Chemical Mediators of Migraine: Preclinical and Clinical Observations

Gupta, Saurabh; Nahas, Stephanie J.; Peterlin, B. Lee

doi:10.1111/j.1526-4610.2011.01929.x

Cited by 37 publications

(31 citation statements)

References 221 publications

(227 reference statements)

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“…3,4 In patients with a history of migraine, an acute headache can be induced by histamine infusion, which can be blocked by co-administration of an antihistamine. 5 These data are consistent with the hypothesis that histamine contributes to migraine pathogenesis, particularly among patients who are prone to allergy, and that centrally-acting anti-histamines may be a useful treatment for acute migraine.…”

supporting

confidence: 87%

Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department–Based Randomized Clinical Trial

Friedman

Cabral

Adewunmi

et al. 2016

Annals of Emergency Medicine

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Background More than one million patients present to US emergency departments (ED) annually seeking care for acute migraine. Parenteral anti-histamines have long been used in combination with anti-dopaminergics such as metoclopramide to treat acute migraine in the ED. High quality data supporting this practice do not exist. We determined whether administration of diphenhydramine 50mg IV + metoclopramide 10mg IV resulted in greater rates of sustained headache relief than placebo+ metoclopramide 10mg IV. Methods This was a randomized, double-blind clinical trial comparing two active treatments for acute migraine in an ED. Eligible patients were adults younger than 65 years presenting with an acute moderate or severe headache meeting International Classification of Headache Disorders-2 migraine criteria. Patients were stratified based on presence or absence of allergic symptoms. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within two hours of medication administration, and maintaining this level of relief without use of any additional headache medication for 48 hours. Secondary efficacy outcomes include mean improvement on a 0 to 10 verbal scale between baseline and one hour, the frequency with which subjects indicated they would want the same medication the next time they present to the ED with migraine, and the ED throughput time. Sample size calculation using a 2-sided alpha of 0.05, a beta of 0.20 and a 15% difference between study arms determined the need for 374 patients. An interim analysis was conducted when data were available for 200 subjects. Results 420 patients were approached for participation. 208 eligible patients consented to participate and were randomized. At the planned interim analysis, the data safety monitoring committee recommended that the study be halted for futility. Baseline characteristics were comparable between the groups. 14% (29/208) of the sample reported allergic symptoms. Of patients randomized to diphenhydramine, 40% (40/100) reported sustained relief at 48 hours, as did 37% (38/103) of patients randomized to placebo (95%CI for difference of 3%: −10, 16%). One hour after medication administration, those randomized to diphenhydramine improved by a mean of 5.1 on the 0 to 10 scale versus 4.8 for those randomized to placebo (95%CI for difference of 0.3: −0.6, 1.1). 85% (84/99) of the patients in the diphenhydramine arm reported they would want the same medication combination during a subsequent ED visit, as did 76% (77/102) of those who received placebo (95%CI for difference of 9%: −2, 20%). Median ED length of stay was 122 minutes (IQR: 84, 180) in the diphenhydramine group and 139 minutes (IQR: 90, 235) in the placebo arm. Rates of side effects, including akathisia, were comparable between the groups. Conclusions Intravenous diphenhydramine, when administered as adjuvant therapy with metoclopramide, does not improve migraine outcomes.

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supporting

confidence: 87%

Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department–Based Randomized Clinical Trial

Friedman

Cabral

Adewunmi

et al. 2016

Annals of Emergency Medicine

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“…AMS headache may result from hypoxia-induced cerebral vasodilatation or its effectors, such as nitric oxide (NO), perhaps through activation of the trigeminovascular system9 and cerebral venous hypertension 10. At low altitude NO plays a role in tension type headache and NO prodrugs are associated with headache and nausea 11. Nitroglycerin causes headache and exacerbates AMS12 as does sildenafil 13.…”

Section: Discussionmentioning

confidence: 99%

Smoking, acute mountain sickness and altitude acclimatisation: a cohort study

Ding²,

Liu³

et al. 2012

Thorax

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RationaleThe relationship between cigarette smoking and acute mountain sickness (AMS) is not clear. Objective To assess AMS risk and altitude acclimatisation in relation to smoking. Methods 200 healthy non-smokers and 182 cigarette smokers were recruited from Han lowland workers. These were men without prior altitude exposure, matched for age, health status and occupation, who were transported to an altitude of 4525 masl. Measurements AMS, smoking habits, arterial saturation (SpO 2 ), haemoglobin (Hb), lung function and mean pulmonary artery pressure (PAPm) were assessed upon arrival and after 3 and 6 months. Main results Compared with non-smokers, smokers had a lower incidence of AMS and lower AMS scores than non-smokers upon arrival; higher Hb and PAPm associated with lower SpO 2 at 3 and 6 months at altitude; and lower forced expiratory volume in 1 s and maximal voluntary ventilation at 3 and 6 months. Conclusions Smoking slightly decreases the risk of AMS but impairs long-term altitude acclimatisation and lung function during a prolonged stay at high altitude.

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“…Thus, NO may be involved in the pathophysiology of neurodegenerative, 1,2,4,6,11,12 inflammatory, 53 vascular, 55-57 metabolic, 58 and traumatic 64 disorders, and in the pathophysiology of pain, including migraine. 65 NO may also have a role in the biology of neoplasms, 66 including gliomas, 67 and may contribute to mechanisms of depression and effects of lithium and antidepressant drugs. 68 With exception of NMDAR antagonists, 12 there are no currently available drugs that affect NO production or its effects in the CNS.…”

Section: Figurementioning

confidence: 98%

Nitric oxide

Benarroch

2011

Neurology

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Nitric oxide (NO) is a gaseous chemical transmitter that is produced from the amino acid L-arginine by the members of the NO synthase (NOS) family of proteins. NO is involved in several important functions in the CNS and peripheral nervous system (PNS), including modulation of neurotransmission and regulation of local blood flow and immune responses. NO interacts with intracellular targets to trigger several signal transduction pathways. In the CNS, NO participates in synaptic modulation and plasticity, control of sleep, body temperature, and neurosecretion. In the PNS, NO mediates vasodilation and relaxation of the visceral smooth muscle. However, when produced in excess and in the setting of oxidative stress, NO becomes toxic, leading to formation of reactive nitrogen species (RNS), which cause cellular damage. These neurotoxic effects of NO derivatives may be involved in the pathogenesis of cerebral ischemia, inflammation, neoplasia, and neurodegenerative disorders. There are several comprehensive reviews on the physiologic and pathophysiologic roles of NO in the nervous system. 1-12 NITRIC OXIDE SYNTHASES Catalytic activity.The NOS family of enzymes catalyzes the oxidation of L-arginine to form L-citrulline and NO (figure 1). NOS is a dimeric enzyme; each monomer is composed of 2 distinct catalytic domains, an amino (NH2)-terminal oxygenase domain and a carboxy (COOH)-terminal reductase domain. The oxygenase domain is the binding site for heme, oxygen (O 2 ), tetrahydrobiopterin (BH4), and L-arginine; the reductase domain binds flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and reduced nicotinamide-adenine dinucleotide phosphate (NADPH). The catalytic mechanism involves flavin-mediated electron transport from NADPH to the heme center, where O 2 is reduced and incorporated into the guanidine nitrogen of L-arginine, producing NO and L-citrulline.

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Chemical Mediators of Migraine: Preclinical and Clinical Observations

Cited by 37 publications

References 221 publications

Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department–Based Randomized Clinical Trial

Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department–Based Randomized Clinical Trial

Smoking, acute mountain sickness and altitude acclimatisation: a cohort study

Nitric oxide

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