Mild
Aspirin or aspirin combinations
As we consider drugs for headache, keep three basic principles in mind. First, antiheadache drugs may be used in two ways: to abort an ongoing attack or to prevent an attack from occurring. Second, not all patients with a particular type of headache respond to the same drugs. Hence therapy must be individualized. Third, several of the drugs employed to treat severe headaches (e.g., ergotamine, opioids) can cause physical dependence. Accordingly, every effort should be made to keep dependence from developing. If dependence does develop, a withdrawal procedure is needed.
Migraine Headache
Characteristics, Pathophysiology, and Overview of Treatment
Characteristics
Migraine headache is characterized by throbbing head pain of moderate to severe intensity that may be unilateral (60%) or bilateral (40%). Most patients also experience nausea and vomiting, along with neck pain and sensitivity to light and sound. Physical activity intensifies the pain. During a prolonged attack, patients develop hyperalgesia (augmented responses to painful stimuli) and allodynia (painful responses to normally innocuous stimuli). Migraines usually develop in the morning after arising. Pain increases gradually and lasts 4 to 72 hours (median duration, 24 hours). On average, attacks occur 1.5 times a month. Precipitating factors include anxiety, fatigue, stress, menstruation, alcohol, weather changes, and tyramine-containing foods.
Migraine has two primary forms: migraine with aura and migraine without aura. In migraine with aura, the headache is preceded by visual symptoms (flashes of light, a blank area in the field of vision, zigzag patterns). Of the two forms, migraine without aura is more common, affecting about 70% of people with migraine.
Migraine afflicts 36 million people in the United States and more than 10% of the population worldwide. The headaches are more common and more severe in females, with a lifetime incidence of 43%, compared with 18% in males. About 65% of people with migraine are women in their late teens, 20s, or 30s. With some women, migraine attacks are worse during menstruation but subside during pregnancy and cease after menopause, indicating a hormonal component to the attacks. A family history of the disease is typical.
Migraine is highly debilitating. An attack can prevent participation in social and leisure activities and can result in lost productivity at home, school, and work. According to the World Health Organization, disability caused by a severe migraine attack equals that caused by quadriplegia, psychosis, or dementia.
Pathophysiology
Migraine headache is a neurovascular disorder that involves dilation and inflammation of intracranial blood vessels. Headache generation begins with neural events that trigger vasodilation. Vasodilation then leads to pain, which leads to further neural activation, thereby amplifying pain-generating signals. Neurons of the trigeminal vascular system, which innervate intracranial blood vessels, are key components.
The exact cause of migraine pain is not completely understood—although vasodilation and inflammation are clearly involved. Available data suggest that two compounds—calcitonin gene–related peptide (CGRP) and serotonin (5-hydroxytryptamine [5-HT])—play important roles. The role of CGRP is to promote migraine, and the role of 5-HT is to suppress migraine. Data that implicate CGRP as a cause of migraine include the following:
• Plasma levels of CGRP rise during a migraine attack.
• Stimulation of neurons of the trigeminal vascular system promotes release of CGRP, which in turn promotes vasodilation and release of inflammatory neuropeptides.
• Dosing with sumatriptan, a drug that relieves migraine, lowers elevated levels of CGRP.
• Sumatriptan can suppress release of CGRP from cultured trigeminal neurons.
Data that support a protective role for 5-HT include the following:
Overview of Treatment
Drugs for migraine are employed in two ways: to abort an ongoing attack and to prevent attacks from occurring. Drugs used to abort an attack fall into two groups: nonspecific analgesics (aspirin-like drugs and opioid analgesics) and migraine-specific drugs (serotonin1B/1D receptor agonists [triptans] and ergot alkaloids). Drugs employed for prophylaxis include beta blockers (e.g., propranolol), tricyclic antidepressants (e.g., amitriptyline), and antiepileptic drugs (e.g., divalproex).
Nondrug measures can help. Patients should try to control or eliminate triggers and should maintain a regular pattern of eating, sleeping, and exercise because, in people with migraine, the brain seems to have a low tolerance for the ups and downs of life. When an attack has begun, the migraineur should retire to a dark, quiet room. Placing an ice pack on the neck and scalp can help.
Abortive Therapy
The objective of abortive therapy is to eliminate headache pain and suppress associated nausea and vomiting. Treatment should commence at the earliest sign of an attack. Because migraine causes gastrointestinal (GI) disturbances (nausea, vomiting, and gastric stasis), oral therapy may be ineffective after an attack has begun. Hence, for treatment of an established attack, a drug that can be administered by injection, nasal spray, or rectal suppository may be best. As noted, two types of drugs are used: nonspecific analgesics and migraine-specific agents. Representative drugs are listed in Table 23.2.
TABLE 23.2
Migraine Headache: Drugs for Abortive Therapy
| Nonspecific Analgesics | Usual Dosage |
| ASPIRIN-LIKE DRUGS | |
| Nonsteroidal antiinflammatory drugs (e.g., aspirin, naproxen, diclofenac) | Per specific drug instructions |
| Acetaminophen + aspirin + caffeine [Excedrin Migraine] | 2 caplets (250 mg/250 mg/65 mg) once at onset |
| Opioid Analgesics | |
| Butorphanol nasal spray | 1 spray (1 mg) in one nostril; may repeat in 60 min |
| MIGRAINE-SPECIFIC DRUGS | See Table 23.3 |
| Selective Serotonin1B/1D Receptor Agonists (Triptans) | |
| Almotriptan [Axert] | |
| Eletriptan [Relpax] | |
| Frovatriptan [Frova] | |
| Naratriptan [Amerge] | |
| Rizatriptan [Maxalt] | |
| Sumatriptan [Imitrex, Sumavel DosePro, Zecuity] | |
| Zolmitriptan [Zomig] | |
| Ergot Alkaloids | |
| Dihydroergotamine intranasal spray [Migranal] | 1 spray (0.5 mg) each nostril and repeat in 15 minutes |
| Ergotamine sublingual [Ergomar] | 1 tablet (2 mg) under tongue at onset; may administer 1 additional tablet at 30-min intervals ×2. |
| Ergotamine + caffeine [Cafergot, Migergot] | 1-2 tablets (1 mg/100 mg) at onset; may administer 1 additional tablet at 30-min intervals ×4. |
Drug selection depends on the intensity of the attack. For mild to moderate symptoms, an aspirin-like drug (e.g., aspirin, naproxen) may be sufficient. For moderate to severe symptoms, patients should take a migraine-specific drug, such as a serotonin1B/1D agonist, or—less frequently used—an ergot alkaloid (ergotamine or dihydroergotamine). If these agents fail to relieve pain, an opioid analgesic (e.g., butorphanol) may be needed. Note that opioids should be reserved for treatment in patients with migraines resistant to all other treatments.
Use of abortive medications (both nonspecific and migraine specific) should be limited to 1 or 2 days a week. More frequent use can lead to medication overuse headache (MOH), also known as drug-induced headache or drug-rebound headache (see section on MOH).
Antiemetics are important adjuncts to migraine therapy. By reducing nausea and vomiting, these drugs can (1) make the patient more comfortable and (2) permit therapy with oral antimigraine drugs. Two antiemetics—metoclopramide [Reglan] and prochlorperazine (formerly available as Compazine)—are used most often. Of the two, metoclopramide is preferred. In addition to suppressing nausea and vomiting, metoclopramide can reverse gastric stasis caused by the attack and can thereby facilitate absorption of oral antimigraine drugs. Like metoclopramide, prochlorperazine suppresses nausea and vomiting. However, because of its anticholinergic actions, prochlorperazine can make gastric stasis even worse.
Analgesics
Aspirin-Like Drugs
Aspirin, acetaminophen, naproxen, diclofenac, and other aspirin-like analgesics can provide adequate relief of mild to moderate migraine attacks. In fact, when combined with metoclopramide (to enhance absorption), aspirin may work as well as sumatriptan, a highly effective antimigraine drug. Moreover, the combination of aspirin plus metoclopramide costs less than sumatriptan and causes fewer adverse effects.
Acetaminophen should be used only in combination with other drugs, not alone. One effective combination, marketed as Excedrin Migraine, consists of acetaminophen, aspirin, and caffeine.
Opioid Analgesics
Opioid analgesics are reserved for severe migraine that has not responded to first-line medications. This is because of the potential for abuse as well as MOH. The recommended agent is butorphanol nasal spray [Stadol NS].
Serotonin1B/1D Receptor Agonists (Triptans)
The serotonin1B/1D receptor agonists, also known as triptans, are first-line drugs for terminating a migraine attack. These agents relieve pain by constricting intracranial blood vessels and suppressing release of inflammatory neuropeptides. All are well tolerated. Rarely, they cause symptomatic coronary vasospasm. Table 23.3 presents the clinical pharmacology of the triptans.
TABLE 23.3
Clinical Pharmacology of the Triptans
| Contraindicated Drugs | |||||||||
| Generic Name [Trade Name] | Route | Onset (min) | Duration | Half-Life (hr) | Dosage | SSRIs, SNRIs, Triptans, Ergots | MAOIs | CYP3A4 Inhibitors | Comments |
| Sumatriptan | |||||||||
| [Imitrex] | Oral | 30-60 | Short | 2.5 | 25, 50, or 100 mg; may repeat in 2 hr (max. 200 mg/24 hr) | ✓ | ✓ | First triptan available and best understood. Available in three fast-acting formulations: nasal spray, an autoinjector for subQ dosing (using a needle), and a needle-free device for subQ dosing [Sumavel DosePro]. | |
| [Imitrex] | Nasal spray | 15-20 | 5 or 20 mg; may repeat in 2 hr (max. 40 mg/24 hr) | ||||||
| [Imitrex] | SubQ, with needle | 10-15 | 6 mg; may repeat in 1 hr (max. 12 mg/24 hr) | ||||||
| [Sumavel DosePro] | SubQ, needle-free | 10 | 6 mg; may repeat in 1 hr (max. 12 mg/24 hr) | ||||||
| Almotriptan [Axert] | Oral | 30-120 | Short | 3-4 | 6.25 or 12.5 mg; may repeat in 2 hr (max. 25 mg/24 hr) | ✓ | Incidence of chest discomfort (pain, tightness, pressure) is lower than with other triptans. Decrease dosage if combined with a CYP3A4 inhibitor. | ||
| Eletriptan [Relpax] | Oral | 60 | Short | 4 | 20 or 40 mg; may repeat in 2 hr (max. 40 mg/24 hr) | ✓ | ✓ | Bioavailability increased by high-fat meal. Good balance between fast onset and long duration. | |
| Frovatriptan [Frova] | Oral | 120-180 | Long | 26 | 2.5 mg; may repeat in 2 hr | ✓ | Slowest onset, longest half-life, and lowest rate of headache recurrence. Decrease dose if combined with propranolol. | ||
| Naratriptan [Amerge] | Oral | 60-180 | Intermediate | 6 | 1 or 2.5 mg; may repeat in 4 hr (max. 5 mg/24 hr) | ✓ | Slower onset and longer duration than most triptans. | ||
Rizatriptan [Maxalt, Maxalt MLT] | Oral | 30-120 | Short | 2-3 | 5 or 10 mg; may repeat in 2 hours (max. 30 mg/24 hr) | ✓ | ✓ | May be the most consistently effective triptan. Decrease dose if combined with propranolol. Available in melt-in-the-mouth wafers [Maxalt MLT] that can be taken without water. | |
| Zolmitriptan | |||||||||
[Zomig, Zomig ZMT] | Oral | 45 | Short | 3 | 2.5 or 5 mg; may repeat in 2 hr (max. 10 mg/24 hr) | ✓ | ✓ | Available in a fast-acting nasal spray, and in melt-in-the-mouth wafers [Zomig ZMT] that can be taken without water. | |
| [Zomig] | Nasal spray | 15 | 5 mg; may repeat in 2 hr (max. 10 mg/24 hr) | ||||||
| [Zecuity] | Transdermal | 60 | Short | 3.1 | 6.5 mg patch; may repeat in 4 hours (max. two patches in 24 hours.) | ✓ | ✓ | Newest form of sumatriptan approved for transdermal use in 2013. Requires use of a metal transdermal system that cannot get wet. | |
Sumatriptan
Sumatriptan [Imitrex, Sumavel DosePro] was the first triptan available and will serve as our prototype for the group. The drug can be administered by mouth, nasal inhalation, or subcutaneous (subQ) injection. Additionally, an iontophoretic transdermal system [Zecuity] was approved in 2013.
Mechanism of Action.
Sumatriptan, an analog of 5-HT, causes selective activation of 5-HT1B and 5-HT1D receptors (5-HT1B/1D receptors). The drug has no affinity for 5-HT2 or 5-HT3 receptors, nor does it bind to adrenergic, dopaminergic, muscarinic, or histaminergic receptors. Binding to 5-HT1B/1D receptors on intracranial blood vessels causes vasoconstriction. Binding to 5-HT1B/1D receptors on sensory nerves of the trigeminal vascular system suppresses release of CGRT, a compound that promotes release of inflammatory neuropeptides. As a result, sumatriptan reduces release of inflammatory neuropeptides and thereby diminishes perivascular inflammation. Both actions—vasoconstriction and decreased perivascular inflammation—help relieve migraine pain.
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