Advances in Migraine Therapy

**11**

**Chapter 2**

**Abstract**

clinical trials.

depression

**1. Introduction**

**2. Signs and symptoms**

Therapy

Recent Advances in Migraine

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

**Keywords:** headache, nutraceutical, prophylaxis, triptans, cortical spreading

The word "migraine" comes from the Greek ἡμικρανία (*hemikrania*), "pain on one side of the head"; ἡμι- (*hemi-*), "half"; and κρανίον (*kranion*), "skull." The disorder may also be described as a vascular headache associated with changes in the size of the arteries within and outside the brain [1]. It is usually accompanied by a plethora of comorbidities influencing its clinical expression and complicating its treatment, making migraine a chronic and debilitating neurological disorder. It is a polygenetic disease with high susceptibility to epigenetic factors affecting millions of people worldwide. This is mainly because of changes in hormonal levels. It is estimated that up to 15% of people suffer from migraine worldwide with 1.4–2.2% affected by the chronic form of the disease [2, 3]. Global data shows the prevalence of migraine increasing during adolescence with peaks in midlife and the prevalence declining rapidly after 50 years. Migraine presents as headache and visual, auditory, olfactory, and cutaneous stimuli hypersensitivity along with nausea and vomiting [4]. Both environmental and genetic factors play a role in the development of migraine with more than two third of cases having familial history [5]. Boys are more affected than girls before puberty, but women are more affected than men as age increases [6].

Migraine is self-limiting, usually presenting as recurrent severe headache. It is associated with autonomic symptoms. It presents with aura in 15–30% and without aura in the rest [7]. Migraine varies from person to person with respect to severity of pain, duration of attack, and its frequency. A migraine lasting longer than 72 h is

*Balaji Ommurugan and Vanishree Rao*

#### **Chapter 2**

## Recent Advances in Migraine Therapy

*Balaji Ommurugan and Vanishree Rao*

#### **Abstract**

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.

**Keywords:** headache, nutraceutical, prophylaxis, triptans, cortical spreading depression

#### **1. Introduction**

The word "migraine" comes from the Greek ἡμικρανία (*hemikrania*), "pain on one side of the head"; ἡμι- (*hemi-*), "half"; and κρανίον (*kranion*), "skull." The disorder may also be described as a vascular headache associated with changes in the size of the arteries within and outside the brain [1]. It is usually accompanied by a plethora of comorbidities influencing its clinical expression and complicating its treatment, making migraine a chronic and debilitating neurological disorder. It is a polygenetic disease with high susceptibility to epigenetic factors affecting millions of people worldwide. This is mainly because of changes in hormonal levels. It is estimated that up to 15% of people suffer from migraine worldwide with 1.4–2.2% affected by the chronic form of the disease [2, 3]. Global data shows the prevalence of migraine increasing during adolescence with peaks in midlife and the prevalence declining rapidly after 50 years. Migraine presents as headache and visual, auditory, olfactory, and cutaneous stimuli hypersensitivity along with nausea and vomiting [4]. Both environmental and genetic factors play a role in the development of migraine with more than two third of cases having familial history [5]. Boys are more affected than girls before puberty, but women are more affected than men as age increases [6].

#### **2. Signs and symptoms**

Migraine is self-limiting, usually presenting as recurrent severe headache. It is associated with autonomic symptoms. It presents with aura in 15–30% and without aura in the rest [7]. Migraine varies from person to person with respect to severity of pain, duration of attack, and its frequency. A migraine lasting longer than 72 h is termed status migrainosus. Different phases of migraine include the prodrome, the aura, the pain, and the postdrome. The prodromal phase occurs hours before the headache in 60% of patients, the aura usually precedes headache in 15–20%, severe headache occurs in the pain phase, and the postdromal phase usually follows the attack of migraine [8].

#### **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-d-aspartate receptor (NMDA) receptors without modulation by brain stem pain centers due to dysfunction of these centers; overactivity of excitatory neurotransmitters like aspartate and glutamate causing neuronal excitability; and finally neurogenic inflammation which play an important role in migraine attack development [9–12].

#### **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 [13] for treatment of acute migraine include pharmacological and non-pharmacological modalities as shown in **Table 1**.


**Table 1.** *Treatment of acute migraine attacks.*

#### **5. Specific treatment**

#### **5.1 Triptans**

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

**13**

**6. Ergot and derivatives**

**7. Nonspecific treatment**

**7.1 Nonsteroidal anti-inflammatory drugs**

*Recent Advances in Migraine Therapy*

*Group 1: fast-acting triptans*

*Group 2: slow-acting triptans*

**Table 2.**

*Triptan characteristics.*

*DOI: http://dx.doi.org/10.5772/intechopen.91286*

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 [14–22]. Characteristics of triptans are summarized in **Table 2**.

**Drugs Half life Maximum daily dose**

Rizatriptan 2–3 h 30 mg (15 mg if on propranolol)

Zolmitriptan 3 h Two tablets or 10 mg maximum oral daily dose.

40 mg intranasal 12 mg subcutaneous

Two sprays or 10 mg intranasal

Sumatriptan 3 h 200 mg oral

Almotriptan 3–4 h 25 mg

Eletriptan 4 h 80 mg

Frovatriptan 26 h 7.5 mg Naratriptan 6 h 5 mg

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

Good quality evidence supports the use of NSAIDs alone or in combination with

specific agents. These drugs in combination with antiemetics are comparable to

and effective but it requires hospital administration [23–25].

*Recent Advances in Migraine Therapy DOI: http://dx.doi.org/10.5772/intechopen.91286*


#### **Table 2.**

*Migraine*

attack of migraine [8].

**3. The pathophysiology of migraine**

termed status migrainosus. Different phases of migraine include the prodrome, the aura, the pain, and the postdrome. The prodromal phase occurs hours before the headache in 60% of patients, the aura usually precedes headache in 15–20%, severe headache occurs in the pain phase, and the postdromal phase usually follows the

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-d-aspartate receptor (NMDA) receptors without modulation by brain stem pain centers due to dysfunction of these centers; overactivity of excitatory neurotransmitters like aspartate and glutamate causing neuronal excitability; and finally neurogenic inflammation which play

It can be divided into treatment of acute attacks and treatment of chronic migraine. As per the US consortium (2000), recommended guidelines [13] for treatment of acute migraine include pharmacological and non-pharmacological

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

**12**

**Table 1.**

**5.1 Triptans**

1.Specific treatment a. Triptans

b. Ergot and its derivatives 2.Nonspecific treatment a. Antiemetics

modalities as shown in **Table 1**.

**4. Treatment of migraine**

*Treatment of acute migraine attacks.*

**5. Specific treatment**

b. NSAIDs and nonnarcotic analgesics c. Narcotics/opiate analgesics

an important role in migraine attack development [9–12].

*Triptan characteristics.*

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 [14–22]. Characteristics of triptans are summarized in **Table 2**.

#### **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 [23–25].

#### **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

#### *Migraine*


#### **Table 3.**

*NSAID characteristics.*

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 [26–29]. Characteristics of different drugs in this group are summarized in **Table 3**.

#### **7.2 Neuroleptics/antiemetics**

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 [30–33]. Characteristics of antiemetics are summarized in **Table 4**.

#### **7.3 Corticosteroids**

Steroids are suggested for acute treatment as well as for status migrainosus [34]. They act by reducing the neurogenic inflammation and vasogenic edema and also play an important role in central serotonergic pathways [35]. 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].


**15**

*Recent Advances in Migraine Therapy*

**7.4 Opioids**

**8. Newer agents**

**8.2 Lasmiditan**

**8.3 Tezampanel**

**8.1 CGRP antagonists**

*DOI: http://dx.doi.org/10.5772/intechopen.91286*

headache and disease progression [38, 39].

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

Based on migraine pathology theories, trigeminal ganglion activation causes

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

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 [42]. Other newer agents are summarized in **Table 5**.

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 [40]. They prevent binding of endogenous CGRP on its receptors and suppress the stimulation of CGRP on trigeminal ganglion neurons. They inhibit cortical spreading depression [40]. 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 [40]. Eptinezumab is a new drug in this class under trial and is

not yet approved by the Food and Drug Administration (FDA).

show high 24-h headache recurrence rate [41].

#### **7.4 Opioids**

*Migraine*

**Table 3.**

*NSAID characteristics.*

are summarized in **Table 3**.

marized in **Table 4**.

**7.3 Corticosteroids**

**7.2 Neuroleptics/antiemetics**

**Drugs Formulation Dose used (the dose wording** 

Aspirin Tablet/oral solution 650–1000 mg Ketorolac Tablet 10 mg Ketoprofen Capsule 50–75 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 Etodolac Tablet/capsule 200–500 mg Naproxen Tablet 120–550 mg Naproxen-controlled release Tablet 750–850 mg maximum

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 [26–29]. Characteristics of different drugs in this group

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 [30–33]. Characteristics of antiemetics are sum-

Steroids are suggested for acute treatment as well as for status migrainosus [34]. They act by reducing the neurogenic inflammation and vasogenic edema and also play an important role in central serotonergic pathways [35]. One study showed that addition of dexamethasone 4 mg per oral to triptans plus NSAID reduces recurrence

**Drug Formulation Dose of migraine** Prochlorperazine Tablet, suppository 5–10 mg

Metoclopramide Tablet 10 mg Chlorpromazine Tablet 10–25 mg Promethazine Tablet 25–50 mg Ondansetron Tablet, oral disintegrating tablet 4 mg

and is well tolerated in patients with frequent attacks [36, 37].

**should be mg')**

25 mg

8 mg

**14**

**Table 4.**

*Antiemetic characteristics.*

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 [40]. They prevent binding of endogenous CGRP on its receptors and suppress the stimulation of CGRP on trigeminal ganglion neurons. They inhibit cortical spreading depression [40]. 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 [40]. Eptinezumab is a new drug in this class under trial and is not yet approved by the Food and Drug Administration (FDA).

#### **8.2 Lasmiditan**

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 [41].

#### **8.3 Tezampanel**

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 [42]. Other newer agents are summarized in **Table 5**.


**Table 5.** *Newer targets and drugs.*

#### **8.4 Prophylaxis**

It is indicated when a patient meets the following criteria [50]:


#### **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


**17**

*Recent Advances in Migraine Therapy*

*DOI: http://dx.doi.org/10.5772/intechopen.91286*

**Drugs Comment**

1. Flunarizine • 5–10 mg (bedtime)

2. Verapamil • 120–640 mg (bid/tid)

**8.6 Carvedilol: novel β blocker in migraine**

efficacy with the drug [53].

*Calcium channel blockers and dosage.*

**Table 7.**

**9. Antiepileptics**

**9.2 Topiramate**

**9.3 Tiagabine**

precipitation of renal calculi.

**9.1 Divalproex sodium**

**8.7 Calcium channel blockers**

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 [51, 52].

trials to prove its efficacy [55]

• 2 trials have shown efficacy better than placebo but more randomized

• Used in Europe

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

It inhibits calcium entry and prevents intoxication of cells exposed to cerebral hypoxia due to cortical spreading depression [54]. 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.

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 gammaaminobutyric acid (GABA) transaminase. Adverse effect includes nausea, vomiting, gastrointestinal distress, alopecia, and craniofacial abnormalities in fetus [56].

Topiramate is a recently approved drug for migraine prophylaxis. Starting dose of 15–25 mg at bedtime and increase 15–25 mg/week [57]. Mechanisms include blocking of the voltage-gated sodium channel and inhibition of activation of AMPAkainate receptor of glutamate, and it also enhances postsynaptic GABAA receptor current. Adverse effects include somnolence, fatigue, weight loss, nervousness, and

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

**Table 6.** *Beta blockers and dosage.* *Recent Advances in Migraine Therapy DOI: http://dx.doi.org/10.5772/intechopen.91286*


**Table 7.**

*Migraine*

**Newer targets and drugs Current status**

4. Orexin receptor antagonism [46]

(filorexant)

**Table 5.**

*Newer targets and drugs.*

**8.4 Prophylaxis**

**8.5 Beta blockers**

5. TRPV1 antagonism (SB-705498) [47]

1. Adenosine receptor agonists [43] • GR79236 and GR190178

3. LY2951742 [45] • Monoclonal antibody to CGRP under trial

• GR79236: carotid vasoconstriction than prejunctional inhibi-

• Trigeminal nociceptors: heat- and capsaicin-gated channel

• Peripheral and central sensitization of trigeminovascular

inhibits CGRP release in preclinical animal models

Orexin: trigeminal nociceptive and CSD

• Decrease inhibition of release of CGRP

tion of CGRP release 2. NXN-188 [44] • A selective nNOS inhibitor + 5-HT1B/5-HT1D receptor agonist

RCT: failed efficacy

TRPV1

system 6. Melatonin [48] • Abnormal levels: decreased inhibitory neurotransmission

7. P2Y purinergic receptors [49] • Involved in pain signaling and future receptor target

It is indicated when a patient meets the following criteria [50]:

• Recurring migraines significantly interfere with daily activity.

• Uncommon migraine conditions—hemiplegic and basilar migraine.

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

• Contraindication/failure/overuse—acute therapies.

**Drugs Daily doses** Propranolol 40–400 mg Nadolol 20–160 mg Metoprolol 100–200 mg Atenolol 50–200 mg Timolol 20–60 mg

• Four or more migraine days per month.

• Overwhelming costs of acute therapies.

**16**

**Table 6.**

*Beta blockers and dosage.*

*Calcium channel blockers and dosage.*

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 [51, 52].

#### **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 [53].

#### **8.7 Calcium channel blockers**

It inhibits calcium entry and prevents intoxication of cells exposed to cerebral hypoxia due to cortical spreading depression [54]. 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. Antiepileptics**

#### **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 gammaaminobutyric acid (GABA) transaminase. Adverse effect includes nausea, vomiting, gastrointestinal distress, alopecia, and craniofacial abnormalities in fetus [56].

#### **9.2 Topiramate**

Topiramate is a recently approved drug for migraine prophylaxis. Starting dose of 15–25 mg at bedtime and increase 15–25 mg/week [57]. Mechanisms include blocking of the voltage-gated sodium channel and inhibition of activation of AMPAkainate receptor of glutamate, and it also enhances postsynaptic GABAA receptor current. Adverse effects include somnolence, fatigue, weight loss, nervousness, and precipitation of renal calculi.

#### **9.3 Tiagabine**

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 [58].

#### **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 [59].

#### **9.5 Zonisamide**

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 [60].

#### **9.6 Antidepressants**

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 [61].

#### **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 [62]. In a comparative study of candesartan vs


**19**

*Recent Advances in Migraine Therapy*

**9.8 Onabotulinum toxin**

research [64].

**9.9 H3 agonists**

analgesics used [65].

inhibitory effect on CSD [66].

**10. Nutraceuticals in migraine**

l-carnitine is a newer preparation available.

**10.2 Coenzyme Q10 (CoQ )**

**9.10 Tonabersat**

**10.1 Magnesium**

*DOI: http://dx.doi.org/10.5772/intechopen.91286*

propranolol for migraine prophylaxis in 72 patients, 43% of patients showed greater than 50% reduction in migraine, and it was equally efficacious to propranolol [63].

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

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

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

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) [67]. Magnesium plus

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%

**Table 8.** *Antidepressant dosage.* propranolol for migraine prophylaxis in 72 patients, 43% of patients showed greater than 50% reduction in migraine, and it was equally efficacious to propranolol [63].

#### **9.8 Onabotulinum toxin**

*Migraine*

remission in migraine [58].

**9.4 Levetiracetam (LCT)**

**9.5 Zonisamide**

**9.6 Antidepressants**

headache frequency and severity [59].

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

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

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

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 [61].

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 [62]. In a comparative study of candesartan vs

patients had a reduction in frequency of migraine attacks [60].

**9.7 Drugs acting on renin-angiotensin system**

**Drugs Daily doses** Amitriptyline 10–400 mg Doxepin 10–300 mg Nortriptyline 10–150 mg Protriptyline 5–60 mg

**18**

**Table 8.**

*Antidepressant dosage.*

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 [64].

#### **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 [65].

#### **9.10 Tonabersat**

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 [66].

#### **10. Nutraceuticals in migraine**

#### **10.1 Magnesium**

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) [67]. Magnesium plus l-carnitine is a newer preparation available.

#### **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 [68].

#### **10.3 Riboflavin**

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 [69]. 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 [70].

#### **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 [71].

#### **10.5 Feverfew**

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 [72].

#### **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 [73].

#### **11. Conclusion**

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.

**21**

**Author details**

Balaji Ommurugan1

\* and Vanishree Rao2

2 Department of Pharmacology, MCOPS, Manipal, India

\*Address all correspondence to: puntermmc@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Quest Life Sciences Private Limited, India

provided the original work is properly cited.

*Recent Advances in Migraine Therapy*

**Conflict of interest**

Nil.

**Abbreviations**

NO nitric oxide

DHE dihydroergotamine ATP adenosine triphosphate ADP adenosine diphosphate

*DOI: http://dx.doi.org/10.5772/intechopen.91286*

NSAIDS nonsteroidal anti-inflammatory drugs GJIC gap junctional intercellular communication

CGRP calcitonin gene-related peptide

NMDA N-methyl-d-aspartate receptor

*Recent Advances in Migraine Therapy DOI: http://dx.doi.org/10.5772/intechopen.91286*

### **Conflict of interest**

Nil.

*Migraine*

**10.3 Riboflavin**

**10.4 Vitamin B12**

**10.5 Feverfew**

reduction in migraine attacks [68].

of trigeminovascular system [71].

**10.6 Petasites (butterbur root)**

vs placebo have shown efficacy [73].

**11. Conclusion**

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%

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 [69]. 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

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

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,

*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

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

40% of patients showed 50% reduction in migraine attacks [70].

and clinical effects were very low with various complications [72].

patient level from acute attack going in for chronic attack.

**20**

#### **Abbreviations**


#### **Author details**

Balaji Ommurugan1 \* and Vanishree Rao2

1 Quest Life Sciences Private Limited, India

2 Department of Pharmacology, MCOPS, Manipal, India

\*Address all correspondence to: puntermmc@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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**23**

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2012;**14**(1):27-35

2002;**23**(2):141-148

*Recent Advances in Migraine Therapy DOI: http://dx.doi.org/10.5772/intechopen.91286*

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[21] Shapiro RE, Tepper SJ. The serotonin syndrome, triptans, and the potential for drug-drug interactions. Headache. 2007;**47**(2):266-269

[22] Gillman K. Serotonin toxicity. Headache. 2008;**48**(4):640-641

[23] Baron EP, Tepper SJ. Revisiting the role of ergots in the treatment of migraine and headache. Headache. 2010;**50**(8):1353-1361

[24] Saper JR, Silberstein S. Pharmacology of dihydroergotamine and evidence for efficacy and safety in migraine. Headache. 2006;**46**(Suppl 4):171-181

[25] Klapper JA, Stanton J. Clinical experience with patient administered subcutaneous dihydroergotamine mesylate in refractory headaches. Headache. 1992;**32**(1):21-23

[26] Rabbie R, Derry S, Moore RA, McQuay HJ. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews. 2010;**10**:CD008039

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[29] Lipton RB, Grosberg B, Singer RP, et al. Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: Results from the

International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia. 2010;**30**(11):1336-1345

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[33] Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the emergency department treatment of migraines: A randomized controlled trial. Journal of Emergency Medicine. 2002;**23**(2):141-148

[34] Gallagher RM. Emergency treatment of intractable migraine. Headache. 1986;**26**:74-75

[35] Saper JR, Silberstein SD, Gordon CD, Hamel RL. Handbook of Headache Management. Baltimore: Williams & Wilkins; 1993. p. 49

[36] Krymchantowski AV, Barbosa JS. Dexamethasone decreases migraine recurrence observed after treatment with a triptan combined with a nonsteroidal anti-inflammatory drug. Arquivos de Neuro-psiquiatria. 2001;**59**(3B):708-711

[37] Hussain A, Young WB. Steroids and aseptic osteonecrosis (AON) in migraine patients. Headache. 2007;**47**(4):600-604

[38] Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;**71**(22):1821-1828

**22**

*Migraine*

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2011;**3**(3):133-136

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[3] Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L, et al. Global prevalence of chronic migraine: A systematic review. Cephalalgia.

[4] Abeer AK, Gihan SL. Flash dissolving sublingual almotriptan malate lyotabs for management of migraine. International Journal of Pharmacy and Pharmaceutical Sciences.

[5] Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;**24**(Suppl 1):9-160

[6] Lay CL, Broner SW. Migraine in women. Neurologic Clinics. 2009;**27**(2):

[7] Gilmore B, Michael M. Treatment of acute migraine headache. American Family Physician. 2011;**83**(3):271-280

Aminoff MJ. Clinical Neurology. 7th ed. New York, NY: Lange Medical Books/

[9] Gasparini C, Sutherland H, Griffiths L. Studies on the pathophysiology and genetic basis of migraine. Current

[8] Simon RP, Greenberg DA,

McGraw-Hill; 2009. pp. 85-88

Genomics. 2013;**14**(5):300

2009;**30**(5):599-609

2017;**9**(1):125-131

503-511

Pharmacy and Pharmaceutical Sciences.

[10] Sarrouilhe D, Dejean C, Mesnil M. Involvement of gap junction channels in the pathophysiology of migraine with aura. Frontiers in Physiology. 2014;**5**:78

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2000;**284**(20):2599-2605

1415-1416

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[52] Bigal ME, Krymchantowski AV, Rapoport AM. Prophylactic migraine therapy: Emerging treatment options. Current Pain and Headache Reports. 2004;**8**:178-184

[53] Kaniecki RG. Migraine prevention with Carvedilol: A prospective, openlabel trial. Headache. 2003;**43**:589

[54] Pietrobon D. Calcium channels and channelopathies of the central nervous system. Molecular Neurobiology. 2002;**25**:31-50

[55] Solomon GD. Verapamil in migraine prophylaxis-a five-year review. Headache: The Journal of Head and Face Pain. 1989;**29**(7):425-427

[56] Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;**58**:1652-1659

[57] Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the

**25**

*Recent Advances in Migraine Therapy*

preclinical aspects of topiramate: Pharmacology, pharmacokinetics, and mechanism of action. Epilepsia.

2000;**41**(Suppl 1):S3-S9

1999;**39**:354

[58] Freitag FG, Diamond S,

Neurology. 2005;**64**:A343

2005;**45**:144-152

2001;**322**:19-22

2003;**289**:65-69

505-518

Diamond ML, et al. The prophylaxis of migraine with the GABA-agonist, tiagabine: A clinical report. Headache.

[59] Vaisleb I, Neft R, Schor N. Role of Levetiracetam in prophylaxis of migraine headaches in childhood.

[60] Krusz JC. Zonisamide in the treatment of headache disorders. Cephalalgia. 2001;**21**:374-375

[61] Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache.

[62] Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic

[63] Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: A randomized controlled trial. JAMA.

[64] Ashkenazi A, Silberstein AD. Botulinum toxin and other new approaches to migraine therapy. Annual Review of Medicine. 2004;**55**:

Pineda-Lucatero AG, Hernández-Benjamín T, Tene CE, Pacheco MF. Nα-methylhistamine safety and efficacy in migraine prophylaxis: Phase I and phase II studies. Headache:

[65] Millán-Guerrero RO,

converting enzyme inhibitor (lisinopril): Randomized, placebo controlled, crossover study. BMJ.

treatment of migraine with angiotensin

*DOI: http://dx.doi.org/10.5772/intechopen.91286*

The Journal of Head and Face Pain.

Schytz HW, Christensen K, Olesen J. Effects of tonabersat on migraine with aura: A randomized, double-blind, placebo-controlled crossover study. The Lancet Neurology. 2009;**8**(8):718-723

2003;**43**(4):389-394

[66] Hauge AW, Asghar MS,

[67] Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: Results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia.

[68] Sandor PS, Di Clemente L,

Q10 in migraine prophylaxis: A

[70] Maizels M, Blumenfeld A,

Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: A randomized trial. Headache. 2004;**44**:885-890

[71] Bianchi A, Salomone S, Caraci F, Pizza V, Bernardini R, D'Amato CC. Role of magnesium, coenzyme Q 10, riboflavin, and vitamin B 12 in migraine prophylaxis. Vitamins & Hormones.

[72] Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database of Systematic Reviews. 2004;**1**:

[73] Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus

root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;**63**:2240-2244

Coppola G, et al. Efficacy of coenzyme

randomized controlled trial. Neurology.

[69] Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis: A randomized controlled trial. Neurology. 1998;**50**:

1996;**16**:257-263

2005;**64**:713-715

2004;**69**:297-312

CD002286

466-470

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*Migraine*

2006;**26**(2):89-97

2007;**28**(11):580-587

2005;**179**(1):207-217

[39] Loder E. Post-marketing experience with an opioid nasal spray for migraine: Lessons for the future. Cephalalgia.

[47] Meents J, Neeb RU. TRPV1 in migraine pathophysiology. Trends in Molecular Medicine. 2010;**16**(4):153-159

[48] Vogler B, Rapoport A, Tepper S, Sheftell F, Bigal M. Role of melatonin in the pathophysiology of migraine. CNS

[49] Magni G, Ceruti S. P2Y purinergic receptors: New targets for analgesic and antimigraine drugs. Biochemical Pharmacology. 2013;**85**(4):466-477

[50] Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.

[51] Buchanan TM, Ramadan NM. Prophylactic pharmacotherapy for migraine headaches. Seminars in Neurology. 2006;**26**(2):188-198

[52] Bigal ME, Krymchantowski AV, Rapoport AM. Prophylactic migraine therapy: Emerging treatment options. Current Pain and Headache Reports.

[53] Kaniecki RG. Migraine prevention with Carvedilol: A prospective, openlabel trial. Headache. 2003;**43**:589

[54] Pietrobon D. Calcium channels and channelopathies of the central nervous system. Molecular Neurobiology.

[55] Solomon GD. Verapamil in migraine

Headache: The Journal of Head and Face

[56] Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology.

[57] Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the

prophylaxis-a five-year review.

Pain. 1989;**29**(7):425-427

2002;**58**:1652-1659

Drugs. 2006;**20**(5):343-350

2000;**55**(6):754-762

2004;**8**:178-184

2002;**25**:31-50

[40] Doods H, Arndt K, Rudolf K, Just S. CGRP antagonists: Unravelling

[41] Färkkilä M, Diener HC, Géraud G, Láinez M, Schoenen J, Harner N, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT 1F receptor agonist, for the acute treatment of migraine: A phase 2 randomized, placebo-controlled, parallel-group, dose-ranging study. The Lancet Neurology. 2012;**11**(5):405-413

[42] Varty G, Grilli M, Forlani A,

[43] Giffin NJ, Kowacs F, Libri V,

Williams P, Goadsby PJ, Kaube H. Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia. 2003;**23**(4):287-292

[44] Lassen LH, Ashina M, Christiansen I, Ulrich V, Grover R, Donaldson J, et al. Nitric oxide synthase inhibition: A new principle in the treatment of migraine attacks. Cephalalgia. 1998;**18**(1):27-32

[45] Tfelt H. Site of effect of LY2951742 for migraine prophylaxis. The Lancet

Neurology. 2015;**14**(1):31-32

2015;**35**(5):379-388

[46] Chabi A, Zhang Y, Jackson S, Cady R, Lines C, Herring WJ, et al. Randomized controlled trial of the orexin receptor antagonist Filorexant for migraine prophylaxis. Cephalalgia.

Fredduzzi S, Grzelak M, Guthrie D, et al. The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mgluR5) antagonists, MPEP and MTEP, and the mgluR1 antagonist, LY456236, in rodents: A comparison of efficacy and sideeffect profiles. Psychopharmacology.

the role of CGRP in migraine. Trends in Pharmacological Sciences.

**24**

preclinical aspects of topiramate: Pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;**41**(Suppl 1):S3-S9

[58] Freitag FG, Diamond S, Diamond ML, et al. The prophylaxis of migraine with the GABA-agonist, tiagabine: A clinical report. Headache. 1999;**39**:354

[59] Vaisleb I, Neft R, Schor N. Role of Levetiracetam in prophylaxis of migraine headaches in childhood. Neurology. 2005;**64**:A343

[60] Krusz JC. Zonisamide in the treatment of headache disorders. Cephalalgia. 2001;**21**:374-375

[61] Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;**45**:144-152

[62] Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): Randomized, placebo controlled, crossover study. BMJ. 2001;**322**:19-22

[63] Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: A randomized controlled trial. JAMA. 2003;**289**:65-69

[64] Ashkenazi A, Silberstein AD. Botulinum toxin and other new approaches to migraine therapy. Annual Review of Medicine. 2004;**55**: 505-518

[65] Millán-Guerrero RO, Pineda-Lucatero AG, Hernández-Benjamín T, Tene CE, Pacheco MF. Nα-methylhistamine safety and efficacy in migraine prophylaxis: Phase I and phase II studies. Headache: The Journal of Head and Face Pain. 2003;**43**(4):389-394

[66] Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J. Effects of tonabersat on migraine with aura: A randomized, double-blind, placebo-controlled crossover study. The Lancet Neurology. 2009;**8**(8):718-723

[67] Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: Results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;**16**:257-263

[68] Sandor PS, Di Clemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: A randomized controlled trial. Neurology. 2005;**64**:713-715

[69] Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis: A randomized controlled trial. Neurology. 1998;**50**: 466-470

[70] Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: A randomized trial. Headache. 2004;**44**:885-890

[71] Bianchi A, Salomone S, Caraci F, Pizza V, Bernardini R, D'Amato CC. Role of magnesium, coenzyme Q 10, riboflavin, and vitamin B 12 in migraine prophylaxis. Vitamins & Hormones. 2004;**69**:297-312

[72] Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database of Systematic Reviews. 2004;**1**: CD002286

[73] Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;**63**:2240-2244

**27**

**Chapter 3**

**Abstract**

non-responding to medical therapies.

patients' everyday life, their families, and the society.

invasive surgery

**1. Introduction**

Minimally Invasive Surgical

*Francesco Simonacci, Nicolò Bertozzi, Gianluigi Lago,* 

**Keywords:** migraine, tension-type headache, surgical therapy, minimally

Migraine headache (MH) is known to affect over 324.1 million people worldwide [1, 2]. However, MH is still widely undiagnosed and undertreated. In US alone, MH treatment cost accounts for over \$17 billion each year, without taking into consideration the indirect costs due to the 112 million annual workdays loss, which has an estimated cost of \$14 billion [2–4]. Furthermore, MH has an even greater burden on

Despite its prevalence and debilitating nature, MH is still widely undiagnosed and undertreated. A combination of pharmacologic (both abortive and preventive drugs) and non-pharmacological interventions (such as behavioral and lifestyle

Migraine headache (MH) is a very common disorder affecting 10–12% of the world's adult population. The first line therapy for migraine is usually a combination of conservative treatments but some patients seem to be refractory. For this group of patients, the minimally invasive surgical treatment of migraine might offer a solution. Migraine is usually caused by extracranial sensitive nerve compression due vascular, fascial or muscular structures nearby. The aim of migraine surgery is to relieve such compression at specific trigger points located in the occipital, temporal and frontal regions. From June 2011 until July 2019, we performed MH decompression surgeries in over 269 patients with either frontal, occipital, or temporal migraine trigger sites. In the occipital and temporal areas, nerve decompression was achieved by occipital and superficial temporal artery ligation, respectively. In patients suffering from frontal headache we performed both endoscopic nerve decompression and transpalpebral decompression. Among patient suffering from occipital migraine, 95% of them showed improvement of their condition, with 86% reporting complete relief. As concern temporal migraine, positive outcome was achieved in 83% of the patients (50% complete elimination and 33% partial improvement). In patient suffering from frontal migraine, positive results were observed in 94% of the patients (32% complete elimination, 62% partial improvement). Migraine is a common and debilitating condition that can be treated successfully with minimally invasive surgical procedure especially for those patients

*Carlo Fante, Giuseppe Sanese and Edoardo Raposio*

Treatment of Migraine

#### **Chapter 3**

## Minimally Invasive Surgical Treatment of Migraine

*Francesco Simonacci, Nicolò Bertozzi, Gianluigi Lago, Carlo Fante, Giuseppe Sanese and Edoardo Raposio*

#### **Abstract**

Migraine headache (MH) is a very common disorder affecting 10–12% of the world's adult population. The first line therapy for migraine is usually a combination of conservative treatments but some patients seem to be refractory. For this group of patients, the minimally invasive surgical treatment of migraine might offer a solution. Migraine is usually caused by extracranial sensitive nerve compression due vascular, fascial or muscular structures nearby. The aim of migraine surgery is to relieve such compression at specific trigger points located in the occipital, temporal and frontal regions. From June 2011 until July 2019, we performed MH decompression surgeries in over 269 patients with either frontal, occipital, or temporal migraine trigger sites. In the occipital and temporal areas, nerve decompression was achieved by occipital and superficial temporal artery ligation, respectively. In patients suffering from frontal headache we performed both endoscopic nerve decompression and transpalpebral decompression. Among patient suffering from occipital migraine, 95% of them showed improvement of their condition, with 86% reporting complete relief. As concern temporal migraine, positive outcome was achieved in 83% of the patients (50% complete elimination and 33% partial improvement). In patient suffering from frontal migraine, positive results were observed in 94% of the patients (32% complete elimination, 62% partial improvement). Migraine is a common and debilitating condition that can be treated successfully with minimally invasive surgical procedure especially for those patients non-responding to medical therapies.

**Keywords:** migraine, tension-type headache, surgical therapy, minimally invasive surgery

#### **1. Introduction**

Migraine headache (MH) is known to affect over 324.1 million people worldwide [1, 2]. However, MH is still widely undiagnosed and undertreated. In US alone, MH treatment cost accounts for over \$17 billion each year, without taking into consideration the indirect costs due to the 112 million annual workdays loss, which has an estimated cost of \$14 billion [2–4]. Furthermore, MH has an even greater burden on patients' everyday life, their families, and the society.

Despite its prevalence and debilitating nature, MH is still widely undiagnosed and undertreated. A combination of pharmacologic (both abortive and preventive drugs) and non-pharmacological interventions (such as behavioral and lifestyle

changes) are still the main treatment for MH patients. Nevertheless, most MH suffers remain refractory and does not achieve satisfactory relief.

Among the numerous hypotheses proposed over the years regarding MH etiology, none has come to clearly highlight its true nature. Some researchers have proposed that MH might be originated from a central neurovascular phenomenon, others have hypnotized a cortical neuronal hyperexcitability, others a cortical spreading depression, others an abnormal modulation of brain nociceptive system, and eventually others have demonstrated a central/peripheral activation with sensitization of the trigeminal system [2, 5]. But still MH pathophysiology is unclear and a matter of international debate.

Plastic surgeons were never looking for a surgical treatment for MH; however, this idea came into their eyes in 1999 following the reports made by patients that underwent corrugator supercilii muscle resection for forehead rejuvenation surgery and experienced elimination or improvement in their MH after [2, 5]. In 2000, Guyuron et al. [5] first reported in a retrospective study this association between corrugator supercilii muscle resection and disappearance or significant improvement in MH attacks, paving the way for a new MH origin and thus a new treatment option. Indeed MH appeared to be triggered by a peripheral activation of the trigeminal nerve, due to overstimulation of its branches (trigger points), followed by peripheral and central sensitization [5] And therefor, surgical decompression of these trigger sites might end up as an effective treatment modality of MH.

In the following years, independent researchers demonstrated the efficacy of botulin toxin injection for the treatment of MH [2]. These evidences supported the hypothesis that MH was determined by the peripheral activation of trigeminal nerve branches.

The trigger site was defined as the point where the MH attack starts and corresponds to the anatomical area of potential irritation of the trigeminal nerve branches [2, 6]. As a pathophysiological consequence of the chronic mechanical stimulation and irritation of the trigeminal nerve terminal branches, calcitonin gene-related peptide, substance P, and neurokinin are released [2, 5, 6]. These neuropeptides may cause the activation of the trigeminovascular system and the neurogenic inflammation leading to meningeal irritation, altered microvascular blood flow, central and peripheral trigeminal sensitization recognized as hyperalgesia, and cutaneous allodynia.

Eventually, multiple anatomical studies strengthened the trigger point theory of MH origin by demonstrating that musculature, vessels, bony foramen, and fascial bands could entrap or compress nerve branches at proposed migraine trigger sites [2, 6, 7].

Over the last 15 years, Guyuron conducted several studies providing foundation for this hypothesis and reported a reduction of the frequency, duration, and intensity of MH by at least half in 80–90% of patients [2, 5, 7–9]. In the same years, other independent groups reported similar findings by employing Guyuron's surgical approach, demonstrating the effectiveness of the procedure and the reproducibility of the results [2, 6]. However, the most striking evidence for the effectiveness of peripheral nerve decompression surgery for MH treatment came from a doubleblind, sham-controlled study of Guyuron et al. [2, 8]. In this trial, 49 patients underwent decompressive surgery, while 26 underwent sham surgery. At least 50% reduction in MH was reported from 57.7% of patients of the sham surgery group and 83.7% in the actual surgery group (p < 0.05). Moreover, 57.1% of actual surgical group reported complete elimination of MH symptoms, compared with only 3.8% of patients in the sham surgery group (p < 0.001). At 1 year, all migraine headache measurements were significantly improved in the actual surgical group and were not influenced by the trigger site.

**29**

**2. Surgical treatment**

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

sponding nerves.

nerve (ATN).

ter.

(LON).

Following these studies, four were the main trigger sites identified:

1.I Trigger Site (Frontal): patients present with frontal symptoms; the glabellar muscles and/or supratrochlear and supraorbital vessels may irritate corre-

2.II Trigger Site (Temporal): patients with temporal headaches; the temporalis muscle or the superficial temporal artery may cause inflammation of the zygomatic temporal branch of the trigeminal nerve (ZTN) or the auriculotemporal

3.III Trigger Site (Rhinogenic): patients complain of paranasal and retrobulbar headaches; deviated septum, contact between the turbinates and the septum, concha bullosa, septa bullosa, and other intranasal abnormalities may irritate the trigeminal end branches. This site will not be covered in the present chap-

4.IV Trigger Site (Occipital): patients refer occipital symptoms: occipitalis, trapezius, and semispinalis capitis muscles, fascial bands, or the occipital artery can irritate the greater occipital nerve (GON) and/or the lesser occipital nerve

Following these evidences, it came to be clearly known that an essential step was detecting the precise site of pain onset (the trigger point) [2, 10–12]. Although patients might report diffuse headache, once they were asked to locate where the pain begins, they could precisely pinpoint it with one fingertip, and that was where the surgical treatment had to be performed in order to release the putative nerve branch. Surgeons' finger compression over the trigger point usually can evoke pain, thus confirming the exact location of trigger point. Nerve blocks and portable Doppler were also successfully investigated in order to confirm the trigger points and help less experienced surgeons, while preoperative botulinum toxin injections proved to be less useful. Lack or incomplete response should be carefully interpreted since it does not automatically exclude the suspected trigger point; indeed, incomplete release might have been performed. Careful analysis of patients' symptoms and meticulous physical examination can reliably guide the surgical planning. Indeed, MH origin and surgical deactivation procedures resembles closely upper limb compressing neuropathies. Therefore, surgical treatment for MH can successfully eliminate or reduce the MH frequency, intensity, and duration in a lasting manner, reducing the economic burden of MH sufferers, improving patients' performances and participation in daily life activities [2, 3–10]. But still, a percentage of patients are refractory to surgery [2, 7]. Possible explanations are that incomplete or incorrect detection of all of the trigger sites have occurred or that irritation sites are not correctly dealt by current surgical approaches [2, 6]. Rigorous patient screening and selection with proper identification of MH trigger points are mandatory for a successful surgical outcome; yet a thorough understanding of the anatomy is essential to ensure complete nerve release and prevent postoperative complications.

In order to be regarded eligible to undergo the surgery patients had to be diagnosed by a board-certified neurologist with: migraine without aura, tension-type headaches, or new daily persistent headaches with 4 or more attack each month for *Migraine*

a matter of international debate.

nerve branches.

ger sites [2, 6, 7].

sia, and cutaneous allodynia.

not influenced by the trigger site.

changes) are still the main treatment for MH patients. Nevertheless, most MH suf-

Plastic surgeons were never looking for a surgical treatment for MH; however, this idea came into their eyes in 1999 following the reports made by patients that underwent corrugator supercilii muscle resection for forehead rejuvenation surgery and experienced elimination or improvement in their MH after [2, 5]. In 2000, Guyuron et al. [5] first reported in a retrospective study this association between corrugator supercilii muscle resection and disappearance or significant improvement in MH attacks, paving the way for a new MH origin and thus a new treatment option. Indeed MH appeared to be triggered by a peripheral activation of the trigeminal nerve, due to overstimulation of its branches (trigger points), followed by peripheral and central sensitization [5] And therefor, surgical decompression of

these trigger sites might end up as an effective treatment modality of MH.

In the following years, independent researchers demonstrated the efficacy of botulin toxin injection for the treatment of MH [2]. These evidences supported the hypothesis that MH was determined by the peripheral activation of trigeminal

The trigger site was defined as the point where the MH attack starts and corresponds to the anatomical area of potential irritation of the trigeminal nerve branches [2, 6]. As a pathophysiological consequence of the chronic mechanical stimulation and irritation of the trigeminal nerve terminal branches, calcitonin gene-related peptide, substance P, and neurokinin are released [2, 5, 6]. These neuropeptides may cause the activation of the trigeminovascular system and the neurogenic inflammation leading to meningeal irritation, altered microvascular blood flow, central and peripheral trigeminal sensitization recognized as hyperalge-

Eventually, multiple anatomical studies strengthened the trigger point theory of MH origin by demonstrating that musculature, vessels, bony foramen, and fascial bands could entrap or compress nerve branches at proposed migraine trig-

Over the last 15 years, Guyuron conducted several studies providing foundation for this hypothesis and reported a reduction of the frequency, duration, and intensity of MH by at least half in 80–90% of patients [2, 5, 7–9]. In the same years, other independent groups reported similar findings by employing Guyuron's surgical approach, demonstrating the effectiveness of the procedure and the reproducibility of the results [2, 6]. However, the most striking evidence for the effectiveness of peripheral nerve decompression surgery for MH treatment came from a doubleblind, sham-controlled study of Guyuron et al. [2, 8]. In this trial, 49 patients underwent decompressive surgery, while 26 underwent sham surgery. At least 50% reduction in MH was reported from 57.7% of patients of the sham surgery group and 83.7% in the actual surgery group (p < 0.05). Moreover, 57.1% of actual surgical group reported complete elimination of MH symptoms, compared with only 3.8% of patients in the sham surgery group (p < 0.001). At 1 year, all migraine headache measurements were significantly improved in the actual surgical group and were

Among the numerous hypotheses proposed over the years regarding MH etiology, none has come to clearly highlight its true nature. Some researchers have proposed that MH might be originated from a central neurovascular phenomenon, others have hypnotized a cortical neuronal hyperexcitability, others a cortical spreading depression, others an abnormal modulation of brain nociceptive system, and eventually others have demonstrated a central/peripheral activation with sensitization of the trigeminal system [2, 5]. But still MH pathophysiology is unclear and

fers remain refractory and does not achieve satisfactory relief.

**28**

Following these studies, four were the main trigger sites identified:


Following these evidences, it came to be clearly known that an essential step was detecting the precise site of pain onset (the trigger point) [2, 10–12]. Although patients might report diffuse headache, once they were asked to locate where the pain begins, they could precisely pinpoint it with one fingertip, and that was where the surgical treatment had to be performed in order to release the putative nerve branch. Surgeons' finger compression over the trigger point usually can evoke pain, thus confirming the exact location of trigger point. Nerve blocks and portable Doppler were also successfully investigated in order to confirm the trigger points and help less experienced surgeons, while preoperative botulinum toxin injections proved to be less useful. Lack or incomplete response should be carefully interpreted since it does not automatically exclude the suspected trigger point; indeed, incomplete release might have been performed. Careful analysis of patients' symptoms and meticulous physical examination can reliably guide the surgical planning. Indeed, MH origin and surgical deactivation procedures resembles closely upper limb compressing neuropathies. Therefore, surgical treatment for MH can successfully eliminate or reduce the MH frequency, intensity, and duration in a lasting manner, reducing the economic burden of MH sufferers, improving patients' performances and participation in daily life activities [2, 3–10]. But still, a percentage of patients are refractory to surgery [2, 7]. Possible explanations are that incomplete or incorrect detection of all of the trigger sites have occurred or that irritation sites are not correctly dealt by current surgical approaches [2, 6]. Rigorous patient screening and selection with proper identification of MH trigger points are mandatory for a successful surgical outcome; yet a thorough understanding of the anatomy is essential to ensure complete nerve release and prevent postoperative complications.

#### **2. Surgical treatment**

In order to be regarded eligible to undergo the surgery patients had to be diagnosed by a board-certified neurologist with: migraine without aura, tension-type headaches, or new daily persistent headaches with 4 or more attack each month for at least 6 months. Also, patients that do not benefit from any medications for their headache might undergo the procedure. However, patients with cluster headache, episodic tension-type headache, or secondary headaches are considered ineligible to undergo our procedure. Furthermore a CT scan or an MRI study must be performed prior to be regarded eligible for migraine deactivation surgery in order to rule out any cause of secondary migraine headache.

#### **2.1 Frontal trigger site**

The supraorbital nerve is a sensory nerve originating from the frontal branch of the ophthalmic division of the trigeminal nerve. In the majority of the cases, it passes through a supraorbital notch, which can be occasionally completed by a fibrous band. Here the nerve displays an intimate relationship with the corrugator supercilii muscle. The reason why some patients do not respond to the surgical decompression of the only supraorbital nerve and need a more medial muscular resection is that the supratrochlear nerve may be involved [2, 13–16]. The supratrochlear nerve is the smallest terminal branch of the frontal nerve, which itself originates from the ophthalmic division of the trigeminal nerve. It emerges between the trochlea and the supraorbital foramen. Another source of compression can be the interaction of nerves with the vascular structures. The main vessels that may be involved are the supratrochlear and the supraorbital arteries.

Patients who suffered from frontal migraine headache can be treated with either endoscopic or transpalpebral approach. In our experience, we performed both procedures to decompress supraorbital and supratrochlear nerves [13–16]. However, endoscopic nerve decompression cannot be performed on patients with long foreheads (8 cm measured from the anterior hairline to the supraorbital ridge) or on patients with significant curvature to the forehead, as endoscopic access would have been difficult to impossible. In our experience, endoscopic approach did not allow to treat the vascular compression of supraorbital and supratrochlear nerves by corresponding ectasic arteries [2, 13–16]. Transpalpebral approach for frontal trigger site deactivation was performed by means a supratarsal crease incision involving up to two-thirds of the medial limit of the caudal portion of the conventional upper blepharoplasty incision. The upper eyelid, glabellar area, and the lower forehead were infiltrated with local anesthesia composed by 40-cc Carbocaine 1% + 40-cc NaCl 0.9% and 20-cc sodium bicarbonate 8.4%. After raising a skin-orbicularis oculi muscle flap above the level of the septum, the orbicularis muscle was dissected in a cephalic direction. The dissection was continued to the supraoribtal rim. The corrugator supercilii muscle protecting the supraorbital and supratrochlear nerves was elevated and by dissection the exposure of depressor supercilii muscle was performed. After selective myotomy of depressor and corrugator supercilii muscles, the lateral fibers of the procerus muscle encasing the supratrochlear nerve were dissected. Once the supraorbital and supratrochlear nerves were isolated, they were decompressed by the cauterization of the concomitant ectasic arteries. The cutaneous access was closed with absorbable sutures, and steri-strips were positioned at level of superior eyelids bilaterally. The endoscopic selective myotomies technique was performed with a single access by mean a specifically modified endoscope (Karl Storz, Tuttlingen, Germany). With the patient supine and the head in a neutral position, frontal trigger nerves were located. Skin markings were drawn above the eyebrow bilaterally, at the mid-pupillary line (supraorbital nerve) and 1 cm medially (supratrochlear nerve). Local anesthesia with diluted 40-cc Carbocaine 1% + 40-cc NaCl 0.9% and 20-cc sodium bicarbonate 8.4% was injected in the forehead, between the glabellar region and about 2 cm behind the anterior hairline. A single 1.5-cm incision was then performed on the midline, 1 cm behind the frontal

**31**

**Figure 1.**

*nerve (STN).*

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

undermined region [2, 13–16] (**Figure 1**).

(V2) of the trigeminal nerve [17–21].

STA-ATN relationship is not intraoperatively observed.

**2.2 Temporal trigger site**

anesthesia [17].

hairline. All tissues were dissected until the periosteum layer. The lateral anatomic limit of the undermined area was the temporal region, bilaterally. In order to lift the frontal skin during the endoscopic procedure (and better visualize the anatomic structures) nylon 1-0 sutures were placed in the superciliary region at each side of both supratrochlear and supraorbital nerves bilaterally. Our modified endoscope (Karl Storz, Tuttlingen, Germany) consists of a 9-mm trocar with an air/insufflator/suction triple valve, a straight Hopkins telescope with fiber-light transmission, a Wittmöser operating sheath with a connection for high-frequency diathermy, and a specifically designed elliptical-tipped wire loop electrode for electrocautery. The modified endoscope was inserted through the incision in the subgaleal plane and used to perform endoscopically assisted section of the corrugator supercilii, depressor supercilii, and procerus muscles bilaterally, with the purpose of decompressing the supraorbital and supratrochlear nerves bilaterally. At the end of the procedure, after an accurate hemostasis, the cutaneous access was closed with absorbable suture, without any drainage; a compressive bandage was positioned all around

The ATN and ZTN are the two primary trigger points in the temporal migraine.

It is our experience that the ATN is more often involved than the ZTN as temporal MH trigger given the close relationship with the superficial temporal artery (STA). Therefore, our surgical procedure primarily aims at eliminating the pulsatile irritation of the STA to the ATN by ligating the artery prior to and above the intersection or coiling segment. However, we perform ZTN decompression whenever

We perform both our personal decompression techniques under local assisted

For ATN decompression surgery, we usually marked a 1.5-cm incision where patients pinpoint the painful spot above the insertion of auricular helix at level of temporal area. A handheld Doppler was regularly used to locate the STA, since we

*Endoscopic selective myotomies of corrugator supercilii muscle (MC) with decompression of supratrochlear* 

The ATN is one of the terminal braches of the mandibular (V1) division of the trigeminal nerve. The ZTN is one of the terminal braches of the maxillary division *Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

*Migraine*

any cause of secondary migraine headache.

involved are the supratrochlear and the supraorbital arteries.

**2.1 Frontal trigger site**

at least 6 months. Also, patients that do not benefit from any medications for their headache might undergo the procedure. However, patients with cluster headache, episodic tension-type headache, or secondary headaches are considered ineligible to undergo our procedure. Furthermore a CT scan or an MRI study must be performed prior to be regarded eligible for migraine deactivation surgery in order to rule out

The supraorbital nerve is a sensory nerve originating from the frontal branch of the ophthalmic division of the trigeminal nerve. In the majority of the cases, it passes through a supraorbital notch, which can be occasionally completed by a fibrous band. Here the nerve displays an intimate relationship with the corrugator supercilii muscle. The reason why some patients do not respond to the surgical decompression of the only supraorbital nerve and need a more medial muscular resection is that the supratrochlear nerve may be involved [2, 13–16]. The supratrochlear nerve is the smallest terminal branch of the frontal nerve, which itself originates from the ophthalmic division of the trigeminal nerve. It emerges between the trochlea and the supraorbital foramen. Another source of compression can be the interaction of nerves with the vascular structures. The main vessels that may be

Patients who suffered from frontal migraine headache can be treated with either endoscopic or transpalpebral approach. In our experience, we performed both procedures to decompress supraorbital and supratrochlear nerves [13–16]. However, endoscopic nerve decompression cannot be performed on patients with long

foreheads (8 cm measured from the anterior hairline to the supraorbital ridge) or on patients with significant curvature to the forehead, as endoscopic access would have been difficult to impossible. In our experience, endoscopic approach did not allow to treat the vascular compression of supraorbital and supratrochlear nerves by corresponding ectasic arteries [2, 13–16]. Transpalpebral approach for frontal trigger site deactivation was performed by means a supratarsal crease incision involving up to two-thirds of the medial limit of the caudal portion of the conventional upper blepharoplasty incision. The upper eyelid, glabellar area, and the lower forehead were infiltrated with local anesthesia composed by 40-cc Carbocaine 1% + 40-cc NaCl 0.9% and 20-cc sodium bicarbonate 8.4%. After raising a skin-orbicularis oculi muscle flap above the level of the septum, the orbicularis muscle was dissected in a cephalic direction. The dissection was continued to the supraoribtal rim. The corrugator supercilii muscle protecting the supraorbital and supratrochlear nerves was elevated and by dissection the exposure of depressor supercilii muscle was performed. After selective myotomy of depressor and corrugator supercilii muscles, the lateral fibers of the procerus muscle encasing the supratrochlear nerve were dissected. Once the supraorbital and supratrochlear nerves were isolated, they were decompressed by the cauterization of the concomitant ectasic arteries. The cutaneous access was closed with absorbable sutures, and steri-strips were positioned at level of superior eyelids bilaterally. The endoscopic selective myotomies technique was performed with a single access by mean a specifically modified endoscope (Karl Storz, Tuttlingen, Germany). With the patient supine and the head in a neutral position, frontal trigger nerves were located. Skin markings were drawn above the eyebrow bilaterally, at the mid-pupillary line (supraorbital nerve) and 1 cm medially (supratrochlear nerve). Local anesthesia with diluted 40-cc Carbocaine 1% + 40-cc NaCl 0.9% and 20-cc sodium bicarbonate 8.4% was injected in the forehead, between the glabellar region and about 2 cm behind the anterior hairline. A single 1.5-cm incision was then performed on the midline, 1 cm behind the frontal

**30**

hairline. All tissues were dissected until the periosteum layer. The lateral anatomic limit of the undermined area was the temporal region, bilaterally. In order to lift the frontal skin during the endoscopic procedure (and better visualize the anatomic structures) nylon 1-0 sutures were placed in the superciliary region at each side of both supratrochlear and supraorbital nerves bilaterally. Our modified endoscope (Karl Storz, Tuttlingen, Germany) consists of a 9-mm trocar with an air/insufflator/suction triple valve, a straight Hopkins telescope with fiber-light transmission, a Wittmöser operating sheath with a connection for high-frequency diathermy, and a specifically designed elliptical-tipped wire loop electrode for electrocautery. The modified endoscope was inserted through the incision in the subgaleal plane and used to perform endoscopically assisted section of the corrugator supercilii, depressor supercilii, and procerus muscles bilaterally, with the purpose of decompressing the supraorbital and supratrochlear nerves bilaterally. At the end of the procedure, after an accurate hemostasis, the cutaneous access was closed with absorbable suture, without any drainage; a compressive bandage was positioned all around undermined region [2, 13–16] (**Figure 1**).

#### **2.2 Temporal trigger site**

The ATN and ZTN are the two primary trigger points in the temporal migraine. The ATN is one of the terminal braches of the mandibular (V1) division of the trigeminal nerve. The ZTN is one of the terminal braches of the maxillary division (V2) of the trigeminal nerve [17–21].

It is our experience that the ATN is more often involved than the ZTN as temporal MH trigger given the close relationship with the superficial temporal artery (STA). Therefore, our surgical procedure primarily aims at eliminating the pulsatile irritation of the STA to the ATN by ligating the artery prior to and above the intersection or coiling segment. However, we perform ZTN decompression whenever STA-ATN relationship is not intraoperatively observed.

We perform both our personal decompression techniques under local assisted anesthesia [17].

For ATN decompression surgery, we usually marked a 1.5-cm incision where patients pinpoint the painful spot above the insertion of auricular helix at level of temporal area. A handheld Doppler was regularly used to locate the STA, since we

#### **Figure 1.**

*Endoscopic selective myotomies of corrugator supercilii muscle (MC) with decompression of supratrochlear nerve (STN).*

observed 100% correlation rate between the trigger point identified and a close ATN-STA relationship (being either a simple crossover or a helical intertwining). Once the incision was made, dissection was taken with the help of blunt tipped scissors to expose and isolate both ATN and STA, which was ligated both proximally and caudally to the area of nerve-artery intersection [17].

When it was necessary to decompress the ZTN, we made 3-cm cutaneous incision 8–10 mm behind the temporal hairline and took dissection deep to the deep temporal fascia by the blunt tip scissors. We opened the inferior temporal septum exposing the inferior temporal compartment that contains the ZTN, sentinel vessels, and temporal branches of facial nerve (that must be carefully preserved by incorporating it in the roof of the elevated flap). Then we widened the exit of the ZTN through temporal muscle and fascia, and the sentinel vessels were cauterized only when patients described a pulsating pain in the temporal region [17] (**Figure 2**).

#### **2.3 Occipital trigger site**

The common occipital headache symptoms here can be caused by the compression of the greater, lesser, and third occipital nerves. This is due to the presence of muscular and fascial entrapments and also because of their interaction with the vascular structures [2, 4, 7, 22]. The greater occipital nerve originates from the medial branch of the C2 dorsal root. It curves to reach the occipital region, running caudal to the inferior oblique muscle and sometimes piercing it. Then it reaches the semispinalis muscle, where it is possible to identify the deepest potential compression point of the nerve. The course of the nerve in the area of the superior nuchal

**33**

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

the principal trigger point of occipital migraine.

between the two external auditory canals.

impingement [7, 23–25].

into the nuchal line [2, 4, 7, 22].

multiple myotomies.

line is variously described, because of the large anatomical variability that these structures present. The latest studies have shown the exact location of the intramuscular course of the nerve: it is located 3 cm below and 1.5 cm lateral to the occipital protuberance [2, 4, 7, 22]. Possible trigger points can be found at its entrance into the deep fascia underlying the semispinalis or the muscle itself or at level of the entrance of the nerve in the semispinalis capitis and trapezius muscles. Other possible compression is where the nerve pierces the tendinous insertion of the trapezius

Because of the surgical decompression of the nerve, the semispinalis capitis and the trapezius together with the splenius and the occipital muscles are resected with

However, based on our study, the close relationship found between the great occipital nerve and the occipital artery in the region of the superior nuchal line is

This artery is the main vessel running through the occipital area. It arises from

Furthermore, minor trigger sites are also described in this area [2, 4, 7, 22]. It is related to the lesser occipital nerves, which can be similarly compressed by fascial bands and the occipital artery branches. If the lesser occipital nerve is affected, it can be responsible of laterally located pain symptoms. It arises from C2 or rarely from C3 dorsal root; it emerges from the posterior border of the sternocleidomastoids, seldom piercing it, and then ascends along it. The emergence point was found with a 3-cm diameter located 6.5 cm from midline and 5.3 cm below the line drawn

Surgical treatment of occipital trigger site aims at removing the potential compression points of the greater and the lesser occipital nerve along their course throughout the semispinalis, the splenius and the trapezius muscles to the subcutaneous tissue of the occipital scalp. The avulsion of the third occipital nerve (TON) during the occipital migraine surgery does not improve clinical outcomes. According to Guyuron et al. [7], Lin et al. [23], Dash et al. [24], and Lee et al. [25], the currently adopted procedure for treatment of the occipital trigger site, undertaken under general anesthesia, relies first on an incision in the occipital scalp and extensive undermining through which a small portion of the semispinalis capitis muscle is removed. This muscle is usually pierced by the greater occipital nerve (GON), lesser occipital nerves (LON) bilaterally. Subsequently, a subcutaneous flap is transposed between the GON and the muscle to avoid nerve

As regards our experience [26–28], we performed the occipital decompression surgical technique with the patient prone, under local assisted anesthesia. After injecting 40-cc of diluted Carbocaine 1% + 40-cc NaCl 0.9% and 20-cc sodium bicarbonate 8.4%, two horizontal occipital scalp incisions 5 cm in length were performed along the superior nuchal line bilaterally, at the location of arterial signal detected preoperatively by portable Doppler. Underneath the subcutaneous tissue, an accurate dissection of occipital, trapezius, splenius capitis and semispinalis capitis muscles allowed to identify the GON and vascular bundle (occipital

the external carotid artery, and it runs medially to the mastoid process on the temporal bone. It then reaches the occipital region, boring the deep cervical fascia between the sternocleidomastoid and the cranial attachment of the trapezius. At this point it can be found in the subcutaneous layer leaving many convoluted branches and anastomosing with the contralateral artery [3]. In more than 50% of the cases, an intimate anatomical relationship was found. There are two possible types of interaction: they can coil together (70%) or the other possibility is a simple

crossing (30%) with the nerve passing superficial to the artery [2, 4, 7, 22].

#### *Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

*Migraine*

**2.3 Occipital trigger site**

observed 100% correlation rate between the trigger point identified and a close ATN-STA relationship (being either a simple crossover or a helical intertwining). Once the incision was made, dissection was taken with the help of blunt tipped scissors to expose and isolate both ATN and STA, which was ligated both proximally

When it was necessary to decompress the ZTN, we made 3-cm cutaneous incision 8–10 mm behind the temporal hairline and took dissection deep to the deep temporal fascia by the blunt tip scissors. We opened the inferior temporal septum exposing the inferior temporal compartment that contains the ZTN, sentinel vessels, and temporal branches of facial nerve (that must be carefully preserved by incorporating it in the roof of the elevated flap). Then we widened the exit of the ZTN through temporal muscle and fascia, and the sentinel vessels were cauterized only when patients

The common occipital headache symptoms here can be caused by the compression of the greater, lesser, and third occipital nerves. This is due to the presence of muscular and fascial entrapments and also because of their interaction with the vascular structures [2, 4, 7, 22]. The greater occipital nerve originates from the medial branch of the C2 dorsal root. It curves to reach the occipital region, running caudal to the inferior oblique muscle and sometimes piercing it. Then it reaches the semispinalis muscle, where it is possible to identify the deepest potential compression point of the nerve. The course of the nerve in the area of the superior nuchal

and caudally to the area of nerve-artery intersection [17].

described a pulsating pain in the temporal region [17] (**Figure 2**).

*Close auriculotemporal nerve (ATN) and superficial temporal artery (STA) relationship.*

**32**

**Figure 2.**

line is variously described, because of the large anatomical variability that these structures present. The latest studies have shown the exact location of the intramuscular course of the nerve: it is located 3 cm below and 1.5 cm lateral to the occipital protuberance [2, 4, 7, 22]. Possible trigger points can be found at its entrance into the deep fascia underlying the semispinalis or the muscle itself or at level of the entrance of the nerve in the semispinalis capitis and trapezius muscles. Other possible compression is where the nerve pierces the tendinous insertion of the trapezius into the nuchal line [2, 4, 7, 22].

Because of the surgical decompression of the nerve, the semispinalis capitis and the trapezius together with the splenius and the occipital muscles are resected with multiple myotomies.

However, based on our study, the close relationship found between the great occipital nerve and the occipital artery in the region of the superior nuchal line is the principal trigger point of occipital migraine.

This artery is the main vessel running through the occipital area. It arises from the external carotid artery, and it runs medially to the mastoid process on the temporal bone. It then reaches the occipital region, boring the deep cervical fascia between the sternocleidomastoid and the cranial attachment of the trapezius. At this point it can be found in the subcutaneous layer leaving many convoluted branches and anastomosing with the contralateral artery [3]. In more than 50% of the cases, an intimate anatomical relationship was found. There are two possible types of interaction: they can coil together (70%) or the other possibility is a simple crossing (30%) with the nerve passing superficial to the artery [2, 4, 7, 22].

Furthermore, minor trigger sites are also described in this area [2, 4, 7, 22]. It is related to the lesser occipital nerves, which can be similarly compressed by fascial bands and the occipital artery branches. If the lesser occipital nerve is affected, it can be responsible of laterally located pain symptoms. It arises from C2 or rarely from C3 dorsal root; it emerges from the posterior border of the sternocleidomastoids, seldom piercing it, and then ascends along it. The emergence point was found with a 3-cm diameter located 6.5 cm from midline and 5.3 cm below the line drawn between the two external auditory canals.

Surgical treatment of occipital trigger site aims at removing the potential compression points of the greater and the lesser occipital nerve along their course throughout the semispinalis, the splenius and the trapezius muscles to the subcutaneous tissue of the occipital scalp. The avulsion of the third occipital nerve (TON) during the occipital migraine surgery does not improve clinical outcomes. According to Guyuron et al. [7], Lin et al. [23], Dash et al. [24], and Lee et al. [25], the currently adopted procedure for treatment of the occipital trigger site, undertaken under general anesthesia, relies first on an incision in the occipital scalp and extensive undermining through which a small portion of the semispinalis capitis muscle is removed. This muscle is usually pierced by the greater occipital nerve (GON), lesser occipital nerves (LON) bilaterally. Subsequently, a subcutaneous flap is transposed between the GON and the muscle to avoid nerve impingement [7, 23–25].

As regards our experience [26–28], we performed the occipital decompression surgical technique with the patient prone, under local assisted anesthesia. After injecting 40-cc of diluted Carbocaine 1% + 40-cc NaCl 0.9% and 20-cc sodium bicarbonate 8.4%, two horizontal occipital scalp incisions 5 cm in length were performed along the superior nuchal line bilaterally, at the location of arterial signal detected preoperatively by portable Doppler. Underneath the subcutaneous tissue, an accurate dissection of occipital, trapezius, splenius capitis and semispinalis capitis muscles allowed to identify the GON and vascular bundle (occipital

**Figure 3.** *Cauterization of ectasic occipital artery (OA) with decompression of greater occipital nerve (GON).*

artery). When we found a dilated (or frankly aneurysmatic) occipital artery in close connection with the GON, we ligated or cauterized the vessel without any other surgical maneuvers except for accurate hemostasis and skin closure.

In the remaining cases in which vascular compression was not found we adopted a more conventional approach based on neurolysis of the GON and LON by undermining the occipital, trapezius, splenius capitis and semispinalis capitis muscles and following the nerve course caudally as possible [26, 27]. At the end of the procedure, after an accurate hemostasis, the cutaneous access was sutured with absorbable threads, without any drainage. No trichotomy was needed, and the scar from the incision was hidden in the patient's hair. The total operative time was no longer than 90 min for bilateral incisions, but often it was less than 60 minutes when the relevant anatomical structures were easily identified [27, 28] (**Figure 3**).

#### **3. Results**

From June 2011 until July 2019, we performed MH decompression surgeries in over 269 patients with either frontal, occipital, or temporal migraine trigger sites [2, 13–17, 26–28].

As concern the frontal migraine we performed 72 decompression surgeries (65 bilateral and 7 unilateral). After a mean follow-up of 24 months (range: 12–97 months), patients with frontal trigger site migraine reported a 94% positive response to surgery (32% complete relief and 62% significant improvement), while 6% had no change in their symptoms. Among total patients underwent MH frontal decompression surgeries, 24 patients (34.2%) experienced secondary trigger point emergence following primary occipital and/or temporal migraine surgery.

**35**

**Figure 4.**

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

important role when evaluating clinical outcomes (**Figure 4**).

occipital) while 4 patients had all three trigger points (**Figure 5**).

*Results of fontal migraine decompression surgeries from June 2011 until July 2019.*

Among these, 20 patients had two trigger points (18 frontal and occipital, 2 frontal and temporal) while 4 patients had all three trigger points. All patients continue to experience a quality of life better than before surgery, and all would have the surgery again. The learning curve and the experience of the operator play also an

Decompression surgeries to treat temporal trigger point were 56. Among these, 53 had monolateral localization, while 3 had bilateral one. Because the ATN-STA close relationship was observed intraoperatively in 47 surgeries the only ATN decompressions were performed. Whereas ZTN deactivation procedures were performed during the same operative session 6 times, since no ATN-STA close relationship was encountered. Therefore, we observed ATN-STA close relationship in 85.3% of patients; single STA-ATN intersection accounted for 83.7% of the cases, while helical intertwining accounted for 16.3%. After a mean follow-up of 24 months (range, 3–67 months), patients complaining for temporal MH had 83% positive surgical outcome (50% complete MH elimination, 33% significant improvement). Among total MH temporal decompression surgeries, 29 patients (49%) experienced secondary or tertiary trigger point emergence following primary migraine surgery. Among these 22 had two trigger points (20 temporal and occipital, 2 frontal and

As concern occipital migraine we performed 141 decompression surgeries (94 bilateral and 47 unilateral). In 119 patients with occipital migraine, we found a dilated occipital artery in close connection with the GON and we ligated the vessel without any other surgical maneuvers. In 22 patients with occipital migraine, vascular compression was not found and we adopted a conventional approach based on neurolysis of the GON and LON from muscles. We gathered data from questionnaires completed before and after surgery. After a mean follow up of 24 months (range: 3–67 months), patients with occipital migraine had positive response in 94.9% (86.8% complete relief and 8.1% significant improvement), and 5.1% did not get any better. As for the 119 patients who underwent dilated occipital artery ligation, positive response 95.5% (90% complete relief and 5.5% significant improvement) and 4.5% did not get any better. As for the 22 patients who did not undergo occipital artery ligation, we observed positive response in 91% (76% complete relief and 15% significant improvement) of the subjects while 9% did not get any better. All the patients without improvement of the symptoms after occipital artery ligation (3.5%) suffered of unilateral occipital migraine and referred complete relief after contralateral secondary surgery. Total patients underwent MH decompression

#### *Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

*Migraine*

artery). When we found a dilated (or frankly aneurysmatic) occipital artery in close connection with the GON, we ligated or cauterized the vessel without any other

*Cauterization of ectasic occipital artery (OA) with decompression of greater occipital nerve (GON).*

In the remaining cases in which vascular compression was not found we adopted a more conventional approach based on neurolysis of the GON and LON by undermining the occipital, trapezius, splenius capitis and semispinalis capitis muscles and following the nerve course caudally as possible [26, 27]. At the end of the procedure, after an accurate hemostasis, the cutaneous access was sutured with absorbable threads, without any drainage. No trichotomy was needed, and the scar from the incision was hidden in the patient's hair. The total operative time was no longer than 90 min for bilateral incisions, but often it was less than 60 minutes when the

From June 2011 until July 2019, we performed MH decompression surgeries in over 269 patients with either frontal, occipital, or temporal migraine trigger sites

As concern the frontal migraine we performed 72 decompression surgeries (65 bilateral and 7 unilateral). After a mean follow-up of 24 months (range: 12–97 months), patients with frontal trigger site migraine reported a 94% positive response to surgery (32% complete relief and 62% significant improvement), while 6% had no change in their symptoms. Among total patients underwent MH frontal decompression surgeries, 24 patients (34.2%) experienced secondary trigger point emergence following primary occipital and/or temporal migraine surgery.

surgical maneuvers except for accurate hemostasis and skin closure.

relevant anatomical structures were easily identified [27, 28] (**Figure 3**).

**34**

**3. Results**

**Figure 3.**

[2, 13–17, 26–28].

Among these, 20 patients had two trigger points (18 frontal and occipital, 2 frontal and temporal) while 4 patients had all three trigger points. All patients continue to experience a quality of life better than before surgery, and all would have the surgery again. The learning curve and the experience of the operator play also an important role when evaluating clinical outcomes (**Figure 4**).

Decompression surgeries to treat temporal trigger point were 56. Among these, 53 had monolateral localization, while 3 had bilateral one. Because the ATN-STA close relationship was observed intraoperatively in 47 surgeries the only ATN decompressions were performed. Whereas ZTN deactivation procedures were performed during the same operative session 6 times, since no ATN-STA close relationship was encountered. Therefore, we observed ATN-STA close relationship in 85.3% of patients; single STA-ATN intersection accounted for 83.7% of the cases, while helical intertwining accounted for 16.3%. After a mean follow-up of 24 months (range, 3–67 months), patients complaining for temporal MH had 83% positive surgical outcome (50% complete MH elimination, 33% significant improvement). Among total MH temporal decompression surgeries, 29 patients (49%) experienced secondary or tertiary trigger point emergence following primary migraine surgery. Among these 22 had two trigger points (20 temporal and occipital, 2 frontal and occipital) while 4 patients had all three trigger points (**Figure 5**).

As concern occipital migraine we performed 141 decompression surgeries (94 bilateral and 47 unilateral). In 119 patients with occipital migraine, we found a dilated occipital artery in close connection with the GON and we ligated the vessel without any other surgical maneuvers. In 22 patients with occipital migraine, vascular compression was not found and we adopted a conventional approach based on neurolysis of the GON and LON from muscles. We gathered data from questionnaires completed before and after surgery. After a mean follow up of 24 months (range: 3–67 months), patients with occipital migraine had positive response in 94.9% (86.8% complete relief and 8.1% significant improvement), and 5.1% did not get any better. As for the 119 patients who underwent dilated occipital artery ligation, positive response 95.5% (90% complete relief and 5.5% significant improvement) and 4.5% did not get any better. As for the 22 patients who did not undergo occipital artery ligation, we observed positive response in 91% (76% complete relief and 15% significant improvement) of the subjects while 9% did not get any better. All the patients without improvement of the symptoms after occipital artery ligation (3.5%) suffered of unilateral occipital migraine and referred complete relief after contralateral secondary surgery. Total patients underwent MH decompression

**Figure 5.** *Results of temporal migraine decompression surgeries from June 2011 until July 2019.*

**Figure 6.**

*Results of occipital migraine decompression surgeries from June 2011 until July 2019.*

surgeries, 42 patients (29.7%) experienced secondary or tertiary trigger point emergence following primary migraine surgery. Among these, 38 patients had two trigger points (18 occipital and frontal, 20 occipital and temporal) while 4 patients had all three trigger points (**Figure 6**).

#### **4. Complications**

Migraine surgery is regarded as a minimally invasive procedure; thus, no concerning side effects are usually reported. Temporary anesthesia occurred in all patients, which lasted 163 days on average [2, 13–17, 26–29]. Minor and transient complications reported in literature are lasting occipital numbness, intense itching after surgery, hypertrophic scar, incisional cellulitis, transient mild incisional alopecia or hair thinning, lasting neck stiffness that have an incidence ranging from 1 to 5% [2, 13–17, 26–29]. As regard our experience, intense itching after surgery was present in 30% of patients, temporary anesthesia in all patients while postoperative infections, seromas, or hematomas were not observed. All patients that were refractory to surgery did not report worsening in their MH at any follow-up. As concern frontal migraine decompression surgeries all patients experienced frontal and/or upper eyelid edema of various degrees. Usually the edema resolves by the

**37**

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

following avulsion of ATN and/or ZTN [2, 13–17, 26–28].

The authors declare no conflict of interest.

\*, Nicolò Bertozzi1

\*Address all correspondence to: francescosimonacci@hotmail.it

provided the original work is properly cited.

and Edoardo Raposio1

, Gianluigi Lago1

1 Department of Medicine and Surgery, Plastic Surgery Unit, University of Parma,

2 Division of Plastic and Reconstructive Surgery, University "Tor Vergata", Rome,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Carlo Fante1

,

**Conflict of interest**

**Author details**

Giuseppe Sanese2

Parma, Italy

Italy

Francesco Simonacci1

fifth postoperative day. Ecchymosis of both upper and lower eyelids follows surgery. No treatment needed to be given as these collateral events resolve by themselves; boric water applications three times a day helped the process of reabsorption of the edema. As previously stated, the only hypothetical serious complication that might occur within the 12 h following the surgery is the compression of the optical nerve due to the descent of the edema into the posterior orbicular space. In these cases, prompt recognition of patient's sight modification is mandatory in order to urgently decompress the optic nerve. Patients with particularly thin skin of the frontal region may develop postoperative burn-like scar because of the endoscopic electrocautery. The most common complication after site temporal migraine surgeries is slight hollowing of the temple (54% incidence rate). Nerve avulsion might be associated with neuroma formation, although it is not reported in literature of any neuroma

Based on our data collected, secondary trigger point emergence following primary occipital migraine surgery occurred in 35% of patients. However, we routinely deactivate the main trigger site first, and then a second or third surgery is performed at the remaining sites 3 months after each surgery. MH recurrence may occur from 1 up to 3 months after surgery; thus the result may be regarded as

permanent only after the third postoperative month [2, 13–17, 26–28].

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

*Migraine*

**Figure 5.**

**Figure 6.**

**36**

surgeries, 42 patients (29.7%) experienced secondary or tertiary trigger point emergence following primary migraine surgery. Among these, 38 patients had two trigger points (18 occipital and frontal, 20 occipital and temporal) while 4 patients

*Results of occipital migraine decompression surgeries from June 2011 until July 2019.*

*Results of temporal migraine decompression surgeries from June 2011 until July 2019.*

Migraine surgery is regarded as a minimally invasive procedure; thus, no concerning side effects are usually reported. Temporary anesthesia occurred in all patients, which lasted 163 days on average [2, 13–17, 26–29]. Minor and transient complications reported in literature are lasting occipital numbness, intense itching after surgery, hypertrophic scar, incisional cellulitis, transient mild incisional alopecia or hair thinning, lasting neck stiffness that have an incidence ranging from 1 to 5% [2, 13–17, 26–29]. As regard our experience, intense itching after surgery was present in 30% of patients, temporary anesthesia in all patients while postoperative infections, seromas, or hematomas were not observed. All patients that were refractory to surgery did not report worsening in their MH at any follow-up. As concern frontal migraine decompression surgeries all patients experienced frontal and/or upper eyelid edema of various degrees. Usually the edema resolves by the

had all three trigger points (**Figure 6**).

**4. Complications**

fifth postoperative day. Ecchymosis of both upper and lower eyelids follows surgery. No treatment needed to be given as these collateral events resolve by themselves; boric water applications three times a day helped the process of reabsorption of the edema. As previously stated, the only hypothetical serious complication that might occur within the 12 h following the surgery is the compression of the optical nerve due to the descent of the edema into the posterior orbicular space. In these cases, prompt recognition of patient's sight modification is mandatory in order to urgently decompress the optic nerve. Patients with particularly thin skin of the frontal region may develop postoperative burn-like scar because of the endoscopic electrocautery. The most common complication after site temporal migraine surgeries is slight hollowing of the temple (54% incidence rate). Nerve avulsion might be associated with neuroma formation, although it is not reported in literature of any neuroma following avulsion of ATN and/or ZTN [2, 13–17, 26–28].

Based on our data collected, secondary trigger point emergence following primary occipital migraine surgery occurred in 35% of patients. However, we routinely deactivate the main trigger site first, and then a second or third surgery is performed at the remaining sites 3 months after each surgery. MH recurrence may occur from 1 up to 3 months after surgery; thus the result may be regarded as permanent only after the third postoperative month [2, 13–17, 26–28].

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Francesco Simonacci1 \*, Nicolò Bertozzi1 , Gianluigi Lago1 , Carlo Fante1 , Giuseppe Sanese2 and Edoardo Raposio1

1 Department of Medicine and Surgery, Plastic Surgery Unit, University of Parma, Parma, Italy

2 Division of Plastic and Reconstructive Surgery, University "Tor Vergata", Rome, Italy

\*Address all correspondence to: francescosimonacci@hotmail.it

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] World Health Organization. The Global Burden of Disease, 2004 Update. Geneva, Switzerland: World Health Organization; 2004

[2] Raposio E, Bertozzi N, Bordin C, Simonacci F. Surgical therapy of migraine and tension-type headaches. In: Turker H, editor. Current Perspectives on Less-Known Aspects of Headache. Zagreb, Croatia: InTech; 2017. pp. 93-114

[3] Faber C, Garcia RM, Davis J, Guyuron B. A socioeconomic analysis of surgical treatment of migraine headaches. Plastic and Reconstructive Surgery. 2012;**129**:871-877

[4] Chmielewski L, Liu MT, Guyuron B. The role of occipital artery resection in the surgical treatment of occipital migraine headaches. Plastic and Reconstructive Surgery. 2013;**131**:351e-356e

[5] Guyuron B, Varghai A, Michelow BJ, Thomas T, Davis J. Corrugator supercilii muscle resection and migraine headaches. Plastic and Reconstructive Surgery. 2000;**106**:429-437

[6] Janis JE, Barker JC, Javadi C, Ducic I, Hagan R, Guyuron B. A review of current evidence in the surgical treatment of migraine headaches. Plastic and Reconstructive Surgery. 2014;**134**:131-141

[7] Guyuron B, Kriegler JS, Davis J, Amini SB. Comprehensive surgical treatment of migraine headaches. Plastic and Reconstructive Surgery. 2005;**115**(1):1-9

[8] Guyuron B, Reed D, Kriegler JS, Davis J, Pashmini N, Amini S. A placebo-controlled surgical trial of the treatment of migraine headaches. Plastic and Reconstructive Surgery. 2009;**124**:461-468

[9] Guyuron B, Kriegler JS, Davis J, Amini SB. Five-year outcome of surgical treatment of migraine headaches. Plastic and Reconstructive Surgery. 2011;**127**:603-608

[10] Punjabi A, Brown M, Guyuron B. Emergence of secondary trigger sites after primary migraine surgery. Plastic and Reconstructive Surgery. 2016;**137**:712e-716e

[11] Guyuron B, Nahabet E, Khansa I, Reed D, Janis JE. The current means for detection of migraine headache trigger sites. Plastic and Reconstructive Surgery. 2015;**136**:860-867

[12] Liu MT, Armijo BS, Guyuron B. A comparison of outcome of surgical treatment of migraine headaches using a constellation of symptoms versus botulinum toxin type A to identify the trigger sites. Plastic and Reconstructive Surgery. 2012;**129**:413-419

[13] Raposio E, Caruana G. Frontal endoscopic myotomies for chronic headache. The Journal of Craniofacial Surgery. 2015;**26**:e201-e203

[14] Raposio E, Caruana G. Minimally invasive endoscopic surgical treatment of headache. In: Raposio E, editor. Atlas of Endoscopic Plastic Surgery. New York, N.Y: Springer; 2016. pp. 17-21

[15] Caruana G, Bertozzi N, Boschi E, Grieco MP, Grignaffini E, Raposio E. Endoscopic forehead surgery for migraine therapy personal technique. Annali Italiani di Chirurgia. 2014;**85**:583-586

[16] Caruana G, Grignaffini E, Raposio E. Endoscopic forehead muscle resection for nerve decompression: A modified procedure. Plastic and Reconstructive Surgery. Global Open. 2015;**3**:e342

**39**

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

> [25] Lee M, Lineberry K, Reed D, Guyuron B. The role of the third occipital nerve in surgical treatment of occipital migraine headaches. Journal of Plastic, Reconstructive & Aesthetic

Surgery. 2013;**66**:1335-1339

[26] Polotto S, Simonacci F,

Grignaffini E, Grieco MP, Raposio E. Surgical treatment of frontal and occipital migraines: A comparison of results. Plastic and Reconstructive Surgery. Global Open. 2016;**4**:e653

[27] Raposio E, Caruana G. Tips for the surgical treatment of occipital nervetriggered headaches. European Journal of Plastic Surgery. 2017;**40**:177-182

[28] Raposio E, Simonacci F, Bertozzi N, Bellini E. Occipital migraine: A vascular approach. Plastic and Reconstructive Surgery. Global Open. 2017;**5**:78

[29] Ducic I, Hartmann EC, Larson EE. Indications and outcomes for surgical treatment of patients with chronic migraine headaches caused by occipital neuralgia. Plastic and Reconstructive

Surgery. 2009;**123**:1453-1461

[17] Bertozzi N, Simonacci F, Lago G, Bordin C, Raposio E. Surgical therapy of temporal triggered migraine headache. Plastic and Reconstructive Surgery.

[18] Chim H, Okada HC, Brown MS, et al. The auriculotemporal nerve in etiology of migraine headaches: Compression points and anatomical variations. Plastic and Reconstructive

[19] Janis JE, Hatef DA, Ducic I, et al. Anatomy of the auriculotemporal nerve: Variations in its relationship to the superficial temporal artery and implications for the treatment of migraine headaches. Plastic and Reconstructive Surgery.

[20] Janis JE, Hatef DA, Thakar H, et al. The zygomaticotemporal branch of the trigeminal nerve: Part II. Anatomical variations. Plastic and Reconstructive

[21] Iwanaga J, Watanabe K, Saga T, et al. Anatomical study of the superficial temporal branches of the auriculotemporal nerve: Application to surgery and other invasive treatments to the temporal region. Journal of Plastic, Reconstructive & Aesthetic Surgery.

[22] Gfrerer L, Raposio E, Ortiz R, Austen WG Jr. Surgical treatment of migraine headache: Back to the future. Plastic and Reconstructive Surgery.

[23] Lin SH, Lin HC, Jeng CH, Hsieh CH,

surgical treatment for occipital migraine in Taiwan. Annals of Plastic Surgery.

[24] Dash KS, Janis JE, Guyuron B. The lesser and third occipital nerves and migraine headaches. Plastic and Reconstructive Surgery.

Lin YH, Chen CC. Experience of

Global Open. 2018;**6**:e1980

Surgery. 2012;**130**:336-341

2010;**125**:1422-1428

2017;**70**:370-374

2018;**142**:1036-1045

2016;**76**:S80-S84

2005;**115**:1752-1758

Surgery. 2010;**126**:435-442

*Minimally Invasive Surgical Treatment of Migraine DOI: http://dx.doi.org/10.5772/intechopen.90285*

[17] Bertozzi N, Simonacci F, Lago G, Bordin C, Raposio E. Surgical therapy of temporal triggered migraine headache. Plastic and Reconstructive Surgery. Global Open. 2018;**6**:e1980

[18] Chim H, Okada HC, Brown MS, et al. The auriculotemporal nerve in etiology of migraine headaches: Compression points and anatomical variations. Plastic and Reconstructive Surgery. 2012;**130**:336-341

[19] Janis JE, Hatef DA, Ducic I, et al. Anatomy of the auriculotemporal nerve: Variations in its relationship to the superficial temporal artery and implications for the treatment of migraine headaches. Plastic and Reconstructive Surgery. 2010;**125**:1422-1428

[20] Janis JE, Hatef DA, Thakar H, et al. The zygomaticotemporal branch of the trigeminal nerve: Part II. Anatomical variations. Plastic and Reconstructive Surgery. 2010;**126**:435-442

[21] Iwanaga J, Watanabe K, Saga T, et al. Anatomical study of the superficial temporal branches of the auriculotemporal nerve: Application to surgery and other invasive treatments to the temporal region. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2017;**70**:370-374

[22] Gfrerer L, Raposio E, Ortiz R, Austen WG Jr. Surgical treatment of migraine headache: Back to the future. Plastic and Reconstructive Surgery. 2018;**142**:1036-1045

[23] Lin SH, Lin HC, Jeng CH, Hsieh CH, Lin YH, Chen CC. Experience of surgical treatment for occipital migraine in Taiwan. Annals of Plastic Surgery. 2016;**76**:S80-S84

[24] Dash KS, Janis JE, Guyuron B. The lesser and third occipital nerves and migraine headaches. Plastic and Reconstructive Surgery. 2005;**115**:1752-1758

[25] Lee M, Lineberry K, Reed D, Guyuron B. The role of the third occipital nerve in surgical treatment of occipital migraine headaches. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2013;**66**:1335-1339

[26] Polotto S, Simonacci F, Grignaffini E, Grieco MP, Raposio E. Surgical treatment of frontal and occipital migraines: A comparison of results. Plastic and Reconstructive Surgery. Global Open. 2016;**4**:e653

[27] Raposio E, Caruana G. Tips for the surgical treatment of occipital nervetriggered headaches. European Journal of Plastic Surgery. 2017;**40**:177-182

[28] Raposio E, Simonacci F, Bertozzi N, Bellini E. Occipital migraine: A vascular approach. Plastic and Reconstructive Surgery. Global Open. 2017;**5**:78

[29] Ducic I, Hartmann EC, Larson EE. Indications and outcomes for surgical treatment of patients with chronic migraine headaches caused by occipital neuralgia. Plastic and Reconstructive Surgery. 2009;**123**:1453-1461

**38**

*Migraine*

**References**

[1] World Health Organization. The Global Burden of Disease, 2004 Update. Geneva, Switzerland: World Health

[9] Guyuron B, Kriegler JS, Davis J, Amini SB. Five-year outcome of surgical treatment of migraine headaches. Plastic and Reconstructive Surgery.

[10] Punjabi A, Brown M, Guyuron B. Emergence of secondary trigger sites after primary migraine surgery. Plastic

[11] Guyuron B, Nahabet E, Khansa I, Reed D, Janis JE. The current means for detection of migraine headache trigger sites. Plastic and Reconstructive

[12] Liu MT, Armijo BS, Guyuron B. A comparison of outcome of surgical treatment of migraine headaches using a constellation of symptoms versus botulinum toxin type A to identify the trigger sites. Plastic and Reconstructive

and Reconstructive Surgery.

Surgery. 2015;**136**:860-867

Surgery. 2012;**129**:413-419

Surgery. 2015;**26**:e201-e203

pp. 17-21

[13] Raposio E, Caruana G. Frontal endoscopic myotomies for chronic headache. The Journal of Craniofacial

[14] Raposio E, Caruana G. Minimally invasive endoscopic surgical treatment of headache. In: Raposio E, editor. Atlas of Endoscopic Plastic Surgery. New York, N.Y: Springer; 2016.

[15] Caruana G, Bertozzi N, Boschi E, Grieco MP, Grignaffini E, Raposio E. Endoscopic forehead surgery for migraine therapy personal technique.

Annali Italiani di Chirurgia.

[16] Caruana G, Grignaffini E,

Raposio E. Endoscopic forehead muscle resection for nerve decompression: A modified procedure. Plastic and Reconstructive Surgery. Global Open.

2014;**85**:583-586

2015;**3**:e342

2011;**127**:603-608

2016;**137**:712e-716e

[2] Raposio E, Bertozzi N, Bordin C, Simonacci F. Surgical therapy of migraine and tension-type headaches.

Perspectives on Less-Known Aspects of Headache. Zagreb, Croatia: InTech;

[4] Chmielewski L, Liu MT, Guyuron B.

[5] Guyuron B, Varghai A, Michelow BJ, Thomas T, Davis J. Corrugator supercilii

Ducic I, Hagan R, Guyuron B. A review of current evidence in the surgical treatment of migraine headaches. Plastic and Reconstructive Surgery.

muscle resection and migraine headaches. Plastic and Reconstructive

[6] Janis JE, Barker JC, Javadi C,

[7] Guyuron B, Kriegler JS, Davis J, Amini SB. Comprehensive surgical treatment of migraine headaches. Plastic and Reconstructive Surgery.

[8] Guyuron B, Reed D, Kriegler JS, Davis J, Pashmini N, Amini S. A placebo-controlled surgical trial of the treatment of migraine headaches. Plastic and Reconstructive Surgery.

Surgery. 2000;**106**:429-437

resection in the surgical treatment of occipital migraine headaches. Plastic and Reconstructive Surgery.

In: Turker H, editor. Current

[3] Faber C, Garcia RM, Davis J, Guyuron B. A socioeconomic analysis of surgical treatment of migraine headaches. Plastic and Reconstructive

Surgery. 2012;**129**:871-877

The role of occipital artery

2013;**131**:351e-356e

2014;**134**:131-141

2005;**115**(1):1-9

2009;**124**:461-468

Organization; 2004

2017. pp. 93-114

**41**

**Chapter 4**

**Abstract**

patient education.

**1. Introduction**

interventions, patient centricity, patient

and What

*Theodoros Mavridis, Marianthi Breza,* 

*Christina I. Deligianni and Dimos D. Mitsikostas*

Therapeutic Management: When

Migraine is a widespread brain disease that is classified as the second most disabling condition and has the third highest prevalence of all medical conditions. Despite its non-emergent or life-threatening nature, migraine can progress to chronic type, a subform associated with significant morbidity and drug overuse. In the management of migraine, it is important therefore to introduce early prophylactic treatment in order to limit migraine chronification. In this chapter, we will go through all the treatment options, both acute and preventive, pharmaceutical and non-pharmaceutical following this flowchart: 1. Introduction; 2. General principles; 2.1 Symptomatic therapy; 2.2 Prophylactic management; 3. Pharmaceutical therapies; 3.1 Symptomatic; 3.1.1 Disease-specific; 3.1.2 No disease-specific; 3.2 Prophylactic; 3.2.1 Disease-specific; 3.2.2 No disease-specific; 3.3 Non-Pharmaceutical therapies; 3.4 Neuromodulation; 3.4.1 Invasive; 3.4.5 Noninvasive; 3.5 Nutrient (nutraceuticals); 3.6 Dietary interventions; 3.7 Acupuncture; 3.8 Physical therapy; 4. Cognitive behavioral therapies; 5. Patient centricity and

**Keywords:** therapy, pharmaceutical therapy, non-pharmaceutical therapy, symptomatic treatment, prophylactic treatment, devices, cognitive behavioral therapy, physical therapy, acupuncture, nutrient, nutraceuticals, dietary

pharmaceutical), summarizing both acute and prophylactic options.

The last decade heralded a new era in migraine therapeutics, with the emergence of novel targeted therapies. Recent advances in the field of migraine research have resulted to newly available acute and preventive treatment options, including gepants (calcitonin gene-related peptide (CGRP)-receptor antagonists), anti-CGRP/R monoclonal antibodies (mAbs), and ditans (5-HT1F receptor agonists). Several advances were also achieved in non-pharmaceutical therapeutics, with the advent of devices for vagus nerve stimulation (VNS), external trigeminal nerve stimulation (eTNS), and transcranial magnetic stimulation (TMS) [1]. This chapter provides a comprehensive overview of available therapeutic approaches in migraine (pharmaceutical and non-

The therapeutic management of migraine is multidisciplinary, including both pharmaceutical and non-pharmaceutical approaches. The choice of pharmaceutical treatment should be individualized, taking into consideration the characteristics of the migraine attack, the patients' comorbidities, and treatment preferences [2, 3].

#### **Chapter 4**

## Therapeutic Management: When and What

*Theodoros Mavridis, Marianthi Breza, Christina I. Deligianni and Dimos D. Mitsikostas*

#### **Abstract**

Migraine is a widespread brain disease that is classified as the second most disabling condition and has the third highest prevalence of all medical conditions. Despite its non-emergent or life-threatening nature, migraine can progress to chronic type, a subform associated with significant morbidity and drug overuse. In the management of migraine, it is important therefore to introduce early prophylactic treatment in order to limit migraine chronification. In this chapter, we will go through all the treatment options, both acute and preventive, pharmaceutical and non-pharmaceutical following this flowchart: 1. Introduction; 2. General principles; 2.1 Symptomatic therapy; 2.2 Prophylactic management; 3. Pharmaceutical therapies; 3.1 Symptomatic; 3.1.1 Disease-specific; 3.1.2 No disease-specific; 3.2 Prophylactic; 3.2.1 Disease-specific; 3.2.2 No disease-specific; 3.3 Non-Pharmaceutical therapies; 3.4 Neuromodulation; 3.4.1 Invasive; 3.4.5 Noninvasive; 3.5 Nutrient (nutraceuticals); 3.6 Dietary interventions; 3.7 Acupuncture; 3.8 Physical therapy; 4. Cognitive behavioral therapies; 5. Patient centricity and patient education.

**Keywords:** therapy, pharmaceutical therapy, non-pharmaceutical therapy, symptomatic treatment, prophylactic treatment, devices, cognitive behavioral therapy, physical therapy, acupuncture, nutrient, nutraceuticals, dietary interventions, patient centricity, patient

#### **1. Introduction**

The last decade heralded a new era in migraine therapeutics, with the emergence of novel targeted therapies. Recent advances in the field of migraine research have resulted to newly available acute and preventive treatment options, including gepants (calcitonin gene-related peptide (CGRP)-receptor antagonists), anti-CGRP/R monoclonal antibodies (mAbs), and ditans (5-HT1F receptor agonists). Several advances were also achieved in non-pharmaceutical therapeutics, with the advent of devices for vagus nerve stimulation (VNS), external trigeminal nerve stimulation (eTNS), and transcranial magnetic stimulation (TMS) [1]. This chapter provides a comprehensive overview of available therapeutic approaches in migraine (pharmaceutical and nonpharmaceutical), summarizing both acute and prophylactic options.

The therapeutic management of migraine is multidisciplinary, including both pharmaceutical and non-pharmaceutical approaches. The choice of pharmaceutical treatment should be individualized, taking into consideration the characteristics of the migraine attack, the patients' comorbidities, and treatment preferences [2, 3].

The symptomatic migraine treatment aims to rapidly relief headache, restore function, and prevent recurrence. To date, simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and triptans are the most widely prescribed medications for acute migraine [1]. Triptans (selective serotonin 5-HT1B/1D receptor agonists) have shown to inhibit the release of calcitonin gene-related peptide (CGRP) and were first approved for acute migraine therapy in the early 1990s [4]. However, these drugs are not efficient in all patients and might have vasoconstrictive properties that could be a contraindication [1], leaving room for new, disease-specific symptomatic treatments. The development of two novel classes of drugs, gepants (CGRP receptor antagonists) and ditans (serotonin 5-HT1F receptor agonists), for the symptomatic treatment of acute migraine allows management of patients that do not tolerate or respond to the above agents [1].

Every year about 3% of patients convert from episodic to chronic migraine (≥15 headache days per month, of which ≥8 migraine days) [1]. It is important therefore to introduce early prophylactic treatment in order to limit migraine chronification. The calcitonin gene-related peptide (CGRP) antagonists were approved in 2018 and represent the first class of novel targeted medications specifically designed and approved for migraine prevention. The newly approved monoclonal antibodies against the ligand CGRP or its receptor (anti-CGRP/R mAbs) are fremanezumab, erenumab, and galcanezumab, while eptinezumab is waiting for approval in 2020 [5]. Ubrogepant, lasmiditan, and rimegepant are emerging acute migraine therapies that are also waiting to be added to the arsenal of current migraine management [6].

The use of non-pharmaceutical approaches is recommended as adjunct therapy or as alternative to the first-line pharmaceutical treatment [7, 8]. Complementary interventions are used to minimize the overuse of acute pain medication or adverse effects (AEs) and as alternative when preventive pharmaceutical therapy fails or is contraindicated. Non-pharmaceutical strategies suggested include approved devices for migraine, cognitive behavioral therapies, physical therapy, improving quality of sleep, acupuncture, and dietary solutions [9–11].

Overall, novel therapies signify a paradigm shift in migraine management and not only bring new hope to patients suffering for migraine but also change the clinician's approach to the treatment of migraine [1]. While migraine therapy is currently undergoing tremendous development, unmet needs of patients remain, which, if addressed, have the potential to further enhance available treatment options and improve the quality of life of migraineurs. Identification of predictive biomarkers for responders and nonresponders to therapies, and elucidation of underlying migraine pathophysiology are still lacking, and are essential for the development of novel therapeutic targets and individualized migraine prevention.

#### **2. General principles**

To date, there is no cure for migraine, but migraine can be successfully treated in many cases.

Therefore, education of patients is of great significance. This could be achieved by thoroughly explaining patients' disorder, purpose, and means of management. Patient information leaflets on migraine and management are available from the Headache Federations (Lifting The Burden) [12]. Prior to treatment and during follow-up assessments, patients should be monitored and evaluated using recommended assessment tools: the HALT-30 Index that assesses burden in terms of lost productive time, the Migraine Disability Assessment Test (MIDAS), the Headache

**43**

avoided [12].

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

acute medication or overuse [12].

and prophylactic treatment is needed [2].

headache specialists [12].

migraine [12].

**2.1 Symptomatic therapy**

Impact Test (HIT-6), which evaluates the headache impact and severity, and the Headache Under-Response to Treatment Questionnaire (HURT), which evaluates efficacy and ensures that the optimal treatment has been reached [12–18]. A calendar is recommended to be used by the patients with migraine, in order to monitor

Regarding triggers and predisposing factors, modification of lifestyle, where applicable, is recommended. However, triggers are not always avoidable. Over the years, the significance of trigger factors in migraine has been overemphasized [2, 12]. Management of migraine in special populations (pregnant women, children, nonresponders, and elderly with comorbidities) should be carried out only by

The purpose of pharmacotherapy of primary headache is mostly to control symptoms in order to minimize the impact of the disorder on each individual patient's life and lifestyle. For treatment to be effective, first, it is crucial that the correct diagnosis has been made. Then, the choice of therapy requires an individual approach, as each patient is unique. Severity and frequency of attacks, disability causing, other symptoms, time to peak, patient preferences, comorbidities, drug interactions, side effects, and prior therapies that failed should be all taken into consideration [2]. Acute treatment should be taken as early as possible in the headache phase to abort an attack. Prophylactic treatment is administered periodically in order to reduce the frequency and severity of migraine attacks. Often a combination of acute

Pharmaceutical treatment for acute attacks is used almost by all patients with migraine. Prophylactic treatment should be recommended in nonresponders to acute treatment or not well-controlled patients, whose quality of life is impaired by

The following recommendations are highlighted from the Headache Consortiums and Federations Management principles, as the main clinical recom-

When migraine attacks are not severe or disabling for less than 4 days per month, only symptomatic therapy is considered [2]. It is important to know when to treat a migraine attack and which therapy and route of administration are preferred, especially in patients experiencing nausea and vomiting. Generally, patients are advised to receive the abortive treatment as early as possible in the attack to reduce the intensity and duration of migraine as well as the accompanying features. In case of an inadequate response, it can be repeated after two hours (same or other treatment). There is a restriction on the duration of usage of symptomatic treatment due to the probability of developing medication overuse headache (MOH). Thus, taking into account the criteria of ICHD-III [19], intake of symptomatic treatment should not exceed 10 days per month for ergotamine, triptans, or combinations of drugs, or 15 days per month for NSAIDs, paracetamol, and aspirin. Non-opioid analgesics (eg. NSAIDs, aspirin and paracetamol, or combinations with caffeine) with the addition of antiemetics (if needed), are the first-line treatment for mild to moderate attacks. Analgesics should be administered early in the attack and in adequate dosage, and during the aura phase for the case of migraine with aura. When vomiting is present, rectal forms of analgesics and use of antiemetics might be suggested. It is noted that paracetamol (1 g) on its own has lower efficacy and it should not be considered as first-line treatment alone. Opioids are thought to be ineffective and potentially addictive; thus, they should be

mendations that should be prioritized in pharmaceutical treatment.

#### *Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*Migraine*

The symptomatic migraine treatment aims to rapidly relief headache, restore function, and prevent recurrence. To date, simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and triptans are the most widely prescribed medications for acute migraine [1]. Triptans (selective serotonin 5-HT1B/1D receptor agonists) have shown to inhibit the release of calcitonin gene-related peptide (CGRP) and were first approved for acute migraine therapy in the early 1990s [4]. However, these drugs are not efficient in all patients and might have vasoconstrictive properties that could be a contraindication [1], leaving room for new, disease-specific symptomatic treatments. The development of two novel classes of drugs, gepants (CGRP receptor antagonists) and ditans (serotonin 5-HT1F receptor agonists), for the symptomatic treatment of acute migraine allows management of patients that

Every year about 3% of patients convert from episodic to chronic migraine (≥15 headache days per month, of which ≥8 migraine days) [1]. It is important therefore to introduce early prophylactic treatment in order to limit migraine chronification. The calcitonin gene-related peptide (CGRP) antagonists were approved in 2018 and represent the first class of novel targeted medications specifically designed and approved for migraine prevention. The newly approved monoclonal antibodies against the ligand CGRP or its receptor (anti-CGRP/R mAbs) are fremanezumab, erenumab, and galcanezumab, while eptinezumab is waiting for approval in 2020 [5]. Ubrogepant, lasmiditan, and rimegepant are emerging acute migraine therapies that are also waiting to be added to the arsenal of current

The use of non-pharmaceutical approaches is recommended as adjunct therapy or as alternative to the first-line pharmaceutical treatment [7, 8]. Complementary interventions are used to minimize the overuse of acute pain medication or adverse effects (AEs) and as alternative when preventive pharmaceutical therapy fails or is contraindicated. Non-pharmaceutical strategies suggested include approved devices for migraine, cognitive behavioral therapies, physical therapy, improving quality of

Overall, novel therapies signify a paradigm shift in migraine management and not only bring new hope to patients suffering for migraine but also change the clinician's approach to the treatment of migraine [1]. While migraine therapy is currently undergoing tremendous development, unmet needs of patients remain, which, if addressed, have the potential to further enhance available treatment options and improve the quality of life of migraineurs. Identification of predictive biomarkers for responders and nonresponders to therapies, and elucidation of underlying migraine pathophysiology are still lacking, and are essential for the development of novel therapeutic targets and individualized migraine

To date, there is no cure for migraine, but migraine can be successfully treated in

Therefore, education of patients is of great significance. This could be achieved by thoroughly explaining patients' disorder, purpose, and means of management. Patient information leaflets on migraine and management are available from the Headache Federations (Lifting The Burden) [12]. Prior to treatment and during follow-up assessments, patients should be monitored and evaluated using recommended assessment tools: the HALT-30 Index that assesses burden in terms of lost productive time, the Migraine Disability Assessment Test (MIDAS), the Headache

do not tolerate or respond to the above agents [1].

sleep, acupuncture, and dietary solutions [9–11].

migraine management [6].

**42**

prevention.

many cases.

**2. General principles**

Impact Test (HIT-6), which evaluates the headache impact and severity, and the Headache Under-Response to Treatment Questionnaire (HURT), which evaluates efficacy and ensures that the optimal treatment has been reached [12–18]. A calendar is recommended to be used by the patients with migraine, in order to monitor acute medication or overuse [12].

Regarding triggers and predisposing factors, modification of lifestyle, where applicable, is recommended. However, triggers are not always avoidable. Over the years, the significance of trigger factors in migraine has been overemphasized [2, 12].

Management of migraine in special populations (pregnant women, children, nonresponders, and elderly with comorbidities) should be carried out only by headache specialists [12].

The purpose of pharmacotherapy of primary headache is mostly to control symptoms in order to minimize the impact of the disorder on each individual patient's life and lifestyle. For treatment to be effective, first, it is crucial that the correct diagnosis has been made. Then, the choice of therapy requires an individual approach, as each patient is unique. Severity and frequency of attacks, disability causing, other symptoms, time to peak, patient preferences, comorbidities, drug interactions, side effects, and prior therapies that failed should be all taken into consideration [2].

Acute treatment should be taken as early as possible in the headache phase to abort an attack. Prophylactic treatment is administered periodically in order to reduce the frequency and severity of migraine attacks. Often a combination of acute and prophylactic treatment is needed [2].

Pharmaceutical treatment for acute attacks is used almost by all patients with migraine. Prophylactic treatment should be recommended in nonresponders to acute treatment or not well-controlled patients, whose quality of life is impaired by migraine [12].

The following recommendations are highlighted from the Headache Consortiums and Federations Management principles, as the main clinical recommendations that should be prioritized in pharmaceutical treatment.

#### **2.1 Symptomatic therapy**

When migraine attacks are not severe or disabling for less than 4 days per month, only symptomatic therapy is considered [2]. It is important to know when to treat a migraine attack and which therapy and route of administration are preferred, especially in patients experiencing nausea and vomiting. Generally, patients are advised to receive the abortive treatment as early as possible in the attack to reduce the intensity and duration of migraine as well as the accompanying features. In case of an inadequate response, it can be repeated after two hours (same or other treatment). There is a restriction on the duration of usage of symptomatic treatment due to the probability of developing medication overuse headache (MOH). Thus, taking into account the criteria of ICHD-III [19], intake of symptomatic treatment should not exceed 10 days per month for ergotamine, triptans, or combinations of drugs, or 15 days per month for NSAIDs, paracetamol, and aspirin.

Non-opioid analgesics (eg. NSAIDs, aspirin and paracetamol, or combinations with caffeine) with the addition of antiemetics (if needed), are the first-line treatment for mild to moderate attacks. Analgesics should be administered early in the attack and in adequate dosage, and during the aura phase for the case of migraine with aura. When vomiting is present, rectal forms of analgesics and use of antiemetics might be suggested. It is noted that paracetamol (1 g) on its own has lower efficacy and it should not be considered as first-line treatment alone. Opioids are thought to be ineffective and potentially addictive; thus, they should be avoided [12].

#### *Migraine*

Triptans are recommended as first-line treatment for patients with moderatesevere migraine attacks, or where analgesics failed. Triptans are more effective when administered while headache is mild, but their use during aura is controversial for safety reasons. Combination therapy using triptans and NSAIDs should also be considered when triptans alone are not efficient to control migraine attacks. Subcutaneously injected sumatriptan (6 mg) should be considered when every other symptomatic treatment has failed, as a rescue medication. Triptans are associated with recurrence of migraine attack within 48 hours in up to 40% of patients that responded and with moderate consistency of efficacy across the attacks. Triptans should be avoided in uncontrolled hypertension, coronary heart disease, cerebrovascular disease or peripheral vascular disease, multiple risk factors for coronary or cerebrovascular disease. Finally, the use of triptans in the elderly should be with great caution due to comorbidities, preferably by headache specialists [12]. There are many strategies from stratified treatment to individual/tailored approach [20]. We suggest that a tailored approach is better as many subgroups of migraineurs exist and many patients exhibit adverse event in one or more therapies [12, 21]. All pharmaceutical symptomatic treatment is summarized in **Table 1**.


**45**

**Table 2.**

*Pharmaceutical preventive treatment in migraine management.*

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

#### **Table 1.**

*Pharmaceutical acute treatment in migraine management.*

#### *Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*Migraine*

Triptans are recommended as first-line treatment for patients with moderatesevere migraine attacks, or where analgesics failed. Triptans are more effective when administered while headache is mild, but their use during aura is controversial for safety reasons. Combination therapy using triptans and NSAIDs should also be considered when triptans alone are not efficient to control migraine attacks. Subcutaneously injected sumatriptan (6 mg) should be considered when every other symptomatic treatment has failed, as a rescue medication. Triptans are associated with recurrence of migraine attack within 48 hours in up to 40% of patients that responded and with moderate consistency of efficacy across the attacks. Triptans should be avoided in uncontrolled hypertension, coronary heart disease, cerebrovascular disease or peripheral vascular disease, multiple risk factors for coronary or cerebrovascular disease. Finally, the use of triptans in the elderly should be with great caution due to comorbidities, preferably by headache specialists [12]. There are many strategies from stratified treatment to individual/tailored approach [20]. We suggest that a tailored approach is better as many subgroups of migraineurs exist and many patients exhibit adverse event in one or more therapies [12, 21]. All pharmaceutical symptomatic treatment is summarized in **Table 1**.

**44**

**Table 1.**

*Pharmaceutical acute treatment in migraine management.*


#### **Table 2.**

*Pharmaceutical preventive treatment in migraine management.*

#### **2.2 Prophylactic management**

Preventive treatment of migraine attacks is recommended when attacks are severe or frequent (more than 4 days per month) or there are contraindications, adverse effects, failure, or inadequate response of proper use of acute medication. The aim is to reduce frequency, duration, and severity of attacks and conversely increase the effect of acute treatment. The most important in preventive treatment of migraine is to know when to start the treatment and to manage and monitor the migraine patient, so that the disease does not switch from episodic to chronic, a subform associated with significant morbidity and drug overuse [22] and/or complicate with medication overuse headache (MOH). Today, we have both pharmaceutical and non-pharmaceutical (devices, nutrients, etc.) treatment options in our arsenal.

Prophylactic pharmaceutical treatment include no disease-specific agents, such as beta-adrenergic blockers without partial agonism (atenolol, bisoprolol, metoprolol, and propranolol), calcium channel antagonists (flunarizine), antidepressants (amitriptyline), anticonvulsants (topiramate, sodium valproate), and botulinum toxin for the case of chronic migraine exclusively, and disease-specific pharmaceutical regiments, namely the newly introduced CGRP monoclonal antibodies (erenumab, fremanezumab, and galcanezumab) [12].

Drugs that appear ineffective should be discontinued only after 2–3 months at minimum, in order to achieve and observe efficacy. Failure of one drug does not predict failure of others in a different class. Tapered withdrawal may be considered after 6 months of good control, and should be considered no later than after 1 year [12]. To increase adherence, it is recommended to start with a low dose and slowly increase the dosage to the preferable one.

The anti-CGRP/R monoclonal antibodies have demonstrated good efficacy and excellent tolerability in phase II and III clinical trials with only injection site reactions to be the most common treatment-related adverse events [22].

The available treatments have different efficacy and adverse events/contradictions, and each option must be individualized and tailored in the patient's profile and needs. All pharmaceutical prophylactic treatment is summarized in **Table 2**.

#### **3. Pharmaceutical therapies**

As previously stated, the pharmaceutical treatment of migraine is divided into symptomatic/acute (to stop the migraine crisis and alleviate the concomitant symptoms, e.g., nausea, vomiting) and preventive/prophylactic (to reduce the frequency, intensity, and severity of the attacks). Drugs from both categories are further divided into substances that have been designed specifically for migraine and to drugs that are used primarily for the treatment of other diseases (non-specific).

#### **3.1 Symptomatic**

#### *3.1.1 Disease-specific*

#### *3.1.1.1 Ergots*

Ergotamine and dihydroergotamine are the two main drugs of this category, and they exert their action via activating 5-HT1B/D receptors located on intracranial blood vessels. They also have affinity for dopamine and noradrenaline receptors [2]. Evidence shows that dihydroergotamine is more effective than ergotamine.

**47**

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*3.1.1.2 Dihydroergotamine (DHE)*

lactation.

*3.1.1.3 Ergotamine*

use or ergot derivatives).

*3.1.1.4 Triptans*

Nowadays, there are some preparations of ergotamine and dihydroergotamine alone or in combinations (usually with antiemetics or caffeine) [23, 24]. Ergots can also induce medication overuse headache (MOH) with very low doses and their use must be limited to less than 10 days per month. Contraindications are coronary artery disease due to the constriction of the coronal vessels [25], arterial hypertension, and cerebrovascular diseases. Due to their impact on the vascular system, they should not be used in combination with other vasoconstrictor drugs. Other contraindications include Raynaud disease, renal or hepatic failure, pregnancy, and

It is available for oral, intravenous (IV), intramuscular (IM), subcutaneous (SC), and intranasal use, whereas the latter route of administration is less reliable and nasal irritation is a common adverse effect [26]. However, its availability varies across countries significantly. The combination of DHE with antiemetics (where the preparation is available) seems to be effective for the treatment of acute migraine. Intravenous formulation of DHE is very effective and well-tolerated for the treatment of migraine [27]. It is proposed as an acute management of chronic migraine in the primary care to the subgroup of patients who do not respond to NSAID-triptan combinations (1 mg of subcutaneous or intramuscular dihydroergotamine) [26]. Nevertheless, two points must be taken into account: (i) DHE route of administration is mostly parenteral, and self-administration is difficult and takes time for the patient to learn. (ii) It is not clear if the addition of an antiemetic

(metoclopramide) in the preparation is responsible for the efficacy of DHE

administration, i.e., 1 mg SC, 2 mg intranasal, and 2.5 mg *per os*.

(unknown if there is an additive action) [24]. Doses vary depending on the route of

Ergotamine is an ergopeptine and the second migraine drug of the ergot family. The most common combination launched in the market is ergotamine tartare + caffeine. Ergotamine has been in clinical practice over 70 years, but there is no common ground for the use of this agent. There are many trials in the literature, which attempts to validate the efficacy of ergotamine. It is recommended for the treatment of acute headache, only in patients with prolonged attacks (>48 hours) or in whom headache recurrence is a substantial issue [28]. This recommendation is in accordance with the European Federation of Neurological Societies' (EFNS) guidelines [20]. EFNS also stated that status migrainosus can be treated by dihydroergotamine (low level of evidence). In many clinical trials [29–32], ergot derivatives showed lower efficacy than triptans and more adverse events (AE). Therefore, these substances should be dealt with caution [2]. Major AEs are nausea, vomiting, and should be avoided in patients who report these common associated symptoms of migraine, or later than >2 hours after the onset of migraine when the gastric stasis has already occurred. Other AEs are paraesthesia, and ergotism (due to long-term

Triptans are 5-HT1B/1D receptor agonists and very effective for the acute management of migraine. They are specific to treat migraine as they act at the pathophysiology of migraine, inducing vasoconstriction, inhibiting pain pathways, and reducing the input to the trigeminal nucleus caudalis. There are many available

#### *Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*Migraine*

our arsenal.

**2.2 Prophylactic management**

Preventive treatment of migraine attacks is recommended when attacks are severe or frequent (more than 4 days per month) or there are contraindications, adverse effects, failure, or inadequate response of proper use of acute medication. The aim is to reduce frequency, duration, and severity of attacks and conversely increase the effect of acute treatment. The most important in preventive treatment of migraine is to know when to start the treatment and to manage and monitor the migraine patient, so that the disease does not switch from episodic to chronic, a subform associated with significant morbidity and drug overuse [22] and/or complicate with medication overuse headache (MOH). Today, we have both pharmaceutical and non-pharmaceutical (devices, nutrients, etc.) treatment options in

Prophylactic pharmaceutical treatment include no disease-specific agents, such as beta-adrenergic blockers without partial agonism (atenolol, bisoprolol, metoprolol, and propranolol), calcium channel antagonists (flunarizine), antidepressants (amitriptyline), anticonvulsants (topiramate, sodium valproate), and botulinum toxin for the case of chronic migraine exclusively, and disease-specific pharmaceutical regiments, namely the newly introduced CGRP monoclonal antibodies

Drugs that appear ineffective should be discontinued only after 2–3 months at minimum, in order to achieve and observe efficacy. Failure of one drug does not predict failure of others in a different class. Tapered withdrawal may be considered after 6 months of good control, and should be considered no later than after 1 year [12]. To increase adherence, it is recommended to start with a low dose and slowly

The anti-CGRP/R monoclonal antibodies have demonstrated good efficacy and excellent tolerability in phase II and III clinical trials with only injection site reac-

The available treatments have different efficacy and adverse events/contradictions, and each option must be individualized and tailored in the patient's profile and needs. All pharmaceutical prophylactic treatment is summarized in **Table 2**.

As previously stated, the pharmaceutical treatment of migraine is divided into symptomatic/acute (to stop the migraine crisis and alleviate the concomitant symptoms, e.g., nausea, vomiting) and preventive/prophylactic (to reduce the frequency, intensity, and severity of the attacks). Drugs from both categories are further divided into substances that have been designed specifically for migraine and to drugs that are used primarily for the treatment of other diseases (non-specific).

Ergotamine and dihydroergotamine are the two main drugs of this category, and they exert their action via activating 5-HT1B/D receptors located on intracranial blood vessels. They also have affinity for dopamine and noradrenaline receptors [2]. Evidence shows that dihydroergotamine is more effective than ergotamine.

tions to be the most common treatment-related adverse events [22].

(erenumab, fremanezumab, and galcanezumab) [12].

increase the dosage to the preferable one.

**3. Pharmaceutical therapies**

**3.1 Symptomatic**

*3.1.1 Disease-specific*

*3.1.1.1 Ergots*

**46**

Nowadays, there are some preparations of ergotamine and dihydroergotamine alone or in combinations (usually with antiemetics or caffeine) [23, 24]. Ergots can also induce medication overuse headache (MOH) with very low doses and their use must be limited to less than 10 days per month. Contraindications are coronary artery disease due to the constriction of the coronal vessels [25], arterial hypertension, and cerebrovascular diseases. Due to their impact on the vascular system, they should not be used in combination with other vasoconstrictor drugs. Other contraindications include Raynaud disease, renal or hepatic failure, pregnancy, and lactation.

#### *3.1.1.2 Dihydroergotamine (DHE)*

It is available for oral, intravenous (IV), intramuscular (IM), subcutaneous (SC), and intranasal use, whereas the latter route of administration is less reliable and nasal irritation is a common adverse effect [26]. However, its availability varies across countries significantly. The combination of DHE with antiemetics (where the preparation is available) seems to be effective for the treatment of acute migraine. Intravenous formulation of DHE is very effective and well-tolerated for the treatment of migraine [27]. It is proposed as an acute management of chronic migraine in the primary care to the subgroup of patients who do not respond to NSAID-triptan combinations (1 mg of subcutaneous or intramuscular dihydroergotamine) [26]. Nevertheless, two points must be taken into account: (i) DHE route of administration is mostly parenteral, and self-administration is difficult and takes time for the patient to learn. (ii) It is not clear if the addition of an antiemetic (metoclopramide) in the preparation is responsible for the efficacy of DHE (unknown if there is an additive action) [24]. Doses vary depending on the route of administration, i.e., 1 mg SC, 2 mg intranasal, and 2.5 mg *per os*.

#### *3.1.1.3 Ergotamine*

Ergotamine is an ergopeptine and the second migraine drug of the ergot family. The most common combination launched in the market is ergotamine tartare + caffeine. Ergotamine has been in clinical practice over 70 years, but there is no common ground for the use of this agent. There are many trials in the literature, which attempts to validate the efficacy of ergotamine. It is recommended for the treatment of acute headache, only in patients with prolonged attacks (>48 hours) or in whom headache recurrence is a substantial issue [28]. This recommendation is in accordance with the European Federation of Neurological Societies' (EFNS) guidelines [20]. EFNS also stated that status migrainosus can be treated by dihydroergotamine (low level of evidence). In many clinical trials [29–32], ergot derivatives showed lower efficacy than triptans and more adverse events (AE). Therefore, these substances should be dealt with caution [2]. Major AEs are nausea, vomiting, and should be avoided in patients who report these common associated symptoms of migraine, or later than >2 hours after the onset of migraine when the gastric stasis has already occurred. Other AEs are paraesthesia, and ergotism (due to long-term use or ergot derivatives).

#### *3.1.1.4 Triptans*

Triptans are 5-HT1B/1D receptor agonists and very effective for the acute management of migraine. They are specific to treat migraine as they act at the pathophysiology of migraine, inducing vasoconstriction, inhibiting pain pathways, and reducing the input to the trigeminal nucleus caudalis. There are many available

triptans, i.e., sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. With the exception of sumatriptan (oral, subcutaneous, and intranasal) and zolmitriptan (oral and intranasal), the other triptans are for oral use only. Generally, triptans are recommended for moderate to severe attacks and there is good evidence (level A) that combining a NSAID with a triptan will prevent from migraine recurrence [2, 12, 20, 21]. The choice of triptan is and should be individualized. Triptans have different pharmacokinetic and pharmacodynamic profile. Subcutaneous sumatriptan (6 mg) is more effective than oral sumatriptan and is preferred when associated symptoms, such as nausea and vomiting, occur. Intranasal spray has fewer side effects than intramuscular sumatriptan (discomfort, nasal irritation, and unpleasant taste). Comparative studies show that eletriptan has the highest efficacy with short-term and sustained effect. The above conclusion is consistent in many studies. Rizatriptan and zolmitriptan are thought to come in second and third place, respectively, in terms of efficacy, although further analysis shows that sumatriptan, rizatriptan, almotriptan, and zolmitriptan are very similar regarding clinical outcome. Naratriptan and frovatriptan have less but longer efficacy than sumatriptan and are relatively safer than other triptans. Naratriptan, frovatriptan, and almotriptan are also preferred for symptomatic treatment in patients that migraine attack recurs after successful treatment (pain free and most bothersome symptom free in 2 hours posttreatment) [2, 12, 20, 21, 24, 33–36]. Triptans can be given in combination with NSAIDs and the effect is considered to be additive. The most common and well-documented combination is that of sumatriptan with naproxen and is the one indicated for migraine attacks that do not respond to oral high efficacy triptans (e.g., eletriptan 40 or 80 mg, or rizatriptan 10 mg) [21]. Another combination that showed effectiveness in acute treatment is frovatriptan with dexketoprofen. Generally, triptans are safe and effective. Due to the vasoconstrictive action, triptan should be avoided to migraineurs with uncontrolled arterial hypertension, cardiovascular and/or cerebrovascular disease, and peripheral vascular disease. Systematical reviews and cohort studies showed that there is not any correlation between the use of triptans and higher cardiovascular risk, however [37, 38]. Nonetheless, the use of triptans is not recommended in highrisk patients. Finally, as with ergots, the use of triptans should be limited to 10 days per month to avoid medication overuse headache [2, 19–21].

#### *3.1.1.5 Ditans*

Ditans are a relatively new and different class of specific acute migraine management. The first and only approved by the Food and Drug Administration (FDA) until now is lasmiditan, a selective 5-HT1F receptor agonist, which shows minimal to zero vasoconstrictor activity in contrast to triptans. It is a suitable candidate for migraineurs where triptans are contraindicated or not well tolerated. Lasmiditan is given orally (starting dose of 50 mg and subsequently increase up to 200 mg if there is no benefit). Because lasmiditan penetrates the blood-brain barrier; it presents common AEs from the central nervous system (CNS, dizziness, somnolence, fatigue, and nausea) that restricts its use to those who drive or operate heavy machinery [39–42].

#### *3.1.1.6 Gepants*

The study of CGRP and its implication to the pathophysiology of migraine has led to discovery of a new class of drugs that are CGRP receptor antagonists. Gepants are suitable for treatment of acute migraine in patients who do not tolerate the triptans or when triptans are contraindicated. The first attempts for the manufacture of

**49**

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*3.1.2.1 Nonsteroidal anti-inflammatory drugs*

efficacy and tolerability [43].

*3.1.2 No disease-specific*

*3.1.2.2 Acetaminophen*

severity attacks [20, 21, 52–54].

*3.1.2.3 Antiemetics/Prokinetics*

these type of drugs led to a dead end, as many of the trials were terminated due to hepatotoxicity. Now, we have two gepants that received FDA approval, ubrogepant (2019) and rimegepant (2020) for the treatment of acute migraine in adult patients. However, more clinical trials and real-world evidence are needed to prove their

The most well-studied drugs of this category include acetylsalicylic acid (ASA) (aspirin 900–1000 mg), ibuprofen (200–800 mg), naproxen (275–825 mg), diclofenac (50–100 mg), tolfenamic acid (200 mg), and dexketoprofen (50 mg) [44–51]. The difference in dosage depends on the available formulation for each country and the proposed guidelines of each Headache Society [2, 12, 20, 21, 24]. The use of NSAID should be as soon as possible to achieve maximal effect and to preempt the gastric stasis. If the migraineur does experiences nausea or vomiting, parenteral formulations (suppository, intramuscular, and intravenous) of the above drugs should be given with combination of a prokinetic (see below Prokinetics) [12]. For moderate to severe attacks, combinations of NSAID with triptans are recommended. All NSAIDs have more or less (depends on the COX-2 selectivity) the same adverse events including GI bleeds, peptic ulceration, hemorrhagic cerebrovascular accidents, and renal impairment. They should not be given in patients with uncontrolled hypertension or history of peptic ulcer. In case of peptic ulcer, they can be prescribed for a small period of time together with protein pump inhibitors (PPIs).

Acetaminophen (paracetamol 1000 mg) is a NSAID with different mechanism of action. It is effective in some patients although it has weaker recommendation than NSAIDs for the management of acute headache [12]. On the other hand, the combination of paracetamol with ASA and caffeine is more effective than single drugs and is recommended for the treatment of mild to moderate

Many antiemetics (metoclopramide, domperidone, chlorpromazine, prochlorperazine, droperidol, ondansetron, and granisetron) have been studied for the treatment of acute migraine, both as monotherapy as well as adjuvants. The main action as prokinetics is via their dopamine receptor antagonism. Many of them show anti-migrainous action. With the exception of metoclopramide and domperidone, the other antiemetics have a higher risk of QT prolongation and higher rates of acute dystonic reactions, akathisia (extrapyramidal action) and mild sedation, and besides their efficacy (even some of them over triptans) [55–59], they are not recommended for the treatment of migraine. On the other hand, metoclopramide is a mild analgesic when given orally and more efficient when given intravenously. Despite monotherapy with antiemetics is not recommended, adjuvant therapy [45], especially when associative symptoms like nausea or vomiting are present, or latter in the course of migraine (gastric stasis has already occurred), is strongly suggested. The usual dose is for domperidone 10 mg (supportive evidence of efficacy is for 20 mg) up to three times per day or 30 mg (by suppository up to twice per day) and for metoclopramide 10 mg (up to three times per day). Metoclopramide

these type of drugs led to a dead end, as many of the trials were terminated due to hepatotoxicity. Now, we have two gepants that received FDA approval, ubrogepant (2019) and rimegepant (2020) for the treatment of acute migraine in adult patients. However, more clinical trials and real-world evidence are needed to prove their efficacy and tolerability [43].

#### *3.1.2 No disease-specific*

*Migraine*

triptans, i.e., sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. With the exception of sumatriptan (oral, subcutaneous, and intranasal) and zolmitriptan (oral and intranasal), the other triptans are for oral use only. Generally, triptans are recommended for moderate to severe attacks and there is good evidence (level A) that combining a NSAID with a triptan will prevent from migraine recurrence [2, 12, 20, 21]. The choice of triptan is and should be individualized. Triptans have different pharmacokinetic and pharmacodynamic profile. Subcutaneous sumatriptan (6 mg) is more effective than oral sumatriptan and is preferred when associated symptoms, such as nausea and vomiting, occur. Intranasal spray has fewer side effects than intramuscular sumatriptan (discomfort, nasal irritation, and unpleasant taste). Comparative studies show that eletriptan has the highest efficacy with short-term and sustained effect. The above conclusion is consistent in many studies. Rizatriptan and zolmitriptan are thought to come in second and third place, respectively, in terms of efficacy, although further analysis shows that sumatriptan, rizatriptan, almotriptan, and zolmitriptan are very similar regarding clinical outcome. Naratriptan and frovatriptan have less but longer efficacy than sumatriptan and are relatively safer than other triptans. Naratriptan, frovatriptan, and almotriptan are also preferred for symptomatic treatment in patients that migraine attack recurs after successful treatment (pain free and most bothersome symptom free in 2 hours posttreatment) [2, 12, 20, 21, 24, 33–36]. Triptans can be given in combination with NSAIDs and the effect is considered to be additive. The most common and well-documented combination is that of sumatriptan with naproxen and is the one indicated for migraine attacks that do not respond to oral high efficacy triptans (e.g., eletriptan 40 or 80 mg, or rizatriptan 10 mg) [21]. Another combination that showed effectiveness in acute treatment is frovatriptan with dexketoprofen. Generally, triptans are safe and effective. Due to the vasoconstrictive action, triptan should be avoided to migraineurs with uncontrolled arterial hypertension, cardiovascular and/or cerebrovascular disease, and peripheral vascular disease. Systematical reviews and cohort studies showed that there is not any correlation between the use of triptans and higher cardiovascular risk, however [37, 38]. Nonetheless, the use of triptans is not recommended in highrisk patients. Finally, as with ergots, the use of triptans should be limited to 10 days

per month to avoid medication overuse headache [2, 19–21].

Ditans are a relatively new and different class of specific acute migraine management. The first and only approved by the Food and Drug Administration (FDA) until now is lasmiditan, a selective 5-HT1F receptor agonist, which shows minimal to zero vasoconstrictor activity in contrast to triptans. It is a suitable candidate for migraineurs where triptans are contraindicated or not well tolerated. Lasmiditan is given orally (starting dose of 50 mg and subsequently increase up to 200 mg if there is no benefit). Because lasmiditan penetrates the blood-brain barrier; it presents common AEs from the central nervous system (CNS, dizziness, somnolence, fatigue, and nausea) that restricts its use to those who drive or operate heavy

The study of CGRP and its implication to the pathophysiology of migraine has led to discovery of a new class of drugs that are CGRP receptor antagonists. Gepants are suitable for treatment of acute migraine in patients who do not tolerate the triptans or when triptans are contraindicated. The first attempts for the manufacture of

**48**

*3.1.1.5 Ditans*

machinery [39–42].

*3.1.1.6 Gepants*

#### *3.1.2.1 Nonsteroidal anti-inflammatory drugs*

The most well-studied drugs of this category include acetylsalicylic acid (ASA) (aspirin 900–1000 mg), ibuprofen (200–800 mg), naproxen (275–825 mg), diclofenac (50–100 mg), tolfenamic acid (200 mg), and dexketoprofen (50 mg) [44–51]. The difference in dosage depends on the available formulation for each country and the proposed guidelines of each Headache Society [2, 12, 20, 21, 24]. The use of NSAID should be as soon as possible to achieve maximal effect and to preempt the gastric stasis. If the migraineur does experiences nausea or vomiting, parenteral formulations (suppository, intramuscular, and intravenous) of the above drugs should be given with combination of a prokinetic (see below Prokinetics) [12]. For moderate to severe attacks, combinations of NSAID with triptans are recommended. All NSAIDs have more or less (depends on the COX-2 selectivity) the same adverse events including GI bleeds, peptic ulceration, hemorrhagic cerebrovascular accidents, and renal impairment. They should not be given in patients with uncontrolled hypertension or history of peptic ulcer. In case of peptic ulcer, they can be prescribed for a small period of time together with protein pump inhibitors (PPIs).

#### *3.1.2.2 Acetaminophen*

Acetaminophen (paracetamol 1000 mg) is a NSAID with different mechanism of action. It is effective in some patients although it has weaker recommendation than NSAIDs for the management of acute headache [12]. On the other hand, the combination of paracetamol with ASA and caffeine is more effective than single drugs and is recommended for the treatment of mild to moderate severity attacks [20, 21, 52–54].

#### *3.1.2.3 Antiemetics/Prokinetics*

Many antiemetics (metoclopramide, domperidone, chlorpromazine, prochlorperazine, droperidol, ondansetron, and granisetron) have been studied for the treatment of acute migraine, both as monotherapy as well as adjuvants. The main action as prokinetics is via their dopamine receptor antagonism. Many of them show anti-migrainous action. With the exception of metoclopramide and domperidone, the other antiemetics have a higher risk of QT prolongation and higher rates of acute dystonic reactions, akathisia (extrapyramidal action) and mild sedation, and besides their efficacy (even some of them over triptans) [55–59], they are not recommended for the treatment of migraine. On the other hand, metoclopramide is a mild analgesic when given orally and more efficient when given intravenously. Despite monotherapy with antiemetics is not recommended, adjuvant therapy [45], especially when associative symptoms like nausea or vomiting are present, or latter in the course of migraine (gastric stasis has already occurred), is strongly suggested. The usual dose is for domperidone 10 mg (supportive evidence of efficacy is for 20 mg) up to three times per day or 30 mg (by suppository up to twice per day) and for metoclopramide 10 mg (up to three times per day). Metoclopramide

20 mg is recommended for adults and adolescents, whereas domperidone 10 mg for children due to the possible side effects (dyskinesia, akathisia) [12, 20].

#### *3.1.2.4 Other drugs*

Other drugs with low level of evidence that are found to be effective in the acute treatment of migraine attacks are intravenous valproate (dose up to 800 mg) [60–62], adjunctive therapy with parenteral dexamethasone (intramuscular or intravenous) for treatment of acute migraine and status migrainosus [20, 21, 63, 64], and a combination of paracetamol with intravenous tramadol [65].

#### **3.2 Prophylactic medications**

#### *3.2.1 Disease-specific*

#### *3.2.1.1 Anti-calcitonin-gene-related peptide/receptor monoclonal antibodies (anti-CGRP/R mAbs)*

All four anti-CGRP/R mAbs share several pharmacokinetic advantages over small anti-CGRP/R molecules (e.g., greater target specificity and prolonged halflife, making them suitable for monthly administration to prevent migraine). Three of these macromolecules target the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab), while a fourth (erenumab) targets the CGRP receptor [66–68]. They require parenteral administration and have a preferential peripheral site of action, since only 0.1–0.5% of the mAb cross the blood–brain barrier due to their large size (molecular weight around 150 kDa) [66, 69–72]. All four mAbs have shown particular effectiveness for the prevention of both episodic and chronic migraine [71, 72]. Besides the initial skepticism regarding their safety and their potential cardiovascular effect (due to preclinical data that came from studying and blocking CGRP,66) and liver toxicity that emerged after the initial failure of gepants, no safety flags occurred during the large program of their development and all four anti-CGRP/R mAbs have shown similar tolerability and safety in Phase II and III trials. The most common AEs, which were reported during clinical trials, are injection site pain, erythema, respiratory infection, nasopharyngitis, sinusitis, influenza, urinary infection, fatigue, nausea, vomiting, joint pain, back pain, headache, abdominal pain, dysmenorrhea, and dry mouth. Real-world evidence revealed constipation as one of the common adverse effects (not in clinical reporting). Anti-CGRP/R mAbs should be avoided in pregnant and nursing women, as well as in patients with psychiatric, pulmonary, and cardiovascular medical history, until more data are available. Regarding their efficacy, there is not much evidence or head-to-head clinical trials to support the superiority of one drug against the other. Due to their mechanism of action, pharmacokinetics, clinical effect, and cost, Headache societies have formulated practical guides on the proper use of anti-CGRP/R mAbs [5, 12, 21].

#### *3.2.1.2 Erenumab*

Erenumab is the first drug of the anti-CGRP/R category and the only until now that prevents native CGRP ligand binding to the CGRP receptor. It is an IgG2 antibody and the only fully human anti-CGRP/R mAb. At 70 mg, the estimated elimination half-life of erenumab is 21 days, supporting monthly subcutaneous dosing and, thus, betterment in patient compliance [73–75]. It is recommended for both

**51**

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

patients compared to oral daily medications.

*3.2.1.3 Fremanezumab*

*3.2.1.4 Galcanezumab*

month [84].

*3.2.1.5 Eptinezumab*

EMA (under development).

coenzyme Q10, NSAIDs, and others).

*3.2.2 No disease-specific*

efficacy and adverse events [79].

episodic and chronic migraine, as well as the treatment of MOH [76]. There are two formulations of erenumab (70 and 140 mg) with almost similar efficacy, and there is a suggestion of starting with the lower dose and increase if there is little efficacy [77]. A review of 3 randomized trials and their extensions suggested that erenumab 140 mg monthly might be preferred over the 70 mg monthly dose in patients with EM or CM and prior preventive treatment failures (>2) [77]. It is administered subcutaneously (SC) once per month, thus achieving better adherence among migraine

Fremanezumab is a fully humanized IgG2 mAb that potently and selectively binds to both α and β isoforms of CGRP [78]. It is effective for the prevention of episodic and chronic migraine. It is administered SC and has one formulation of 225 mg, which can be administered either once per month, or three consecutive doses (total of 675 mg) every 3 months. Both dosage options have shown similar

Galcanezumab is a humanized IgG4 mAb with a long half-life (~28 days) that binds to both α- and β-CGRP isoforms with approximately equal affinity [80]. Again, several trials have proven its efficacy for the preventive treatment of migraine [81–83]. As the other two aforementioned mAbs, galcanezumab is subcutaneously administered. The suggested starting dose is 240 mg (2 consecutive doses of 120 mg formulation) as a starting dose and then 120 mg subcutaneously every

Eptinezumab is the last anti-CGRP/R mAb discovered till now. It is a humanized IgG1 antibody that potently and selectively binds to both α and β forms of human CGRP [85]. The plasma half-life of eptinezumab after an intravenous infusion of 1000 mg is 31 days. There are two clinical trials (PROMISE-1 and PROMISE-2) that support its efficacy in episodic and chronic migraine prevention [86, 87]. Eptinezumab is the only intravenously anti-CGRP/R mAb and the recommended dose is 100 mg over 30 minutes every 3 months. It is not yet approved by the FDA or

Several drug classes, originally developed for other diseases (e.g., epilepsy, hypertension), have shown efficacy for the preventive treatment of migraine. Repurposed drugs may lack the disease-specific mechanism of action and have several adverse effects and contraindication, but show comparable efficacy to CGRP mAbs and are less expensive. As with the use of disease-specific treatments, when using nonspecific drugs, our main goal is individualizing our choice, taking into account the clinical characteristics, medical history, and comorbidities of the patient (e.g., sex, weight, anxiety/depression, hypertension, endocrinological disorders, pregnancy, etc.). The main categories are anticonvulsants, antihypertensive and antidepressant drugs, and other agents (e.g., onabotulinumtoxinA, butterbur,

#### *Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

episodic and chronic migraine, as well as the treatment of MOH [76]. There are two formulations of erenumab (70 and 140 mg) with almost similar efficacy, and there is a suggestion of starting with the lower dose and increase if there is little efficacy [77]. A review of 3 randomized trials and their extensions suggested that erenumab 140 mg monthly might be preferred over the 70 mg monthly dose in patients with EM or CM and prior preventive treatment failures (>2) [77]. It is administered subcutaneously (SC) once per month, thus achieving better adherence among migraine patients compared to oral daily medications.

#### *3.2.1.3 Fremanezumab*

*Migraine*

*3.1.2.4 Other drugs*

**3.2 Prophylactic medications**

*(anti-CGRP/R mAbs)*

the proper use of anti-CGRP/R mAbs [5, 12, 21].

*3.2.1 Disease-specific*

20 mg is recommended for adults and adolescents, whereas domperidone 10 mg for

Other drugs with low level of evidence that are found to be effective in the acute treatment of migraine attacks are intravenous valproate (dose up to 800 mg) [60–62], adjunctive therapy with parenteral dexamethasone (intramuscular or intravenous) for treatment of acute migraine and status migrainosus [20, 21, 63,

children due to the possible side effects (dyskinesia, akathisia) [12, 20].

64], and a combination of paracetamol with intravenous tramadol [65].

*3.2.1.1 Anti-calcitonin-gene-related peptide/receptor monoclonal antibodies* 

All four anti-CGRP/R mAbs share several pharmacokinetic advantages over small anti-CGRP/R molecules (e.g., greater target specificity and prolonged halflife, making them suitable for monthly administration to prevent migraine). Three of these macromolecules target the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab), while a fourth (erenumab) targets the CGRP receptor [66–68]. They require parenteral administration and have a preferential peripheral site of action, since only 0.1–0.5% of the mAb cross the blood–brain barrier due to their large size (molecular weight around 150 kDa) [66, 69–72]. All four mAbs have shown particular effectiveness for the prevention of both episodic and chronic migraine [71, 72]. Besides the initial skepticism regarding their safety and their potential cardiovascular effect (due to preclinical data that came from studying and blocking CGRP,66) and liver toxicity that emerged after the initial failure of gepants, no safety flags occurred during the large program of their development and all four anti-CGRP/R mAbs have shown similar tolerability and safety in Phase II and III trials. The most common AEs, which were reported during clinical trials, are injection site pain, erythema, respiratory infection, nasopharyngitis, sinusitis, influenza, urinary infection, fatigue, nausea, vomiting, joint pain, back pain, headache, abdominal pain, dysmenorrhea, and dry mouth. Real-world evidence revealed constipation as one of the common adverse effects (not in clinical reporting). Anti-CGRP/R mAbs should be avoided in pregnant and nursing women, as well as in patients with psychiatric, pulmonary, and cardiovascular medical history, until more data are available. Regarding their efficacy, there is not much evidence or head-to-head clinical trials to support the superiority of one drug against the other. Due to their mechanism of action, pharmacokinetics, clinical effect, and cost, Headache societies have formulated practical guides on

Erenumab is the first drug of the anti-CGRP/R category and the only until now that prevents native CGRP ligand binding to the CGRP receptor. It is an IgG2 antibody and the only fully human anti-CGRP/R mAb. At 70 mg, the estimated elimination half-life of erenumab is 21 days, supporting monthly subcutaneous dosing and, thus, betterment in patient compliance [73–75]. It is recommended for both

**50**

*3.2.1.2 Erenumab*

Fremanezumab is a fully humanized IgG2 mAb that potently and selectively binds to both α and β isoforms of CGRP [78]. It is effective for the prevention of episodic and chronic migraine. It is administered SC and has one formulation of 225 mg, which can be administered either once per month, or three consecutive doses (total of 675 mg) every 3 months. Both dosage options have shown similar efficacy and adverse events [79].

#### *3.2.1.4 Galcanezumab*

Galcanezumab is a humanized IgG4 mAb with a long half-life (~28 days) that binds to both α- and β-CGRP isoforms with approximately equal affinity [80]. Again, several trials have proven its efficacy for the preventive treatment of migraine [81–83]. As the other two aforementioned mAbs, galcanezumab is subcutaneously administered. The suggested starting dose is 240 mg (2 consecutive doses of 120 mg formulation) as a starting dose and then 120 mg subcutaneously every month [84].

#### *3.2.1.5 Eptinezumab*

Eptinezumab is the last anti-CGRP/R mAb discovered till now. It is a humanized IgG1 antibody that potently and selectively binds to both α and β forms of human CGRP [85]. The plasma half-life of eptinezumab after an intravenous infusion of 1000 mg is 31 days. There are two clinical trials (PROMISE-1 and PROMISE-2) that support its efficacy in episodic and chronic migraine prevention [86, 87]. Eptinezumab is the only intravenously anti-CGRP/R mAb and the recommended dose is 100 mg over 30 minutes every 3 months. It is not yet approved by the FDA or EMA (under development).

#### *3.2.2 No disease-specific*

Several drug classes, originally developed for other diseases (e.g., epilepsy, hypertension), have shown efficacy for the preventive treatment of migraine. Repurposed drugs may lack the disease-specific mechanism of action and have several adverse effects and contraindication, but show comparable efficacy to CGRP mAbs and are less expensive. As with the use of disease-specific treatments, when using nonspecific drugs, our main goal is individualizing our choice, taking into account the clinical characteristics, medical history, and comorbidities of the patient (e.g., sex, weight, anxiety/depression, hypertension, endocrinological disorders, pregnancy, etc.). The main categories are anticonvulsants, antihypertensive and antidepressant drugs, and other agents (e.g., onabotulinumtoxinA, butterbur, coenzyme Q10, NSAIDs, and others).

#### *3.2.2.1 Anticonvulsants*

#### *3.2.2.1.1 Topiramate*

Topiramate is one of the most studied drugs for the prevention of migraine, with several clinical studies, systematical reviews, and meta-analysis, showing its efficacy for both episodic and (fewer evidence) chronic migraine [26, 88–93]. Usual dosage ranges between 25 and 100 mg daily (in two divided doses) and there is suggestion, with the risk of more adverse events, of increasing the total dose up to 200 mg daily when the effect is suboptimal [2, 12, 20, 21, 26]. Main AEs of topiramate are paresthesia/numbness (results in intolerance), fatigue, anorexia/ weight loss, memory and concentration difficulties, and renal calculi (uncommon but serious adverse effect). It is contraindicated in pregnant women as it increases the risk of facial clefts and lowers birth weight. Due to the weight loss, topiramate is recommended to obese migraine patients [89, 90, 94].

#### *3.2.2.1.2 Valproate*

Whereas valproate is indicated for the preventive treatment of episodic migraine, its side effects (nausea, somnolence, dizziness, weight gain, and hair loss) and the contraindication to women in childbearing age and pregnancy (teratogenic) have limited its use. Usual doses range between 500 and 1800 mg per day and there is limited evidence of intravenous administration of valproate in status migrainosus [2, 12, 20, 21, 95].

#### *3.2.2.2 Other anticonvulsants*

Other anticonvulsants, such as gabapentin, have not proven their efficacy for prevention of episodic migraine and therefore are not recommended [96, 97] .

#### *3.2.2.2.1 Antihypertensive*

The two major categories of antihypertensive drugs that show migraine preventive effect are beta-blockers and calcium channel blockers. Most of the evidence emerged from studies regarding hypertension reported fewer headaches in the intervention group vs. the placebo group [98].

#### *3.2.2.3 Beta-blockers*

Beta-blockers that are available in almost every country and are recommended from almost all Headache Societies for the preventive treatment of episodic migraine are metoprolol (50–200 mg daily) and propranolol (40–240 mg daily). Other beta-blockers with fewer studies are atenolol (25–100 mg daily), nadolol (20–240 mg daily), timolol (10–30 mg daily), and bisoprolol (5–10 mg daily). Betablockers are recommended in hypertensive patients who are under 60 years old or nonsmokers [94, 99, 100]. Due to their mechanism of action and their dosage that is proven to be efficacious for migraine prevention, are not well tolerated and are contraindicated in patients with bradycardia, low blood pressure, cardiac conduction blocks, asthma, depression, and Raynaud phenomenon [2, 12, 20, 21, 101].

#### *3.2.2.4 Calcium channel blockers*

The only drug of this category with good level of evidence is flunarizine, a nonspecific calcium channel blocker, with calmodulin binding properties and histamine

**53**

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

not universally approved [2, 12, 20, 21].

*inhibitors*

*3.2.3.1 Antidepressants*

*3.2.4 Other drugs*

*3.2.4.1 OnabotulinumtoxinA*

**3.3 Non-pharmaceutical therapies**

H1 blocking activity. Recommended dose ranges between 5 and 10 mg daily and is prescribed to hypertensive patients older than 60 or smokers, as well as to patients with Raynaud syndrome. The most common AEs are weight gain, daytime sedation, stomach complaints, and dry mouth, and while there are reports of depression and extrapyramidal symptoms, there is no confirmation [102]. Verapamil is another calcium channel blocker with migraine preventive properties, but it has conflicting supporting data and many Headache Societies do not accept its use for episodic migraine [2, 12, 20, 21, 103].

*3.2.3 Angiotensin receptor blockers (ARBs)/angiotensin converting enzyme (ACE)* 

There is also data supporting the use of ACE inhibitors and ARBs as preventive migraine treatments. Candesartan, a specific ARB, has shown positive results in smallscale crossover studies and is used for migraine prophylaxis (16–32 mg) [104, 105]. The most common AEs include back pain, dizziness, flu-like symptoms, sore throat, and nasal congestion. Similarly, a small-scale double-blind cross-over study, found lisinopril (ACE inhibitor) to be effective in episodic migraine [106]. The above data are

Antidepressants are recommended as a second-line drugs with level B documentation [20]. The two drugs of this category are amitriptyline and venlafaxine. Among the two amitriptyline, a tricyclic antidepressant has been studied the most [103]. The usual dose ranges between 10 and 150 mg. Its sedative properties have limited its use and it is suggested only at bedtime and especially to those who suffer from insomnia. It also has a place as a second choice drug for chronic migraine [26]. Except sedation, amitriptyline's AEs include dry mouth, urinary retention, constipation, weight gain, blurred vision, and tachycardia. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, has a weaker recommendation as migraine prophylaxis and is preferred to those who suffer from depression and/or anxiety and those who have also tension-type headaches

(TTH). The usual dose ranges between 37.5 and 150 mg daily [2, 12, 20, 21, 94].

Whereas many randomized trials did not prove onabotulinumtoxinA's efficacy for treating episodic migraine (EM) and it is not recommended [107–109], data extracted from chronic migraine (CM) trials recommend onabotulinumtoxinA as an effective and well-tolerated treatment. OnabotulinumtoxinA has a good level of documentation (Level A), and there is specific protocol regarding its use (PREEMPT protocol), monitoring of the patients, and evaluating their response. It should be administered according to the PREEMPT injection protocol, i.e., injecting 155 U–195 U to 31–39 sites every 12 weeks. The most common reported AEs are neck pain, muscular weakness, eyelid ptosis, and injection-site pain, and the sub-analysis of the PREEMPT studies found that adverse events decreased over time [26, 110–112]. Its use in CM with MOH is debatable after a recent trial that showed no superiority against acute withdrawal alone [113].

Like the pharmaceutical, the non-pharmaceutical treatments—neuromodulation devices in particular—gain even more ground in the treatment of migraine.

#### *Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*Migraine*

*3.2.2.1 Anticonvulsants*

Topiramate is one of the most studied drugs for the prevention of migraine, with several clinical studies, systematical reviews, and meta-analysis, showing its efficacy for both episodic and (fewer evidence) chronic migraine [26, 88–93]. Usual dosage ranges between 25 and 100 mg daily (in two divided doses) and there is suggestion, with the risk of more adverse events, of increasing the total dose up to 200 mg daily when the effect is suboptimal [2, 12, 20, 21, 26]. Main AEs of topiramate are paresthesia/numbness (results in intolerance), fatigue, anorexia/ weight loss, memory and concentration difficulties, and renal calculi (uncommon but serious adverse effect). It is contraindicated in pregnant women as it increases the risk of facial clefts and lowers birth weight. Due to the weight loss, topiramate is

Whereas valproate is indicated for the preventive treatment of episodic migraine, its side effects (nausea, somnolence, dizziness, weight gain, and hair loss) and the contraindication to women in childbearing age and pregnancy (teratogenic) have limited its use. Usual doses range between 500 and 1800 mg per day and there is limited evidence of intravenous administration of valproate in status migrainosus [2, 12, 20, 21, 95].

Other anticonvulsants, such as gabapentin, have not proven their efficacy for prevention of episodic migraine and therefore are not recommended [96, 97] .

The two major categories of antihypertensive drugs that show migraine preventive effect are beta-blockers and calcium channel blockers. Most of the evidence emerged from studies regarding hypertension reported fewer headaches in the

Beta-blockers that are available in almost every country and are recommended

The only drug of this category with good level of evidence is flunarizine, a nonspecific calcium channel blocker, with calmodulin binding properties and histamine

from almost all Headache Societies for the preventive treatment of episodic migraine are metoprolol (50–200 mg daily) and propranolol (40–240 mg daily). Other beta-blockers with fewer studies are atenolol (25–100 mg daily), nadolol (20–240 mg daily), timolol (10–30 mg daily), and bisoprolol (5–10 mg daily). Betablockers are recommended in hypertensive patients who are under 60 years old or nonsmokers [94, 99, 100]. Due to their mechanism of action and their dosage that is proven to be efficacious for migraine prevention, are not well tolerated and are contraindicated in patients with bradycardia, low blood pressure, cardiac conduction blocks, asthma, depression, and Raynaud phenomenon [2, 12, 20, 21, 101].

recommended to obese migraine patients [89, 90, 94].

*3.2.2.1.1 Topiramate*

*3.2.2.1.2 Valproate*

*3.2.2.2 Other anticonvulsants*

*3.2.2.2.1 Antihypertensive*

*3.2.2.3 Beta-blockers*

*3.2.2.4 Calcium channel blockers*

intervention group vs. the placebo group [98].

**52**

H1 blocking activity. Recommended dose ranges between 5 and 10 mg daily and is prescribed to hypertensive patients older than 60 or smokers, as well as to patients with Raynaud syndrome. The most common AEs are weight gain, daytime sedation, stomach complaints, and dry mouth, and while there are reports of depression and extrapyramidal symptoms, there is no confirmation [102]. Verapamil is another calcium channel blocker with migraine preventive properties, but it has conflicting supporting data and many Headache Societies do not accept its use for episodic migraine [2, 12, 20, 21, 103].

#### *3.2.3 Angiotensin receptor blockers (ARBs)/angiotensin converting enzyme (ACE) inhibitors*

There is also data supporting the use of ACE inhibitors and ARBs as preventive migraine treatments. Candesartan, a specific ARB, has shown positive results in smallscale crossover studies and is used for migraine prophylaxis (16–32 mg) [104, 105]. The most common AEs include back pain, dizziness, flu-like symptoms, sore throat, and nasal congestion. Similarly, a small-scale double-blind cross-over study, found lisinopril (ACE inhibitor) to be effective in episodic migraine [106]. The above data are not universally approved [2, 12, 20, 21].

#### *3.2.3.1 Antidepressants*

Antidepressants are recommended as a second-line drugs with level B documentation [20]. The two drugs of this category are amitriptyline and venlafaxine. Among the two amitriptyline, a tricyclic antidepressant has been studied the most [103]. The usual dose ranges between 10 and 150 mg. Its sedative properties have limited its use and it is suggested only at bedtime and especially to those who suffer from insomnia. It also has a place as a second choice drug for chronic migraine [26]. Except sedation, amitriptyline's AEs include dry mouth, urinary retention, constipation, weight gain, blurred vision, and tachycardia. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, has a weaker recommendation as migraine prophylaxis and is preferred to those who suffer from depression and/or anxiety and those who have also tension-type headaches (TTH). The usual dose ranges between 37.5 and 150 mg daily [2, 12, 20, 21, 94].

#### *3.2.4 Other drugs*

#### *3.2.4.1 OnabotulinumtoxinA*

Whereas many randomized trials did not prove onabotulinumtoxinA's efficacy for treating episodic migraine (EM) and it is not recommended [107–109], data extracted from chronic migraine (CM) trials recommend onabotulinumtoxinA as an effective and well-tolerated treatment. OnabotulinumtoxinA has a good level of documentation (Level A), and there is specific protocol regarding its use (PREEMPT protocol), monitoring of the patients, and evaluating their response. It should be administered according to the PREEMPT injection protocol, i.e., injecting 155 U–195 U to 31–39 sites every 12 weeks. The most common reported AEs are neck pain, muscular weakness, eyelid ptosis, and injection-site pain, and the sub-analysis of the PREEMPT studies found that adverse events decreased over time [26, 110–112]. Its use in CM with MOH is debatable after a recent trial that showed no superiority against acute withdrawal alone [113].

#### **3.3 Non-pharmaceutical therapies**

Like the pharmaceutical, the non-pharmaceutical treatments—neuromodulation devices in particular—gain even more ground in the treatment of migraine.

A set of variables arrange this alternative so far, therapeutic approach. First, the pathophysiology of migraine refers to a multidisciplinary spectrum of mechanisms; second, the disease is among the most disabling medical conditions requiring application of all available treatment options; third, the existing medicinal selections (symptomatic or preventative) are related with poor adherence due to safety and poor response rates ; and finally, there is an international movement encouraging non-pharmaceutical interventions in medicine, including the community mitigation strategies. Patients' preferences rate the non-pharmaceutical interventions for migraine highly [3]. All these factors create large space for non-pharmaceutical treatment options in migraine, which can be used alone or as adjunct therapy to pharmacological agents minimizing unnecessary drug exposure. There is good evidence for neuromodulation and biobehavioral therapies, including cognitive behavioral therapy (CBT), biofeedback, and relaxation training. Less evidence suggests physical therapy, sleep management, acupuncture, and dietary modifications.

#### **3.4 Neuromodulation**

Neuromodulation approaches for migraine treatment includes invasive and noninvasive ones. Both procedures act by stimulating the nervous system centrally or peripherally, leading to pain relief, either acutely or preventively. They are constantly gaining space in the treatment of migraine and are addressed either to refractory patients or to patients who do not want medical treatment. All neuromodulation devices are summarized in **Table 3**.

#### *3.4.1 Invasive*

There are three invasive neurostimulation methods investigated for migraine and available, yet in very limited use because of the high cost of the device, the surgical implementation needed, and the lack of good evidence of efficacy. In addition, their accessibility and reimbursement vary by country significantly. Thus, they are recommended for patients with refractory forms of CM only. The most common AEs include migration of the leads, infection, and paraesthesias [7].

#### *3.4.2 Invasive occipital nerve stimulation (iONS)*

Invasive occipital nerve stimulation (iONS) has been used to treat refractory CM cases. The exact mechanism of the neuromodulation effect in CNS remains unclear. From three randomized, sham-controlled studies [114–116], only one showed a significant improvement of migraines in the treated group comparing to sham group or the medication treated group [115]. Electrodes must be implanted subcutaneously above the great occipital nerve (GON), which present great anatomical variability among individuals [117]. The leads are implanted bilaterally, while a small generator is implanted subaxillary. The AEs include lead migration, paraesthesias, infections, and battery depletion, but safety data look better than the other invasive procedures [116].

#### *3.4.3 Vagal nerve stimulation (VNS)*

Vagal nerve stimulation (VNS) is already applied in patients with refractory epilepsy. The stimulation of vagal afferents decreases the activity of the nociceptive neurons of the spinothalamic and spinoreticular tract, which, in their turn, inhibit the nociceptive transmission in spinal and trigeminal nucleus complex, leading to

**55**

be safe.

**Table 3.**

*3.4.4 High cervical spinal cord stimulation*

*Neuromodulation in migraine management.*

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

cephalic pain control. There is data from case series with refractory CM only showing that patients with implanted VNS (iVNS) reached more than 50% reduction in headache frequency and severity [118, 119]. The scarce clinical experience in this field make iVNS not a common treatment option, for the time being, since it is an invasive procedure with adverse effects (infection, muscle cramps, local pain, and battery depletion), though the clinical experience in the field of epilepsy shows to

This invasive procedure trialed in open label studies in patients suffering from CM and showed a significant reduction in headache frequency and intensity in

treated patients, but further investigation is required [120, 121].


#### *Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*Migraine*

**3.4 Neuromodulation**

*3.4.1 Invasive*

modulation devices are summarized in **Table 3**.

*3.4.2 Invasive occipital nerve stimulation (iONS)*

invasive procedures [116].

*3.4.3 Vagal nerve stimulation (VNS)*

A set of variables arrange this alternative so far, therapeutic approach. First, the pathophysiology of migraine refers to a multidisciplinary spectrum of mechanisms; second, the disease is among the most disabling medical conditions requiring application of all available treatment options; third, the existing medicinal selections (symptomatic or preventative) are related with poor adherence due to safety and poor response rates ; and finally, there is an international movement encouraging non-pharmaceutical interventions in medicine, including the community mitigation strategies. Patients' preferences rate the non-pharmaceutical interventions for migraine highly [3]. All these factors create large space for non-pharmaceutical treatment options in migraine, which can be used alone or as adjunct therapy to pharmacological agents minimizing unnecessary drug exposure. There is good evidence for neuromodulation and biobehavioral therapies, including cognitive behavioral therapy (CBT), biofeedback, and relaxation training. Less evidence suggests physical therapy, sleep management, acupuncture, and dietary modifications.

Neuromodulation approaches for migraine treatment includes invasive and noninvasive ones. Both procedures act by stimulating the nervous system centrally or peripherally, leading to pain relief, either acutely or preventively. They are constantly gaining space in the treatment of migraine and are addressed either to refractory patients or to patients who do not want medical treatment. All neuro-

There are three invasive neurostimulation methods investigated for migraine and available, yet in very limited use because of the high cost of the device, the surgical implementation needed, and the lack of good evidence of efficacy. In addition, their accessibility and reimbursement vary by country significantly. Thus, they are recommended for patients with refractory forms of CM only. The most common

Invasive occipital nerve stimulation (iONS) has been used to treat refractory CM cases. The exact mechanism of the neuromodulation effect in CNS remains unclear. From three randomized, sham-controlled studies [114–116], only one showed a significant improvement of migraines in the treated group comparing to sham group or the medication treated group [115]. Electrodes must be implanted subcutaneously above the great occipital nerve (GON), which present great anatomical variability among individuals [117]. The leads are implanted bilaterally, while a small generator is implanted subaxillary. The AEs include lead migration, paraesthesias, infections, and battery depletion, but safety data look better than the other

Vagal nerve stimulation (VNS) is already applied in patients with refractory epilepsy. The stimulation of vagal afferents decreases the activity of the nociceptive neurons of the spinothalamic and spinoreticular tract, which, in their turn, inhibit the nociceptive transmission in spinal and trigeminal nucleus complex, leading to

AEs include migration of the leads, infection, and paraesthesias [7].

**54**

#### **Table 3.**

*Neuromodulation in migraine management.*

cephalic pain control. There is data from case series with refractory CM only showing that patients with implanted VNS (iVNS) reached more than 50% reduction in headache frequency and severity [118, 119]. The scarce clinical experience in this field make iVNS not a common treatment option, for the time being, since it is an invasive procedure with adverse effects (infection, muscle cramps, local pain, and battery depletion), though the clinical experience in the field of epilepsy shows to be safe.

#### *3.4.4 High cervical spinal cord stimulation*

This invasive procedure trialed in open label studies in patients suffering from CM and showed a significant reduction in headache frequency and intensity in treated patients, but further investigation is required [120, 121].

#### *3.4.5 Noninvasive*

Noninvasive neuromodulation devices provide a safe and well-tolerated therapeutical option in symptomatic and prophylactic treatment of migraine alone or in combination with pharmaceutical treatment. Their evidence of efficacy is moderate to good and almost equivalent to that of drug treatments, while their safety profile may outperform them. There are accessibility, reimbursement, and price issues, however.

#### *3.4.6 Supraorbital nerve stimulation*

This is a peripheral noninvasive nerve stimulation or an external trigeminal nerve stimulation device which initiates transcutaneously a mild electric current via leads that are placed on the forehead, stimulating supraorbital and supratrochlear nerves. There is evidence of dysregulated central and peripheral pathways in migraine and evidence that external trigeminal nerve stimulation may normalize function of these pathways [122]. Sham-controlled studies showed that 1-hour stimulation with this device reliefs headache pain during a migraine attack significantly [123], while daily 20-minute treatment decreases the monthly migraine days in patients suffering from EM [124]. The device is FDA approved and CE marked as preventive and acute therapy in migraine. Only mild AES are reported and despite some concerns related to the methodology followed in the preventive trial, its efficacy seems comparable to pharmaceutical preventive treatments [122, 125].

#### *3.4.7 Transcranial magnetic stimulation (TMS)*

TMS is a well-established and safe procedure already applied in other neurological diseases, modulating the excitability of cortical neurons dependently on the frequency of the stimulus. Thus, only the single-pulse stimulation (sTMS) and the repetitive-pulse stimulation (rTMS) are used to treat migraine.

sTMS is proved to inhibit both mechanical and chemically-induced cortical spreading depression in animals [126]. In addition, sTMS attenuates the evoked firing rate of third-order thalamocortical projection neurons, indicating the probable neuromodulatory effect in migraine [126]. Overall, sTMS interrupts the brain hyperactivity associated with migraine. sTMS devices are portable and patient-controlled and are applied over the occipital cortex in patients with either migraine with aura (MwA) or migraine without aura (MwoA) for acute or preventive treatment. One sham-controlled study showed that sTMS caused higher rates in 2-hour pain relief posttreatment than the sham group in patients with MwA [127]. Open-label studies have shown an efficacy either in acute or preventive treatment in MwA or MwoA [128–131]. The most common AEs recorded in the trials were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%) [131]. The device is FDA approved for acute and preventive treatment of migraine for people aged more than 12 years.

rTMS and especially high frequency rTMS seem to have a positive effect in the prevention of both EM and CM. Treatment with rTMS caused a significant decrease of monthly headache days over sham-treated patients, for both cases of CM [132] and EM [133], but another sham-controlled study did not confirm the results in CM, probably because of a large effect size [134]. Overall, the majority of rTMS studies reported reductions in headache frequency, duration, intensity, abortive medication use, depression, and functional impairment, with no significant adverse events [135]. Further investigation is needed, however.

**57**

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*3.4.8 Noninvasive vagus nerve stimulation (nVNS)*

for the symptomatic treatment of migraine.

*3.4.9 Remote electrical neuromodulation (REN)*

FDA approved for the symptomatic treatment of migraine.

*3.4.10 Transcranial direct current stimulation (tDCS)*

investigation currently [147–150].

*3.4.11 Percutaneous mastoid stimulation*

As in iNVS, the nVNS results in an ascending antinociceptive on trigeminal nucleus complex. In addition, nVNS inhibits cortical spreading depression in rats [136]. In migraineurs, the device is applied on the neck, and it produces an electrical stimulus of adjustable intensity, and therefore, stimulates transcutaneously the cervical part of vagus nerve. The evidence of efficacy in symptomatic treatment of migraine is good [8]. One sham-controlled, class 1 study has showed its efficacy in acute treatment of migraine [137], whereas its efficacy in migraine prevention remains debatable [138–140]. It is used in acute treatment of migraine with consisted results similar to the use of NSAIDs or triptans [141]. In a small-size open-label study, nVNS showed promising results as mini-prophylactic treatment of the menstrual migraine [142]. Reported AEs are neck twitching, change in voice, and redness at the site of stimulation. It is generally well tolerated by the patients, however. The portable nVNS device has received FDA approval and is CE marketed

Not only cranial nerves but also peripheral somatic nerve stimulation may also modulate cephalic pain processing, via descending endogenous analgesic mechanisms (conditioned pain modulation). There is evidence that the stimulation of upper arm peripheral nerves (median and musculocutaneous) controls cephalic pain [143]. A noninvasive, portable, and wireless device, applied on the lateral upper arm between the bellies of deltoid and triceps muscles, delivers electrical stimuli that alleviate migraine pain [144]. The device has been tested for acute migraine treatment in one randomized, sham-controlled study showing superiority over sham stimulation in achieving pain relief and freedom and relief of most bothering symptoms without significant AEs [145]. Notably, the treatment efficacy is comparable with this of the current use pharmaceutical ones [146]. Its use is contraindicated to patients with other active implantable medical devices and it is

There is some evidence suggesting that tDCS modulates cortical hyperexcitability and therefore it serves as a preventive treatment for CM and EM. The small-size, sham-controlled studies based on both rationales of anodal stimulation (excitatory) and cathodal (inhibitory) on visual cortex mostly have shown positive effect—with limitations—on reduction in monthly migraine days, headache frequency, pain duration, and severity. Contradictions include previous stroke or epilepsy and comorbidity with psychiatric disorders, among others. This procedure is under

There is evidence suggesting that the stimulation of fastigial nucleus displays neuroprotective, in particular the stimulation of fastigial nucleus elicits longlasting suppression of periinfarction depolarizing waves and protect rats against cerebral ischemia [151]. Because cortical spreading depression shares characteristics with periinfarction depolarizing waves, it was speculated that this stimulation of this nucleus may be useful in migraine prevention [152]. The new device for this purpose has electrodes that are placed on the bilateral ear mastoid over the skin.

*Migraine*

however.

*3.4.5 Noninvasive*

*3.4.6 Supraorbital nerve stimulation*

treatments [122, 125].

*3.4.7 Transcranial magnetic stimulation (TMS)*

repetitive-pulse stimulation (rTMS) are used to treat migraine.

events [135]. Further investigation is needed, however.

Noninvasive neuromodulation devices provide a safe and well-tolerated therapeutical option in symptomatic and prophylactic treatment of migraine alone or in combination with pharmaceutical treatment. Their evidence of efficacy is moderate to good and almost equivalent to that of drug treatments, while their safety profile may outperform them. There are accessibility, reimbursement, and price issues,

This is a peripheral noninvasive nerve stimulation or an external trigeminal nerve stimulation device which initiates transcutaneously a mild electric current via leads that are placed on the forehead, stimulating supraorbital and supratrochlear nerves. There is evidence of dysregulated central and peripheral pathways in migraine and evidence that external trigeminal nerve stimulation may normalize function of these pathways [122]. Sham-controlled studies showed that 1-hour stimulation with this device reliefs headache pain during a migraine attack significantly [123], while daily 20-minute treatment decreases the monthly migraine days in patients suffering from EM [124]. The device is FDA approved and CE marked as preventive and acute therapy in migraine. Only mild AES are reported and despite some concerns related to the methodology followed in the preventive trial, its efficacy seems comparable to pharmaceutical preventive

TMS is a well-established and safe procedure already applied in other neurological diseases, modulating the excitability of cortical neurons dependently on the frequency of the stimulus. Thus, only the single-pulse stimulation (sTMS) and the

sTMS is proved to inhibit both mechanical and chemically-induced cortical spreading depression in animals [126]. In addition, sTMS attenuates the evoked firing rate of third-order thalamocortical projection neurons, indicating the probable neuromodulatory effect in migraine [126]. Overall, sTMS interrupts the brain hyperactivity associated with migraine. sTMS devices are portable and patient-controlled and are applied over the occipital cortex in patients with either migraine with aura (MwA) or migraine without aura (MwoA) for acute or preventive treatment. One sham-controlled study showed that sTMS caused higher rates in 2-hour pain relief posttreatment than the sham group in patients with MwA [127]. Open-label studies have shown an efficacy either in acute or preventive treatment in MwA or MwoA [128–131]. The most common AEs recorded in the trials were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%) [131]. The device is FDA approved for acute and preventive treatment of migraine for people aged more

rTMS and especially high frequency rTMS seem to have a positive effect in the prevention of both EM and CM. Treatment with rTMS caused a significant decrease of monthly headache days over sham-treated patients, for both cases of CM [132] and EM [133], but another sham-controlled study did not confirm the results in CM, probably because of a large effect size [134]. Overall, the majority of rTMS studies reported reductions in headache frequency, duration, intensity, abortive medication use, depression, and functional impairment, with no significant adverse

**56**

than 12 years.

#### *3.4.8 Noninvasive vagus nerve stimulation (nVNS)*

As in iNVS, the nVNS results in an ascending antinociceptive on trigeminal nucleus complex. In addition, nVNS inhibits cortical spreading depression in rats [136]. In migraineurs, the device is applied on the neck, and it produces an electrical stimulus of adjustable intensity, and therefore, stimulates transcutaneously the cervical part of vagus nerve. The evidence of efficacy in symptomatic treatment of migraine is good [8]. One sham-controlled, class 1 study has showed its efficacy in acute treatment of migraine [137], whereas its efficacy in migraine prevention remains debatable [138–140]. It is used in acute treatment of migraine with consisted results similar to the use of NSAIDs or triptans [141]. In a small-size open-label study, nVNS showed promising results as mini-prophylactic treatment of the menstrual migraine [142]. Reported AEs are neck twitching, change in voice, and redness at the site of stimulation. It is generally well tolerated by the patients, however. The portable nVNS device has received FDA approval and is CE marketed for the symptomatic treatment of migraine.

#### *3.4.9 Remote electrical neuromodulation (REN)*

Not only cranial nerves but also peripheral somatic nerve stimulation may also modulate cephalic pain processing, via descending endogenous analgesic mechanisms (conditioned pain modulation). There is evidence that the stimulation of upper arm peripheral nerves (median and musculocutaneous) controls cephalic pain [143]. A noninvasive, portable, and wireless device, applied on the lateral upper arm between the bellies of deltoid and triceps muscles, delivers electrical stimuli that alleviate migraine pain [144]. The device has been tested for acute migraine treatment in one randomized, sham-controlled study showing superiority over sham stimulation in achieving pain relief and freedom and relief of most bothering symptoms without significant AEs [145]. Notably, the treatment efficacy is comparable with this of the current use pharmaceutical ones [146]. Its use is contraindicated to patients with other active implantable medical devices and it is FDA approved for the symptomatic treatment of migraine.

#### *3.4.10 Transcranial direct current stimulation (tDCS)*

There is some evidence suggesting that tDCS modulates cortical hyperexcitability and therefore it serves as a preventive treatment for CM and EM. The small-size, sham-controlled studies based on both rationales of anodal stimulation (excitatory) and cathodal (inhibitory) on visual cortex mostly have shown positive effect—with limitations—on reduction in monthly migraine days, headache frequency, pain duration, and severity. Contradictions include previous stroke or epilepsy and comorbidity with psychiatric disorders, among others. This procedure is under investigation currently [147–150].

#### *3.4.11 Percutaneous mastoid stimulation*

There is evidence suggesting that the stimulation of fastigial nucleus displays neuroprotective, in particular the stimulation of fastigial nucleus elicits longlasting suppression of periinfarction depolarizing waves and protect rats against cerebral ischemia [151]. Because cortical spreading depression shares characteristics with periinfarction depolarizing waves, it was speculated that this stimulation of this nucleus may be useful in migraine prevention [152]. The new device for this purpose has electrodes that are placed on the bilateral ear mastoid over the skin.

After few open label studies, one sham-controlled showed a significant reduction in migraine days and response rate vs. sham group in patients suffering from EM, without AEs [152]. The device is under development and further studies are needed.

#### **3.5 Nutrient (nutraceuticals)**

Nutraceuticals have been defined as, "a food (or part of a food) that provide medical or health benefits, including the prevention and/or treatment of a disease" [153]. There is an increasingly and demanding use of them by sufferers of chronic diseases including migraine [154], for which there is evidence supporting cerebral energy deficiency [155]. Nutraceuticals may cover this metabolic gap in brain, but the equality of data is low to moderate, however.

#### *3.5.1 Riboflavin*

Riboflavin (vitamin B2) is an essential component and precursor of riboflavin 5-phosphate, and modulates the electron transport chain, contributing in energy production in mitochondria. There is evidence indicating that oxygen metabolism is impaired in migraineurs' mitochondria resulting in energy insufficiency [155]. Results from placebo-controlled studies showed efficacy in reducing the frequency of headache days in adult migraineurs [156], but not children [157], or when administered as component in compliment [158]. According to available evidence, riboflavin could be suggested as preventive treatment in adults with EM in a daily dose of 400 mg [20, 159, 160].

#### *3.5.2 Coenzyme Q10*

Coenzyme Q10 has a similar action with riboflavin. In placebo-controlled studies, CoQ10 reduced the monthly headache days in adults with EM [161] but its efficacy in children and adolescents remains unclear [115]. There is Level C recommendation for its use as prophylactic treatment in EM [20, 160], and strong recommendation from the Canadian Headache Society (CHS) [159] in a dosage of 100 mg TID.

#### *3.5.3 Magnesium*

Magnesium deficiency may increase migraine susceptibility. Oral magnesium has been studied in migraine prophylaxis largely [162], as the intravenous MgSO4 for the symptomatic treatment of migraine [163]. Oral magnesium is suggested for migraine prophylaxis with level B or C of evidence [20, 160], in a daily dose of 600 mg. A later meta-analysis downgraded the level of evidence, however [162]. Adverse events with magnesium are soft stool, diarrhea, and flushing. For the symptomatic treatment of migraine, intravenous MgSO4 has failed to show beneficial effect in terms of reduction of pain and rescue medications, while several adverse effects reported questioning the clinical relevance of this symptomatic treatment [163].

#### *3.5.4 Petasites hybridus or Butterbur*

Petasites is a herbal extract, with moderate to good evidence of efficacy in migraine prevention [164, 165]. However, there are safety issues related with liver toxicity [166]. Yet, it is recommended as a second-choice treatment for the prevention of migraine [20, 167].

**59**

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*3.5.5* Tanacetum parthenium *(Feverfew)*

*3.5.6 Ginkgolide-B*

confirmation.

(level B) and EFNS as possibly effective (level C).

*3.5.7 Omega-3 polyunsaturated fatty acids (OPFAs)*

reduction of migraine days [171].

have been reported, however [174].

**3.8 Physical therapy**

**3.6 Dietary interventions**

**3.7 Acupuncture**

Feverfew is a medicinal plant that has been investigated for the migraine prophylaxis with controversial results. A recent review presents some positive findings in comparison to previous ones [168, 169]. Not major AEs are reported (usually mouth ulcers and gastrointestinal complaints). CHS does not recommend the use of Feverfew for migraine prevention; AAN/AHS recommends it as probably effective

Ginkgolide-B is an extract from *Ginkgo biloba* tree that has shown efficacy in the prevention of migraine in a small-size, open label study [170], without any other

The exact mechanism of OPFAs in migraine is unknown. One placebo-controlled study showed no significant difference between active and placebo group in

Different types of dietary interventions have been suggested and studied in migraine prevention such as weight loss diet, low fat diets, ketogenic diets, and elimination diets, being the most popular and well-studied ones, and there are reports for several others. Because of the high comorbidity of headache with obesity, weight loss diet is a promising approach linked through inflammatory mediators that are released from adipose tissue. Nevertheless, it does not come out that weight loss or change in dietary intake may attenuate migraine frequency [172].

Unrelated to placebo effect, a proportion of patients respond to acupuncture treatment in practice. From recently reviews, acupuncture shows at least not inferior efficacy in the prevention of migraine comparing to conventional prophylactic treatment at a 3-month follow-up vs. placebo, although there is lot of discussion about the high proportion of placebo effect in this procedure (no significant difference between verum acupuncture vs. sham acupuncture groups) [173, 174]. Only minor gastrointestinal AEs are reported. Despite the debatable mechanism of action and the methodological shortcomings of the relative research, the evidence suggests its use in migraine prevention, representing a therapeutic option for those patients who do not prefer medicinal treatments or display nocebo behaviors, which are very prevalent among migraineurs [11]. High recurrence rates after 6-month follow-up

The use of physical activity in alleviating the burden of migraine is unclear and data are missing. A cross-sectional study showed that physically active respondents had lower odds of migraine than moderately active respondents [175]. Physical treatment may have an effect, however, several musculoskeletal dysfunctions, in particular neck pain and vestibular symptoms have been reported to coexist with

#### *3.5.5* Tanacetum parthenium *(Feverfew)*

Feverfew is a medicinal plant that has been investigated for the migraine prophylaxis with controversial results. A recent review presents some positive findings in comparison to previous ones [168, 169]. Not major AEs are reported (usually mouth ulcers and gastrointestinal complaints). CHS does not recommend the use of Feverfew for migraine prevention; AAN/AHS recommends it as probably effective (level B) and EFNS as possibly effective (level C).

#### *3.5.6 Ginkgolide-B*

*Migraine*

*3.5.1 Riboflavin*

**3.5 Nutrient (nutraceuticals)**

dose of 400 mg [20, 159, 160].

*3.5.2 Coenzyme Q10*

100 mg TID.

*3.5.3 Magnesium*

treatment [163].

*3.5.4 Petasites hybridus or Butterbur*

tion of migraine [20, 167].

the equality of data is low to moderate, however.

After few open label studies, one sham-controlled showed a significant reduction in migraine days and response rate vs. sham group in patients suffering from EM, without AEs [152]. The device is under development and further studies are needed.

Nutraceuticals have been defined as, "a food (or part of a food) that provide medical or health benefits, including the prevention and/or treatment of a disease" [153]. There is an increasingly and demanding use of them by sufferers of chronic diseases including migraine [154], for which there is evidence supporting cerebral energy deficiency [155]. Nutraceuticals may cover this metabolic gap in brain, but

Riboflavin (vitamin B2) is an essential component and precursor of riboflavin 5-phosphate, and modulates the electron transport chain, contributing in energy production in mitochondria. There is evidence indicating that oxygen metabolism is impaired in migraineurs' mitochondria resulting in energy insufficiency [155]. Results from placebo-controlled studies showed efficacy in reducing the frequency of headache days in adult migraineurs [156], but not children [157], or when administered as component in compliment [158]. According to available evidence, riboflavin could be suggested as preventive treatment in adults with EM in a daily

Coenzyme Q10 has a similar action with riboflavin. In placebo-controlled studies, CoQ10 reduced the monthly headache days in adults with EM [161] but its efficacy in children and adolescents remains unclear [115]. There is Level C recommendation for its use as prophylactic treatment in EM [20, 160], and strong recommendation from the Canadian Headache Society (CHS) [159] in a dosage of

Magnesium deficiency may increase migraine susceptibility. Oral magnesium has been studied in migraine prophylaxis largely [162], as the intravenous MgSO4 for the symptomatic treatment of migraine [163]. Oral magnesium is suggested for migraine prophylaxis with level B or C of evidence [20, 160], in a daily dose of 600 mg. A later meta-analysis downgraded the level of evidence, however [162]. Adverse events with magnesium are soft stool, diarrhea, and flushing. For the symptomatic treatment of migraine, intravenous MgSO4 has failed to show beneficial effect in terms of reduction of pain and rescue medications, while several adverse effects reported questioning the clinical relevance of this symptomatic

Petasites is a herbal extract, with moderate to good evidence of efficacy in migraine prevention [164, 165]. However, there are safety issues related with liver toxicity [166]. Yet, it is recommended as a second-choice treatment for the preven-

**58**

Ginkgolide-B is an extract from *Ginkgo biloba* tree that has shown efficacy in the prevention of migraine in a small-size, open label study [170], without any other confirmation.

#### *3.5.7 Omega-3 polyunsaturated fatty acids (OPFAs)*

The exact mechanism of OPFAs in migraine is unknown. One placebo-controlled study showed no significant difference between active and placebo group in reduction of migraine days [171].

#### **3.6 Dietary interventions**

Different types of dietary interventions have been suggested and studied in migraine prevention such as weight loss diet, low fat diets, ketogenic diets, and elimination diets, being the most popular and well-studied ones, and there are reports for several others. Because of the high comorbidity of headache with obesity, weight loss diet is a promising approach linked through inflammatory mediators that are released from adipose tissue. Nevertheless, it does not come out that weight loss or change in dietary intake may attenuate migraine frequency [172].

#### **3.7 Acupuncture**

Unrelated to placebo effect, a proportion of patients respond to acupuncture treatment in practice. From recently reviews, acupuncture shows at least not inferior efficacy in the prevention of migraine comparing to conventional prophylactic treatment at a 3-month follow-up vs. placebo, although there is lot of discussion about the high proportion of placebo effect in this procedure (no significant difference between verum acupuncture vs. sham acupuncture groups) [173, 174]. Only minor gastrointestinal AEs are reported. Despite the debatable mechanism of action and the methodological shortcomings of the relative research, the evidence suggests its use in migraine prevention, representing a therapeutic option for those patients who do not prefer medicinal treatments or display nocebo behaviors, which are very prevalent among migraineurs [11]. High recurrence rates after 6-month follow-up have been reported, however [174].

#### **3.8 Physical therapy**

The use of physical activity in alleviating the burden of migraine is unclear and data are missing. A cross-sectional study showed that physically active respondents had lower odds of migraine than moderately active respondents [175]. Physical treatment may have an effect, however, several musculoskeletal dysfunctions, in particular neck pain and vestibular symptoms have been reported to coexist with

migraine [176, 177]. Thus, physical interventions may improve clinical outcomes when combined with pharmacotherapy. These include manual treatment of trigger points and stretching of the sternocleidomastoid and upper trapezius muscles, among other techniques (e.g., relaxation and aerobic exercise). Although physical therapy is recommended [178], the evidence of efficacy is very limited, and the documentation is rather empirical. A meta-analysis of controlled trials found that physical therapy techniques reduced the duration of migraine attacks but had no effect on pain intensity and attack frequency [179]. Thus, further investigation is needed.

#### **4. Cognitive behavioral therapies**

Though it is generally believed that biofeedback, relaxation training, and CBT improve migraine treatment outcomes either alone, or more often, in combination with medications, the evidence is poor. In one randomized trial among young patients (10–17 years old) suffering from chronic migraine, the use of CBT (10 sessions) plus amitriptyline resulted in greater reductions in days with headache and migraine-related disability compared with the use of headache education plus amitriptyline [180]. A recent meta-analysis found that 54% of individuals with migraine reported at least 50% reduction in migraine frequency after psychological therapy, vs. 24% of controls [181]. Because CBT differs substantially from traditional psychotherapy, it focuses on here and now and it is typically time limited; this therapeutic option may help practitioners in migraine management, in pediatric populations in particular [182].

#### **5. Patient centricity and patient education**

Migraine is a heterogeneous disease with a spectrum of clinical manifestations varying between individuals. The choice of therapy requires an individual approach, as each patient is unique. Severity and frequency of attacks, disability causing, other symptoms, time to peak, patient preferences, comorbidities, drug interactions, side effects, and prior therapies that failed should be all taken into consideration [2]. Before proposing any therapeutic approach, local availability and accessibility to medications should also be considered. Patient preferences and needs of each individual are essential to achieve treatment adherence and patientreported satisfaction. Fast-acting drugs are generally preferred from patients with migraine during acute attacks [183]. Effectiveness of drugs seems to be the most important issue regarding prophylactic treatment, followed by time to effect and adverse events [184]. Although patient centricity has been established in the last years, it is not yet a standard practice to include patients at all appropriate levels of decision-making processes that are related to their health and well-being. Patient education is also of great significance to ensure treatment adherence. This could be achieved by thoroughly explaining patients' disorder, purpose, and means of management. Ineffective clinician-patient communication is a major reason for patient treatment nonadherence. Patients thus should be counseled in advance on the potential benefits of the proposed therapy as well as on the treatment-related adverse effects that may appear. In conclusion, clinicians should always individualize their treatment strategy to the specific needs of each migraine sufferer, with multidisciplinary approaches, usually both pharmaceutical and non-pharmaceutical. Patients should be encouraged to take an active role in their own therapy [21]. Due to the heterogeneity of migraine, developers of guidelines should engage

**61**

**Author details**

Theodoros Mavridis1

and Dimos D. Mitsikostas1

\*, Marianthi Breza1

2 Neurology Department, Athens Naval Hospital, Athens, Greece

\*Address all correspondence to: mavridismdr@gmail.com

Kapodistrian University of Athens, Athens, Greece

provided the original work is properly cited.

1 1st Department of Neurology, Eginition Hospital, Medical School, National and

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

patients and patients' organizations to identify and ensure that patient preferences and values are taken into account. Patient engagement should be a major part of migraine care decision-making, avoiding a population level "one-size-fits-all"

, Christina I. Deligianni1,2

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

solution.

*Therapeutic Management: When and What DOI: http://dx.doi.org/10.5772/intechopen.93096*

*Migraine*

needed.

**4. Cognitive behavioral therapies**

populations in particular [182].

**5. Patient centricity and patient education**

migraine [176, 177]. Thus, physical interventions may improve clinical outcomes when combined with pharmacotherapy. These include manual treatment of trigger points and stretching of the sternocleidomastoid and upper trapezius muscles, among other techniques (e.g., relaxation and aerobic exercise). Although physical therapy is recommended [178], the evidence of efficacy is very limited, and the documentation is rather empirical. A meta-analysis of controlled trials found that physical therapy techniques reduced the duration of migraine attacks but had no effect on pain intensity and attack frequency [179]. Thus, further investigation is

Though it is generally believed that biofeedback, relaxation training, and CBT improve migraine treatment outcomes either alone, or more often, in combination with medications, the evidence is poor. In one randomized trial among young patients (10–17 years old) suffering from chronic migraine, the use of CBT (10 sessions) plus amitriptyline resulted in greater reductions in days with headache and migraine-related disability compared with the use of headache education plus amitriptyline [180]. A recent meta-analysis found that 54% of individuals with migraine reported at least 50% reduction in migraine frequency after psychological therapy, vs. 24% of controls [181]. Because CBT differs substantially from traditional psychotherapy, it focuses on here and now and it is typically time limited; this therapeutic option may help practitioners in migraine management, in pediatric

Migraine is a heterogeneous disease with a spectrum of clinical manifestations varying between individuals. The choice of therapy requires an individual approach, as each patient is unique. Severity and frequency of attacks, disability causing, other symptoms, time to peak, patient preferences, comorbidities, drug interactions, side effects, and prior therapies that failed should be all taken into consideration [2]. Before proposing any therapeutic approach, local availability and accessibility to medications should also be considered. Patient preferences and needs of each individual are essential to achieve treatment adherence and patientreported satisfaction. Fast-acting drugs are generally preferred from patients with migraine during acute attacks [183]. Effectiveness of drugs seems to be the most important issue regarding prophylactic treatment, followed by time to effect and adverse events [184]. Although patient centricity has been established in the last years, it is not yet a standard practice to include patients at all appropriate levels of decision-making processes that are related to their health and well-being. Patient education is also of great significance to ensure treatment adherence. This could be achieved by thoroughly explaining patients' disorder, purpose, and means of management. Ineffective clinician-patient communication is a major reason for patient treatment nonadherence. Patients thus should be counseled in advance on the potential benefits of the proposed therapy as well as on the treatment-related adverse effects that may appear. In conclusion, clinicians should always individualize their treatment strategy to the specific needs of each migraine sufferer, with multidisciplinary approaches, usually both pharmaceutical and non-pharmaceutical. Patients should be encouraged to take an active role in their own therapy [21]. Due to the heterogeneity of migraine, developers of guidelines should engage

**60**

patients and patients' organizations to identify and ensure that patient preferences and values are taken into account. Patient engagement should be a major part of migraine care decision-making, avoiding a population level "one-size-fits-all" solution.

### **Author details**

Theodoros Mavridis1 \*, Marianthi Breza1 , Christina I. Deligianni1,2 and Dimos D. Mitsikostas1

1 1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

2 Neurology Department, Athens Naval Hospital, Athens, Greece

\*Address all correspondence to: mavridismdr@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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a randomized, placebo-controlled trial. Journal of the Medical Association of Thailand. 2012;**95**(8):1003-1012

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cerebral ischemia: Conditioned central neurogenic neuroprotection. Brain Research. 1998;**780**(1):161-165

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management: A review of the evidence. Cephalalgia. 2016;**36**(12):1112-1133

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Sándor PS, Schoenen J. The metabolic face of migraine—From pathophysiology to treatment. Nature Reviews. Neurology.

controlled trial. Neurology.

[157] MacLennan SC, Wade FM,

Forrest KML, Ratanayake PD, Fagan E, Antony J. High-dose riboflavin for migraine prophylaxis in children: A double-blind, randomized, placebocontrolled trial. Journal of Child Neurology. 2008;**23**(11):1300-1304

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2019;**15**(11):627-643

1998;**50**(2):466-470

1998;**16**(8):728-731

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[146] Rapoport AM, Bonner JH, Lin T, Harris D, Gruper Y, Ironi A, et al. Remote electrical neuromodulation (REN) in the acute treatment of migraine: A comparison with usual care and acute migraine medications. The Journal of Headache and Pain.

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[148] Antal A, Kriener N, Lang N, Boros K, Paulus W. Cathodal

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transcranial direct current stimulation of the visual cortex in the prophylactic treatment of migraine. Cephalalgia.

[150] Auvichayapat P, Janyacharoen T,

2019;**20**(1):83

2012;**52**(8):1283-1295

2011;**31**(7):820-828

2017;**69**(4):714-721

Rotenberg A, Tiamkao S, Krisanaprakornkit T, Sinawat S, et al. Migraine prophylaxis by anodal transcranial direct current stimulation,

[145] Yarnitsky D, Dodick DW, Grosberg BM, Burstein R, Ironi A, Harris D, et al. Remote electrical neuromodulation (REN) relieves acute migraine: A randomized, double-blind, placebo-controlled, multicenter trial. Headache. 2019;**59**(8):1240-1252

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[163] Choi H, Parmar N. The use of intravenous magnesium sulphate for acute migraine: Meta-analysis of randomized controlled trials. European Journal of Emergency Medicine. 2014;**21**(1):2-9

[164] Agosti R, Duke RK, Chrubasik JE, Chrubasik S. Effectiveness of petasites hybridus preparations in the prophylaxis of migraine: A systematic review. Phytomedicine. 2006;**13**(9):743-746

[165] Prieto JMJBTT. Update on the efficacy and safety of Petadolex®, a butterbur extract for migraine prophylaxis. 2014;**4**:1-9

[166] Rajapakse T, Pringsheim T. Nutraceuticals in migraine: A summary of existing guidelines for use. Botanics: Targets and Therapy. 2016;**56**(4):808-816

[167] Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: [RETIRED]. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. 2012;**78**(17):1346-1353

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Section 3

The Chronic Face of

Migraine - Two Approaches

**75**

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Section 3
