Acute & Prophylactic Treatments for Migraine Headache

Transcription

1 Acute & Prophylactic Treatments for Migraine Headache Release Date: 03/08/2012 Expiration Date: 03/08/2015 FACULTY: Lenore Howe, BS, MS FACULTY AND ACCREDITOR DISCLOSURE STATEMENTS: Ms. Howe has no actual or potential conflict of interest in relation to this program. ACCREDITATION STATEMENT: Pharmacy PharmCon Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Program No.: H01-P Credits: 2 contact hours, 0.2 CEU Nursing Pharmaceutical Education Consultants, Inc. has been approved as a provider of continuing education for nurses by the Maryland Nurses Association which is accredited as an approver of continuing education in nursing by the American Nurses Credentialing Center s Commission on Accreditation. Program No.: N-746 Credits: 2 contact hours, 0.2 CEU

2 TARGET AUDIENCE: This accredited program is targeted pharmacists and nurses practicing in hospital and community pharmacies. Estimated time to complete this monograph and posttest is 120 minutes. DISCLAIMER: PharmCon, Inc does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources. Program Overview: To provide participants with an understanding of treatments for migraine headaches OBJECTIVES: After completing this program, participants will be able to: Identify the pathophysiology of migraines Describe the symptoms and criteria for a migraine headache and migraine diagnosis Outline the non-pharmacologic and behavioral therapies that may treat or prevent migraines Describe the first line treatments for migraines Outline the first-line prophylactic treatments for migraines

3 Migraine is a genetically influenced condition characterized by short, violent, recurring attacks of moderate to severe throbbing headache. The headaches typically begin during adolescence, and women often exhibit a hormonal component to their migraine headache patterns. Over 25% of sufferers experience more than three headache days each month. When headaches occur this frequently, they are usually treated prophylactically to avoid overuse of medications that can cause chronic headache. 4 Pathophysiology Migraine headaches are thought to originate as a neurologic dysfunction in the brain that gradually involves the trigeminal nerve and cranial vessels. The tendency to have migraines is inherited and may involve episodic instability of the neurovascular system where neurotransmitters like serotonin play a role. Concentrations of serotonin may be diminished periodically or neuronal receptors may be less sensitive to neurotransmitters. In addition, the nuclei of the trigeminal nerve cells periodically appear to become hypersensitive and overactive. Impulses emanating from this nerve travel to the cranial vessels and trigger releases of substances that promote inflammation around the blood vessels and cause them to dilate. Other areas of the brain including the brain stem and hypothalamus may dysfunction and cause nausea and intolerance to light, sounds, and odors. The inflamed areas around the blood vessels send signals back to irritate the trigeminal nerve, which in turn, sends signals back to the trigeminal neurons in the brain to start the cycle anew. As this central sensitization cycle continues, the patient experiences scalp sensitivity and pain called cutaneous allodynia. 5 Symptoms / Diagnosis An aura may occur as an initial migraine symptom although only about 15-20% of sufferers ever experience auras or other prodromal effects. 5 An aura is defined as a visual or Howe - Migraines Page 1

4 neurologic deficit that lasts less than an hour before it may or may not be followed with the actual headache. The aura typically starts as a small area of disturbance in the visual field, most commonly as a sensation of flashing lights that gradually spreads across the entire visual field. Other prodromal symptoms may include tremor, pallor, vertigo, and short-term aphasia. Occasionally, the aura involves a tingling weakness that spreads up and down the arms or legs, or it may continue for many hours before the migraine begins. Long lasting prodromal symptoms may also include changes in mood or personality, or periods of fatigue or hyperactivity. 5 Classic migraine headache symptoms include: Severe, one-sided, throbbing, frontal or temporal pain Nausea Vomiting Diarrhea Vertigo Tremors Photophobia Phonophobia Sweating and chills. Migraines in women may coincide with hormonal changes during menstrual cycles, while taking birth control pills, or during pregnancy or menopause. 1 Diagnosis is clinical through observation of signs and symptoms based on a set of criteria. The gold standard criteria at present are published by the Headache Classification Subcommittee of the International Headache Society. 6 The POUND Mnemonic 7 is handy in that a finding of 4 out of the following 5 symptoms indicates a 92% probability that the Howe - Migraines Page 2

5 headache is a migraine, a finding of 3 indicates a 64% probability and a finding of 0-2 indicates a 17% probability: Pulsing or throbbing One day duration on average Unilateral location Nausea or vomiting Disabling in severity The first diagnostic step is a detailed history that includes information about functional disabilities experienced during the previous three months; it can be developed informally or with a validated questionnaire. Information required for diagnosis includes the timing, frequency and duration of headaches; accompanying symptoms such as nasal stuffiness, runny nose, tearing or drooping eyelid; and detailed descriptions of the headache itself. The headache will be described in terms of: type of pain (throbbing, sharp, pressing), location of pain (one sided, bilateral, or changing sides) Pain severity Factors that cause or aggravate the headache (may include stress, anxiety, bright lights, odors, disrupted sleep, irregular meal times, etc.) History of other medical problems Treatments and whether they have been effective Presence and type of aura A physical exam, including a focused neurological exam is done to rule out secondary causes of headache, which may be more serious than a migraine diagnosis. Secondary headache may be caused by a large variety of diseases and conditions including brain Howe - Migraines Page 3

6 tumor, temporal arteritis, aneurysm, arteriovenous malformation, sinus infection, ear infection, dental disease, sleep apnea, endocrine disorders, anemia, sepsis, and hypertension. Any symptoms discovered in the history or during the physical exam that are causes for concern must be further evaluated as they may be serious or life-threatening. Migraine is a disorder that is underdiagnosed. Even when treated for migraine, over 50% of patients were prescribed narcotics or opioid analgesics, neither of which is approved by the FDA for treatment of migraine. 8 Migraine Treatment Treatment goals for migraine headache are two-fold; first is to reduce the considerable discomfort of a headache in its acute stage, and second is to prevent future headaches if they occur frequently. Patients diagnosed with migraine are typically asked to keep a diary to clarify frequency, severity, triggers, and response to treatments. Data from the diary will illustrate the need for lifestyle changes, many of which can help decrease headache frequency. Specific foods and alcohol may act as triggers and should be restricted or eliminated. Other lifestyle changes that should be instituted are stress reduction, regular patterns of eating and sleeping, and regular aerobic exercise. Stress reduction through relaxation training, biofeedback therapy, stress-management training, and physical treatments (acupuncture, cervical manipulation and mobilization therapy) may be preferred by some patients although research evidence of their efficacy is lacking. 7 The list of migraine triggers is extensive. While one trigger may provoke the migraine attack, it is likely that more than one factor is involved. The list of potential triggers includes: Howe - Migraines Page 4

7 Exposure to heat or cold Injury to neck or head Odors (smoke, perfume) Bright lights or glare Changes in the weather Air travel (high altitude) Noise Motion Physical strain Chronic high stress Disturbed sleep Skipping meals Hormonal changes (puberty, menstrual cycle, oral contraceptives or estrogen, menopause, pregnancy) Anxiety Anger Depression Excitement Let down after excitement Medications (nitroglycerin, nifedipine, oral contraceptives, hormone therapy Foods (inconsistent): citrus, caffeine, chocolate, nitrites, aspartame, aged cheese, alcohol, monosodium glutamate Treatment early in the migraine course may shorten the duration and severity of the headache symptoms and reduce associated disability. To avoid medication-overuse chronic daily headaches, headache medications should be used no more often than twice per week. Howe - Migraines Page 5

8 In spite of recent advances in migraine treatment, it is often not possible to eliminate primary migraine headaches completely. 4 Acute treatment for existing migraine headache NSAIDS alone or in caffeine-containing combination analgesics If the migraine is mild, its symptoms can usually be managed by the patient with over-the counter analgesics. In most cases, this means acetaminophen, although it is not recommended to be used alone and has not been shown to be effective unless it is combined with caffeine and aspirin. 1 Other NSAIDS (aspirin, ibuprofen, naproxen, and others) in combination with various agents can also be effective as first line treatments for mild headache. 9 Cold packs, pressure on the temple and sleep can all work with over the counter medications to reduce the symptoms of mild migraine. 5 Up to 88% of mild migraines progress to a more severe status, however, and studies show that triptans given at an early stage are more effective at ending headache symptoms than when they are given later. 4 Excedrin Migraine (acetaminophen, aspirin and caffeine) Excedrin Migraine was approved by the FDA in January 1998 for treatment of pain associated with mild-to-moderate migraine headache and was the first over-the-counter drug approved for this indication. Excedrin Migraine is available as geltabs, tablets, and caplets, all with the same active ingredients: 250 mg acetaminophen, 250 mg aspirin and 65 mg caffeine. The aspirin and acetaminophen interfere with substances in the body that cause inflammation and the caffeine increases their effectiveness. The maximum dose for adults is two per 24 hour period 10 but it is not recommended for children under 14 years of Howe - Migraines Page 6

9 age due to the risk of Reye s syndrome. If taken as directed, Excedrin Migraine produces few minor side effects such as nausea or vomiting, stomach upset, difficulty falling asleep, or a shaky feeling. Any of the NSAIDS may cause occasional allergic reactions (hives, facial swelling, asthma, wheezing, or shock), stomach pain, or ringing in the ears, changes in blood counts, and liver damage. 11 When used regularly for long periods and then discontinued, Excedrin Migraine may cause rebound headache. Triptans (Selective Serotonin Receptor Agonists) Triptans are now considered first line abortive therapy for moderate to severe migraines. They have replaced older, nonspecific 5-HT 1 agonists including ergotamine and its synthetic form, dihydroergotamine, which carried risks of ergot poisoning, medication overuse headaches, initiating labor in pregnant women, and peripheral vasoconstriction. 1 In addition to their better safety profiles, triptans are tolerated better, are more effective, and can be administered orally, nasally, and parenterally to bypass gastrointestinal symptoms of many migraine headaches. 1 The mechanism of action for all triptans is similar. They act as agonists on the 1 B and 1 D serotonin receptors in neurons and cerebral vessels to reduce inflammation and constrict blood vessels. They are effective at completely or significantly relieving migraine pain and other symptoms within 2 hours of administration in 65-70% of patients. 5 They are most effective when taken early in the attack and produce few side effects that tend to be mild including dizziness, sedation, or mild chest tightness of a non-cardiac nature. 5 In up to 30% of patients, however, the headache returns within 24 hours, and a second dose is required. Triptans can be combined with an NSAID for better headache relief and a lower likelihood that the headache will return. 5 Individual triptans show similar efficacy and tolerability but Howe - Migraines Page 7

10 differ in speed of onset and duration of action. These differences allow for selection of an agent that corresponds to a patient s headache symptom pattern. 7 Contraindications In general, triptans should not be taken with monoamine oxidase inhibitors (MAOIs) or by patients with a risk or history of heart disease, high blood pressure, high cholesterol, angina, peripheral vascular disease, impaired liver function, stroke, or diabetes. 8 Triptans should not be given within 24 hours of administration of ergotamine-containing or ergottype medications or of other triptans. Triptans are not indicated for treatment of hemiplegic or basilar migraine and should not be used by patients with known hypersensitivity to triptan medications or any of their ingredients. Complicating factors and adverse effects Serious cardiac events have been reported within a few hours of the administration of triptans. Other adverse effects may include sensations of pain and tightness or pressure in the chest, throat, neck and jaw; stroke and other cerebrovascular events; peripheral vascular ischemia and colonic ischemia; increases in blood pressure; hypersensitivity to sulfonamides; and long-term ophthalmologic effects. There is a risk that a potentially lifethreatening serotonin syndrome may develop with triptans, especially in patients who are also taking selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Almotriptan malate (Axert 12, 13 ) Overview Axert was approved by the FDA in May 2001 for the acute treatment of migraine with or without aura in adults with a history of migraine. Axert was given exclusive approval (among all triptans) by the FDA in January 2009 for treatment of acute headache pain in Howe - Migraines Page 8

11 adolescents age years that have a history of migraine attacks with or without aura and that last 4 or more hours if untreated. 12 The efficacy of almotriptan 12.5 mg is comparable to sumatriptan 50 mg, but in comparative studies, almotriptan received a higher patient acceptability rating regarding adverse effects. 13 Almotriptan should be used only in patients who have been diagnosed with migraine. If a patient has no response from the first time administration of the drug, it should not be repeated and the diagnosis of migraine should be reconsidered. Axert should not be used as prophylactic therapy for migraine. Pharmacokinetics/pharmacodynamics Almotriptan is minimally protein bound (only about 35%). The mean oral absolute bioavailability of almotriptan is 70% and peak plasma concentrations (of approximately 40ng/mL) are reached within 1-3 hours after a single 12.5 mg dose. Food does not affect its rate or extent of absorption nor does administration during a migraine attack. Almotriptan is metabolized through deamination and oxidation to indoleacetic acid or gamma-aminobutyric acid by three alternative pathways. The mean half-life of almotriptan is 3-4 hours and it is primarily (roughly 75%) eliminated through the kidneys with approximately 40% exiting as unchanged drug. Approximately 13% of the administered dose is eliminated in feces. Dosages and formulations Axert tablets are available in two strengths: 6.25 mg and 12.5 mg. The lower dose is sometimes effective, so the choice of dose should be made on an individual basis. The higher dose has been shown to be slightly more effective in adults. If the headache returns within 2 hours, a second dose may be given, but the maximum daily dose should not exceed 25 mg. The recommended starting dose for adults with hepatic or renal impairment is 6.25 mg, and their maximum dose should not exceed 12.5 mg in a 24 hour period. Howe - Migraines Page 9

12 Eletriptan hydrobromide (Relpax 14, 15 ) Overview Relpax was approved by the FDA in December 2002 for the acute treatment of migraine with or without aura in adults. Relpax is another selective 5-hydroxytryptamine 1B/1D (5- HT 1B/1D ) receptor agonist with qualities similar to the other triptans. 14 In studies comparing eletriptan to sumatriptan, eletriptan 40 mg was superior to sumatriptan 50 or 100 mg in headache response rate at 2 hours, pain-free response rate and functional improvement. Patients acceptance of 40 or 80 mg eletriptan was superior to 50 mg sumatriptan. 15 Pharmacokinetics/pharmacodynamics Eletriptan is absorbed quickly after oral administration with a bioavailability of 50% (compared to 15% for sumatriptan) and with peak plasma concentration reached in 1.5 hours. It has an affinity for lipids and the Cmax of eletriptan is increased by 20-30% following a high fat meal. The protein binding of eletriptan is approximately 85% and is considered clinically insignificant. Metabolism is through demethylation to an active metabolite with a half-life of 13 hours and a plasma level of approximately 11% that of eletriptan. Approximately 9% of unchanged eletriptan is excreted in the urine within 24 hours of administration. Non-renal elimination accounts for approximately 90% of the total clearance. Dosages and formulations Relpax is available as 20 mg and 40 mg doses of eletriptan. In clinical studies, more patients had a response to the 40 mg dose than the lower dose; but individuals may respond differently so that the choice of dose should be made on a case by case basis. The maximum recommended dose is 40 mg. In the event of a return of headache symptoms Howe - Migraines Page 10

13 after a positive response from a first dose, a second 40 mg dose may be taken at least 2 hours after the first. The maximum daily dose is 80 mg. Contraindications Renal impairment did not significantly alter clearance, but blood pressure elevations were observed in these patients. Eletriptan is metabolized by the CYP3A4 enzyme and should not be administered to patients who are taking CYP3A4 inhibitors such as ketoconazole, erythromycin, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. Complicating factors and adverse effects Eletriptan is excreted in human milk and is not recommended for use in patients under 18 years. Frovatriptan succinate (Frova 16, 17 ) Overview Frovatriptan is another serotonin-receptor agonist indicated for the treatment of acute migraine attacks with or without aura but not for migraine prevention or for other forms of migraine headaches. As with eletriptan, frovatriptan is more lipophilic than sumatriptan and was found to be a more contractile agent than sumatriptan on basilar artery tissue. Frova has a lower rate of headache recurrence than other triptans, probably due to its longer halflife of 26 hours, its increased lipophilicity and powerful contractile effects. Pharmacokinetics/pharmacodynamics After oral administration, frovatriptan exhibits minimal protein binding (approximately 15%) and has a mean elimination half-life of 26 hours. The absolute bioavailability of frovatriptan varies by gender 20% in males and 30% in females, although the difference has no impact Howe - Migraines Page 11

14 on dosing. Peak plasma levels occur in 2-4 hours after oral administration; food has no significant impact on its bioavailability but may delay the Tmax by one hour. Frovatriptan is metabolized by cytochrome P450 1A2 and, unlike other triptans, does not inhibit monoamine oxidase or hepatic cytochrome P450 microsomal isozymes, which minimizes drug interactions compared to the rest of its class. Few of frovatriptan s metabolites have an affinity for the 5-HT 1 receptor. Approximately 30% of the oral dose is eliminated through the kidneys and 60% is eliminated in feces. Dosages and formulations Frova is available in 2.5 mg tablets, and the recommended dose is a single tablet taken with fluids. If a headache recurs after an initial response, a second tablet may be taken after a 2 hour interval. The maximum daily dose of frovatriptan should not exceed 3 tablets or 7.5 grams per day. Complicating factors and adverse effects It is not known whether frovatriptan is excreted in human milk, and it is not recommended for patients younger than 18 years. Sumatriptan (Alsuma, Imitrex, Sumavel DosePro Needleless-System) 18 Overview Sumatriptan as a subcutaneous injection was approved by the FDA in December 1992 for the treatment of migraine with or without aura and of cluster headaches; it was immediately lauded as a miracle drug by migraine sufferers. While it has been shown to be quick and effective at aborting migraine symptoms, headache recurrence has been a problem. Oral sumatriptan was cleared for marketing in 1995 and the nasal spray formulation was approved for adults by the FDA in Sumatriptan is the only triptan currently available as a generic version. Howe - Migraines Page 12

15 In 2004, the FDA approved a rapidly dissolving Imitrex tablet to be swallowed whole, which replaced the original tablet. The rapid disintegration of the newer tablets may result in quicker onset of action. The manufacturer is also developing a suppository form of sumatriptan. In 2006, the FDA approved the Imitrex STAT dose System, which contains a single 4 mg subcutaneous dose with an autoinjector pen. In 2009, a prefilled 6 mg single dose, needle-free SC delivery system was granted FDA approval. The manufacturer (GlaxoSmithKline) does not recommend the use of sumatriptan in children or the elderly because of the possibility of serious adverse events. Pharmacokinetics/pharmacodynamics Sumatriptan can be administered orally, nasally, and subcutaneously and, regardless of mode of administration, it is widely distributed throughout the body. Sumatriptan exhibits protein binding in the range of 14-21%, and approximately 80% of a dose is metabolized in the liver to an inactive metabolite. Its mean half-life is 1.9 hours, which may account for the high headache recurrence rate (75%) experienced by patients in studies. 18 When taken orally, sumatriptan s onset of relief of migraine symptoms is rapid at about 60 minutes, and peak relief occurred in about 2 hours for 54% of patients and 4 hours for another 17% in clinical studies. Bioavailability with oral administration is only about 15% due to incomplete absorption and first-pass hepatic metabolism. Approximately 60% is excreted in the urine and 40% is excreted in the feces. When sumatriptan is administered subcutaneously, more consistent plasma peak concentrations can be achieved than with oral or nasal administration. Peak concentration is achieved within 5-20 minutes, and pain relief can occur in as little as 10 minutes with up to 80% of patients achieving relief within 60 minutes. Peak relief occurs within 1 hour with Howe - Migraines Page 13

16 68% of patients and within 2 hours for an additional 13%. Bioavailability is about 97%, and distribution half-life is about 13 minutes. Approximately 22% of the dose is excreted unchanged, and 38% is excreted as an indole acetic acid metabolite in the urine; a small amount is excreted in the feces. When administered intranasally, absorption of sumatriptan is rapid with peak concentration achieved within hours. Dosages and formulations Imitrex tablets are available in 25 mg, 50 mg, and 100 mg doses of sumatriptan succinate. Individuals vary in their reactions to the dose so choice of dose should be made on an individual basis. If a headache recurs after initial relief, the dose may be repeated after 2 hours with the maximum daily dose not to exceed 200 mg. If a headache recurs after an Imitrex injection, additional single tablets up to 100 mg per day may be given with an interval of at least two hours between doses. 19 Alsuma Auto-injector, Sumavel, Imitrex Statdose, and Sumavel DosePro Needle-free System are available as a single 6 mg dose of sumatriptan in 0.5 ml solution for injection in the thigh or upper arm (Sumavel DosePro is recommended for injection in the abdomen or thigh). The maximum recommended dose is two 6 mg doses separated by at least 1 hour in a 24 hour period. 20 Imitrex Nasal Spray is available in 5 mg and 20 mg doses of sumatriptan. A 10 mg dose may be achieved by a 5 mg dose in each nostril. The dose should be decided for each patient individually. If the headache returns, the dose may be repeated once after 2 hours with a maximum daily dose not to exceed 40 mg. 21 Howe - Migraines Page 14

17 Complicating factors and adverse effects Imitrex tablets should not be given to patients with hepatic impairment as the liver plays an important role in clearing orally administered sumatriptan. Sumatriptan is excreted in human milk following subcutaneous injection and is not recommended for patients under 18 years old. Sumatriptan is not recommended for elderly patients because they are more likely to have impaired liver function. 22, 23 Rizatriptan benzoate (Maxalt, Maxalt-MLT ) Overview Maxalt was approved by the FDA in July 1998 for acute treatment of migraine in adults with or without aura, and it was approved for pediatric patients, age 6-17 years, in December As another of the central serotonin-receptor 1 B and 1 D agonists, Maxalt shares its mechanism of action and contraindications with other triptans. One difference is that rizatriptan appears to be dose dependent--the 10 mg dose appears to be more effective and causes more adverse effects than the 5 mg dose. It is also more lipophilic than sumatriptan, which leads to a higher bioavailability and greater central nervous system penetration than sumatriptan. In studies, more patients receiving rizatriptan achieved headache pain relief within 2 hours than those taking sumatriptan. 23 Pharmacokinetics/pharmacodynamics Rizatriptan does not accumulate with repeated dosing and is metabolized via oxidative deamination to an inactive indole acetic acid metabolite and, in small degree, to N- monodesmethyl-rizatriptan, which has similar activity to the parent compound. It undergoes significant first-pass metabolism with 14% of the oral dose excreted unchanged in the urine and 51% excreted as the indole acetic acid metabolite. Its half-life averages 2-3 hours. After oral administration, it is rapidly absorbed with a bioavailability of 45%. It takes hours to reach peak plasma concentrations; food does not affect its availability, but it does Howe - Migraines Page 15

18 slow its time to peak concentration by an hour. The bioavailability of Maxalt and Maxalt-MLT is similar although the time to peak plasma concentration is longer with Maxalt-MLT at hours. Dosages and formulations Maxalt tablets are available in 5 mg and 10 mg doses of rizatriptan. Maxalt-MLT is available as an orally disintegrating tablet in 5 mg and 10 mg doses of rizatriptan. The standard dose for Maxalt is 5 or 10 mg for adults, with a repeat dose after at least 2 hours and a maximum dose of 30 mg in any 24 hour period. For pediatric patients 6-17 years weighing less than 40 kg (88 lb), the standard dose is 5 mg; for pediatric patients 6-17 years weighing more than 40 kg (88 lb), the standard dose is up to 10 mg. Maxalt-MLT may be administered with or without liquid. For adult patients taking propranolol, only the 5 mg dose is recommended up to a maximum of 3 doses in any 24 hour period (15 mg). For pediatric patients weighing more than 40kg (88 lb) taking propranolol, only a single 5 mg dose in any 24 hour period is recommended. Maxalt is not recommended for pediatric patients weighing less than 40 kg (88 lbs) who are taking propranolol. Complicating factors and adverse effects The dose of Maxalt should be adjusted in patients who are also taking propranolol as propranolol has been shown to increase the plasma AUC by 70%. It is not known whether Maxalt is secreted in human milk. 24, 25 Naratriptan hydrochloride (Amerge ) Overview Naratriptan is a similar serotonin-receptor agonist to sumatriptan, but it has a longer halflife and correspondingly longer duration of action. It was slightly less effective than Howe - Migraines Page 16

19 sumatriptan in clinical trials, but it was better tolerated by patients, and they experienced lower rates of migraine recurrence. Naratriptan was approved by the FDA in 1998 for acute treatment of migraine with or without aura in adults. Pharmacokinetics/pharmacodynamics Naratriptan is well absorbed after oral administration with peak concentrations occurring in 2-3 hours; it is slightly better absorbed by females. If taken during a migraine, absorption is slower and peak concentrations are reached in 3-4 hours. Food does not alter the absorption of naratriptan. Onset of headache relief after a 2.5 mg dose was 21% at 1 hour post dose, 48% at 2 hours, 60% at 3 hours, and 67% at 4 hours. Naratriptan has a volume of distribution of 170L, is 28-31% bound to proteins, and is metabolized by cytochrome P450 isozymes into inactive metabolites. It is mostly eliminated by the kidneys with 50% being excreted unchanged and 30% as metabolites. Naratriptan s mean half-life is 6 hours. Dosages and formulations Amerge tablets are available in two doses of naratriptan hydrochloride 1 mg and 2.5 mg. The dose should be based on individual patient response. If a headache returns or a patient has a partial response, the dose may be repeated once after 4 hours for a maximum dose of 5 mg in any 24 hour period. Complicating factors and adverse effects Naratriptan should not be used in patients with severe renal or hepatic impairment due to decreased clearance of the drug. In patients with mild renal or hepatic impairment, the maximum daily dose should not exceed 2.5 mg over a 24 hour period. Amerge is not recommended for elderly patients and is not approved for pediatric use. It is not known whether naratriptan is excreted in human milk. Howe - Migraines Page 17

20 Zolmitriptan (Zomig, Zomig Nasal Spray, Zomig 26, 27, 28 ZMT) Overview Zomig was approved by the FDA in November 1997 for acute treatment of migraine with or without aura in adults. In February 2001, the FDA approved its orally disintegrating tablet for adults, and in October 2003, Zomig Nasal Spray was approved for adults. Zolmitriptan is a serotonin-receptor agonist similar to sumatriptan except that it can cross the blood brain barrier to act centrally on the trigeminovascular system. In clinical trials, zolmitriptan had response rates of up to 81% within 2 hours of dosing. Pharmacokinetics/pharmacodynamics Zolmitriptan is administered orally and nasally. The drug is well absorbed after oral administration with peak plasma concentration occurring in 2 hours, although absorption is slower if taken during a moderate to severe migraine attack. Its mean absolute bioavailability is about 40% with food having no effect. First pass metabolism of zolmitriptan is more extensive in men than in women. Zolmitriptan is metabolized to an active N- desmethyl metabolite, which is 2-6 times more potent than the parent compound, and two inactive metabolites. The active metabolite may contribute substantially to the effects of zolmitriptan, and its maximum concentration will occur in approximately 2-3 hours. Zolmitriptan is 25 % bound to plasma protein and approximately one-sixth of the total plasma clearance is through the kidneys. Dosages and formulations Zomig is available in tablet form as 2.5 mg and 5 mg doses of zolmitriptan. Zomig-ZMT is available as 2.5 mg and 5 mg orally disintegrating tablets. Zomig Nasal Spray is available as a single 5 mg dose of zolmitriptan in a plastic device. Patients should be started on the lowest dose of Zomig, at 2.5 mg or lower (the 2.5 mg tablets can be broken in half manually to achieve an approximate 1 mg dose). It is not recommended to break the Howe - Migraines Page 18

21 Zomig-ZMT tablet. If a headache returns, a second dose can be given after 2 hours with the maximum dose not to exceed 10 mg within a 24 hour period. Complicating factors and adverse effects Zolmitriptan should be used with caution in elderly patients and in patients with liver disease. It is not known if zolmitriptan is excreted in human milk; it is not recommended for use in pediatric patients. Naproxen; Sumatriptan Combination (Treximet ) 29 Treximet, a tablet that combines 500 mg of naproxen sodium and 85 mg sumatriptan, was approved by the FDA in April 2008 for the acute treatment of migraine attacks with or without aura in adults. Administering the two drugs together appears to provide pain relief after 2 hours in more patients than when either drug is taken alone. The combination also appears to be helpful in patients who are taking sumatriptan and experience high rates of headache recurrence. No comparative data exists for administration of Treximet as compared with administration of naproxen sodium and sumatriptan as individual components. Ergots Dihydroergotamine (DHE 45, Migranal 30, 31 ) Overview DHE 45 is a partially synthetic ergot alkaloid that is administered parenterally or by nasal spray as Migranal to treat acute symptoms of severe migraine headache. While DHE 45 injection was approved by the FDA in 1946 and has been used for a long time to treat severe migraine, there are now less toxic drugs available that are more appropriate for mild to moderate migraine symptoms. The nasal spray form (Migranal ) was approved for acute treatment of migraine with or without aura in December Howe - Migraines Page 19

22 Mechanism of action The therapeutic effect of DHE is thought to be due to its agonist activity on the 5-HT 1D receptors located on intracranial blood vessels, which may cause vasoconstriction that relieves migraine pain along the trigeminal nerve pathway. Pharmacokinetics/pharmacodynamics Dihydroergotamine mesylate is poorly absorbed from the GI tract and is poorly bioavailable. When it is administered as a nasal spray, however, the mean bioavailability increases to 32% of that achieved through administration by injection. It is 93% protein bound and is metabolized to four metabolites, only one of which exhibits similar affinity to receptors as its parent compound. Extensive metabolism occurs in the liver. Most of the dihydroergotamine is excreted in the feces with about 2% of the intranasal dose and 6% of the intramuscular dose excreted through the kidneys. Dosages and formulations Migranal is available in a nasal spray device that delivers a 0.5 mg dose of dihydroergotamine with each spray. The recommended dose is one spray in each nostril with a second dose of one spray in each nostril followed 15 minutes later. The maximum recommended dose is 2.0 mg (four sprays) in a 24 hour period. Contraindications Migranal should not be used for chronic daily administration, nor should it be administered to patients who are taking CYP 3A4 inhibitors. Migranal is not appropriate for patients with cardiovascular diseases, uncontrolled hypertension, and hemiplegic or basilar migraine. Migranal should not be used within 24 hours of administration of other 5-HT1 agonists, ergot-type medications, or methysergide. Howe - Migraines Page 20

23 Complicating factors and adverse effects Various fibrotic complaints (pleural and retroperitoneal fibrosis; cardiac valvular fibrosis) have been reported after prolonged daily use of Migranal. Cardiac ischemia and other cardiovascular events, vasospastic reactions, increases in blood pressure, and local irritation of nose and throat have been reported in patients using dihydroergotamine injection or nasal spray. Medications in development A New Drug Application (NDA) for Levadex is currently under review by the FDA. Levadex is a novel formulation of dihydroergotamine (DHE) to be delivered with a self-administered inhaler. Clinical trials have shown statistically significant pain relief and freedom from nausea, phonophobia, and photophobia at 2 hours after dosing, and it was well tolerated by patients. The FDA is expected to take action on the NDA in March Treatments to prevent migraine headache Patients who report more than two headaches per month, are disabled for three or more days per month as a result of their migraines, or require acute headache treatment two or more times per month should be considered for preventive therapy. 1 The goals of prophylaxis are to reduce the number and severity of migraines, to improve a patient s response to acute treatments, and to improve their level of functioning. Patients can play a role in prevention by tracking, identifying, and avoiding migraine triggers, and by developing regular sleeping and dining patterns. A regular exercise program may also help. 1 Howe - Migraines Page 21

24 There is evidence that some alternative treatments such as feverfew, butterbur root, riboflavin (vitamin B 2 ), and magnesium may be safe and effective for preventing migraine headaches. All herbal remedies should be taken under the supervision of a physician since they may interact with prescription drugs. In particular, feverfew may increase bleeding time and enhance the effects of aspirin and warfarin. In addition, acupuncture, cognitive behavioral treatment, biofeedback, and relaxation therapy may provide benefits. 33 Prophylactic pharmacologic treatment of migraine is recommended when the frequency of headaches is increasing (to four or more per month) and/or a possibility exists that a patient is overusing acute therapies. Regular use of acute medications may cause kidney and liver damage as well as reduced response and rebound headaches. 2 Medications used to prevent headaches should be started at their minimum doses. Long-acting formulations may improve patient compliance as the effects of preventative medications may not be seen for two to three months. 1 First line prophylactic treatment Many medications are used for migraine prophylaxis and various reference articles list them in differing priority based on their effectiveness. Using the most current information available based on research studies and expert opinion about the quality of existing evidence and potential adverse effects, first line treatment for migraine prophylaxis includes (in priority order 7 ) propranolol (Inderal), timolol (Blocadren), amitriptyline (Elavil), divalproex sodium (Depakote ER), and topiramate (Topamax.) Selection from among this list should be made based on the patient s personal preferences, comorbidities such as hypertension and depression, and any concern about the medication including cost, efficacy, pharmacokinetics, adverse effects, and medication interactions. 7 34, 35 Propranolol hydrochloride (Inderal -LA) Howe - Migraines Page 22

25 Overview Propranolol is a non-selective beta-blocker (beta-adrenergic receptor antagonist) that was approved for treatment of hypertension by the FDA in Inderal-LA is a long-acting formulation of propranolol that is recommended for prophylaxis of migraine headache. Mechanism of action Propranolol (as with all beta-blockers) competes with adrenergic neurotransmitters for binding at sympathetic receptor sites, which causes decreases in blood pressure through multiple mechanisms. Its effect in migraine may be due to inhibition of vasodilation or arteriolar spasms over the brain cortex. Pharmacokinetics/pharmacodynamics Propranolol is quickly absorbed from the GI tract and undergoes significant first-pass elimination due to its high hepatic clearance with only about 25% reaching circulation. Peak plasma concentrations are obtained within minutes after administration and plasma half-life is 2-3 hours. Propranolol is mainly excreted through the kidneys as its metabolites, with only about 1-4% of a dose excreted in feces as unchanged drug. Inderal-LA is a special formulation of propranolol hydrochloride enclosed in a capsule with a sustained-release coating. In healthy volunteers, steady state was achieved after 2-3 days, peak plasma levels were reached in about 6 hours and the half-life is hours (2-3 times that of conventional tablets.) Over a 24 hour period, blood levels are constant for about 12 hours and then decline. Dosages and formulations Inderal-LA is available in capsules with a sustained-release coating at four strengths: 60 mg, 80 mg, 120 mg, and 180 mg of propranolol hydrochloride. The initial recommended dose for migraine prophylaxis is 80 mg once daily, and the usual effective dose is in the Howe - Migraines Page 23

26 range of mg once daily. The dose may be increased gradually to achieve optimum effect, but if no satisfactory result is achieved after 4-6 weeks of reaching the maximum dose of 320 mg once daily, the Inderal-LA should be withdrawn gradually over several weeks and discontinued. Contraindications Patients with cardiogenic shock, sinus bradycardia, greater than first-degree AV block, bronchiospastic diseases, or known hypersensitivity to the drug should not take propranolol hydrochloride. Complicating factors and adverse effects Propranolol crosses the blood-brain barrier and the placenta, and it is excreted in breast milk. Propranolol may exacerbate angina, cardiac failure, and bronchospastic lung disease, and should be used with caution in patients with impaired kidney and liver function. Timolol maleate (Blocadren ) 36 Overview Timolol is another nonselective, beta-adrenergic receptor antagonist similar to propranolol. Timolol maleate was first approved by the FDA for optical use in 1978 and for oral use in Mechanism of action Timolol is similar to other beta-blockers in its mechanism for preventing migraine headaches. Pharmacokinetics/pharmacodynamics Howe - Migraines Page 24

27 Timolol is absorbed rapidly after oral administration and is completely absorbed although the amount of drug reaching systemic circulation varies widely among patients due to its extensive first pass metabolism. It is metabolized almost completely into inactive metabolites that are excreted by the kidneys. Bioavailability is approximately 50% and the onset of activity is 30 minutes, with peak plasma concentrations achieved in 1-2 hours. It shows a dose-dependent duration of activity of up to 24 hours, and food has no effect on its absorption. Plasma half-life is approximately 4 hours. Dosages and formulations Blocadren is available in 5 mg, 10 mg and 20 mg tablets of timolol maleate. The recommended initial dose is 10 mg twice per day, although it may be administered as a single 20 mg dose once daily. The daily dose may be increased to a maximum of 30 mg in two doses, or it may be decreased to 10 mg per day if the clinical response is good and the dose is well tolerated. If the desired response is not achieved within 6-8 weeks using the maximum dose, Blocadren should be discontinued. Contraindications Timolol has the same contraindications as propranolol above. Complicating factors and adverse effects Timolol should be used with caution in patients with impaired kidney and liver function. Timolol is excreted in breast milk. Amitriptyline (Tryptanol, Vanatrip 37, 38, 39 ) Overview Howe - Migraines Page 25

28 Amitriptyline is a tertiary amine tricyclic antidepressant. The use of antidepressants for migraine prophylaxis has not been approved by the FDA but studies have shown that they can be effective, especially in the case of amitriptyline. 38 Mechanism of action The mechanism of action of tricyclic antidepressants is not well understood, but it is thought that they decrease the reuptake of norepinephrine and serotonin. 39 Pharmacokinetics/pharmacodynamics Amitriptyline is usually well absorbed from the GI tract, but this varies among individuals. It may take several weeks before the full antidepressant effects are felt, but adverse effects may appear immediately after the first dose. Peak plasma concentrations are reached within 2-12 hours after administration, and the effects are long lasting. Amitriptyline is metabolized in the liver to nortriptyline, which crosses the blood-brain barrier, and the placenta and is excreted in breast milk. Between 25-50% of a single dose is excreted in the urine within 24 hours, and a small amount of excretion occurs in the feces. Dosages and formulations Amitriptyline is available in 10 mg, 25 mg, 50 mg, 75 mg, 100 mg and 150 mg tablets. The dose for adults should be titrated to response from 10 mg per day up to 300 mg per day. Contraindications Amitriptyline should not be used with patients who are in the acute recovery phase after myocardial infarction, who have any cardiac disease, or who are taking MAOI therapy (or within 14 days of discontinuing treatment with an MAOI). Discontinuation of amitriptyline, especially after prolonged high doses, should be gradual to avoid symptoms of cholinergic Howe - Migraines Page 26

29 rebound. Amitriptyline should be used with caution in patients with hematological disease, alcoholism, asthma, cardiac conduction defects, glaucoma, diabetes, GI disease, or BPH. Amitriptyline should not be administered to children, and administered with caution to elderly patients and breastfeeding mothers. Complicating factors and adverse effects A long list of adverse effects includes anxiety and other psychological symptoms, orthostatic hypertension and other cardiac effects, sleep disturbances and drowsiness, weight gain, tremor, seizures, blurred vision, sexual dysfunction, and serotonin syndrome. Valproic Acid, Divalproex sodium (Depakote Delayed Release Tablets, Depakote ER, Stavzor ) 40 Overview Divalproex sodium is an anticonvulsant that has been shown to decrease migraine frequency and severity. Since Divalproex sodium is rapidly converted to valproic acid in the body, the two drugs show similar properties. Depakote ER, a once daily formulation, was approved by the FDA for migraine prophylaxis in August In July 2008, a delayedrelease valproic acid capsule formation (Stavzor) was approved by the FDA for migraine prophylaxis. 40 Mechanism of action The exact mechanism of action for valproic acid is unknown although it is believed to increase brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. Valproic acid may inhibit the catabolism of GABA or block its reuptake into nerve endings. It may also work by inhibiting voltage-sensitive sodium channels and thereby inhibiting repetitive neuronal firing. Howe - Migraines Page 27

30 Pharmacokinetics/pharmacodynamics In terms of plasma concentrations, patient responses to a given dose vary widely. Valproic acid is approximately 90% protein-bound, but protein binding decreases as the concentration of the drug increases, which may affect its clearance from the body. Valproic acid is metabolized in the liver to more than ten metabolites and at least one of the metabolites acts in a similar way to the original compound. Its half-life is 6-16 hours in adults and it is eliminated through the kidneys with very little as unchanged drug. Following oral administration, its bioavailability is almost 100%. Food can delay the rate but not the extent of absorption. Depakote ER is not bioequivalent to Depakote delayed release tablets even at the same daily dosage. After multiple doses, Depakote ER given daily produces fluctuations in concentration up to 20% lower than Depakote delayed release given 2, 3 or 4 times daily. Peak plasma concentrations are reached within 3-5 hours for Depakote delayed release tablets and within 4-17 hours for Depakote ER. In either case, full therapeutic effects require several days of treatment. Dosages and formulations Depakote is available in 125 mg, 250 mg and 500 mg tablets of divalproex sodium delayed release formula. The recommended initial dose of Depakote for migraine prophylaxis in adults and adolescents older than 16 is 250 mg taken twice daily. The dose can be titrated upwards as needed to 500 mg twice daily. Elderly patients should be started at a reduced initial dose with a slower dose titration. In patients with decreased food or fluid intake or experiencing excessive drowsiness, the dose should be reduced or eliminated. Depakote ER is available as 250 mg and 500 mg of valproic acid equivalent in extended release tablets. The recommended initial dose of Depakote ER in adults and adolescents older than 16 is 500 mg once daily for 1 week. It can then be increased to 1000 mg once daily, which should be the maximum dose. Dose adjustment may be necessary depending Howe - Migraines Page 28

31 on tolerability and response, especially in patients with decreased food or fluid intake or excessive somnolence. If a patient requires smaller does adjustments than is allowed with Depakote ER, Depakote should be used instead. Stavzor is available as 125 mg, 250 mg and 500 mg of valproic acid in delayed-release capsules. The initial dose for adults is 250 mg twice daily which can be titrated as needed up to a maximum of 500 mg twice daily. In the elderly, a reduced initial dose and slower dose titration may be necessary. As with other formulations, dose adjustment may be necessary depending on tolerability and response, especially in patients with decreased food or fluid intake or excessive somnolence. Contraindications Patients with liver disease or urea cycle disorders should not be given valproic acid. It should be used with caution in patients with renal disease and patients with known hypersensitivity to the drug should not use Depakote. Complicating factors and adverse effects Adverse effects include liver failure, pancreatitis, suicidal behavior, thrombocytopenia, hyperammonemia, hypothermia, multi-organ hypersensitivity reactions, and extreme drowsiness in the elderly. Valproic acid is distributed in spinal fluid, saliva, and milk, and crosses the blood-brain barrier. It should not be used during pregnancy. Topiramate (Topamax ) 41 Overview Topiramate is an antiepileptic drug that acts by blocking the spread of seizures rather than by raising the seizure threshold. In August 2004, topiramate was approved by the FDA for the prophylactic treatment of migraines in adults. Howe - Migraines Page 29