Sumatriptan attenuates fear-learning despair induced by social isolation stress in mice: Mediating role of hypothalamic-pituitary-adrenal axis.

OBJECTIVES: Research has demonstrated that chronic stress experienced early in life can lead to impairments in memory and learning. These deficits are attributed to an imbalance in the interaction between glucocorticoids, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoid receptors in brain regions responsible for mediating memory, such as the hippocampus. This imbalance can result in detrimental conditions like neuroinflammation. The aim of this study was to assess the impact of sumatriptan, a selective agonist for 5-HT 1B/1D receptors, on fear learning capabilities in a chronic social isolation stress model in mice, with a particular focus on the role of the HPA axis. METHODS: Mice were assigned to two opposing conditions, including social condition (SC) and isolated condition (IC) for a duration of five weeks. All mice underwent passive avoidance test, with their subsequent freezing behavior serving as an indicator of fear retrieval. Mice in the IC group were administered either a vehicle, sumatriptan, GR-127935 (a selective antagonist for 5-HT 1B/1D receptors), or a combination of sumatriptan and GR-127935 during the testing sessions. At the end, all mice were sacrificed and samples of their serum and hippocampus were collected for further analysis. RESULTS: Isolation was found to significantly reduce freezing behavior (p<0.001). An increase in the freezing response among IC mice was observed following the administration of varying doses of sumatriptan, as indicated by a one-way ANOVA analysis (p<0.001). However, the mitigating effects of sumatriptan were reversed upon the administration of GR-127935. An ELISA assay conducted before and after the passive avoidance test revealed no significant change in serum corticosterone levels among SC mice. In contrast, a significant increase was observed among IC mice, suggesting hyper-responsiveness of the HPA axis in isolated animals. This hyper-responsiveness was ameliorated following the administration of sumatriptan. Furthermore, both the sumatriptan and SC groups exhibited a similar trend, showing a significant increase in the expression of hippocampal glucocorticoid receptors following the stress of the passive avoidance test. Lastly, the elevated production of inflammatory cytokines (TNF-α, IL-1ß) observed following social isolation was attenuated in the sumatriptan group. CONCLUSION: Sumatriptan improved fear learning probably through modulation of HPA axis and hippocampus neuroinflammation.

Status migrainosus.

Status migrainosus is one of the recognized complications of migraine with or without aura, defined as a persistent debilitating migraine attack lasting for more than 72h with little reprieve, leading to functional disability. The individual impact of status migrainosus and the substantial healthcare burden are highlighted. Current case series which inform our understanding of this condition are examined with two groups emergent, those with classic status migrainosus and those with episodic status migrainosus. The question as to whether status migrainosus is a distinct biological state beyond the established migraine pathophysiology is examined. With the underlying pathophysiology not fully understood, attention is turned to therapeutic considerations and the available evidence informing practice. A practical approach to treatment of status migrainosus is presented. Given the severity and need for emergency care, options detailed are in line with recommendations for acute migraine care: with a staged approach initially combining subcutaneous sumatriptan with parenteral options including dopamine receptor antagonists, nonsteroidal anti-inflammatories and acetaminophen. The place of combination treatment with parenteral magnesium sulfate, dihydroergotamine, antiepileptics, corticosteroids, and anesthetic agents is outlined. With a paucity of high-quality evidence to consolidate current clinical approaches, consideration of future therapies and research questions is raised.

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.

OBJECTIVE: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. BACKGROUND: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co-administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5-HT1B/1D receptor agonist. METHODS: We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. RESULTS: Sumatriptan as well as PL37 each produced a dose-dependent inhibition of ISDN-induced cephalic MH. Median effective dose (ED50 ) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. CONCLUSION: These results suggest that PL37 acts synergistically with sumatriptan to produce an anti-allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. PLAIN LANGUAGE SUMMARY: There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.

PACAP-38 related modulation of the cranial parasympathetic projection: A novel mechanism and therapeutic target in severe primary headache.

BACKGROUND AND PURPOSE: Little is known of how cranial autonomic symptoms (CAS) in cluster headache and migraine may contribute to their severe headache phenotype. This strong association suggests the involvement of the cranial parasympathetic efferent pathway. To investigate its contribution, we studied the role of pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), a potent sensory and parasympathetic neuropeptide, in modulating pre- and post-ganglionic cranial parasympathetic projection neurons, and their influence on headache-related trigeminal-autonomic responses. EXPERIMENTAL APPROACH: Using PACAP-38 and PACAP-38 responsive receptor antagonists, electrophysiological, behavioural and facial neurovascular-blood flow was measured in rats to probe trigeminal- and parasympathetic-neuronal, periorbital thresholds and cranial-autonomic outcomes, as they relate to primary headaches. KEY RESULTS: Sumatriptan attenuated the development of PACAP-38 mediated activation and sensitization of trigeminocervical neurons and related periorbital allodynia. PACAP-38 also caused activation and enhanced responses of dural-responsive pre-ganglionic pontine-superior salivatory parasympathetic neurons. Further, the PACAP-38 responsive receptor antagonists dissected a role of VPAC1 and PAC1 receptors in attenuating cranial-autonomic and trigeminal-neuronal responses to activation of the cranial parasympathetic projection, which requires post-ganglionic parasympathetic neurotransmission. CONCLUSION AND IMPLICATIONS: Given the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP-38 mediated receptor activation modulates headache-related cranial-autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine, and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP-38 or PACAP-38 responsive VPAC1 /PAC1 receptors.

Oxidation of amine-based pharmaceuticals with unactivated peroxymonosulfate: Kinetics, mechanisms, and elimination efficiency of NDMA formation.

Amine-based pharmaceuticals are a significant class of N-nitrosodimethylamine (NDMA) precursors. This study investigated the use of unactivated peroxymonosulfate (PMS) to control amine-based pharmaceuticals and their NDMA formation potential. Kinetic analysis and product identification revealed that sumatriptan and doxylamine primarily underwent reactions at their tertiary amine group, while ranitidine and nizatidine had both tertiary amine and thioether group as reaction sites. The NDMA formation from sumatriptan and doxylamine during post-chloramination was significantly reduced with the abatement of the parent contaminants, while the formation of NDMA remained high even if full abatement of ranitidine and nizatidine was achieved. Product formation kinetics and reference standard tests revealed the great contribution of transformation products to NDMA formation. Ranitidine could be oxidized to sulfoxide-type product ranitidine-SO and N-oxide type product ranitidine-NO. Ranitidine-SO exhibited a high NDMA yield comparable to that of ranitidine (>90%), while ranitidine-NO showed a low NDMA yield (2%). With further oxidation of ranitidine-SO at the tertiary amine group, NDMA formation was reduced by more than 90%. The underlying mechanism for the importance of the tertiary amine group in NDMA formation was demonstrated by quantum chemical calculation. These findings underscore the potential of PMS pre-oxidation on NDMA control.

[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. 

Quality by design for sumatriptan loaded nano-ethosomal mucoadhesive gel for the therapeutic management of nitroglycerin induced migraine.

Migraine is a progressive neurological condition often accompanied by nausea and vomiting. Various drugs have recently been used in the treatment of migraine, including sumatriptan (SUT). However, SUT has poor pharmacological effects mainly due to its reduced permeability, blood brain barrier (BBB) effect, half-life and bioavailability. Herein, we developed SUT loaded nano-ethosomes (SUT-NEs) for intranasal (IN) delivery, after their incorporation into chitosan based mucoadhesive gel (SUT-NEsG). The observed mean particle size of SUT-NEs was 109.45 ± 4.03 nm with spherical morphology, mono dispersion (0.191 ± 0.001), negatively charged (-20.90 ± 1.98 mV) and with excellent entrapment efficiency (96.90 ± 1.85 %). Fourier-transform infrared (FTIR) spectra have depicted the compatibility of the components. Moreover, SUT-NEsG was homogeneous having suitable viscosity and mucoadhesive strength. In vitro release and ex vivo permeation analysis showed sustained release and improved permeation of the SUT-NEsG, respectively. Additionally, histopathological studies of nasal membrane affirmed the safety of SUT-NEsG after IN application. In vivo pharmacokinetic study demonstrated improved brain bioavailability of SUT-NEsG as compared to orally administered sumatriptan solution (SUT-SL). Furthermore, significantly enhanced pharmacological effect of SUT-NEsG was observed in behavioral and biochemical analysis, immunohistochemistry for NF-κB, and enzyme linked immuno assay (ELISA) for IL-1ß and TNF-α in Nitroglycerin (NTG) induced migraine model. It can be concluded that migraine may be successfully managed through IN application of SUT-NEsG owing to the direct targeted delivery to the brain.

Electro-oxidation sensing of sumatriptan in aqueous solutions and human blood serum by Zn(II)-MOF modified electrochemical delaminated pencil graphite electrode.

An electrochemical sensory platform is presented for determination of sumatriptan (SUM) in aqueous solutions and human blood serum. A pencil graphite electrode (PGE) was electrochemically delaminated by cyclic voltammetry technique, and then further modified using nanoparticles of a zinc-based metal-organic framework (Zn(II)-MOF). The fabricated Zn(II)-MOF/EDPGE electrode was utilized for sensitive electrochemical detection of SUM via an electro-oxidation reaction. The Zn(II)-MOF was hydrothermally synthesized and characterized by various techniques. The electrochemical delamination of PGE results in a porous substrate, facilitating the effective immobilization of the modifier. The designed sensor benefits from both enhanced surface area and an accelerated electron transfer rate, as evidenced by the chronocoulogram and Nyquist plots. Under optimized conditions, the developed sensor exhibited a linear response for 0.99-9.52 µM SUM solutions. A short response time of 5 s was observed for the fabricated sensor and the detection limit was found to be 0.29 µM. Selectivity of Zn(II)-MOF/EDPGE towards SUM was evaluated by examining the interference effect of codeine, epinephrine, acetaminophen, ascorbic acid, and uric acid, which are commonly found in biological samples. The developed sensor shows excellent performance with recovery values falling within the range of 96.6 to 111% for the analysis of SUM in human blood serum samples.

Management of cluster headache: Treatments and their mechanisms.

BACKGROUND: The management of cluster headache is similar to that of other primary headache disorders and can be broadly divided into acute and preventive treatments. Acute treatments for cluster headache are primarily delivered via rapid, non-oral routes (such as inhalation, nasal, or subcutaneous) while preventives include a variety of unrelated treatments such as corticosteroids, verapamil, and galcanezumab. Neuromodulation is becoming an increasingly popular option, both non-invasively such as vagus nerve stimulation when medical treatment is contraindicated or side effects are intolerable, and invasively such as occipital nerve stimulation when medical treatment is ineffective. Clinically, this collection of treatment types provides a range of options for the informed clinician. Scientifically, this collection provides important insights into disease mechanisms. METHODS: Two authors performed independent narrative reviews of the literature on guideline recommendations, clinical trials, real-world data, and mechanistic studies. RESULTS: Cluster headache is treated with acute treatments, bridge treatments, and preventive treatments. Common first-line treatments include subcutaneous sumatriptan and high-flow oxygen as acute treatments, corticosteroids (oral or suboccipital injections) as bridge treatments, and verapamil as a preventive treatment. Some newer acute (non-invasive vagus nerve stimulation) and preventive (galcanezumab) treatments have excellent clinical trial data for episodic cluster headache, while other newer treatments (occipital nerve stimulation) have been specifically tested in treatment-refractory chronic cluster headache. Most treatments are suspected to act on the trigeminovascular system, the autonomic system, or the hypothalamus. CONCLUSIONS: The first-line treatments have not changed in recent years, but new treatments have provided additional options for patients.

Glassy Carbon Electrode Modified with CB/TiO2 Layer for Sensitive Determination of Sumatriptan by Means of Voltammetry and Flow Injection Analysis.

Sumatriptan is an organic chemical compound from the tryptamine group. It is used as a medicine for migraine attacks and in the treatment of cluster headaches. In this work, a new voltammetric method is proposed for highly sensitive SUM determination, using glassy carbon electrodes modified with carbon black and titanium dioxide suspension. The novelty of the presented work is the usage of the mixture of carbon black and TiO2 as glassy carbon electrode modifier for the first time for SUM determination. The mentioned sensor was characterized by great repeatability and sensitivity of measurements, which resulted in the obtention of a wide range of linearity and a low detection limit. The electrochemical properties of the CB-TiO2/GC sensor was characterized using the LSV and EIS method. The effect of different factors on the SUM peak, such as supporting electrolyte type, preconcentration time and potential, or influence of interferents, were tested using the square wave voltammetry technique. The linear voltammetric response for the analyte was obtained in the concentration range of 5 nmol L-1 to 150 µmol L-1 with a detection limit of 2.9 nmol L-1 for a preconcentration time of 150 s in the 0.1 mol L-1 phosphate buffer pH 6.0. The proposed method was successfully applied for highly sensitive sumatriptan determination in complex matrices, such as tablets, urine, and plasma, with a good recovery parameter (94-105%). The presented CB-TiO2/GC electrode is characterized by great stability, it was used for 6 weeks without significant changes in the SUM peak current. Amperometric and voltammetric measurements of SUM under the flow injection conditions were also performed to indicate the possibility of its fast and accurate determination with a time of single analysis of approx. 30 s.

Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms.

Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.

European Academy of Neurology guidelines on the treatment of cluster headache.

BACKGROUND AND PURPOSE: Cluster headache is a relatively rare, disabling primary headache disorder with a major impact on patients' quality of life. This work presents evidence-based recommendations for the treatment of cluster headache derived from a systematic review of the literature and consensus among a panel of experts. METHODS: The databases PubMed (Medline), Science Citation Index, and Cochrane Library were screened for studies on the efficacy of interventions (last access July 2022). The findings in these studies were evaluated according to the recommendations of the European Academy of Neurology, and the level of evidence was established using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RECOMMENDATIONS: For the acute treatment of cluster headache attacks, there is a strong recommendation for oxygen (100%) with a flow of at least 12 L/min over 15 min and 6 mg subcutaneous sumatriptan. Prophylaxis of cluster headache attacks with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy and tolerability) is recommended. Corticosteroids are efficacious in cluster headache. To reach an effect, the use of at least 100 mg prednisone (or equivalent corticosteroid) given orally or at up to 500 mg iv per day over 5 days is recommended. Lithium, topiramate, and galcanezumab (only for episodic cluster headache) are recommended as alternative treatments. Noninvasive vagus nerve stimulation is efficacious in episodic but not chronic cluster headache. Greater occipital nerve block is recommended, but electrical stimulation of the greater occipital nerve is not recommended due to the side effect profile.

Comparative efficacy of different treatments for menstrual migraine: a systematic review and network meta-analysis.

BACKGROUND: Menstrual migraine is a subtype of migraine disease that is typically more disabling, longer-lasting, and more challenging to treat. The purpose of this network meta-analysis (NMA) is to compare the relative efficacy of treatments for menstrual migraine. METHODS: We systematically searched databases, including PubMed, EMBASE, and Cochrane, and included all eligible randomized controlled trials in the study. We conducted the statistical analysis using Stata version 14.0, based on the frequentist framework. We used the Cochrane Risk of Bias tool for randomized trials version 2 (RoB2) to assess the risk of bias of the included studies. RESULTS: This network meta-analysis included 14 randomized controlled trials with 4601 patients. For short-term prophylaxis, frovatriptan 2.5 mg twice daily had the highest probability of effectiveness [OR = 1.87 (95% CI: 1.48 to 2.38)] compared to placebo. For acute treatment, the results showed that sumatriptan 100 mg [OR = 4.32 (95% CI: 2.95 to 6.34)] was the most effective treatment compared to placebo. CONCLUSIONS: These findings suggest that frovatriptan 2.5 mg twice daily was best for short-term prevention, sumatriptan 100 mg were best for acute treatment. More high-quality randomized trials are required to determine the most effective treatment.

Duality in response of intracranial vessels to nitroglycerin revealed in rats by imaging photoplethysmography.

Among numerous approaches to the study of migraine, the nitroglycerin (NTG) model occupies a prominent place, but there is relatively insufficient information about how NTG affects intracranial vessels. In this study we aim to assess the effects of NTG on blood-flow parameters in meningeal vessels measured by imaging photoplethysmography (iPPG) in animal experiments. An amplitude of the pulsatile component (APC) of iPPG waveform was assessed before and within 2.5 h after the NTG administration in saline (n = 13) or sumatriptan (n = 12) pretreatment anesthetized rats in conditions of a closed cranial window. In animals of both groups, NTG caused a steady decrease in blood pressure. In 7 rats of the saline group, NTG resulted in progressive increase in APC, whereas decrease in APC was observed in other 6 rats. In all animals in the sumatriptan group, NTG administration was accompanied exclusively by an increase in APC. Diametrically opposite changes in APC due to NTG indicate a dual effect of this drug on meningeal vasomotor activity. Sumatriptan acts as a synergist of the NTG vasodilating action. The results we obtained contribute to understanding the interaction of vasoactive drugs in the study of the headache pathophysiology and methods of its therapy.

Rapid and naked-eye colorimetric detection of ultra trace sumatriptan in drinking water, saliva, and human urine samples based on the aggregation of gold nanoparticles.

In this study, the determination of sumatriptan (SUM) was performed using a simple, rapid, and precise colorimetric method based on the surface plasmon resonance (SPR) feature of gold nanoparticles (AuNPs). By adding SUM, the aggregation was observed in AuNPs with red-to-blue color shifts. The size distribution of NPs was estimated before and after adding SUM via dynamic light scattering (DLS), which was found to be 15.34 and 97.45 nm, respectively. Characterization of AuNPs, SUM, and AuNPs in combination with SUM was investigated using transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Examining the effect of pH, the volume of buffer, the concentration of AuNPs, interaction time, and ionic strength revealed that their optimal values were 6, 100 µL, 5 µM, 14 min, and 12 µg L-1, respectively. The suggested method was able to determine the amount of SUM in a linear range of 10 to 250 µg L-1 with a limit of detection (LOD) and limit of quantification (LOQ) of 0.392 and 1.03 µg L-1, respectively. This approach was successfully applied to determine SUM in drinking water, saliva, and human urine samples with relative standard deviations (RSD) lower than 0.03%, 0.3%, and 1.0%, respectively.

Sumatriptan, a serotonin 5HT1B receptor agonist, acutely reduces insulin secretion and sensitivity and glucose effectiveness in overweight humans: A double-blinded placebo-controlled cross-over trial.

AIM: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B -receptor agonist) would alter glucose homeostasis in humans. MATERIALS AND METHODS: We conducted a two-visit random-order double-blinded placebo-controlled cross-over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60-min intravenous glucose tolerance test, followed by a 120-min hyperinsulinaemic euglycaemic clamp. RESULTS: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0-60 min 316 (268-333) vs. 251 (197-319) min/mmol/L p = .047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0-10 min 1626 (1103-2733) vs. 2336 (1702-3269) min/pmol/L, p = .005], reduced insulin sensitivity [M/I-value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p = .010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p = .027]. CONCLUSIONS: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness.

The efficacy and safety of metoclopramide in relieving acute migraine attacks compared with other anti-migraine drugs: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Many drugs are prescribed in relieving acute migraine attacks, we aim to compare metoclopramide with other antimigraine drugs. METHODS: We searched online databases like PubMed, Cochrane Library, Scopus, and Web of Science till June 2022 for RCTs that compared metoclopramide alone with placebo or active drugs. The main outcomes were the mean change in headache score and complete headache relief. The secondary outcomes were the rescue medications need, side effects, nausea and recurrence rate. We qualitatively reviewed the outcomes. Then, we performed the network meta-analyses (NMAs) when it was possible. which were done by the Frequentist method using the MetaInsight online software. RESULTS: Sixteen studies were included with a total of 1934 patients: 826 received metoclopramide, 302 received placebo, and 806 received other active drugs. Metoclopramide was effective in reducing headache outcomes even for 24 h. The intravenous route was the most chosen route in the included studies and showed significant positive results regarding headache outcomes; however, the best route whether intramuscular, intravenous, or suppository was not compared in the previous studies. Also, both 10 and 20 mg doses of metoclopramide were effective in improving headache outcomes; however, there was no direct comparison between both doses and the 10 mg dose was the most frequently used dosage. In NMA of headache change after 30 min or 1 h, metoclopramide effect came after granisetron, ketorolac, chlorpromazine, and Dexketoprofen trometamol. Only granisetron's effect was significantly higher than metoclopramide's effect which was only significantly higher than placebo and sumatriptan. In headache-free symptoms, only prochlorperazine was non-significantly higher than metoclopramide which was higher than other medications and showed significantly higher effects only with placebo. In rescue medication, metoclopramide's effect was only non-significantly lower than prochlorperazine and chlorpromazine while its effect was higher than other drugs and showed higher significant effects only than placebo and valproate. In the recurrence rate, studies showed no significant difference between metoclopramide and other drugs. Metoclopramide significantly decreased nausea more than the placebo. Regarding side effects, metoclopramide showed a lower incidence of mild side effects than pethidine and chlorpromazine and showed a higher incidence of mild side effects than placebo, dexamethasone, and ketorolac. The reported extrapyramidal symptoms with metoclopramide were dystonia or akathisia. CONCLUSION: A dose of 10 mg IV Metoclopramide was effective in relieving migraine attacks with minimal side effects. Compared to other active drugs, it only showed a lower significant effect compared with granisetron regarding headache change while it showed significantly higher effects only with placebo in both rescue medication needs and headache-free symptoms and valproate in only rescue medication need. Also, it significantly decreased headache scores more than placebo and sumatriptan. However, more studies are needed to support our results.

Gastroprotective effect of sumatriptan against indomethacin-, stress- and ethanol-induced gastric damage in male rats: Possible modulatory role of 5-hydroxytryptamine 1B/1D receptors and pro-inflammatory cytokines.

The current study was aimed to investigate the beneficial effect of sumatriptan, a 5-hydroxytryptamine 1B/1D (5HT1B/1D ) receptor agonist, on gastric ulcer in rats via stimulating 5HT1B/1D receptors and suppressing pro-inflammatory cytokines. Rats were allocated into three models of gastric ulcer: indomethacin (30 mg/kg, PO), water immersion restraint stress (WRS) and ethanol (5 ml/kg PO). Animals were administered with sumatriptan (0.01, 0.1, 0.3 and 1 mg/kg, i.p) 30 min before gastric ulcer induction. GR-127935 (0.01 mg/kg, i.p, a selective 5HT1B/1D antagonist) was administered 30 min before sumatriptan (0.1 mg/kg) injection. Macroscopic assessments (J-score), ELISA analysis of tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) and histopathological changes were performed on the rat's stomach tissues. Gastric ulcer induction in three models caused an increase in J-score, TNF-α, IL-1ß and microscopic features. Sumatriptan (0.1 mg/kg) significantly improved gastric injury induced by indomethacin, WRS and ethanol through the reduction in the J-score, TNF-α, IL-1ß and microscopic lesions. Concurrent administration of GR-127935 (0.01 mg/kg) with sumatriptan (0.1 mg/kg) reversed the gastroprotective effect of sumatriptan in three models. Sumatriptan possessed gastroprotective effects on indomethacin-, WRS- and ethanol-induced gastric damage in rats via the possible involvement of the 5HT1B/1D receptors.

The Efficacy of Different Triptans for the Treatment of Acute Headache in Pediatric Migraine: A Systematic Review.

BACKGROUND: Serotonin receptors 5-HT1B and 5-HT1D in the cerebral arteries are activated by the 5-hydroxytryptophan agonists (triptans) to relieve the discomfort associated with migraines. Even though triptans are often used to treat acute migraines, there is some debate over their effectiveness. OBJECTIVE: Our systematic review aimed to evaluate the effectiveness of triptans for acute treatment of migraine in young individuals. METHODS: Utilizing the databases of Google Scholar, Cochrane Library, and PubMed, a literature search was conducted, and all papers published till July 2022 were included. This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. In addition to the Boolean operators AND, OR, and NOT, the following descriptive terms were also used: "Triptans," "Pediatric Migraine," "Migraine disorders," "Headache," "Children," and "Adolescent." RESULTS: A total of 1047 studies were identified, and 25 articles were finally included in the study. 17 of them were RCTs while the remaining were non-randomized trials. Most studies recruited participants aged between 12-17 years. Among 25 studies, 7 reported sumatriptan use, 3 assessed a combination of sumatriptan and naproxen, 4 were on almotriptan, 1 on eletriptan, 6 on rizatriptan, and 4 on zolmitriptan use. CONCLUSION: We found that rizatriptan (good tolerability profile with a dose of 5 mg) and sumatriptan (nasal spray, 10 mg and 20 mg) had higher efficiency as compared to other triptans. Regardless of type or dose, all triptans are generally well tolerated by patients, but a few adverse effects such as light-headedness (sumatriptan), nasopharyngitis, and, muscular spasms (sumatriptan/ naproxen), somnolence, and dry mouth (rizatriptan), and dizziness (zolmitriptan group) were reported with the triptans.