Migraine

Riesco, Nuria; García-Cabo, Carmen; Pascual, Julio
doi:10.1016/j.medcle.2016.04.048
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Options for the symptomatic treatment of migraine&#46; NSAIDs&#58; nonsteroidal anti-inflammatory drugs&#59; IV&#58; intravenous&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Most headaches are primary headaches&#46; By primary headaches it is understood headaches with no demonstrable cause and whose diagnosis lies in clinical criteria related to anamnesis and a normal examination&#46; More than 90&#37; of primary headaches are migraine or a tension headache&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> Approximately 15&#37; of the population meets the diagnostic criteria for migraine&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> Migraine is 2&#8211;3 times more common in females&#46; The prevalence of active migraine decreases from the age of 50&#46; In our area&#44; the prevalence of chronic migraine is 2&#46;4&#37; of the population&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> and the prevalence of chronic migraine with analgesic overuse criteria&#44; 0&#46;9&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">These data show that migraine&#44; an entity to which medical professionals often do not pay enough attention due to not being life threatening&#44; is a disease that should be recognized and treated&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Aetiology and pathophysiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Migraine has a strong inherited component&#46; 3 genes have been identified for an extremely rare&#44; migraine autosomal-dominant variant&#58; the familial hemiplegic migraine&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> The three genes involved are actually neuronal membrane channels involved in ion exchange processes&#46; In summary&#44; these mutations result in increased intracellular calcium and extracellular potassium and glutamate&#44; which determines a state of cell hyperexcitability capable of generating the cortical spreading depression phenomenon&#44; responsible for the aura&#46; The wide genetic association studies or GWAS &#40;<span class="elsevierStyleItalic">genome-wide association studies</span>&#41; have identified up to 42 <span class="elsevierStyleItalic">loci</span> potentially associated with common forms of migraine&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a> At the moment&#44; none of these <span class="elsevierStyleItalic">loci</span> has identified a gene that explains consistently and jointly migraine pathogenesis&#46; In light of these findings&#44; migraine might not be a single entity&#44; but the common phenotypic expression of heterogeneous genetic changes&#44; or a polygenic condition in which genetic changes interact with various environmental factors&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The pathophysiology of migraine is known in considerable detail&#46; The brainstem is the generator of migraine&#44; specifically the area that corresponds to the locus coeruleus and raphe nuclei&#44; innervation cerebral sources for catecholamines and serotonin&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> The aura is due to a phenomenon of cortical spreading depression&#44; which is a cortical depolarization wave which advances forward at a rate of 3<span class="elsevierStyleHsp" style=""></span>mm&#47;min from the occipital lobe&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> Trunk activation results in activation of the so-called trigeminal vascular system&#44; formed by the trigeminal nerve and the parasympathetic nerve portion of the facial nerve&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> When activated&#44; this system&#39;s terminations dilate the cranial vessels sensitive to pain&#44; mostly leptomeningeal&#44; and release algogenic neuropeptides mainly by the trigeminal&#44; the <span class="elsevierStyleItalic">calcitonin gene-related peptide</span> &#40;CGRP&#41;&#44; and by the parasympathetic autonomic system&#44; the vasoactive intestinal peptide&#44; which induce dilation and sterile inflammation&#46; Both vascular phenomena&#44; dilation and leptomeningeal inflammation&#44; are responsible for migraine pain and are negatively controlled by two serotonin receptors&#44; the 5-HT1B receptor&#44; located postsynaptically on the vascular wall and responsible for vasodilation&#44; and 5-HT1D&#44; located in the presynaptic terminals and trigeminal nerve responsible for peptide release&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> It has been shown that frequent release of these algogenic peptides may induce a phenomenon of sensitization of the central lines of pain control&#44; which would be the pathophysiological substrate of migraine chronicity&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Diagnosis</span><p id="par0025" class="elsevierStylePara elsevierViewall">The diagnosis of migraine is clinical&#46; The most common form of migraine is called &#8220;migraine without aura&#8221;&#46; Diagnostic criteria are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> As we will next review&#44; migraine is a chameleonic disease&#44; and sometimes more complex than these simple criteria indicate&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Migraine is an entity both chronic and episodic&#44; often precipitated by various triggers&#46; It manifests itself in the form of crisis or attacks&#44; and between these&#44; the patient is fine&#46; The attacks begin very characteristically in the first 2 decades of life&#44; never above 50 years of age&#46; The frequency of episodes is variable&#44; ranging between one a year and several a week&#44; although a typical migraine patient has between one crisis every two months and one every week&#46; Migraine attacks are composed of 3 major and distinct phases&#58; prodrome&#44; aura and headache and associated symptoms&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The prodrome precedes the rest of migraine symptoms between a few hours and a maximum of 2 days&#46; Approximately one third of patients with migraine refer prodromal symptoms&#44; either <span class="elsevierStyleItalic">inhibitory</span>&#44; such as mental sluggishness&#44; fatigue or anorexia&#44; or <span class="elsevierStyleItalic">excitatory</span>&#44; such as irritability&#44; euphoria&#44; yawning or craving for certain foods&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Up to a third of patients occasionally experience &#8220;aura&#8221; that is&#44; transient focal symptoms of pain immediately before or coinciding with its appearance&#46; We must be familiar with the semiotics of migraine aura&#44; not only for its significant frequency&#44; but because the migraine aura itself is one of the reasons that most often lead the patient to the doctor&#46; Migraine aura symptoms must be reversible in 60<span class="elsevierStyleHsp" style=""></span>min&#44; maximum&#44; they develop gradually&#44; and typically include positive phenomena&#44; photopsias type&#44; coloured zigzag images or paresthesias&#46; More than 90&#37; of the auras have a visual component and nearly two thirds of patients with migraine have auras with isolated visual symptoms&#46; The characteristic visual aura begins as a scotoma&#44; which appears on the point of vision and grows larger in a visual hemifield&#46; Typically&#44; the edges of the scotoma are bright and colourful in nature&#44; a phenomenon known by the name of &#8220;fortification spectra&#8221;&#46; The sensory symptoms are second in frequency&#44; between 30&#8211;40&#37; of auras occur with cheiro-oral paresthesias established progressively in minutes&#46; In less than 20&#37; of auras&#44; the symptoms include aphasia&#44; and except in the hemiplegic migraine variant&#44; motor symptoms are exceptional&#44; which&#44; along with positive visual symptoms&#44; help regarding differential diagnosis with transient stroke&#46; There is migraine variant&#44; with basilar aura&#44; in the form of bilateral visual blur&#44; dizziness&#44; diplopia&#44; ataxia&#44; paresthesias or bilateral weakness and decreased level of consciousness&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Many migraine patients only experience the headache phase &#40;and associated symptoms&#41;&#46; The duration of pain ranging from 4 &#40;without treatment&#41; to 72<span class="elsevierStyleHsp" style=""></span>h &#40;median 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h&#41; except in children&#44; in which the duration may be less than 4<span class="elsevierStyleHsp" style=""></span>h&#46; Pain is only hemicranial in 50&#37; of cases&#46; Most patients with bilateral pain&#44; however&#44; report that this rests primarily in the anterior region &#40;temple or periocular&#41; of one of the hemicrania&#46; A small percentage of patients&#44; those with basilar migraine&#44; experience occipital pain&#46; The migraine attack begins as hemicranial discomfort&#44; which&#44; between 30 and 120<span class="elsevierStyleHsp" style=""></span>min&#44; transforms gradually into moderate pain &#40;interferes with common tasks&#41; or severe pain &#40;prevents them&#41;&#46; The pain is referred to as pulsatile and is aggravated by light &#40;photophobia&#41;&#44; noises &#40;phonophobia&#41; and physical exercise&#44; and is accompanied by symptoms&#44; generally digestive in nature&#44; especially nausea and&#44; to a lesser extent&#44; diarrhoea or vomiting&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">We know there are certain syndromes in childhood that are precursors of migraine in adulthood&#46; These include cyclic vomiting&#44; abdominal migraine and benign paroxysmal vertigo&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Chronic migraine</span><p id="par0055" class="elsevierStylePara elsevierViewall">In short&#44; it is understood that chronic migraine is a clinical situation in which a patient with a history of migraine has headaches during 15 or more days a month&#44; who retains migraine characteristics during at least 8 days a month&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> More than a third of patients who consult meet criteria for painkiller abuse&#59; that is&#44; they take simple analgesics or nonsteroidal anti-inflammatory drugs &#40;NSAIDs&#41; more than 15 days a month&#44; or ergotics&#44; triptans or opiates more than 10 days a month&#46; Chronic migraine justifies one in 25 standard Neurology consultations in our country and is difficult to treat entity&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">12&#44;13</span></a> Because many cases are associated with analgesic and drug abuse&#44; with vasoconstrictor effects&#44; it is not uncommon to find that these patients have a history of hypertension or gastric problems &#40;gastritis&#44; peptic ulcer&#44; hiatal hernia&#44; etc&#46;&#41;&#46; The list of co-morbidities and predisposing factors does not end here&#46; It is well known that these patients have a higher than expected overweight&#44; depression&#44; anxiety&#44; personality disorder or fibromyalgia incidence&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Complications of migraine</span><p id="par0060" class="elsevierStylePara elsevierViewall">The migraine attacks that go over 72<span class="elsevierStyleHsp" style=""></span>h are renamed as <span class="elsevierStyleItalic">status migrainosus</span>&#44; which requires specific hospital treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> Many of these patients with status migrainosus have chronic migraine and meet the painkiller abuse criteria&#46; In a minority of patients&#44; the aura lasts for over a week with no evidence of ischaemia in neuroimaging&#46; This clinical condition is known as <span class="elsevierStyleItalic">persistent aura without infarction</span> and it is usually visual&#44; bilateral and lasts for months or years&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> In a minority of patients&#44; an epileptic seizure occurs within a migraine aura&#46; This clinical condition is known as <span class="elsevierStyleItalic">migralepsy</span> and must be differentiated from the headache that occurs after an epileptic seizure&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> Any symptoms of migraine aura that are associated with cerebral ischaemic injury confirmed by neuroimaging&#44; clinically consistent with the aura are considered as a <span class="elsevierStyleItalic">migrainous infarction</span>&#46; The real migrainous infarction occurs mainly in the posterior circulation and affects young women&#44; and its diagnosis also requires the lack of any other cause&#46; Several population studies have shown that patients&#44; mainly women younger than 45&#44; suffering migraine with aura&#44; double the risk of ischaemic stroke&#46; However&#44; it should be noted that many of these strokes are not true migrainous infarctions and we do not know the relationship between the frequency and the pathophysiology of the aural symptoms denoting increased risk&#46; Most studies have shown a lack of association between migraine without aura and ischaemic stroke&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Complementary studies and differential diagnosis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Simply applying the criteria&#44; differential diagnosis of migraine with other primary headaches&#44; such as tension headache&#44; cluster headache or hemicrania continua&#44; is simple&#46; There are no findings in laboratory parameters or neurophysiological and neuroimaging studies that allow diagnosis confirmation&#46; In the future&#44; the serum levels of CGRP and vasoactive intestinal peptide may be able to help in the diagnosis of migraine&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">14&#44;15</span></a> The diagnosis of migraine does not require any additional study in a patient with a normal physical examination that presents with painful episodic attacks of migrainous characteristics&#46; This implies that in more than 90&#37; of patients with migraine&#44; diagnosis is made solely with a formal medical history and a standard physical examination&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">When should we request additional studies in patients with migraine and what kind of studies&#63; The neuroimaging &#40;CT or cranial MRI&#41; are only indicated in patients with atypical migraine attacks&#44; in patients with non-visual migraine aura&#44; if the pain is always located on the same side of the head and in patients with a recent increase in the frequency of their attacks&#46; It is important to insist that the only evidence able to rule out headache secondary to a structural process are neuroimaging techniques&#59; that is&#44; tests such as electroencephalogram are not indicated in the routine differential diagnosis of headaches&#44; unless we think it might be a case of migralepsy&#46; In patients with atypical auras &#40;e&#46;g&#46;&#44; those including hemiparesis or lasting more than 60<span class="elsevierStyleHsp" style=""></span>min&#41;&#44; apart from neuroimaging studies&#44; antiphospholipid antibodies or thrombophilia studies can be requested&#46; There are some entities&#44; including CADASIL&#44; reversible cerebral vasoconstriction syndrome&#44; pseudomigraine with pleocytosis&#44; SMART or MELAS&#44; which may mimic a migraine headache with atypical aura&#44; but a regulated medical history should enable us to get close to a diagnosis and then request the appropriate complementary studies in each case&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Treatment</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">General measures</span><p id="par0075" class="elsevierStylePara elsevierViewall">After the diagnosis of migraine&#44; an understandable explanation of the process needs to be given to the patient&#46; It is important to explain that migraine is a recurrent and episodic disease for which there is no cure&#44; but in general&#44; it can be controlled&#46; Clarify the differences between the treatment of acute attacks and the preventive treatment&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The next step is to identify possible triggers&#46; These are varied and complex&#44; since they are particular to each patient&#46; In addition&#44; many of these potential factors are impossible to avoid in patients with migraine&#46; For the vast majority of patients&#44; treatment solely based on preventing the triggers may achieve a marginal therapeutic effect&#44; at the most&#44; and&#44; today&#44; drug treatment is necessary&#46; In any case&#44; we must recommend the patient to have a healthy lifestyle&#44; being as orderly as possible regarding daily schedules&#44; doing regular exercise and trying to avoid overweight&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Symptomatic or attack treatment</span><p id="par0085" class="elsevierStylePara elsevierViewall">Symptomatic treatment is mandatory in all migraineurs&#46; Medications for the treatment of migraine may be divided into nonspecific&#44; specific and adjuvants&#46; Nonspecific medications include analgesics and NSAIDs&#46; Specific drugs include ergotics and 5-HT 1B&#47;D receptors agonists&#44; commonly known as &#8220;triptans&#8221;&#46; The adjuvants are fundamentally antiemetic&#47;prokinetics medications &#40;domperidone&#44; metoclopramide&#41;&#44; required in patients with nausea and vomiting&#46; Analgesics have a very limited use in the treatment of migraine&#44; so their indication is very limited &#40;migraine in childhood and adolescence&#41;&#46; It is advisable to avoid combinations of analgesics with barbiturates&#44; codeine and&#47;or caffeine because of the risk of developing chronic headache due to abuse of these drugs&#46; Because of their side effects and because&#44; in our country&#44; commercial presentations include other analgesics&#44; caffeine and&#47;or barbiturates&#44; ergotics are not recommended&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Symptomatic treatment of migraine resides therefore in the judicious use of triptans and NSAIDs&#46; Patients with mild to moderate migraine attacks may be treated initially with oral NSAIDs&#44; preferably in combination with metoclopramide or domperidone&#46; Not all NSAIDs are useful in migraine&#46; NSAIDs with well proven efficacy available in our area are&#58; acetylsalicylic acid&#44; naproxen sodium&#44; ibuprofen and dexketoprofen&#46; Patients with mild-moderate attacks and lack of response or intolerance to NSAIDs have to be treated with triptans&#46; Triptans are drugs with proven efficacy in the symptomatic treatment of migraine attacks&#44; being of choice in moderate-severe type&#46; Its contraindication is ischaemic heart disease&#46; Triptans marketed and their specific indications are collected in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; There are currently seven triptans marketed&#44; which do not differ in their mechanism of action&#44; but have relevant pharmacokinetic differences that make certain triptans more suitable than others depending on the type of attack&#46; In patients with nausea or vomiting&#44; liotab or nasal formulations may be used&#46; If the patient does not respond to these options&#44; we can use the subcutaneous formulation of sumatriptan and&#47;or dexketoprofen trometamol or parenteral diclofenac with parenteral metoclopramide &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Preventive treatment</span><p id="par0095" class="elsevierStylePara elsevierViewall">It is estimated that at least 25&#37; of patients who consult need preventive treatment&#46; Preventive treatment has as main objective to reduce the frequency of attacks and make these milder and therefore easier to deal with&#46; This treatment is our unfinished business in this field&#58; it is estimated that less than 10&#37; of patients who consult receive it&#46; It is indicated for those who have 3 or more migraine attacks per month&#46; It has to be maintained for a recommended period of 6&#8211;12 months&#44; with a minimum of 3 months&#46; Preventive treatment should be kept at least for 6 weeks before considering that the drug that is being used does not have therapeutic utility&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Drugs with proven efficacy in the preventive treatment of standard migraine &#40;without aura or with typical aura&#41; are&#58; some beta-blockers&#44; candesartan&#44; flunarizine&#44; amitriptyline and some antiepileptic drugs&#46; Indications&#44; recommended dose and adverse effects of these drugs are variable and are listed in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; Beta blockers are of choice in patients with migraine without aura and have no use contraindications &#40;asthma and diabetes&#44; mainly&#41;&#46; The most commonly used in our area are propranolol and nadolol at doses of between 40 and 80<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a> One option of recently demonstrated efficacy in patients with contraindications to beta-blockers is candesartan at doses of 8&#8211;32<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a> Traditionally&#44; in our area&#44; flunarizine &#40;2&#46;5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;dinner&#41; was the drug of choice for patients without efficacy or intolerance&#47;contraindication to the use of beta-blockers&#46; AEDs are the most recommended drugs for most of the people who have not responded to beta-blockers or candesartan&#44; except children and very thin women without a history of depression&#44; as their side effects are mainly overweight and depression&#46; 2 antiepileptic drugs with well proven efficacy in migraine are topiramate &#40;ideal dose 100<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and valproic acid &#40;usual dose 500&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#46; Valproic acid needs lab tests to control the possibility of inducing fulminant hepatitis or disorders in the blood count&#46; Topiramate advantages relate to its quick efficacy&#44; which does not require lab tests control and being the only drug which does not induce overweight&#46; Therefore&#44; topiramate should be the antiepileptic drug of choice&#46; However&#44; 20&#37; of patients cannot tolerate it due to adverse effects&#44; including distal paresthesias&#44; difficulty in mental concentration&#44; abdominal pain&#44; weight loss&#44; depression&#44; acute glaucoma&#44; and renal calculi&#46; Data from open series of patients indicate that zonisamide &#40;100&#8211;300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#44; a drug profile very similar to topiramate is also useful in preventing migraine&#46; Amitriptyline&#44; at low doses of between 10 and 50<span class="elsevierStyleHsp" style=""></span>mg &#40;evening dinner&#47;supper&#41; is the only antidepressant with proven efficacy in preventing migraine&#44; especially when associated with tension headache&#46; Fluoxetine and other serotonin reuptake inhibitors have not proven effective in preventing migraine&#44; regardless of their antidepressant effect&#44; which can be useful in these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">In refractory patients with chronic migraine&#44; clinical practice has proven that combinations of these drugs&#44; in general&#44; a beta blocker or candesartan with topiramate&#44; are useful as they induce a synergistic effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">19&#44;20</span></a> If there is no response or an antiepileptic &#40;preferably topiramate&#41; and&#47;or a beta blocker or candesartan are not tolerated in patients with chronic migraine&#44; quarterly pericranial injections of botulinum toxin type A are indicated&#44; which&#44; at doses of between 155 and 195 units at least 31 points&#44; have shown efficacy over placebo controlled trials&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> It has been shown that the toxin does not act due to its muscle relaxant effect&#44; but appears to decrease the pericranial release of algogenic peptides mainly CGRP&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> In clinical practice botulinum toxin type A achieves a significant reduction of migraine attacks as regards number of episodes&#44; but mainly in relation to severity&#44; in 70&#37; of patients with chronic migraine&#44; with excellent tolerability&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a> Other advantages are that this drug produces no systemic or central nervous system effects&#44; and can be combined with oral preventive drugs&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Special situations</span><p id="par0110" class="elsevierStylePara elsevierViewall">In children&#44; adjusting doses to the weight&#44; the recommendations of symptomatic and preventive treatment are similar to those of adults for most drugs&#46; Among triptans&#44; sumatriptan nasal 10<span class="elsevierStyleHsp" style=""></span>mg and almotriptan have studies in children&#47;adolescents with positive results&#46; As to preventive treatment&#44; a drug that is not recommended in adults&#44; but it can be effective in children&#44; is cyproheptadine&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Migraine is the main neurological disease during pregnancy&#44; regarding frequency&#46; Some migraine patients go through an ordeal during pregnancy&#44; as all kinds of medication are denied to them&#44; except paracetamol&#46; Clinical practice and prospective pregnancy registries have shown that sumatriptan and propranolol are safe during pregnancy as symptomatic and preventive treatment&#44; respectively&#46; Not only can we prescribe these drugs in pregnant women with incapacitating migraine attacks&#44; after the appropriate patient explanation of the risk&#47;benefit ratio&#44; but we should consider prescribing these drugs also to women likely to get pregnant&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The aura will have to be treated in a minority of patients due to their frequency or because of their incapacitating symptoms &#40;e&#46;g&#46;&#44; basilar migraine&#41;&#46; In these cases&#44; lamotrigine is indicated at doses between 100 and 200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0125" class="elsevierStylePara elsevierViewall">Dr&#46; Julio Pascual has been a scientific advisor to Allergan&#46; The other authors declare no conflicts of interest&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Riesco N&#44; Garc&#237;a-Cabo C&#44; Pascual J&#46; Migra&#241;a&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;35&#8211;39&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Options for the symptomatic treatment of migraine&#46; NSAIDs&#58; nonsteroidal anti-inflammatory drugs&#59; IV&#58; intravenous&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">A&#46; At least five attacks that meet the B&#8211;D criteria</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">B&#46; 4&#8211;72</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">h long headache episodes &#40;untreated or unsuccessfully treated&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&#46; Unilateral location&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2&#46; Pulsatile character&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>4&#46; Routine physical activity is made worse by it or causes its abandonment &#40;e&#46;g&#46;&#44; walking or climbing stairs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">D&#46; At least has one of the following during the headache&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&#46; Nausea and&#47;or vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2&#46; Photophobia and phonophobia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">E&#46; No better explanation by another diagnosis</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Compound&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Formulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Indication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sumatriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcutaneous 6<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe attacks resistant to oral and nasal route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nasal 20<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Attacks resistant to oral route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients with vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nasal 10<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Children and adolescents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 50<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Standard migraine patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patient likely to get pregnant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zolmitriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 2&#46;5&#8211;5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Standard migraine patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nasal 5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Attacks resistant to oral route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients with vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Naratriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild to moderate long-term attacks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adverse effects with other triptans&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rizatriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 10<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe&#44; fast and short attacks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Almotriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Standard migraine patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Side effects with other triptans&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Eletriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 20 and 40<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe attacks&#44; long duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Frovatriptan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild to moderate attacks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long duration attacks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adverse effects with other triptans&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Compound</th><th class="td" title="table-head  " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Indications</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse effects</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Beta-blockers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine without aura&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fatigue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dizziness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bradycardia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and shaking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Orthostatic hypotension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bronchoconstriction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Impotence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insomnia&#47;nightmares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Distal coldness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Candesartan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine with&#47;without aura&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fatigue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Kidney failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hyperkalaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Teratogenicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Topiramate&#47;zonisamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine with&#47;without aura&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Distal paresthesias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Glaucoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chronic migraine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cognitive symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrolithiasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and overweight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intestinal disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weightloss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Valproic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory migraine with&#47;without aura&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nausea&#47;vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chronic migraine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Drowsiness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ovarian cysts&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overweight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Thrombocytopenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shaking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alopecia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Teratogenicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Flunarizina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine with and without aura in children&#47;adolescents or thin adults without tendency to depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Parkinsonism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Drowsiness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Galactorrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overweight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Amitriptyline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and tension headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Drowsiness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cognitive symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Constipation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Urinary retention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Migraine and insomnia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overweight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Glaucoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Skin&#47;mucous dryness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Palpitations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Botulinum toxin type A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chronic migraine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ptosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diplopia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cervicalgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dysphagia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Indications and major adverse effects of drugs effective in the preventive treatment of migraine&#46;</p>"
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