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The ketogenic diet (KD) is gaining attention as a preventive treatment for migraine, which is sustained by many pre-clinical and clinical data. KD is also used for weight loss, and there is a relation between migraine and weight excess, but it is speculated that KD efficacy on migraine may go beyond this effect. We conducted a retrospective observational study on 23 migraine patients who received a KD and were evaluated at the baseline and then after 3 months both from a neurological and a nutritional point of view, including body mass composition analysis. We observed a reduction in monthly headache days (12.5 ± 9.5 vs. 6.7 ± 8.6; < 0.001) and in days of acute medication intake (11.06 ± 9.37 vs. 4.93 ± 7.99; = 0.008). We also observed a reduction in patients' weight (73.8 ± 15.2 vs. 68.4 ± 14.6; < 0.001) and BMI (26.9 ± 6.2 vs. 23.7 ± 8.1; < 0.001) with a decrement of the fat mass (28.6 ± 12.5 vs. 20.6 ± 9.8; < 0.001). Patients who responded to KD and those who did not had no differences with respect to weight or fat mass loss. These data corroborate the utilization of KD as a preventive treatment for migraine and suggest that the efficacy of such an intervention is not only due to weight or fat mass loss but probably relies on other mechanisms specific to KD.
Learn More >Alterations in white matter microstructure and functional activity have been demonstrated to be involved in the central nervous system mechanism of classic trigeminal neuralgia (CTN). However, the rich-club organization and related topological alterations in the CTN brain networks remain unclear.
Learn More >Immediately following spinal cord injury (SCI) patients experience pain, associated with injury to the spinal cord and nerves as well as accompanying peripheral injuries. This pain is usually treated with opioids, and most commonly with morphine. However, in a rodent model we have shown that, irrespective of the route of administration, morphine administered in the acute phase of SCI undermines long-term locomotor recovery. Our previous data suggests that activation of kappa opioid receptors (KORs) mediate these negative effects. Blocking KORs with nor-Binaltorphimine (norBNI), prior to a single dose of epidural morphine, prevented the morphine-induced attenuation of locomotor recovery. Because numerous cellular changes occur with chronic opioid administration compared to a single dose, the current study tested whether norBNI was also effective in a more clinically relevant paradigm of repeated, intravenous morphine administration after SCI. We hypothesized that blocking KOR activation during repeated, intravenous morphine administration would also protect recovery. Supporting this hypothesis, we found that blocking KOR activation in young, male rats prevented the negative effects of morphine on locomotor recovery, although neither norBNI nor morphine had an effect on long-term pain at the doses used. We also found that norBNI treatment blocked the adverse effects of morphine on lesion size. These data suggest that a KOR antagonist given in conjunction with morphine may provide a clinical strategy for effective analgesia without compromising locomotor recovery after SCI.
Learn More >Melatonin, through its G protein-coupled MT receptor, is implicated in analgesia, but the relationship between MT receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured, SNI), the selective melatonin MT agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the non-selective opioid antagonist naloxone and the selective MOR antagonist CTOP blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral-ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pro-nociceptive ON-cells, and the enhancement of the firing of the anti-nociceptive OFF-cells, induced by the microinjection of the MT agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT receptors are expressed in both excitatory (CaMKIIα ) and inhibitory (GAD65 ) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons co-expressed MOR and MT receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT receptor agonism requires MORs to exert its antiallodynic effects, mostly through an inter-neuronal circuit involving MOR and MT receptors. This article is protected by copyright. All rights reserved.
Learn More >This is the English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence-based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, descriptions of three new drugs, namely, dupilumab, delgocitinib, and baricitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.
Learn More >In chronic LBP (CLBP), guideline-endorsed treatment is to stay active, return to normal activity, and to exercise. Several reviews on various exercise types used in CLBP have been published. We aimed to identify systematic reviews of common exercise types used in CLBP, to appraise their quality, and to summarize and compare their effect on pain and disability.
Learn More >Pain and itch are recognized as antagonistic sensations; pain suppresses itch and inhibition of pain generates itch. There is still a lack of evidence about the neural mechanism of the interaction between pain and itch in the central nervous system. In this study, we focused on the orexin (ORX) neurons in the lateral hypothalamus (LH), which mediate various "defense responses" when animals confront stressors. We found that the scratching behaviors induced by the pruritogen were significantly suppressed in ORX-neuron-ablated (ORX-abl) mice. The exaggerated pain behavior and attenuated itch behavior observed in ORX-abl mice indicated that ORX neurons modulate pain and itch in an opposite way, i.e., pain relief and itch exacerbation. In addition, most of the ORX neurons responded to both pain and itch input. Our results suggest that ORX neurons inversely regulate pain- and itch-related behaviors, which could be understood as a defense response to cope with stress environment.
Learn More >Opioid use disorder is one of the most pressing public health problems of our time. Mobile health tools, including wearable sensors, have great potential in this space, but have been underutilized. Of specific interest are digital biomarkers, or end-user generated physiologic or behavioral measurements that correlate with health or pathology. The current manuscript describes a longitudinal, observational study of adult patients receiving opioid analgesics for acute painful conditions. Participants in the study are monitored with a wrist-worn E4 sensor, during which time physiologic parameters (heart rate/variability, electrodermal activity, skin temperature, and accelerometry) are collected continuously. Opioid use events are recorded via electronic medical record and self-report. Three-hundred thirty-nine discreet dose opioid events from 36 participant are analyzed among 2070 h of sensor data. Fifty-one features are extracted from the data and initially compared pre- and post-opioid administration, and subsequently are used to generate machine learning models. Model performance is compared based on individual and treatment characteristics. The best performing machine learning model to detect opioid administration is a Channel-Temporal Attention-Temporal Convolutional Network (CTA-TCN) model using raw data from the wearable sensor. History of intravenous drug use is associated with better model performance, while middle age, and co-administration of non-narcotic analgesia or sedative drugs are associated with worse model performance. These characteristics may be candidate input features for future opioid detection model iterations. Once mature, this technology could provide clinicians with actionable data on opioid use patterns in real-world settings, and predictive analytics for early identification of opioid use disorder risk.
Learn More >Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic peripheral polyneuropathy that results in disability through immune mediated nerve injury, but which not uncommonly has residual and irreversible neurologic deficits after the active inflammatory component of the disorder has been treated. Management of the condition entails addressing both the abnormal immune activity that drives ongoing or active deficits while also managing residual symptoms through supportive interventions. Immune based treatments are grounded in several important principles. First, early treatment is guided by evidence-based proven effective therapies that sequentially escalate depending on the response. Second, optimization or personalization of first line treatments is needed in order to understand the ideal dose for any given patient, and whether long term treatment is needed at all. Third, although many immunosuppressive agents may be utilized in non-responding patients or when intravenous immunoglobulin (IVIG)/corticosteroid sparing intervention is desired, all are unproven and require a delicate balance between risk, cost, and unknown likelihood of benefit that is tailored to each individual patient's unique circumstances. There is no reliable disease activity biomarker that can be used to guide treatment – a reality that makes it very challenging to optimize treatment to individual patient needs. Serial clinical assessments are key to understanding the value of continued immunotherapy or if long-term therapy is needed at all. Regardless of the immunotherapy status of a patient, equally important is addressing residual deficits through supportive interventions including physical therapy, adaptive equipment, pain management, and emotional support. This article is protected by copyright. All rights reserved.
Learn More >Dorsal root ganglion stimulation (DRG-S) is a form of selective neuromodulation therapy that targets the dorsal root ganglion. DRG-S offers analgesia in a variety of chronic pain conditions and is approved for treatment of complex regional pain syndrome (CRPS) by the US Food and Drug Administration (FDA). There has been increasing utilization of DRG-S to treat various neuropathic pain syndromes of the lower extremity, although evidence remains limited to one randomized controlled trial and 39 observational studies. In this review, we appraised the current evidence for DRG-S in the treatment of lower extremity neuropathic pain using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The primary outcome was change in pain intensity after DRG-S compared to baseline. We stratified presentation of results based of type of neuropathy (CRPS, painful diabetic neuropathy, mononeuropathy, polyneuropathy) as well as location of neuropathy (hip, knee, foot). Future powered randomized controlled trials with homogeneous participants are warranted.
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