Migraine Headache Management

Therapy decisions are made based on the severity of the headache.  

Severity Categories  

Moderate  

The patient is not completely incapacitated, but daily activities are greatly hindered by headache.  

Severe  

The patient’s daily activities are not performed, or they are greatly altered because of the headache.  

Status Migrainosus  

The patient has a severe headache that lasts for >72 hours.  

Evaluation to Determine if Patient Should Receive Migraine Prophylactic Treatment  

When indicated, prophylactic treatment should be used in addition to acute therapy.  

Indications for Prophylactic Therapy

• Frequency of attacks is ≥4 days per month
• Patients feel that migraines are significantly interfering with their normal daily activities even with acute treatment lasting for ≥4 days per month
• Failure and contraindication of acute therapies
• Overuse of acute therapy defined as:
  • ≥10 days per month for combination analgesics, ergot derivatives, opioids, triptans, and a combination of drugs from different classes that are not individually overused
  • ≥15 days per month for Paracetamol, non-opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) including Aspirin
• Adverse effects from acute therapies
• Patient preference
• Menstrual migraine
• Cost of acute therapy
• Presence of neurologic damage from uncommon migraine types
• Duration of individual attacks >24 hours

ACUTE TREATMENT

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) including Analgesics 

Example drugs: Aspirin, Ibuprofen, Ketoprofen, Naproxen  

Analgesics are the first-line agents for moderate migraine attacks. The efficacy and tolerability of NSAIDs have been shown in a number of clinical trials. Paracetamol is recommended as acute treatment for moderate migraine. This may be considered for patients with acute migraine headaches with contraindications to other therapies or during pregnancy. Aspirin is recommended for acute treatment in patients with all severities of migraine. Intravenous Aspirin with or without Metoclopramide is the first choice in patients with severe migraine in an emergency situation. For resistant attacks, NSAIDs (oral, rectal or intramuscular) can be given following, or added to, a triptan. The use of selective COX-2 inhibitors in acute migraine treatment has been investigated in clinical trials.

Triptans (Serotonin 5HT1 Receptor Agonists)  

Example drugs: Eletriptan, Frovatriptan, Rizatriptan, Sumatriptan, Zolmitriptan  

The efficacy of triptans ranges in comparative efficacy as shown in clinical trials; however, there are unpredictable individual variations in response to different triptans. They have better efficacy when given at the very onset of the headache or while the migraine pain is at a mild level. These are not safe and effective when administered during the aura. Oral triptans are recommended for acute treatment of migraine with all severities if previous attacks are not controlled by simple analgesics. Their use is limited to a maximum of 9 days/month.  

Sumatriptan is available in nasal, subcutaneous (SC) and rectal formulations. The SC Sumatriptan has the fastest onset of efficacy, yet also has the highest recurrence rate; it may also be considered in the treatment of severe migraine. The nasal formulation is not recommended if vomiting precludes oral therapy since its bioavailability depends largely on ingestion. Suppositories should be given to patients with vomiting. The use of Zolmitriptan nasal formulation is considered in patients with severe migraine; it may also be used even if vomiting is already occurring since up to 30% is absorbed through the mucosa. It is confirmed in several trials that patients who fail to obtain adequate relief with one triptan can benefit from another in subsequent attacks. Each triptan should be tried in three attacks before it is rejected. A change in dosage and route of administration should be considered.  

Ergot Alkaloids  

Ergot alkaloids are used in patients with very long migraine attacks or with regular recurrence due to their lower recurrence rate. Their use has been limited by their high potential to cause medication overuse headache and rebound headache. The intake should be limited to 10 days/month.  

Ergotamine  

Ergotamine in combination with Caffeine, Butalbital and/or Belladonna are available. Historically, this has been used to treat moderate to severe migraine headaches. This is restricted in patients with very long migraine attacks or with regular recurrence due to its longer half-life and lower recurrence rate. Its use has been limited by high potential to cause medication overuse headache and rebound headache. A suppository formulation is available. This should not be taken concomitantly with any triptan.  

Dihydroergotamine (DHE)  

Dihydroergotamine is available in rectal, parenteral and nasal formulations. The nasal formulation is effective and safe as monotherapy. This is more appropriately used in severe migraines. This is recommended as treatment for status migrainosus.

5-HT_1F Receptor Agonist  

Example drug: Lasmiditan  

5-HT_1F receptor agonist is currently approved for the acute treatment of migraine, with or without aura, in adults. Two randomized, double-blind, placebo-controlled trials demonstrated the effectiveness of Lasmiditan for the acute treatment of migraine.  

Antiemetics  

Antiemetics have been used in conjunction with migraine medications to control nausea and vomiting. Fair evidence has shown that Metoclopramide may be effective as monotherapy for acute attacks. It has a mild analgesic efficacy in migraine when given orally and higher efficacy when given IV. Domperidone is less sedating than Metoclopramide and also has less risk of extrapyramidal effects. Antiemetics are available in different forms (eg oral, parenteral, rectal).







Other Drugs  

Opioid Analgesics  

Opiates and tranquilizers are not recommended in the treatment of acute migraine. There are no studies that support the effectiveness of opiates.  

Calcitonin Gene-Related Peptide (CGRP) Antagonists  

Example drugs: Rimegepant, Ubrogepant, Zavegepant  

Calcitonin gene-related peptide (CGRP) antagonists are approved by the US FDA for acute treatment for patients unresponsive or intolerant to at least two triptans. Rimegepant and Ubrogepant are oral agents approved for the acute treatment of migraine with or without aura. Zavegepant is available as a nasal spray and is approved for the acute treatment of migraine with or without aura in adults. Ubrogepant and Zavegepant are not recommended for the preventive treatment of migraine.

Combination Therapy  

There is some evidence that the combination of Sumatriptan and Naproxen is superior to either drug alone. This combination reduces the development of headache recurrence and may be considered for the treatment of patients with acute migraine. Fixed combinations containing Paracetamol, Aspirin and caffeine have been shown to be effective. They are better than single substances or combinations without caffeine. Caffeine should be added as the first choice in treating intermittent, infrequent headaches.  

Other combinations:

• Oral analgesic or NSAID with or without antiemetic plus specific anti-migraine drugs, followed by
• Rectal analgesic with or without antiemetic plus specific anti-migraine drugs

Menstrual Migraine  

Acute treatment of menstrual migraine is the same as that of non-menstrual headache. It may be necessary to repeat the treatment since menstrual attacks may have a longer duration.  

Migraine in Pregnancy

Paracetamol may be used if a migraine occurs anytime during pregnancy. In the second trimester of pregnancy, NSAIDs can be given, however, non-pharmacological management is preferred. Biofeedback, relaxation, transcutaneous supraorbital nerve stimulation and physical therapy may be tried. Ergotamine and dihydroergotamine are contraindicated during pregnancy.  

Status Migrainosus  

Status migrainosus is usually a severe and debilitating migraine headache that requires aggressive treatment. This is often caused by medication (eg analgesic) overuse. The treatment may start with IV fluids and electrolyte replacement if indicated. Some patients may need hospitalization for rehydration, control of vomiting by giving antiemetics and abortive therapy. Abortive therapy includes parenteral triptan without ergot and/or Dihydroergotamine 8-12 hours after the last dosage of triptan. Ketorolac IM/IV or sodium valproate can be given if Dihydroergotamine or triptan is contraindicated or ineffective.

PROPHYLAXIS  

Prophylactic Treatments  

Antiepileptic Drugs  

Valproic acid, Divalproex sodium and Topiramate have been shown to be effective in preventing migraines. Their efficacy is comparable with Metoprolol, Propranolol and Flunarizine. Topiramate has been considered as one of the drugs of first choice for migraine prophylaxis. Sodium valproate is used as a second-line prophylactic agent for chronic migraine.  

Antidepressants  

Example drugs: Amitriptyline, Nortriptyline, Protriptyline, Venlafaxine  

Antidepressants are useful in patients with coexisting depression or insomnia. However, not all antidepressants are effective. Amitriptyline has been studied more than any other antidepressant. This has been shown statistically to be effective in preventing migraines. This is recommended as a first-line agent for chronic migraine prophylaxis. Venlafaxine may also be recommended as a first-line agent for migraine prophylaxis. Nortriptyline and Protriptyline are considered second-line agents for chronic migraine prophylaxis in patients refractory to the first-line agents. Fluoxetine has been studied with inconclusive evidence of efficacy.  

Beta-Blockers  

Example drugs: Propranolol, Metoprolol, Timolol  

Beta-blockers are useful in patients with coexisting essential tremors, anxiety and/or panic attacks. These are not recommended for migraine prevention in patients >60 years and in smokers. Propranolol, Metoprolol and Timolol have been shown to be consistently effective in preventing migraines. Propranolol is recommended as a first-line agent for chronic migraine prophylaxis. Atenolol, Bisoprolol and Nadolol have shown limited effectiveness.  

OnabotulinumtoxinA (Botulinum toxin A)  

OnabotulinumtoxinA is currently approved for prophylaxis of chronic migraine headaches. This is given approximately every 12 weeks as multiple injections around the head and neck. This should be discontinued if the frequency of headache days per month did not reduce by at least 30% after two treatment cycles or if their condition changed to episodic migraine for three consecutive months.

Calcium Channel Blockers  

Example drugs: Flunarizine, Verapamil  

Flunarizine has shown efficacy in migraine prophylaxis in several studies. Flunarizine has been recommended for prophylaxis. This is a treatment option for women of childbearing age. Verapamil may be an alternative for chronic migraine prophylaxis in patients who are refractory to the first-line agents.  

Calcitonin Gene-Related Peptide (CGRP) Antagonists  

Example drugs: Eptinezumab, Erenumab, Fremanezumab, Galcanezumab  

Calcitonin gene-related peptide (CGRP) antagonists act by binding to and subsequently inhibiting the CGRP receptor or ligand. These are human monoclonal antibodies acting as CGRP antagonists. These are currently approved subcutaneous injectables for episodic and chronic migraine prophylaxis who have at least four migraine days per month. Atogepant and Rimegepant are oral CGRP antagonists approved for the preventive treatment of episodic migraine. These are effective for patients who failed prior prophylactic therapy and in patients on concurrent oral prophylactic therapy. These have been shown to reduce the number of migraine or headache days and the number of days using acute medications, and improve disability. There is no need for gradual dose titration unlike oral prophylaxis. These should be discontinued if the frequency of migraines did not reduce by at least 50% in episodic migraine and at least 30% in chronic migraine.  

Calcitonin gene-related peptide (CGRP) antagonists are indicated when patient is ≥18 years old and diagnosed with migraine with or without aura and intolerant or unresponsive to a 6-week trial of at least two of the following: Beta-blocker (Atenolol, Metoprolol, Nadolol, Propranolol, Timolol), Divalproex sodium/ valproate sodium, serotonin-norepinephrine reuptake inhibitor (Duloxetine, Venlafaxine), tricyclic antidepressant (Amitriptyline, Nortriptyline), or Topiramate and with at least moderate disability or diagnosed with chronic migraine and intolerant or unresponsive to a 6-week trial of at least two of the following: Beta-blocker (Atenolol, Metoprolol, Nadolol, Propranolol, Timolol), Divalproex sodium/Valproate sodium, serotonin-norepinephrine reuptake inhibitor (Duloxetine, Venlafaxine), tricyclic antidepressant (Amitriptyline, Nortriptyline), or Topiramate or intolerant or unresponsive to a minimum of two quarterly injection of OnabotulinumtoxinA.  

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)  

Nonsteroidal anti-inflammatory drugs may be considered in patients in need of migraine prophylaxis. These should be used with caution, as prolonged use (≥15 days/month) may cause medication overuse headache.

Other Drugs  

Angiotensin Receptor Blockers  

Candesartan has shown limited effectiveness in preventing migraines. This can be considered as an alternative for chronic migraine prophylaxis in patients refractory to first-line agents.  

Serotonergic Antagonists  

The use of Methysergide is limited to short-term prophylaxis (maximum of 6 months) because of adverse effects and is also associated with severe rebound headache. Pizotifen is not recommended because of its poor efficacy and severe side effects.

Triptans  

Example drugs: Frovatriptan, Naratriptan, Zolmitriptan  

Frovatriptan should be considered as a prophylactic treatment in women with perimenstrual migraine 2 days prior to up to 3 days after bleeding starts.  

Herbal Treatments/Vitamin/Mineral Supplements  

Although the level of evidence is low, the following have been recommended for migraine prophylaxis due to fewer side effects and modest efficacy:

• Co-enzyme Q10: One randomized placebo-controlled trial has shown that co-enzyme Q10 has decreased migraine attack frequency with good tolerability
• Magnesium
• Riboflavin

Hormone-Related Migraine  

Prophylaxis should be tried for a minimum of three cycles at maximum dose before it is deemed ineffective. Triptans (eg Frovatriptan, Naratriptan, Zolmitriptan) have been studied in clinical trials of short-term prophylaxis of menstrual migraine. There are limited studies available on the use of ergot alkaloids as cyclic prophylaxis. Hormones are considered supplements in patients with menstrual migraine. In a patient with an intact uterus and menstruating regularly, progestogens are not necessary. Patients suffering from menstrual migraine can benefit from the combined hormonal contraceptives (CHC), progestogen-only oral Desogestrel, subdermally-implanted Etonogestrel and injectable depot progestogen. The use of combined hormonal contraceptives is contraindicated in migraine with aura and migraine treated with ergot derivatives.  

Migraine in Pregnancy  

Most women with migraine improve during pregnancy, hence prophylaxis is not usually needed. If prophylaxis is necessary, Magnesium and Metoprolol are recommended. Propranolol has the best safety profile. Amitriptyline in the lowest effective dose can also be used.

Patient Education  

Individuals need to understand that migraine headache is a physiological disorder with genetic predisposition or a primary brain disorder with no structural lesion in the brain. The patients are predisposed to blood vessel and inflammatory responses in the brain, which cause pain. The patients need to be educated about controlling acute attacks and preventive therapy. The patients should be made aware of the potential for medication-induced headache (manifested as chronic daily headache), which can be caused by the overuse of analgesics and acute migraine drugs. If treating acute headache >2x/week, the patient should consider prophylaxis treatment to prevent medication-induced headache. When creating a management plan, involve the patient in the decision-making process. Discuss therapeutic options including risks versus benefits and medication-induced headache. The patient should be encouraged to keep a headache diary or calendar to record the frequency, duration and severity of each headache attack, take note of any resulting disability and treatment used for the headache and its effects (including adverse reactions to the medication).

Rescue Medication  

Clinical consideration to self-administered rescue medication for patients who have severe migraines that do not respond to other treatments. This may consist of an opioid or a Butalbital-containing combination that the patient may use at home. This enables the patient to administer pain relief without the need for a physician clinic or emergency department visit. The patient must be educated on the appropriate use of rescue medication. There should be an adequate trial of preventive therapy because clinical benefit manifests after 2-3 months.  

Lifestyle Modification  

Predisposing Factors Recognition and Trigger Avoidance  

Patients should be educated about the many influences that can lead to a migraine attack. Identify and differentiate between predisposing and precipitating or trigger factors. Some predisposing factors cannot always be avoided but can be treated. The factors triggering an acute attack in one patient may not trigger an attack in another patient. Predisposing factors are stress, depression, anxiety, menstruation, menopause, and head or neck trauma. Most patients benefit from adequate hydration, regular eating patterns and sleep schedules, regular aerobic exercise and stress reduction. Patients also prefer to stay in a dark and quiet room during the attacks.

Behavioral and Physical Methods for Migraine Prophylaxis  

Behavioral and physical methods are appropriate for patients who prefer non-pharmacological methods, who do not respond to prophylactic medication, who cannot tolerate or in whom pharmacologic agents are contraindicated, those with history of medication overuse, pregnant, lactating or women planning to get pregnant and patients who have significant stress or deficient stress-coping skills. These may combine behavioral or physical treatments with pharmacotherapy if necessary. These have been shown to provide more benefits than either modality alone.  

Goals of Therapy  

The goals of these therapies are to reduce the frequency and intensity of headache, to reduce reliance on pharmacotherapy, to reduce disability caused by headache, to increase personal control over headache, and to decrease headache-related distress and psychological symptoms.  

Relaxation Training, Stress Reduction, and Coping Strategies  

Relaxation training, stress reduction and coping strategies are considered first-line treatments where a specific indication exists (eg stress, anxiety). Yoga and meditation are said to enhance stress management. These would train patients to control muscle tension, use mental relaxation and/or visual imagery. These has been found to be somewhat effective in preventing migraines.  

Biofeedback Therapy  

Standard thermal and electromyographic (EMG) biofeedback training are usually the techniques of choice. Thermal biofeedback combined with relaxation training may be somewhat effective. This should be conducted by a trained healthcare provider. It is time-consuming and requires patient commitment.  

Cognitive-Behavioral Therapy (CBT)  

Psychotherapeutic intervention’s goal is to teach skills to identify and control stress and minimize its effects. Hypnotherapy has also been used. Cognitive-behavioral therapy may be considered somewhat effective.  

Physical Therapy  

Physical therapy may be useful where a specific condition exists (eg migraine due to neck dysfunction). Improving physical fitness may decrease susceptibility to migraine. This may be beneficial in the therapy of chronic migraine in patients with constant muscle tension.  

Acupuncture  

Acupuncture is done when fine needles pierce skin at specific “pressure points” to relieve pain. It is believed that endorphins are released into the patient’s system, which relieve pain. Consider a course of acupuncture over 5 to 8 weeks for patients who are unresponsive or intolerant to beta-blockers, antiepileptics and antidepressants. Controlled studies have produced mixed findings for the effectiveness of acupuncture.







Neuromodulation Techniques  

Examples: Transcutaneous electrical nerve stimulation (TENS), remote electrical neuromodulation (REN), non-invasive vagus nerve stimulation (nVNS), single-pulse transcranial magnetic stimulation (sTMS)  

Neuromodulation techniques involve stimulating the nervous system centrally or peripherally with the use of an electric current or a magnetic field. These are options for patients with poor response, intolerance or contraindications to drug treatments or who prefer non-pharmacologic treatments. Single-pulse transcranial magnetic stimulation and electrical trigeminal nerve/supraorbital nerve stimulation are recommended for acute and preventive treatment of migraine. Transcranial magnetic stimulation may be used as a second-line modality for patients with episodic migraine with aura who are unresponsive or intolerant to first-line therapy with triptans or other drugs. Transcutaneous supraorbital nerve stimulation was found to be beneficial for patients with episodic migraine. Non-invasive vagus nerve stimulation is recommended for the acute treatment of migraine.