Accepted

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons. Importantly, butterbur diminishes the production of inflammatory mediators by inhibiting activities of cyclooxygenases, lipoxygenases and phospholipase A2 and desensitizes nociception by acting on TRPA1 and TRPPV1 ion channels. It inhibits the release of calcitonin-gene related peptide (CGRP) of meningeal afferents during migraine attacks. We also evaluated the safety of a butterbur root extract in repeated dose studies for up to 6 months. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At supratherapeutic doses, i.e., 45-90-fold MCD, we observed bile duct hyperplasia, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Additionally, liver function tests were performed in cultures of primary human hepatocytes and did not evidence hepatotoxicity at therapeutic butterbur level and with migraine co-medications. Lastly, in randomized, double-blinded and placebo-controlled trials with Petadolex® migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported. Together, butterbur is effective in the prevention of migraine attacks by blocking CGRP signaling.

Advances in molecular biology and neuroscience have led to the discovery of calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide that plays a critical role in the pathogenesis of migraine. CGRP receptor antagonist, also known as gepant, is an oral medication that inhibits the CGRP-related nociceptive signaling pathway. To date, three gepants are approved by the FDA for migraine treatment. Atogepant is a 2nd-generation gepant that non-competitively antagonizes CGRP receptors inhibiting neurogenic inflammation and pain sensitization. With its long half-life and minimal cardiovascular or liver toxicity, it is the first in its class approved primarily for migraine prevention. This article will discuss the evidence, safety, and rationale of atogepant for use in clinical practice.

Neurovascular compression (NVC) is considered as the main factor leading to the classical trigeminal neuralgia (CTN), and a part of idiopathic TN (ITN) may be caused by NVC (ITN-nvc). This study aimed to explore the risk factors for unilateral CTN or ITN-nvc (UC-ITN), which have bilateral NVC, using machine learning (ML).

For decades, -methyl–aspartate (NMDA) receptors have been known to play a critical role in the modulation of both acute and chronic pain. Of particular interest are NMDA receptors expressed in the superficial dorsal horn (SDH) of the spinal cord, which houses the nociceptive processing circuits of the spinal cord. In the SDH, NMDA receptors undergo potentiation and increases in the trafficking of receptors to the synapse, both of which contribute to increases in excitability and plastic increases in nociceptive output from the SDH to the brain. Research efforts have primarily focused on postsynaptic NMDA receptors, despite findings that presynaptic NMDA receptors can undergo similar plastic changes to their postsynaptic counterparts. Recent technological advances have been pivotal in the discovery of mechanisms of plastic changes in presynaptic NMDA receptors within the SDH. Here, we highlight these recent advances in the understanding of presynaptic NMDA receptor physiology and their modulation in models of chronic pain. We discuss the role of specific NMDA receptor subunits in presynaptic membranes of nociceptive afferents and local SDH interneurons, including their modulation across pain modalities. Furthermore, we discuss how barriers such as lack of sex-inclusive research and differences in neurodevelopmental timepoints have complicated investigations into the roles of NMDA receptors in pathological pain states. A more complete understanding of presynaptic NMDA receptor function and modulation across pain states is needed to shed light on potential new therapeutic treatments for chronic pain.

To evaluate the effectiveness of any form of physiotherapy intervention for the management of central neuropathic pain (cNeP) due to any underlying cause.

Chronic pain affects almost 20% of the European adult population and it significantly reduces patients' quality of life. Chronic pain is considered a multidimensional experience determined by the interaction of several genetic and environmental factors. The effect of specific genetic contributions is often unclear, and the interpretation of the results from studies focused on genetic influences on pain has been complicated by the existence of multiple pain phenotypes. A step forward from genetics could be given by the application of metabolomics and microbiomics tools. Metabolomics is a powerful approach for hypothesis generation in biology, and it aims to analyze low molecular weight compounds, either metabolic intermediates or metabolic end-products, resulting from human or microbial metabolism. Microbiomics is a fast-growing field in which all the microbes are examined together, and as a result, its perturbation may indicate the development of chronic diseases. By applying these methodologies for the study of chronic pain, several differences have been identified. The alteration of the choline-PAF pathway is an intriguing finding recognized by several groups. In our opinion, metabolomics and microbiomics techniques will allow significant progress into the medical field. Patients may benefit from the possibility of being stratified and classified based on their metabolic and microbial profile, which, in the next future, may lead to personalized therapy.