Treatment of acute migraine attacks.
Migraine characterized by recurrent headache episodes presents with aura or without. Various treatment modalities ranging from 5-HT1B/1D agonists, nonsteroidal anti-inflammatory drugs (NSAIDs), to steroids are available for acute treatment of migraine. Prophylaxis for chronic cases usually encompasses β blockers, calcium channel blockers, and antiepileptics. Many nutraceutical preparations are helpful in migraine, including riboflavin and vitamin B12. This review focuses on the newer agents available for treatment of migraine with some insights into their clinical trials.
- cortical spreading depression
The word “migraine” comes from the
2. Signs and symptoms
Migraine is self-limiting, usually presenting as recurrent severe
3. The pathophysiology of migraine
The best solutions to medical conditions come only from understanding the pathophysiology of the disease state. As per Wolff’s vascular theory, vascular constriction leading to hypoperfusion of the cortex later followed by vascular dilation was put forward as the main pathophysiological mechanism. Currently neurovascular hypothesis involving the trigeminovascular system is considered. Another hypothesis includes mutations of neuronal calcium channels, leading to hypersensitivity, resulting in migraine attacks. It is also postulated that increased dopaminergic activity in the thalamus/hypothalamus causing modulation in central pain pathways also plays a role in migraine attacks. Other mechanisms put forward include cortical spreading depression; release of vasoactive peptides like substance P, calcitonin gene-related peptide (CGRP) from trigeminal neural endings, nitric oxide, and serotonin; excess activation of N-methyl-
4. Treatment of migraine
It can be divided into treatment of acute attacks and treatment of chronic migraine. As per the US consortium (2000), recommended guidelines  for treatment of acute migraine include pharmacological and non-pharmacological modalities as shown in Table 1.
5. Specific treatment
Triptans are selective agonists of 5-HT1B and 5-HT1D receptors. The mechanism of action includes intracranial vessel vasoconstriction (5-HT1B), peripheral neuronal inhibition (5-HT1D), and presynaptic dorsal horn stimulation (5-HT1D), producing second-order brain stem neuronal inhibition. Triptans influence the function of 5-hydroxytryptamine 1F (5-HT1F) receptors and enhance descending inhibitory pain pathways. Triptans reduce—to a considerable extent—pain severity in 2 h as per randomized controlled trials. Oral formulations are usually preferred over other formulations, but 6 mg subcutaneous injection of sumatriptan appears to be the most efficacious. As per current evidence, all oral formulations have equal efficacy except for frovatriptan which is less efficacious but has longer duration action. Parenteral preparations are more useful than oral ones, but the choice of medications depends on the clinician as well as the patient. Triptans are the first-line drugs used in acute treatment of moderate-to-severe migraine with the best pain relief occurring if it is taken within 30 min of attack, and a second dose is usually recommended after 2–4 h of initial dose. It is best used in combination with antiemetics and NSAIDs. Adverse effects include serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (SSRIs), and it should be used with caution in patients having ischemic heart disease [14, 15, 16, 17, 18, 19, 20, 21, 22]. Characteristics of triptans are summarized in Table 2.
|Drugs||Half life||Maximum daily dose|
|Group 1: fast-acting triptans|
|Sumatriptan||3 h||200 mg oral|
40 mg intranasal
12 mg subcutaneous
|Rizatriptan||2–3 h||30 mg (15 mg if on propranolol)|
|Almotriptan||3–4 h||25 mg|
|Zolmitriptan||3 h||Two tablets or 10 mg maximum oral daily dose. Two sprays or 10 mg intranasal|
|Eletriptan||4 h||80 mg|
|Group 2: slow-acting triptans|
|Frovatriptan||26 h||7.5 mg|
|Naratriptan||6 h||5 mg|
6. Ergot and derivatives
Ergots act on multiple receptors including the 5-HT ones, and these account for a robust side effect profile. It is used in acute management of migraine. Side effect includes nausea as well as severe vasoconstriction. It is contraindicated in patients with vascular disease, hepatic problems, renal dysfunction, and hypertension. It is avoided in pregnancy. Dihydroergotamine (DHE) is the only preparation available and is used both parentally and intranasally. Repeated administration of DHE is very effective in refractory cases as well as status migrainosus. It is relatively safe and effective but it requires hospital administration [23, 24, 25].
7. Nonspecific treatment
7.1 Nonsteroidal anti-inflammatory drugs
Good quality evidence supports the use of NSAIDs alone or in combination with specific agents. These drugs in combination with antiemetics are comparable to lower doses of oral triptans. Recently, powdered preparation of diclofenac sodium is approved for treatment of acute attack. Ketorolac, administrated IV, can be used for emergency management of migraine. NSAIDs need to be used with caution in patients with renal toxicity [26, 27, 28, 29]. Characteristics of different drugs in this group are summarized in Table 3.
|Drugs||Formulation||Dose used (the dose wording should be mg’)|
|Aspirin||Tablet/oral solution||650–1000 mg|
|Ketoprofen-extended release||Capsule||200 mg|
|Diclofenac potassium||Tablet/powder||50 mg|
|Meclofenamate||Capsule||50 mg, 100 mg|
|Ibuprofen||Capsule, tablet, oral suspension||400–1, 0 g|
|Naproxen-controlled release||Tablet||750–850 mg maximum|
Dopamine D2 receptor antagonists can be used alone or in combination to treat headache as well as nausea. It is mostly used in emergency settings and is available in oral, parenteral, and suppository forms, but concerns over extrapyramidal side effects, tardive dyskinesia, and lack of familiarity in their effect on migraine attacks restrict their use to a great extent [30, 31, 32, 33]. Characteristics of antiemetics are summarized in Table 4.
|Drug||Formulation||Dose of migraine|
|Prochlorperazine||Tablet, suppository||5–10 mg|
|Ondansetron||Tablet, oral disintegrating tablet||4 mg|
Steroids are suggested for acute treatment as well as for status migrainosus . They act by reducing the neurogenic inflammation and vasogenic edema and also play an important role in central serotonergic pathways . One study showed that addition of dexamethasone 4 mg per oral to triptans plus NSAID reduces recurrence and is well tolerated in patients with frequent attacks [36, 37].
Opioids are the most prescribed drug for acute and rescue therapy in migraine in America. Recent studies have discouraged the use of opioids mainly because it decreases gray matter, increases CGRP release, releases pro-inflammatory peptides, and also causes glutamate receptor activation. It also results in degranulation of mast cells and causes vasodilation. There are many side effects, such as overuse headache and disease progression [38, 39].
8. Newer agents
8.1 CGRP antagonists
Based on migraine pathology theories, trigeminal ganglion activation causes the activation of nociceptive neurons which leads to subsequent release of CGRP. Increased CGRP levels cause plasma protein extrusion, vasodilation, and mast cell degranulation, ultimately leading to neurogenic inflammation. Drugs which antagonize CGRP include olcegepant, telcagepant, and latest approved monoclonal antibodies, namely, erenumab, fremanezumab, and galcanezumab . They prevent binding of endogenous CGRP on its receptors and suppress the stimulation of CGRP on trigeminal ganglion neurons. They inhibit cortical spreading depression . They lack vasoconstrictive effect. Olcegepant is as effective as oral triptans with less cardiovascular side effects such as blood pressure increase and tachycardia. But one major limitation is intravenous dosing. Telcagepant was initially claimed to be as potent as rizatriptan, causing pain relief in 2 h and also sustained pain relief at 24 h and relief of migraine-associated symptoms with overall good tolerability profile, but later the phase II trial was terminated, claiming the drug showed increase in liver transaminases . Eptinezumab is a new drug in this class under trial and is not yet approved by the Food and Drug Administration (FDA).
It is a 5-HT1F receptor agonist. In experimental model, it blocks neurogenic inflammation, decreases c-fos expression, and lacks vasoconstriction. The main postulated mechanisms include inhibition of protein leakage, blockage of secondary trigeminal neuronal activation, and inhibition of neuropeptide release like glutamate. In a double-blind placebo-controlled parallel group study in 512 patients, the oral form and dose of 50, 100, 200, and 400 mg in moderate-to-severe migraine attacks proved that it is as effective as sumatriptan without causing vasoconstriction, but the significant drawback is its major side effects in the central nervous system. Studies also show a great improvement in headache response in 2 h but also show high 24-h headache recurrence rate .
Tezampanel acts as a competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor (subtype GluR5) of the ionotropic glutamate receptor family. A randomized triple-blind parallel group double-dummy, multicenter trial showed 1.2 mg tezampanel had 69% headache response rate when compared to 6 mg s.c. sumatriptan which had a response rate of 86%. It is effective and well tolerated in migraine. It can be used only via intravenous route. Dasolampanel is an orally bioavailable analog of tezampanel. Both drugs were never marketed . Other newer agents are summarized in Table 5.
|Newer targets and drugs||Current status|
|1. Adenosine receptor agonists |
|2. NXN-188 |
|3. LY2951742 |
|4. Orexin receptor antagonism  (filorexant)||Orexin: trigeminal nociceptive and CSD|
RCT: failed efficacy
|5. TRPV1 antagonism|
|6. Melatonin |
|7. P2Y purinergic receptors |
It is indicated when a patient meets the following criteria :
Four or more migraine days per month.
Recurring migraines significantly interfere with daily activity.
Overwhelming costs of acute therapies.
Uncommon migraine conditions—hemiplegic and basilar migraine.
8.5 Beta blockers
Various beta blockers used are summarized in Table 6. The mechanisms by which they act include inhibition of central beta receptors and antagonism of 5-HT1A and 5-HT1B receptors, thereby reducing neuronal excitability. It inhibits nitric oxide (NO) production by blocking inducible nitric oxide synthase and inhibits excitatory activity of glutamate, thereby reducing neuronal activity. They also inhibit kainate-induced currents (synergistic with NMDA blockers) and reduce neuronal activity and also have additional membrane-stabilizing action [44, 45].
8.6 Carvedilol: novel β blocker in migraine
In an open-label trial of 76 patients, a dose of 3.125–6.25 mg twice a week was used, and it was found that 60% of patients had 50% reduction in monthly migraine attack frequency and severity, but in 26% of patients, there was lack of efficacy with the drug .
8.7 Calcium channel blockers
It inhibits calcium entry and prevents intoxication of cells exposed to cerebral hypoxia due to cortical spreading depression . Various drugs used are summarized in Table 7. Other possible mechanisms include inhibition of 5-HT release, inhibition of neurovascular inflammation, and cortical spreading depression.
9.1 Divalproex sodium
It is a combination of valproic acid and sodium valproate. It is used at a dose of 500–1500 mg/day. Mechanisms include prolongation of sodium channel inactivation, suppression of calcium-mediated T current, and inhibition of gamma-aminobutyric acid (GABA) transaminase. Adverse effect includes nausea, vomiting, gastrointestinal distress, alopecia, and craniofacial abnormalities in fetus .
Topiramate is a recently approved drug for migraine prophylaxis. Starting dose of 15–25 mg at bedtime and increase 15–25 mg/week . Mechanisms include blocking of the voltage-gated sodium channel and inhibition of activation of AMPA-kainate receptor of glutamate, and it also enhances postsynaptic GABAA receptor current. Adverse effects include somnolence, fatigue, weight loss, nervousness, and precipitation of renal calculi.
It inhibits GABA transporter (GAT-1) and thereby reduces GABA uptake into the neurons and glia. It is still not approved by the FDA. In an open-label trial of 41 patients who failed with treatment of valproates with 4 mg QID, 33/41 patients showed 50% reduction in migraine attacks, and 5 patients showed complete remission in migraine .
9.4 Levetiracetam (LCT)
It modifies synaptic release of glutamate/GABA by binding to specific synaptic protein (SV2A). Anecdotal evidence says prevention of migraine. A 10-week open-label study, evaluating efficacy and safety of LCT for pediatric migraine in a population of 30 children or adolescents aged 6–19 years, showed a reduction in headache frequency and severity .
It blocks voltage-dependent sodium and T-type calcium channels and decreases glutamate-mediated excitatory neurotransmission. Also, it inhibits excessive NO production and helps in scavenging NO and hydroxyl radicals. In an open-label trial, 33 patients with migraine headache, refractory to other preventive therapies, were given a dose of 100–600 mg every third day. Results showed that 65% of patients had a reduction in frequency of migraine attacks .
Possible mechanisms include reuptake inhibition of serotonin and noradrenaline, α-adrenergic and NMDA-receptor antagonism, sodium and calcium channel blocking action, and potassium channel activation. Increase in GABAB receptor action and opioid receptor binding/opioid-mediated effect is another minor action. It reduces inflammation by decreasing prostaglandin (PGE2) and tumor necrosis factor (TNF-α). Various drugs are summarized in Table 8. Venlafaxine is used at a dose of 75–225 mg: a double-blind placebo controlled trial showed that the drug was better than placebo, starting with 37.5 mg extended release tablet/week followed by 75 mg for another week and then 150 mg extended release in the morning .
9.7 Drugs acting on renin-angiotensin system
The renin-angiotensin system plays a role in neurogenic inflammation and causes increased susceptibility to oxidative stress. It also causes endothelial dysfunction and neuromodulator in nociception. Lisinopril alters sympathetic activity and inhibits free radical activation. It also increases prostacyclin synthesis and blocks the degradation of bradykinin, substance P, and encephalin. In a double-blind placebo-controlled crossover study, patients aged 19–59 years with migraine were treated with 20 mg Lisinopril for 11 weeks—21% of patients showed 50% reduction in migraine attacks . In a comparative study of candesartan vs propranolol for migraine prophylaxis in 72 patients, 43% of patients showed greater than 50% reduction in migraine, and it was equally efficacious to propranolol .
9.8 Onabotulinum toxin
It is the FDA-approved drug for prophylaxis of chronic migraine at doses ranged from 155 to 195 IU, and it is injected in seven craniofacial and neck muscles, usually the temporalis. It inhibits neurogenic inflammation by inhibiting the release of nociceptive mediators like glutamate, substance P, and CGRP from the peripheral terminals of the efferent nerves. The analgesic action of onabotulinum toxin is central but yet to be proved. It will effect 3 h after injection and last for at least 7 days. Novel delivery routes such as topical/subcutaneous applications are under research .
9.9 H3 agonists
It is used to limit the excessive inflammatory response through H3 receptor activation. Drugs include Nα-methylhistamine and investigational drug SCH 50971. Phase III double-blind placebo-controlled trial for 12 weeks in 60 patients with a dose of 1–3 mg twice a week caused a reduction in headache frequency, intensity, and duration in 80% of patients. It helps in reducing the dose of analgesics used .
Preclinical studies showed inhibition of cortical spreading depression by the drug. It inhibits neurogenic inflammation and also the gap junctional intercellular communication (GJIC) between the neurons and satellite glial cells. Various randomized double-blind parallel group placebo-controlled multicenter studies for acute migraine were tried. There are conflicting reports of headache relief at 2/4 h and reasons are not found. In one study with 40 mg on 39 patients, it was found to be effective for migraine with aura when compared to that without it, reinforcing its inhibitory effect on CSD .
10. Nutraceuticals in migraine
Multiple studies show migraine is associated with low levels of magnesium. It causes an influx of calcium into the neurons, causing glutamate release into the neurons, which results in neuronal activation. The onset and propagation of cortical spreading depression is delayed and decreases. It also causes change in neurotransmitter secretion and intensifies the secretion of substance P. It is used in patients with aura and premenstrual migraine and is used at a dose of 1, 0 g IV and 300–600 mg orally in chelated magnesium (taurate, glycinate, oxide) . Magnesium plus
10.2 Coenzyme Q10 (CoQ)
It promotes electron transfer from complex I and II to cytochrome C and helps in ATP production. It protects the mitochondria from free radical damage. A study of 1478 migraine patients of age range 3–22 years showed low levels of CoQ in 33% of patients. A randomized controlled trial of 42 patients receiving 100 mg TID for 3 months found it superior to placebo, and 48% of subjects have greater than 50% reduction in migraine attacks .
It is a cofactor in the Krebs cycle. Abnormal phosphorylation of ADP to ATP is prevented with riboflavin. A randomized controlled trial with 400 mg riboflavin taken daily for 3 months was superior to placebo for reduction of migraine frequency . A randomized controlled trial with 400 mg of riboflavin plus feverfew and low-dose magnesium was comparable to a 25 mg active riboflavin. Greater than 40% of patients showed 50% reduction in migraine attacks .
10.4 Vitamin B12
It helps in the conversion of homocysteine to methionine. Studies show vitamin B12 deficiency causes increase levels of urine methylmalonic acid levels in patients and worsens migraine. A possible mechanism of vitamin B12 action in migraine includes its excitatory role in the CNS by acting on NMDA receptors. It also plays a significant role in initiation, duration, and progression of migraine and activation of trigeminovascular system .
It is sold as capsules of dried leaves of the weed plant Tanacetum parthenium. Animal models show feverfew acts by inhibition of nitroglycerine-induced fos expression and inhibition of nuclear factor-kappa β. An open-label trial with T. parthenium (300 mg) plus Salix alba (white willow) for 12 weeks showed a decrease in pain intensity and duration of migraine. A randomized double-blind placebo-controlled trial (riboflavin 400 mg + magnesium 300 mg + feverfew 100 mg) for 3 months showed positive results. Recently two randomized clinical trials (RCT) of a purified stable extract of feverfew, MIG99, were ineffective in migraine, and clinical effects were very low with various complications .
10.6 Petasites (butterbur root)
Petasites hybridus is a potential poisonous plant but the detoxified root extract is safe. Mechanisms include inhibition of the synthesis of leukotrienes. It also decreases the intracellular concentration of calcium. It is used in the prophylaxis of migraine in children. A small study of 100 mg/day and a larger one of 150 mg/day vs placebo have shown efficacy .
With many newer agents now under clinical trials as well as in use, physicians should be aware of these drugs and their side effects, so they can use these agents for treating recurrent and chronic cases of migraine. Also, further well-designed clinical trials are needed to prove the efficacy of these agents in treatment of migraine. So, further research is needed to find out the safest and most effective treatment for chronic migraine, further designing proper animal models for studying migraine, to identify newer drug targets and how to prevent the migraine at the patient level from acute attack going in for chronic attack.
Conflict of interest
NSAIDS nonsteroidal anti-inflammatory drugs GJIC gap junctional intercellular communication CGRP calcitonin gene-related peptide NO nitric oxide NMDA N-methyl-d-aspartate receptor DHE dihydroergotamine ATP adenosine triphosphate ADP adenosine diphosphate
|NSAIDS||nonsteroidal anti-inflammatory drugs|
|GJIC||gap junctional intercellular communication|
|CGRP||calcitonin gene-related peptide|