Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain.

Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities and are thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant the search for more effective therapeutic targets for pain management. This scoping review focuses on human studies of common pathogenic factors in migraine and NP, with reference to available preclinical evidence to explore potential novel therapeutic targets. CGRP inhibitors and monoclonal antibodies alleviate inflammation in the meninges; targeting transient receptor potential (TRP) ion channels may help prevent the release of nociceptive substances, and modifying the endocannabinoid system may open a path toward discovery of novel analgesics. There may exist a potential target in the tryptophan-kynurenine (KYN) metabolic system, which is closely linked to glutamate-induced hyperexcitability; alleviating neuroinflammation may complement a pain-relieving armamentarium, and modifying microglial excitation, which is observed in both conditions, may be a possible approach. Those are several potential analgesic targets which deserve to be explored in search of novel analgesics; however, much evidence remains missing. This review highlights the need for more studies on CGRP modifiers for subtypes, the discovery of TRP and endocannabinoid modulators, knowledge of the status of KYN metabolites, the consensus on cytokines and sampling, and biomarkers for microglial function, in search of innovative pain management methods for migraine and NP.

[Sumatriptan-naproxen sodium fix-dose combination for acute migraine treatment, a review]. / Szumatriptán­naproxén-nátrium fix dózisú kombinációja a migrén akut kezelésében ­ irodalmi áttekintés.

Migraine as a common primary headache disorder has a significant negative effect on quality of life of the patients. Its pharmacotreatment includes acute and preventative therapies. Based on the shared therapeutic guideline of the European Headache Federation and the European Academy of Neurology for acute migraine treatment a combination of triptans and non-steroidal anti-inflammatory drugs is recommended for acute migraine treatment in triptan-nonresponders. In this short review we summarized the results of the randomized controlled clinical trials evaluating the effectiveness and safety of sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination. It was revealed that the fix-dose combination was better than placebo for the primary outcomes of exemption of pain and headache relief at 2 hours. Furthermore the combination showed beneficial effect on accompanying symptoms of migraine attack (i.e. nausea, photo- and phonophobia). Adverse events were mild or moderate in severity and rarely led to withdrawal of the drug.
It can be concluded that sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination is effective, safe and well-tolerated in the acute treatment of migraine. 

[Neurosyphilis or not - a case of a differential diagnostic challenge]. / Neurosyphilis vagy nem ­ egy differenciáldiagnosztikai kihívás esete.

We report the case of a 42-year-old woman with paraparesis associated with transverse myelitis. For differential diagnostics detailed microbiological, cerebrospinal fluid (CSF) and neuroimaging examinations were performed. Syphilis was confirmed, but diagnosis of neurosyphilis was only probable based on the CSF microbiological test results. The beneficial treatment response to application of the therapeutic protocol for syphilis supported the supposed diagnosis of syphilis-associated myelitis in our case. In this case report we reviewed the differential diagnostic tools of myelopathies/myelitis.
Nowadays regarding to growing prevalence of syphilis worldwide physicians should face on its presence and medical consequences.

Prophylactic Drug Treatment of Migraine in Children and Adolescents: An Update.

Migraine as a highly disabling pain condition influences the daily activities of those affected, including children and adolescents. The pathomechanism of migraine is not fully understood, and the different types of prophylactic antimigraine drugs that are applied are not specific for migraine. There is a need for preventive treatment in the event of frequent migraine attacks, an impairment of the quality of life, severe accompanying or aura symptoms, and the failure of acute drug treatment. The following pharmacological classes are recommended: antidepressants, antiepileptics, antihistamines, beta-adrenergic receptor blockers, and calcium ion channel antagonists, besides onabotulinum toxin A and nutraceuticals (butterbur). The most urgent goal as concerns pharmaceutical innovation is the development of pathomechanism-based antimigraine drugs and personalized therapy tailored to the children and adolescents.

Chronic Migraine as a Primary Chronic Pain Syndrome and Recommended Prophylactic Therapeutic Options: A Literature Review.

Chronic pain conditions have a high socio-economic impact and represent a burden for patients, and their management is a challenge for healthcare professionals. Chronic migraine is one of the chronic primary headache disorders, which belong to chronic primary pain syndromes as per the new concept of multiple parenting. The aims of this review were to provide an overview of the latest classification systems involving both entities, the epidemiological data, and the currently recommended prophylactic treatment options for chronic migraine. Randomized controlled clinical trials, meta-analyses, real-world data, and review articles were analyzed. Chronic migraine is a prevalent and highly burdensome disease and is associated with high headache-related disability and worsening health-related quality of life. Treatment of chronic migraine includes pharmacological or, in drug-refractory cases, non-pharmacological (e.g., neuromodulatory) approaches. Among pharmacological treatment options, injectable botulinum toxin type A and calcitonin gene-related peptide-targeting human and fully humanized monoclonal antibodies (i.e., eptinezumab, erenumab, fremanezumab, and galcanezumab) are highly recommended in the preventive treatment of chronic migraine. Novel migraine-specific therapies offer a solution for this devastating and difficult-to-treat chronic pain condition.

The pharmacotherapeutic management of episodic and chronic migraine with gepants.

INTRODUCTION: The small molecule non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists named gepants offer a breakthrough novel approach in migraine acute and prophylactic drug treatment. This review aimed to determine the place of gepants in the treatment of episodic and chronic migraine. AREAS COVERED: The new generation gepants are ubrogepant, atogepant, rimegepant, and zavegepant. Ubrogepant is ratified for acute migraine treatment, atogepant is validated for preventive therapy, whereas rimegepant is ratified for both indications, all via oral administration and while zavegepant is administered intranasally for migraine attacks. Gepants are effective, safe, and well-tolerated in acute or prophylactic therapy. The PubMed literature search included randomized controlled trials, meta-analyses, real-world data, and review articles published in English until January 2023. EXPERT OPINION: Whether gepants will be real game changers in the acute treatment of migraine compared to triptans and ditans or in the prophylactic therapy compared to standard-of-care preventive drugs or CGRP-targeting monoclonal antibodies cannot be answered yet based on the available literature data.

[Botulinum neurotoxin--a therapy in migraine]. / Botulinum neurotoxin--a terápia migrénben.

Although migraine is a common, paroxysmal, highly disabling disorder, the primary cause and the pathomechanism of migraine attacks are enigmatic. Experimental results suggest that activation of the trigeminovascular system is crucial in its pathogenesis. This activation leads to the release of vasoactive neuropeptides (calcitonin gene-related peptide - CGRP, and substance P - SP) and to neurogenic inflammation, and peripheral and central sensitisation are expressed. Botulinum neurotoxin-A (BoNT-A), a potent toxin produced by Clostridium botulinum, affects the nervous system through specific cleavage of the soluble NSF-attachment protein receptor complex (SNARE), like synaptosomal-associated protein of 25 kDa (SNAP-25). The result of this multistage process is blockade of the presynaptic release of pain neurotransmitters such as CGRP, SP and glutamate. A pooled analysis of the data from two programmes of Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT 1 and 2) with BoNT-A in chronic migraine demonstrated significant benefit of BoNT-A over placebo with regard to the numbers of headache days and migraine episodes. BoNT-A diminished the frequency of acute headache pain medication intake, and resulted in reductions in headache impact and improvements in scores on the Migraine-Specific Quality of Life Questionnaire. The treatments with BoNT-A proved safe and were well tolerated.

Effects of valproate on the dopaminergic system in mice.

Valproate is a widely used antiepileptic drug with a known tremor-inducing effect. In this study, we tested the behavioral changes induced by valproate and its effect on the dopaminergic cells in the substantia nigra of mice. This treatment led to a spontaneous locomotor activity, while the explorative behavior was unaltered. The number of dopaminergic cells in the substantia nigra was reduced after valproate treatment. These data are indicative of dopaminergic toxicity, but further studies are needed to demonstrate the exact mechanism.

Prion diseases: New considerations.

The transmissible spongiform encephalopathies, which include Creutzfeldt-Jakob disease, are fatal neurodegenerative disorders caused by the pathological accumulation of abnormal prion protein. The diagnosis of Creutzfeldt-Jakob disease is complex. The electroencephalogram, magnetic resonance imaging, lumbar puncture and genetic testing findings can help in the differential diagnosis of rapidly progressive dementia. There has recently been considerable debate as to whether proteins involved in the development of neurodegenerative diseases should be regarded as prions or only share prion-like mechanisms. Two recent reports described the detection of abnormal prion protein in the nasal mucosa and urine of patients with Creutzfeldt-Jakob disease. These findings raise major health concerns regarding the transmissibility of human prion diseases. We set out to address this neurological hot topic and to draw conclusions on the basis of what is known in the literature thus far.

Alleviation of pain in painful diabetic neuropathy.

INTRODUCTION: Painful diabetic neuropathy (PDN) is a disabling pain condition. Its pathomechanism remains unknown, but a sensitization and neuronal hyperexcitabilty have been suggested. Only symptomatic pharmacological pain management treatment is currently available. AREAS COVERED: The origin of PDN is enigmatic, and the evidence-based therapeutic guidelines therefore consist only of antidepressants and antiepileptics as first-line recommended drugs. This article relates to a MEDLINE/PubMed systematic search (2005-2015). EXPERT OPINION: The results of the meta-analysis from the aspect of the efficacy of amitriptyline, duloxetine, venlafaxine, gabapentin and pregabalin are favorable, but the placebo response rate is relatively high in patients with neuropathic pain. For personalization of the medication of PDN patients, the optimum dosing, the genotyping of the metabolizing enzymes and optimum biomarkers are needed. As concerns the future perspectives, specific sodium channel subtype inhibitors acting on peripheral nociceptive neurons or modified T-type voltage-gated calcium channel blockers may be promising targets for pharmaceutical innovations. Another attractive strategy for the treatment is based on the effects of monoclonal antibodies against nerve growth factor, sodium channels, specific receptor and cytokines. Botulinum toxin A, capsaicin patch and spinal cord stimulation therapies are the nearest future therapeutic options for the treatment of PDN patients.

Treatment of Chronic Migraine with OnabotulinumtoxinA: Mode of Action, Efficacy and Safety.

BACKGROUND: Chronic migraine is a common, highly disabling, underdiagnosed and undertreated entity of migraine. It affects 0.9%-2.2% of the general adult population. The present paper overviews the preclinical and clinical data regarding the therapeutic effect of onabotulinumtoxinA in chronic migraineurs. METHODS: A literature search was conducted in the database of PubMed up to 20 May 2015 for articles related to the pathomechanism of chronic migraine, the mode of action, and the efficacy, safety and tolerability of onabotulinumtoxinA for the preventive treatment of chronic migraine. RESULTS: The pathomechanism of chronic migraine has not been fully elucidated. The mode of action of onabotulinumtoxinA in the treatment of chronic migraine is suggested to be related to the inhibition of the release of calcitonin gene-related peptide and substance P in the trigeminovascular system. Randomized clinical trials demonstrated that long-term onabotulinumtoxinA fixed-site and fixed-dose (155-195 U) intramuscular injection therapy was effective and well tolerated for the prophylactic treatment of chronic migraine. CONCLUSIONS: Chronic migraine is a highly devastating entity of migraine. Its exact pathomechanism is unrevealed. Two-third of chronic migraineurs do not receive proper preventive medication. Recent clinical studies revealed that onabotulinumtoxinA was an efficacious and safe treatment for chronic migraine.

CGRP antagonists and antibodies for the treatment of migraine.

Introduction: Migraine is a highly devastating neurovascular disorder that affects up to 16% of the population worldwide. In spite of intensive research, its origin remains enigmatic with no therapeutic option appropriate for all migraine patients. One of the leading hypotheses is related to the function of the calcitonin gene-related peptide (CGRP). Regardless, the pharmaceutical options currently applied for the acute and prophylactic treatment of migraine are not appropriate for all migraine patients. Areas covered: This article is based on a literature review using the PubMed database and highlights the CGRP theory of the pathomechanism of migraine. Expert opinion: Since migraine is a CGRP-related disorder, it appeared obvious to develop CGRP receptor antagonists that exert high efficacy, both intravenously and orally. Unfortunately, the frequent use of these antagonists results in an elevated liver transaminase level. In an attempt to bypass these harmful side effects, efforts should be made to modify these pharmacons. The use of fully humanized monoclonal antibodies (mAbs) that target CGRP and its receptors may also be possible. However, while Phase I and II clinical trials are promising, a long-term follow-up of these therapies is still needed.

Drug safety in acute migraine treatment.

INTRODUCTION: A number of drugs are available for acute migraine treatment, but they are not all effective for all patients and all attacks. The safety profiles of migraine drugs limit their use in patients with certain comorbid conditions, and adverse effects may also reduce the level of patient compliance. AREAS COVERED: The different types of acute migraine drugs are discussed, with particular regard to safety issues and potential adverse effects. The frequent use of analgesics, ergot alkaloids and triptans may result in the development of medication overuse headache (MOH). EXPERT OPINION: The initiation of a migraine attack is not fully understood, and therefore treatment aimed at causative factors is currently not available. The tolerability and adverse effects of the drugs available at present often limit their use. NSAIDs are frequently associated with gastrointestinal, and possibly also cardiovascular side effects. Ergot alkaloids may induce arterial vasoconstriction, while the administration of triptans is contraindicated in cardiovascular, cerebrovascular and peripheral vascular diseases. The frequent use of these drugs poses the risk of the development of MOH. There is a need for pathomechanism-based drugs, and for the future achievement of personalized medicine.

Drug safety and tolerability in prophylactic migraine treatment.

INTRODUCTION: Migraine is a frequent, disabling primary headache disorder, whose pathomechanism is not yet fully understood. Prophylactic treatment is advisable for migraineurs with severe or highly frequent attacks, which impair the quality of life. AREAS COVERED: The different types of prophylactic migraine drugs are discussed, with particular regard to potential adverse effects and safety issues. ß-Adrenergic blockers, antiepileptic drugs and calcium-channel blockers are drugs widely used for migraine prevention, whereas complementary medicine and onabotulinumtoxin A can be used in selected cases. EXPERT OPINION: The background of the recurrence and chronification of migraine attacks has not been fully clarified, and causative preventive therapy is therefore not currently available. The tolerability and adverse effects of the currently used medications often limit their use. ß-Adrenergic receptor blockers may induce adverse cardiovascular events, whereas flunarizine is frequently associated with a weight gain and depression. As most migraine sufferers are young women of child-bearing age, the use of valproate is limited. Topiramate is associated with central nervous system-related side effects. There is a need for future development of pathomechanism-based preventive drugs, and personalized therapy tailored to the patient.

Migraine and neuropeptides.

Migraine is a common disabling neurovascular primary headache disorder. The pathomechanism is not clear, but extensive preclinical and clinical studies are ongoing. The structural basis of the leading hypothesis is the trigeminovascular system, which includes the trigeminal ganglion, the meningeal vasculature, and the distinct nuclei of the brainstem, the thalamus and the somatosensory cortex. This review covers the effects of sensory (calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide and substance P), sympathetic (neuropeptide Y) and parasympathetic (vasoactive intestinal peptide) migraine-related neuropeptides and the functions of somatostatin, nociceptin and the orexins in the trigeminovascular system. These neuropeptides may take part in neurogenic inflammation (plasma protein extravasation and vasodilatation) of the intracranial vasculature and peripheral and central sensitization of the trigeminal system. The results of human clinical studies are discussed with regard to the alterations in these neuropeptides in the plasma, saliva and cerebrospinal fluid during or between migraine attacks, and the therapeutic possibilities involving migraine-related neuropeptides in the acute and prophylactic treatment of migraine headache are surveyed.

Novel kynurenic acid analogues in the treatment of migraine and neurodegenerative disorders: preclinical studies and pharmaceutical design.

Though migraine and neurodegenerative disorders have a high socioeconomic impact, their therapeutic management has not been fully addressed. Their pathomechanisms are not completely understood, but glutamateinduced excitotoxicity, mitochondrial disturbances and oxidative stress all seem to play crucial roles. The overactivation of glutamate receptors contributes to the hyperexcitability observed in migraine and also to the neurodegenerative process. The kynurenine pathway of the tryptophan metabolism produces the only known endogenous Nmethyl- D-aspartate receptor antagonist, kynurenic acid, which has been proven in different preclinical studies to exert a neuroprotective effect. Influencing the kynurenine pathway might be beneficial in migraine and neurodegenerative diseases, and in the normalization of glutamatergic neurotransmission and the prevention of excitotoxic neuronal damage. The synthesis of kynurenic acid analogues may offer a valuable tool for drug development.

Novel strategies for the treatment of migraine attacks via the CGRP, serotonin, dopamine, PAC1, and NMDA receptors.

INTRODUCTION: Migraine is a common, paroxysmal, and disabling primary headache with a high personal and socioeconomic impact. It involves ∼ 16% of the general population. During the years, a number of hypotheses have been put forward concerning the exact pathomechanism, but the final solution is still undiscovered. AREAS COVERED: Although the origin is enigmatic, parallel therapeutic efforts have been developed. Current attack therapy does not meet the expectations of the patients or the doctors. This article, based on a PubMed search, reviews the novel pharmacological possibilities that influence the peripheral and central sensitization involved in the disease. EXPERT OPINION: In order to overcome the therapeutic insufficiency, a calcitonin gene-related peptide receptor antagonist without the side-effect of liver transaminase elevation is required. Another therapeutic option is to develop a neurally acting antimigraine agent, such as a serotonin-1F receptor agonist, with low adverse central nervous system events. Development of a potent dopamine receptor antagonist is necessary to diminish the premonitory symptoms of migraine. A further option is to decrease the headache intensity with a pituitary adenylate cyclase-activating polypeptide type 1 receptor blocker which can cross the blood-brain barrier. Finally, synthetic kynurenine analogues are required to block the pain transmission in the activated trigeminal system.

Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion -- interaction with the sensory system.

Clinical studies have suggested a link between the sensory trigeminal system and the parasympathetic ganglia. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which plays an important role in vasodilatation and pain transmission in craniocervical structures. The present study was designed to examine if CGRP and CGRP receptor components are present in the human sphenopalatine ganglion (SPG) in order to reveal an interaction between the sensory and parasympathetic systems. Indirect immunofluorescence technique was used for immunohistochemical demonstration of CGRP, the calcitonin receptor-like receptor (CLR) and the receptor activity modifying protein 1 (RAMP1) in human and rat SPG. Cryostat sections were examined and images were obtained using a light- and epifluorescence microscope coupled to a camera to visualize co-labeling by superimposing the digital images. In addition, Western blot technique was used to demonstrate the existence of CGRP receptor components in rat SPG. CGRP immunoreactive fibers were frequently found intraganglionic in the SPG in the vicinity of neurons. CLR immunoreactivity was observed in satellite glial cells (SGCs) as well as in nerve fibers, but not in neurons. RAMP1 immunoreactivity was localized in many neurons and SGCs. Thus, the two CGRP receptor components together were found in the SGCs. In addition, Western blot revealed the presence of RAMP1 and CLR in rat SPG. Our results suggest a possible sensory influence in the parasympathetic cranial ganglia. The sensory CGRP-containing fibers probably originate in the trigeminal ganglion, project to the SPG and act on CGRP receptors on SGCs.