In laparoscopy, the presence of endometriosis and/or peritoneal adhesions was confirmed. Then, the sensitivity and specificity and the positive and negative predictive value of endometriosis symptoms or abnormalities in the gynecological examination were statistically calculated. Results: After previous surgery, adhesions were found in almost half (47%) of patients. In patients without a history of surgery, adhesions were diagnosed in 6.34% of patients. Endometriosis without coexisting adhesions was more often diagnosed in women without previous surgery (34.9%), compared to 10.58% in the group with a history of surgery ( Chronic pelvic pain (CPP) affects approximately 15% 5.7–26.6%) of women of reproductive age 6.6% of w,4. EndomAssessment of the results of a laparoscopic examination of ailments in women with chronic pelvic pain in whom endometriosis was suspected based on a medical interview and clinical examination.Assessment of the sensitivity, specificity, positive predictive value, and negative predictive value of individual elements of the interview and clinical examination in the diagnosis of endometriosis, where laparoscopy was the method of verifying the diagnosis.Assessment of the causes of pain in patients with CPP, including earlier surgical procedures.Aim of the study:The study included 148 women hospitalized at the Department of Gynaecology, Endocrinology, and Gynaecological Oncology, Pomeranian Medical University in Szczecin, with pelvic pain, and who, based on the interview and clinical examination, had at least one of the symptoms suggesting endometriosis; such as pain increasing during menstruation, pain during intercourse, bleeding and/or pain during defecation, or micturition intensifying during menstruation, infertility, retroverted uterus and its soreness while moving, thickening of the sacrouterine ligaments, nodular lesions, and/or soreness in the pouch of Douglas. Inclusion criteria for the study were: age <55 years and chronic pelvic pain (over 6 months), as well as infertility with coexisting chronic pelvic pain. Patients who qualified for the study group reported pain lasting more than 6 months, significantly reducing their quality of life and requiring the use of periodic and permanent pain medications. On the VAS scale, the pain intensity was ≥3. Exclusion criteria were the lowering of pelvic organs above POPQ II degree, diagnosed chronic cystitis, diseases of the gastrointestinal tract , and diseases of the sacrolumbar spine. The study also excluded patients whose imaging tests revealed focal nodular cystic or solid lesions and those who had undergone uterine or endometrial surgery, enucleation of uterine fibroids, or urogynaecological operations related to the repair of statics of the pelvic organs. The age of the patients ranged between 19 and 53 years. The mean age was 33.39 years (SD 9.06). A detailed interview was collected for all patients. The interview included, apart from the above-mentioned criteria for inclusion in the study, colic pain, periovulatory pain, dysuric ailments, and irregular menstrual cycles. Data on past surgical procedures were also collected. The gynecological examination included symptoms constituting the inclusion criteria for the study. Diagnostic laparoscopy was performed in each patient with CPP. During laparoscopy, the reproductive organ was assessed: the uterus, appendages , the presence of endometriosis foci on the cruciate ligaments, peritoneum, and the vesical uterine crease. If adhesions or endometriosis foci were found during laparoscopy, surgical laparoscopy was performed, during which the adhesions were released and the foci of endometriosis were removed. The size was also assessed, together with the severity of the adhesions and the amount of peritoneal fluid. The results of the study were compiled statistically by calculating the sensitivity and specificity, as well as the positive and negative predictive value of each history of endometriosis symptoms and the abovementioned deviations in the gynaecological examination. The sensitivity and specificity of the two and three most frequently coexisting symptoms in the medical history and gynecological deviations were also calculated. The aim of this was to check whether endometriosis can be more accurately diagnosed by taking into account two or three parameters at the same time. To evaluate whether adhesions are the cause of CPP, they compared symptoms in patients who had had procedures such as: caesarean section, appendix removal, or surgery on the appendages in the past and those who had no history of surgery. The second were patients who had not undergone surgery in the past. This division was aimed at assessing the presence of adhesions as the cause of CPP.p ≤ 0.05.Statistical analysis was performed with the use of the licensed Statistica 13 program. The data were presented using descriptive statistics, mainly means, standard deviations, and median, as well as numbers and percentages. The chi-square test was used to evaluate the qualitative data in individual groups, and if the group was of a low size, the chi-square test with Yates’ correction was used. The normality of distribution was tested using the Shapiro–Wilk test. Quantitative data was analyzed using non-parametric Mann–Whitney U tests. The statistical significance level was Our study was a retrospective study based on data from the patient’s medical history, physical examination, and data from the results of diagnostic laparoscopy; if necessary, operative. All patients agreed to undergo laboratory and imaging diagnostics during hospitalization and undergo surgery. All of them gave their written consent to use all the results obtained during the hospitalization for research purposes.In the entire study group of 148 examined by laparoscopy, endometriosis was found in 54 (36.48%) patients, including 23 (15.54%) with adhesions associated with endometriosis. Isolated adhesions were found in 44 (29.7%) patients. In two (1.35%) patients dilated veins were found. In 48 (32.4%) patients, no possible causes of pelvic pain were found.The 148 patients examined were divided into those who had not undergone pelvic surgery (63) and those who had undergone surgical procedures such as appendectomy, caesarean section, and surgeries on the uterine appendages (85). The results are shown in In the group of patients with a positive history of surgery, only adhesions were found in almost half (47%) of the patients. In the group without a history of surgery, isolated adhesions without endometriosis were diagnosed in only 6.34% of patients. These differences were highly significant.p < 0.05.Endometriosis without coexisting adhesions was diagnosed more often in the group without previous surgery (34.9%), compared to 10.58% in the group with the positive history of surgery; these differences were significant at Significantly more often, the causes of pain were not found in women who had not undergone surgery.p = 0.63330Endometriosis in patients with a history of surgery was diagnosed (with and without adhesions) in 31.75% of patients, while in those who had not undergone surgery it was 42.8%. However, the differences were not significant, at The sensitivity, specificity, positive predictive value, and negative predictive value for individual symptoms of endometriosis occurring in the studied group of 148 patients are presented in None of the patients reported dysuric conditions, pain during defecation, or bleeding during micturition or from the lower gastrointestinal tract. The highest sensitivity was shown for pain increasing during menstruation, at 88.9%; the positive predictive value of this parameter was 41.38% and the negative predictive value was 81.25%. However, this parameter was characterized by low specificity, reaching 27.66%.Other reported ailments were periovulatory, colic, and intercourse pain, and changes in a gynecological examination . These symptoms were characterized by low sensitivity and specificity and low positive predictive values. The number of women with these symptoms in our study was small.The sensitivity, specificity, positive predictive value, and negative predictive value of the two most frequently coexisting symptoms in diagnosed endometriosis are presented in The highest specificity, reaching 98%, was found for these two simultaneously occurring symptoms: pain increasing during menstruation and infertility. At the same time, these symptoms occurring together were characterized by low sensitivity. The remaining pairs of symptoms showed moderate sensitivity and specificity. These concerned 13 patients. The most reliable, due to the number of cases (87), seem to be the results of sensitivity and specificity, as well as the positive predictive value and negative predictive value, for painful and irregular menstruations occurring simultaneously.In the study group, pain increasing during menstruation and retroversion of the uterus occurred in 12 (8.1%) patients, pain increasing during menstruation along with nodular lesions in one patient, pain increasing during menstruation and thickened sacrouterine ligaments in four (2.7%) patients, and pain increasing during menstruation and infertility in 13 (8.78%) patients.The sensitivity, specificity, positive predictive value, and negative predictive value of three symptoms occurring together were not calculated as there were only a few individual patients in whom three symptoms occurred simultaneously ,16.Endometriosis is a disease that often manifests itself with non-specific symptoms. Ectopic foci of the endometrium are found in approximately 10% of women of reproductive age. The predominant symptom in endometriosis is pain located in the lower abdomen. However, not all lower abdominal pain is caused by endometriosis. According to Ricci et al., endometriosis is diagnosed more often in patients who report severe and prolonged pelvic pain . Pelvic Distinguishing pain in endometriosis from its other causes is also difficult because it is similar in nature to other diseases. Not all endometriosis patients report pelvic pain. According to some authors, only 70% of patients with endometriosis diagnosed in laparoscopy reported chronic pelvic pain in their medical history . Other aIn 48 (32.4%) patients, no cause of CPP was identified. Perhaps it was retroperitoneal, deep infiltrating endometriosis, which is difficult to recognize with laparoscopy. These patients were further diagnosed in search of the causes of pain. They had, among others, a colonoscopy and magnetic resonance imaging CT scheduled. In these patients, possible causes of CPP could be, among others, intestinal diverticulosis and irritable bowel syndrome. These patients should also be diagnosed for pelvic congestion syndrome [It should be noted that intraperitoneal adhesions may also cause pain in the lower abdomen. In our study group, in approximately 29.73% of patients, intraperitoneal adhesions without endometriosis foci were diagnosed, and the highest number was in women who had a history of surgery within the pelvis . Perhaps in this group of patients a preoperative suspicion of adhesion syndrome as the cause of CPP would be more accurate than the suspicion of endometriosis. The reason for the incorrect initial diagnosis could be that the presence of intraperitoneal adhesions may imitate the presence of endometriosis, due to similar symptoms. However, in the group of 54 patients with endometriosis, adhesions were found in 42.6%, and mainly in patients (33.3%) who reported a history of surgery. Therefore, it seems that in patients with chronic lower abdominal pain who report having undergone surgery in the past, intraperitoneal adhesions should be suspected in the first place. They are the probable cause of pain in this group of patients. In these women, diagnostic laparoscopy with conversion to operative laparoscopy offers a real chance of removing the cause of chronic pain. In this case, suspecting endometriosis and therefore applying pharmacotherapy without prior peritoneal examination may be only a symptomatic treatment, and in the case of isolated adhesions without coexisting endometriosis, even a mistake. The presence of adhesions without a positive history of surgery may be caused by, for example, transfusion of pelvic inflammations. The most common cause of post-inflammatory adhesions is chlamydiosis, which is often asymptomatic. The causes of isolated adhesions should be further assessed.The guidelines recognize the limited value of symptoms and physical examination. They are to be used to consider the diagnosis of endometriosis. In order to confirm this diagnosis, further assessment is recommended. Empirical therapies can be used to confirm endometriosis . LaparosIn our studies, for two symptoms, pain intensifying during menstruation and menstrual disorders, the highest sensitivity and specificity, as well as the highest negative predictive value, occurred simultaneously. In the case of pain that intensifies during menstruation and infertility, the specificity was very high with, unfortunately, low sensitivity. Mowers EL. et al. reported that endometriosis is diagnosed in approximately 30% of infertility patients having undergone surgery. If these patients also reported painful periods in their medical history, this percentage increased to 50% . Out of The result of the clinical trial is also important. According to the recommendations of scientific societies, endometriosis should be suspected in patients who report continuous or periodic pain in the minor pelvis, painful menstruations, and pain during intercourse, and where a gynecological examination shows limited uterine mobility, retroversion of the uterus, thickening or soreness of the sacrouterine ligaments, or adnexal tumors ,24. HoweAbott J et al. believe that, since the symptoms are diverse, varying in intensity, and not characteristic only of endometriosis, diagnosis based on medical history and physical examination is often very difficult, or even impossible. Some patients with endometriosis may not complain of CPP. How difficult it is to diagnose endometriosis based only on a medical interview is emphasized by the fact that the diagnosis is made after many years, even though the first symptoms appear in adolescence or early youth. According to literature data, there is a long delay in diagnosis from the onset of symptoms ,26,27,28Ricci et al. attempted to diagnose endometriosis on the basis of a questionnaire in which the answers would identify patients at high risk of endometriosis. This would bring forward diagnostics and allow making a diagnosis based on symptoms. Diagnosing endometriosis based on a questionnaire that can be complemented in adolescence, allows, according to the authors of the study, accelerating diagnostics and treatment, and thus increasing the reproductive potential of the patient .On the basis of the conducted research, it can be concluded that a diagnosis of endometriosis relying simply on a medical interview and physical and imaging examination is only probable. Further work is required to establish the diagnostic minimum for the diagnosis of endometriosis before beginning treatment, especially hormonal treatment, and in a much larger number of patients. At present, to make a reliable and complete diagnosis of intraperitoneal endometriosis, it still seems necessary to perform laparoscopy combined with vaporization of endometriosis foci and cutting adhesions in medical centers specializing in endoscopy. Similar suggestions are contained in the NICE report from 2017 .Due to the limited number of patients, our study requires further research based on a larger number of patients.In women with chronic pelvic pain and the presence of one of the symptoms suggesting endometriosis, it is diagnosed only in 1/3 of cases.Intraperitoneal adhesions are most common in women post-pelvic surgery and with chronic ailments.The highest sensitivity and negative predictive values in the diagnosis of endometriosis in women with chronic pelvic pain were demonstrated for pain that intensifies during menstruation. At the same time, the specificity for this symptom was low. The best results for sensitivity, specificity, positive predictive value, and negative predictive value in the diagnosis of this disease were found in women with irregular menstruations during which the pain increases.Laparoscopy still remains the primary diagnostic and therapeutic method in women with chronic pelvic pain and with a medical interview and physical examination suggesting endometriosis.In some patients, it is not possible to find the cause of CPP using the data from the history, physical examination, and laparoscopy. They require in-depth diagnostics to explain the cause of pain.


Burning mouth syndrome is a chronic idiopathic intractable intraoral dysaesthesia that remains a challenge to clinicians due to its poorly understood pathogenesis and inconsistent response to various treatments.This review aimed to study the short- (≤3 months) and long-term (>3 months) effectiveness and sustainable benefit of different burning mouth syndrome treatment strategies and the associated side effects.Randomised controlled trials of burning mouth syndrome treatment compared with placebo or other interventions with a minimum follow up of 2 months were searched from the PubMed, Embase and Cochrane database (published to July 2020).Twenty-two studies were selected based on the inclusion and exclusion criteria and analysed. Nine categories of burning mouth syndrome treatment were identified: Anticonvulsant and antidepressant agents, phytomedicine and alpha lipoic acid supplements, low-level laser therapy, saliva substitute, transcranial magnetic stimulation, and cognitive behaviour therapy. Cognitive behaviour therapy, topical capsaicin and clonazepam, and laser therapy demonstrated favourable outcome in both short- and long-term assessment. Phytomedicines reported a short-term benefit in pain score reduction. The pooled effect of alpha lipoic acid (ALA) pain score improvement was low, but its positive effects increased in long term assessment.A more significant volume in terms of sample size, multi-centres, and multi-arm comparison of therapeutic agents with placebo and longitudinal follow-up studies is recommended to establish a standardised burning mouth syndrome treatment protocol. Further studies are required to assess the analgesic benefits of topical clonazepam and capsaicin, alternative medicines with neurodegenerative prevention capability and psychology support in treating burning mouth syndrome and reducing systemic adverse drug reactions.Registration International Prospective Register of Systematic Reviews (PROSPERO):Protocol ID - CRD42020160892. Burning mouth syndrome (BMS) is defined as idiopathic orofacial pain with intraoral burning or dysaesthesia recurring daily for more than 2 hours per day and more than 3 months, without any identifiable causative lesions, with and without somatosensory changes in International Classification of Orofacial Pain, 2020 1). BMS prevalence ranges from 0.1% to 3.9% and is primarily present in postmenopausal women aged between 50 and 70 . BMS commonly manifests as burning, prickling, tingling, itching or numbness affecting the tongue, lip, palate, gums and other oral mucosae . The pai. BMS pre9The study was carried out following the PRISMA guidelines . An elecThe search results were screened based on the relevant title and abstract by two independent authors. Where information from the abstract was inadequate to allow a decision, a full report was obtained. The full text was obtained for articles fulfilling the inclusion criteria. Any disagreements were resolved by discussion between the authors, and the review authors were not blinded to articles’ authorship. Studies meeting the inclusion criteria underwent data extraction and were evaluated for study risk of bias. The following data were obtained and recorded in a standardised proforma sheet on author and year of publication; study design or methodology; sample size and participant inclusion and/or exclusion criteria; types of intervention and follow-up time; the outcome and/or adverse effect from the intervention; statistical methods employed .We used the Cochrane risk of bias assessment tool , which iWe analysed outcome data based on short term (≥2 month to ≤3 months) and long term (>3 months) changes in symptoms. The assessment method used in the included studies should be of equal measure. The standardised mean difference (SMD) in pain score (VAS) of treatment groups and placebo and their relative risk ratio (RR) for BMS pain improvement was recorded from the relevant studies with the 95% confidence interval (CI) where possible. Estimates of effect (and associated CI) were combined and pooled for studies reporting the same treatment.Mean difference (MD) of the pre- to post-treatment VAS change scores were extracted from studies. For each study with comparisons between treatment and placebo at short term (≤3 months) and/or long term (>3 months), standardised mean differences (SMDs) of the VAS scores were calculated using pre-to-post-intervention change score (means) and post-intervention SDs . Means and/or standard deviations for baseline and post-treatment pain intensity were calculated for two studies based on the length of error bars in graphs and a ruler and two other studies using raw data (provided in papers). Continuous data were pooled using the Hedges g statistic as a formulation for the SMD under the fixed effects model. For categorical (dichotomous) outcomes , relative risks (RRs) and associated 95% CI were calculated to express the estimate of treatment effect . Where zA total of 95 full text published articles were reviewed; 22 were included in this review , and 73 All 22 included studies were randomised controlled clinical trials with one triple-blinded study  , 14 doub19333718232727243018Twenty studies were randomised controlled trials (RCT) with placebo parallel-group comparison –29,31–38311826352131The total pool of treated participants was 623, with a wide age range from 43 to 89 years. All BMS participants were appropriately defined as having chronic pain for more than 3 months, with normal oral mucosa and absence of contributing local or systemic factors, except De Rivera Campillo et al.  duratio average duratio  or visual numerical scale (VNS) of either 0–10 or 0–100 scores were the primary assessment tools in measuring post-therapy pain improvement 27,33–35,3833The substantial heterogeneity in the treatment methodology and regime, the follow-up time and inadequately reported statistical data precluded formal meta-analysis on the efficacy of a treatment in this review. However, combined SMD VAS scores or RR of studies with similar interventions were pooled with 95% CI. Two studies without comparison with placebo ,39 and aThe effectiveness of various treatments and pooled efficacy for similar treatments for BMS between short- and long-term outcomes are shown in The efficacy of clonazepam in reducing BMS pain symptoms was reported in two studies with oral ,39 and op = 0.83) and salivary flow (p = 0.03). Clonazepam did not improve patients’ ZMS mood and BDI depression scores.Treating BMS pain symptoms with daily oral systemic clonazepam 0.5 mg has shown favourable results of pain score reduction but was not statistically significant in the SMD analysis  . Despitep < 0.001)  . Eight o< 0.001) . The app< 0.001)  , with half of the total number of patients evidencing improvement in pain or total pain recovery . A more p < 0.001)  . Six of p < 0.01), but there was no significant difference with the placebo group  (p > 0.05). One patient in the trazodone group reported a worsening of symptoms. Both the trazodone and placebo groups significantly improved their BDI depression scores (p < 0.01). The most common side effects were dizziness and drowsiness, with seven patients dropping out due to dizziness. Other side effects included abdominal pains, headache, palpitation, tremor, xerostomia, and urinary incontinence.Administration of 100 mg trazodone daily for the first 4 days followed by 200 mg for 8 weeks significantly decreased patients’ VNS pain intensity against baseline  . If the p < 0.001) (p = 0.98). The Hamilton questionnaires analysis revealed a significant reduction of depression and anxiety scores, with an average recovery percentage of improvement of 30.57% (SD 15.81) and 15.44% (SD 11.86), respectively. There was no significant difference in comparison between both groups in depression  or anxiety .The use of citalopram 10 mg daily followed by an increment to 20 mg after 1 week showed an improvement of VAS score of 87.45%  . Howeverp < 0.01) with 76% of participants reporting an improvement in symptoms, but one patient-reporting a worsening  compared to lysozyme-lactoperoxidase, boric acid rinse and ALA  benefit with 1200 mg/day umPEA in BMS patients  but declining pain relief at 4 months  compared to placebo group . There wp ≤ 0.001). The mean reduction of the face score were 1.6 and 1.5 for 8 and 12 weeks, respectively, while there were no changes in participants’ happiness in the control group with a similar mean reduction faces scale scores of 0.6 at 8 and 12 weeks. The majority of patients tolerated the treatment well, with none of the patients in the test group reporting xerostomia. The side effects reported by patients that took Catuama included somnolence and weight gain (n = 1), insomnia (n = 1), and exacerbation of the pain symptoms intensity in the first week of treatment (n = 2). A drop-out of eight (21.1%) participants in the treatment group, and four (11.8%) in the placebo group were reported.Catuama shows promising VNS (0–10) score reduction results compared to placebo with a minimal adverse effect of sleep alteration observed in the study  . CatuamaAt the end of 12 weeks of therapy, there was a reduction in the number of oral mucosa burning sites and improved ability to cope with the burning pain, there was no statistically significant difference with the placebo group  . The HADp < 0.001) and has a similar improvement 87.5% of burning mouth score as citalopram  and burning  compared to baseline, but there was no significant difference (p = 0.99) when compared with the placebo group  compared to placebo (p = 0.72), reflecting the heterogeneity across studies . Long-term use of ALA did not result in any statistically significant improvement over placebo, suggested by the pooled VAS mean score changes  (p = 0.18)  ,33 and t = 0.18) ,23,33.p > 0.05). Three out of 25 patients reported side effects, including mild nausea (n = 2) and myalgia (n = 1)  showed no significant improvement at 4 months of assessment  . A 1-yea (n = 1) .p < 0.001) of decrease pain intensity while ALA only has four times the likelihood of beneficial effect .A combination of 600 mg ALA and 300 mg gabapentin in a randomised, double-blind clinical trial described a notable pain reduction, with 70% of patients demonstrating a partial or complete improvement in pain intensity compared to 15% in the placebo group . The comp = 0.047) and a further reduction in VAS score was noted 2 months after termination of treatment  (p = 0.60) and long-term assessment (0.79). ALA as a monotherapy led to a higher reduction in VAS score at 2 months  but no statistically significant difference compared to placebo (p = 0.60) compared to baseline, but there was no significant difference between the ALA (monotherapy), ALA and vitamin (combination) and placebo groups. No adverse effects were reported in the study  . Howeverhe study .p > 0.05). Two patients in the melatonin group demonstrated a positive correlation between decreased VAS scores and increased sleep hours. The Hamilton rating scale for anxiety (HAM) assessment scores was always higher in the melatonin group than placebo, with a statistically significant decrease in the melatonin group’s anxiety score (p < 0.05). An approximate two-fold of patients reported sleep impairment using melatonin  compared to placebo . Mild daytime sleepiness was seen in melatonin and placebo groups, with high ESS scores but not significant between them (p > 0.05). The main adverse effect of melatonin that leads to the discontinuation of treatment on four patients were heavy tremor, sexual disturbances, blurred vision, and severe heavy headedness. Four patients were dropped from the study due to lack of efficacy, pain improvement, and follow-up loss.A cross-over clinical trial involving intervention with a high melatonin dosage (12 mg/day) did not provide pain relief  and sleep score improvement compared to placebo (p = 0.13) and infrared laser (IR1W p = 0.004 and IR3W p < 0.001) (A significant reduction in pain score by three to five units was observed in the study using the red (< 0.001) . The red< 0.001) . No sidep = 0.04). No adverse effects were reported.A recent trial has suggested the advantage of photobiomodulation in treating orofacial neuropathic pain, including BMS with a significant 4.5-fold likelihood of pain reduction in comparison to placebo  and a more than 1-point decrease in VAS  , but no Lysozyme lactoperoxidase (Biotene) rinse was prescribed to BMS patients diagnosed with xerostomia  and repop = 0.01), but there was no significant difference between lysozyme lactoperoxidase with capsaicin rinse and oral ALA, respectively   (p = 0.88), although clinically 58.3% of patients demonstrated a reduction in pain intensity.Statistical analysis showed no statistically significant difference between the application of 10% urea for 3 months and the placebo group (50–1.80) . There ip = 0.002) with 75% of patients reporting a decrease in pain intensity of more than 50% compared to baseline (p = 0.005) . There was a significant improvement in sensory SFMPQ in the rTMS group  but no difference in the SFMPQ affective scores and present pain intensity. PGIC and CGO-I assessments described positive changes from the patient in the rTMS group. There were no significant changes in patient mood based on PHQ-9 .Ten days of 30,000 pulses of rTMS therapy over the left GDLPFC significant reduced VAS score   and non-wearer with habitual avoidance reminder  . Particip < 0.001).At the end of weekly behavioural therapy for 12–15 weeks, patients reported a significant improvement in their pain score for both short-  and the long-term effects were sustained over 6 months post-treatment:  . There wDRD2) 957C>T genotype and the association between BMS and other neurological diseases such as Parkinson’s disease  and long term (> 3 months) treatments .The majority of the included studies had small sample sizes. The diversified BMS patients’ characteristics such as presence or absence of psychological disorders, taste disturbance, and xerostomia make recruitment for a larger homogenous sample group difficult in a clinical trial. The concurrent use of psychotherapeutic drugs or therapies and anti-inflammatory analgesic medications in patients may influence the presentation of the BMS population trials due to the ambiguity of whether these psychological disorders preceded BMS ,32,35,38Both oral ingestion and topical application of clonazepam have showed a favourable result on BMS pain relief up from 2–6 months ,20,39. TMeanwhile, intraoral topical clonazepam has shown to be superior to oral ingestion in providing much rapid pain analgesia but a shorter duration of action. Patients reported rapid positive effects within 10 min upon dissolving the clonazepam tablet intraorally and recurrence of pain in 3–4 hours . The topThe use of amitriptyline, a tricyclic antidepressant, commonly used to treat chronic neuropathic pain, has not been widely mentioned in BMS studies. This may be the result of the frequent xerostomia induced by amitriptyline, whiich aggravates the pre-existing BMS-related xerostomia. A retrospective study has reported a superior rapid decrease of VAS pain scores outcome for clonazepam drops (n = 23) compared to amitriptyline drops (n = 16) at 6 weeks but no statistical difference between them .Gabapentin and pregabalin have been the favourable drug choice in treating neuropathic pain conditions such as diabetic neuropathy and postherpetic neuralgia due to its hepatic safety profile . SimilarBMS has been strongly associated with depression and anxiety, and the lack of clarity between them is unsettling. This neurophysiological mechanism in BMS was shown in functional magnetic resonance imaging (fMRI)  and quanTrazodone is a second-generation antidepressant that has been considered a multifunctional drug and acts as a serotonin reuptake inhibitor. Trazodone has been used in treating anxiety and pain symptoms, including fibromyalgia . HoweverCitalopram has shown to be able to reduce pain intensity . A revieThe perspective of using herbal medicine or phytomedicine has been established and increased in primary health care . The effCapsaicin has shown to be an effective pain desensitiser especially with oral topical application for up to 4 months . Transie64A study showed no difference between systemic and topical capsaicin efficacy in BMS . Howeverin vivo and in vitro  (The short-term use of hypericum perforatum in BMS has shown a favourable outcome but not significantly better than placebo . Hyperics (MAOI) . Its acts (MAOI) .Hypericum perforatum rarely causes any adverse drug reactions, except for dizziness, and is usually well tolerated by the elderly . It has Although it is relatively safe, clinicians should be wary of prescribing hypericum perforatum with other medications as it may elicit severe clinical adverse drug interaction effects. Hypericum perforatum activates the cytochrome P450 enzymes involved in drug metabolism, and reduces the plasma concentration and potency of a number of drugs such as warfarin (risk of thrombosis), cyclosporin (risk of transplant rejection), oral contraceptives (unintended pregnancy), anticonvulsant (uncontrolled seizures), digoxin (cardiac arrhythmia), theophylline (poor asthmatic control), and HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (diminution in HIV suppression) . CautionCrocin is a carotenoid chemical compound found in the flowers crocus and gardenia and is responsible for the colour of saffron. Crocin prevents neuroinflammation and neurodegeneration by decreasing oxidative stress and cell death  by inhibLycopene is naturally found in red carotenoid pigmented food, such as in tomatoes. It has antioxidant, anti-inflammatory, and anti-apoptotic properties. These benefits have been seen in reducing cancer and cardiovascular risk with the consumption of lycopene and VOO ,93. CombALA is the most studied treatment in BMS. Although the VAS findings from the pooled ALA analysis suggested there was no significant reduction in pain intensity relative to placebo treatment, a significantly higher proportion of patients reported pain reduction with ALA. As such, it suggests ALA as a treatment for BMS, but the evidence is not conclusive due to the variability of the studies treatment regimens and short- and long-term study results –11.ALA is a naturally occurring compound found in the body and vegetables such as tomatoes, potatoes, broccoli, and brussels sprouts. It acts as an enzymatic cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes in glucose and lipid metabolism. ALA is a robust universal antioxidant and can chelate and remove heavy metals from the body. Thus, it reduces oxidative stress-induced inflammation and damage to the nerve. ALA's advantages and safety were demonstrated in the treatment of diabetic polyneuropathy pain and paraesthesia by preventing nerve fibre degeneration ,96. HencALA and gabapentin have shown a superior result, with mild adverse effects reported . CombineThere was insufficient evidence of the benefit of melatonin in BMS. The relationship between pain and sleep is inextricable, in which poor sleep quality is a risk factor for chronic pain development, and pain disrupts the sleep pattern . MelatonPhotobiomodulation with low-level laser therapy (LLLT) effectively reduces chronic pain such as low back pain, temporomandibular joint disorder, and osteoarthritis . LLLT faBMS patients often complain of dry mouth discomfort . The lowAnecdotal patient claims suggest regular sips of ice water help elevate the pain, which may be due to stimulation of transient receptor potential melastatin 8 (TRPM8) cold receptors or antagonist effect on TRPV1 found in the oral mucosa. The role of TRPM8 in pain analgesia has been widely contradictory debated, which may depend on its anatomical site and degree of activation .Neuroimaging studies have demonstrated BMS patients to have similar brain pain matrix changes with increased functional connectivity and reduced grey matter volume as seen in other chronic pain imaging studies, indicating dysfunction of pain regulation at the CNS level ,114. It A tongue protector has been shown to reduce discomfort and improve oral health and quality of life . BMS oftBergdahl et al. reported an impressive reduction of three units of pain scores for both short and long-term assessment . The stuIn summary, the statistical analysis on the RCTs comparing intervention with placebo suggests a strong favourable outcome (SMD > 1.000) for cognitive behavioural therapy, capsaicin, topical clonazepam, and laser therapy (highest to lowest) in both short- and long-term assessment. There was some evidence on the use of phytomedicines such as umPEA, herbal catuama and hypericum perforatum in short-term pain score reduction. There were negligible changes in short term pain improvement in both trazodone and ALA (pooled effects) studies. However, the positive effects of ALA increase in long-term assessment. Although the pooled effect of ALA pain score improvement is low, the number of patients responding to ALA and its combination with gabapentin or a vitamin were high in both short- and long-term assessments. Capsaicin, topical clonazepam and saliva substitute lysozyme lactoperoxidase showed consistent treatment effectiveness or improvement in pain comparing with placebo in both short- and long-term analysis.There is emerging interest in acupuncture as an adjunct therapy to pharmacological treatment for BMS patients due to its encouraging analgesic results on significant VAS score reduction within the first 2 months of therapy –125. LonThere was a substantial amount of heterogeneity in the therapeutic intervention types and method of delivery. None of the included studies has a high-grade quality of evidence in both short- and long-term outcome assessment. Short-term changes in pain score, quality of life, and adverse therapy effects may not reflect the clinical practice’s real implication. Long-term outcomes data availability was minimal, with reports only on cognitive therapy, ALA, capsaicin, umPEA, topical clonazepam, and low-level laser therapy. There were other trials with similar or other treatments reported in this review but these were not included mainly due to short-term assessment of as little as 2 weeks ,68. PublIn perspective, it is suggested that multicentre trials investigate various therapeutic techniques in regulating BMS pain and increase participant numbers to conclude the treatment guidelines for BMS. The sustainability of pain reduction or remission is not adequately studied due to a short assessment period of less than a year. No treatment achieves a 50% pain remission in BMS. Investigating the influence of BMS’s biopsychosocial and neurophysiological mechanisms will provide a robust framework for integrating its various confounding aetiology factors. Studies should be ideally designed with multi-arm comparison for various pharmacological and non-pharmacological treatments to grade the treatment efficacy based on the universally accepted BMS disease’s diagnosis criteria. Likewise, a greater volume for sample size, multicentre studies, and longitudinal follow-up studies will enhance BMS treatment strategies’ value. The beneficial effects exhibited for neuroprotective and analgesic auxiliary therapies such as phytomedicine and rTMS, and the behavioural therapy CBT, could be valuable alternatives or applied in conjunction with synthetic systemic drugs, with a lesser risk of adverse drug effects, and tailored, holistic individual patient treatment, rather than the disease itself.This paper systematically reviews the evidence base for medicines in treating BMS based on the recent ICOP definition.This reviews RCTs with a minimum follow-up of 2 months, which had not been conducted by any previous systematic review.There is evidence on the benefit of topical oral clonazepam and capsaicin and alternative medicines such as neuroprotective agents and cognitive behavioural therapy.There is still insufficient long term follow up on the sustainable benefits of each treatment and its side effects.


The Itch Numeric Rating Scale (NRS), Skin Pain NRS, and Atopic Dermatitis Sleep Scale (ADSS) are self-administered patient-reported outcome (PRO) instruments developed to assess symptoms in patients with atopic dermatitis (AD). The objective of this study was to evaluate the psychometric properties  and interpretability thresholds of these PROs using data from three pivotal Phase 3 studies in adults.BREEZE-AD1, BREEZE-AD2, and BREEZE-AD5 evaluated the safety and efficacy of baricitinib in adults with moderate-to-severe AD. Clinician-reported outcomes and other PROs commonly assessed in patients with AD were used to estimate meaningful changes and evaluate test–retest reliability, convergent and divergent validity, known-groups validity, responsiveness, and meaningful change thresholds (MCTs) of the Itch NRS, Skin Pain NRS, and ADSS.r > 0.4) at baseline and Week 16 were generally observed between each measure and other PROs measuring the same concept, supporting convergent validity. Small-to-moderate correlations with clinician-reported outcomes demonstrated divergent validity. Each instrument was able to distinguish between known groups of disease severity as assessed using other indicators of AD severity. The responsiveness of the Itch NRS, Skin Pain NRS, and ADSS scales was demonstrated through significant differences in their change scores from baseline to Week 16 between categories of change in another PRO also from baseline to Week 16. Thresholds for interpreting meaningful change were estimated as − 4.0 for the 0–10 Itch and Skin Pain NRS items; − 1.25 for the 0–4 ADSS Items 1 and 3 and; − 1.50 for the 0–29 ADSS Item 2, these equivalent to moderate degrees of change.The test–retest reliability of the Itch NRS, Skin Pain NRS, and ADSS was evidenced by generally large intraclass correlation coefficients (> 0.7) in stable groups of patients between baseline and Week 1 and Weeks 4 and 8. Moderate-to-large correlations (Results of this study demonstrate that the psychometric properties of the Itch NRS, Skin Pain NRS, and ADSS are good to excellent. These findings support the use of these instruments in daily assessment of AD symptoms in adults with moderate-to-severe AD.Trial registration ClinicalTrials.gov numbers: NCT03334396, NCT03334422, and NCT03435081. Patients with moderate-to-severe atopic dermatitis (AD) experience a heavy disease burden that substantially impacts both physical and mental functioning. Intense itch, skin pain, and related sleep disturbance are highly prevalent symptoms that patients with AD report as significantly affecting their quality of life (QoL) , 2. The The Itch Numeric Rating Scale (NRS), Skin Pain NRS, and Atopic Dermatitis Sleep Scale (ADSS) are PROs designed to specifically measure the severity of a patient’s itch and skin pain, and assess impact of itch on sleep, respectively. These tools were developed according to the Food and Drug Administration (FDA) PRO guidelines , as simpBREEZE-AD1 (AD1), BREEZE-AD2 (AD2), and BREEZE-AD5 (AD5) were three multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 clinical trials that evaluated the safety and efficacy of once daily, oral baricitinib 1 mg, and 2 mg, and 4 mg (in AD1 and AD2 only) versus placebo in adult patients with moderate-to-severe AD. In each trial, patients were ≥ 18 years old and intolerant or inadequate responders to topical therapy. At screening and baseline, patients were required to have an EASI score ≥ 16, a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD™) score ≥ 3, and a body surface area (BSA) involvement ≥ 10%. Full details of each study, including the primary efficacy and safety outcomes, have been reported previously . Each stThe Itch NRS is a single item designed to capture information on self-reported severity of worst itching each day. Patients were asked to rate itching severity based on the worst level of itching in the past 24 h using an 11-point scale from 0 (“no itch”) to 10 (“worst itch imaginable”). The single-item Skin Pain NRS assesses self-reported severity of worst skin pain each day. For this, patients were asked to select a number from 0 (“no pain”) to 10 (“worst pain imaginable”) that best described the worst level of skin pain in the past 24 h. The three-item ADSS captures self-reported impact of itch on sleep disturbance each day, including: difficulty falling asleep (Item 1); number of night-time awakenings (Item 2) and; difficulty falling back asleep after waking (Item 3) during the previous night. Each ADSS item was scored individually. For Items 1 and 3, patients were asked to select a score ranging from 0  to 4 (“very difficult”). For Item 2, patients selected the number of times they woke up each night, ranging from 0 to 29 times. Patients only answered Item 3 if their answer to Item 2 was greater than 0. These three PROs were self-assessed using a daily electronic diary, starting at screening through Week 16. Information was entered into the electronic diary at the end of each patient’s day. For each measure, weekly mean scores using the previous 7 days were calculated if at least 4 of the 7 diary values were non-missing. Weekly averages were calculated at baseline (Week 0) and Weeks 1, 2, 4, 8, 12, and 16.The PROs used to evaluate the psychometric properties of the Itch NRS, Skin Pain NRS, and ADSS included: (1) the Dermatology Life Quality Index (DLQI) , a self-The following psychometric evaluation methods used in this study are in accordance with the published FDA guidance for assessing the measurement properties of PROs  and receTest–retest reliability, which measures if instrument scores are reproducible across time, was assessed in a stable patient population during the interval between Week 0 and Week 1 as well as between Weeks 4 and 8. Stable patients were defined as those in the ITT population with weekly mean PGI-S-AD scores between − 0.50 and + 0.50 during each time interval. Intra-class correlation coefficients (ICCs) were calculated between the initial and retest periods. An ICC of ≥ 0.70 was considered acceptable agreement –15.Construct validity refers to the degree to which scores from one measure are theoretically consistent with those of another measure. Convergent and divergent validity were assessed using Spearman’s correlations between each of the Itch NRS, Skin Pain NRS, and ADSS items, and the scores of the PGI-S-AD, DLQI, POEM, and EASI. All analyses were conducted at Weeks 0 and 16. The strength of correlations was interpreted using Cohen’s conventions, where > 0.70 is large, 0.40–0.70 is moderate, and < 0.40 is small , 16, 17.It was hypothesized that convergent validity, evidenced by moderate or large correlations, would be demonstrated at Weeks 0 and 16 between each of the Itch NRS, Skin Pain NRS, and ADSS items with the other PROs related to AD symptoms , and that divergent validity, evidenced by small-to-moderate correlations, would be demonstrated between each of the instruments of interest with the more distally related clinician-completed assessment (EASI).Known-groups validity was assessed by exploring the ability of each instrument to discriminate between subgroups of patients with different underlying disease severity. Based on the evaluation of construct validity, measures correlating with the Itch NRS, Skin Pain NRS, or ADSS above the 0.35 criterion for acceptable correlations , 19 weret-tests (2 groups) and analysis of covariance (ANCOVA) controlling for the effects of age, race, and gender (> 2 groups). When ANCOVA was used, post hoc t-tests assessed the mean weekly score between consecutive severity groups. Any severity group with < 20 patients were omitted from the analysis to ensure sufficient data for interpretation.Patients were stratified into severity groups based on baseline scores of PGI-S-AD (weekly mean score of < 3 “no symptoms to mild symptoms” and ≥ 3 “moderate-to-severe symptoms”) and POEM  [Responsiveness, the ability of the measure to detect change when change in the construct of relevance has occurred, was evaluated using ANCOVAs and post-hoc paired an (SRM)  was usedan (SRM) , SRMs ofan (SRM) .t-tests and SRMs between consecutive change groups were also conducted.Mean changes were assessed within 4 change categories of the POEM: (1) “much improved” patients who moved more than one health category to a better health category (> 1 category improvement); (2) “improved” patients who moved by one health category to a better health category (1 category improvement); (3) “stable” patients who remained in the same health category (no category change); and (4) “declined” patients who moved to a worse health category (≥ 1 category worsening). These categories were based on changes from baseline to the respective time point in the POEM severity category , patients were classified into response groups based on their level of change in the PGI-S-AD between baseline and Weeks 4 and 16. These groups included “very marked improvement” (≤ −2.5 weekly average score change), “marked improvement” (> −2.5 and ≤ −1.5), “minimal improvement” (> −1.5 and ≤ −0.5), “no change” (> −0.5 and < 0.5), “minimal worsening” (≥ 0.5 and < 1.5), and “marked worsening” (≥ 1.5). MCTs on the Itch NRS, Skin Pain NRS, and ADSS items were based on change from baseline to Week 16  and baseline to Week 4  within PGI-S-AD severity groups. A range of MCT estimates  were computed for changes in each measure based on observed changes in the minimal, marked, and very marked PGI-S-AD improvement groups. A final MCT estimate for each measure was taken as the MCT equivalent to a moderate degree of change.Meaningful change analyses were also supported by distribution-based methods, which identify the raw score change on a measure that will produce a prespecified effect size and which identify a change which is beyond measurement error . DistribFor Weeks 1, 2, 4, 8, and 12, weekly mean scores for Itch NRS, Skin Pain NRS, and ADSS items were set to missing if there were fewer than 4 non-missing values in the 7-day period before the respective clinic visit. For Week 0 and Week 16 analyses, if there were fewer than 4 non-missing assessments during the week prior to the visit, the 7-day window was extended by 1 day at a time  until there were at least 4 non-missing values.A total of 624 patients in AD1, 615 patients in AD2, and 440 patients in AD5 were included. Patients’ baseline demographics and scores for the instruments of interest and other assessments are listed in Table The results of the test–retest analysis for each instrument in each study are provided in Table r range: 0.483–0.762 at baseline and 0.586–0.834 at Week 16) and the Skin Pain NRS (r range: 0.474–0.727 at baseline and 0.549–0.768 at Week 16) supported convergent validity. Similarly, moderate correlations, supporting convergent validity, were generally observed between the PRO assessments and ADSS Item 1 (r range: 0.499–0.651 at baseline and 0.508–0.670 at Week 16), Item 2 (r range: 0.368–0.468 at baseline and 0.424 and 0.516 at Week 16), and Item 3 (r range: 0.403–0.639 at baseline and 0.466–0.809 at Week 16).Results supporting convergent and divergent validity of the Itch NRS, Skin Pain NRS, and ADSS items are shown in Table r range: 0.223–0.229 at baseline and 0.398–0.505 at Week 16); Skin Pain NRS (r range: 0.222–0.251 at baseline and 0.338–0.455 at Week 16); ADSS Item 1 (r range 0.140–0.281 at baseline and 0.363–0.403 at Week 16); ADSS Item 2 (r range: 0.131–0.245 at baseline and 0.254–0.357 at Week 16), and; ADSS Item 3 (r range 0.152–0.298 at baseline and 0.237 and 0.394 at Week 16).Small-to-moderate correlations, supporting divergent validity, were observed between the clinical assessment and the following: Itch NRS (p < 0.0001), skin pain (p < 0.0001), sleep disturbance (p < 0.0001), night-time awakenings (p < 0.01), and difficulty falling back asleep after waking (p < 0.0001) as demonstrated by higher mean scores on Itch NRS, Skin Pain NRS, ADSS Items 1, 2, and 3, respectively. These findings suggest that the Itch NRS, Skin Pain NRS, and ADSS items are able to distinguish between known groups based on disease severity.Table p < 0.001 for Itch NRS, p < 0.05 for Skin Pain NRS), and the “improved” category statistically significantly differed from the “stable” group (p < 0.0001 for both). In each study, at Week 16, the scores of each ADSS item increased with each improvement category; however, not all comparisons between consecutive improvement categories were statistically significant  for each measure are listed in Table Distribution-based MCTs are listed in Table This study evaluated the psychometric properties of the Itch NRS, Skin Pain NRS, and ADSS using data from three clinical trials of patients with moderate-to-severe AD. For each measure, assessment of test–retest reliability found high levels of agreement in stable groups of patients across all three studies for both 1-week and 4-week comparisons, indicating reliability of each instrument when no change would be expected. As hypothesized, the construct validity of each measure was also demonstrated, with moderate-to-large correlations with other PROs  supporting convergent validity and smaller correlations with the more distally-related provider assessment (EASI) supporting divergent validity. These findings suggest that the Itch NRS, Skin Pain NRS and ADSS measure the underlying concept of AD symptomatology and, moreover, encapsulate unique information regarding disease symptoms, which can complement clinician-reported assessments in clinical trials. In addition, comparisons of the Itch NRS, Skin Pain NRS, and each ADSS item between PGI-S-AD and POEM severity categories demonstrated each measure’s ability to distinguish between known groups based on disease severity. Responsiveness was established through the ability of each instrument to discriminate significantly between subgroups of patients based on four change categories of the POEM . Overall, the Itch NRS, Skin Pain NRS, and ADSS were determined to be highly reliable, valid, and responsive, supporting the use of these PRO instruments in daily assessment of AD symptoms in adults with moderate-to-severe AD.Using anchor- and distribution-based analyses, thresholds for interpreting change of each measure were derived as criteria to assess treatment benefits in patients with AD. Four-point changes in the Itch NRS and Skin Pain NRS were found to demonstrate clinically meaningful responses in itch and skin pain severity, respectively. This 4-point change in the Itch NRS is consistent with minimal clinically important differences reported for similar itch scales , 24. ChaThe potential importance of these measures in clinical practice is indicated by the fact that patients with AD have identified itch, skin pain, and sleep disturbance as bothersome and distressing symptoms of their disease , but theThough this study demonstrated strong evidence for the reliability, validity, and responsiveness of the Itch NRS, Skin Pain NRS, and ADSS, the data used in this psychometric validation are from a clinical trial and hence may not be generalizable to clinical practice. In addition, the inclusion and exclusion criteria of the three underlying studies limit this validation to adult patients with moderate-to-severe AD. Only a few patients were available in the mild group for assessing known-groups validity of each instrument using PGI-S-AD and POEM subgroups to define AD severity. The results of this study are also limited to a subset of patients who fluently spoke a language into which the assessment tool had been translated. The FDA recommends daily assessment of symptoms by patients as a shorter recall period allows for more reliable interpretation of symptom data . HoweverThe results of this study demonstrate that the Itch NRS, Skin Pain NRS, and ADSS are highly reliable, valid, and responsive measures of symptoms that are important to patients with AD. In addition, each PRO is able to measure clinically important symptom changes in these patients. These findings support the use of these PRO instruments in clinical trials of patients with moderate-to-severe AD.