MigraineRecent Advances

INDEX• Overview of Migraine• Preventive Migraine therapy• Role of Amitriptyline• Role of Memantine

Overview of Migraine

HEADACHE CLASSIFICATIONPrimary Headaches• Migraine• Tension-type• Cluster Headache

Secondary Headaches• Tumor• Meningitis• Giant cell arteritis

A COMMON DISORDER?• WHO data: 19th among all causes of tears lived with disability (YDL)

• Migraine occurs in 10-20% of population at any given time

• Ratio of women: men is 3:1

• Inherited disorder: 50-90% have first degree relative with migraines

PREVALENCE OF MIGRAINE GLOBALLY

France 5 -12%Denmark 10%Germany 11%Italy 12%Taiwan 9.1%UK 07%USA 9 -

12%

Lipton RB, et al Headache. 1994;34:319-328. Indian Pediatrics 2003; 40:665-669; Lipton, Diamond et al, 2000

9 % in boys and 14% in girls

The prevalence of migraine is increasing in India

India

MIGRAINE PREVALENCE BY AGE AND GENDER

MIGRAINE TRIGGERS• Hormonal changes

• during puberty, menstruation, pregnancy, menopause & with OCPs and HRT • Changes in daily schedule

• Oversleeping, not getting enough sleep, skipping a meal, a rest after a hectic schedule

• Weather• Change in pressure, temperature or humidity.

• Foods • ↑ tyramine (aged cheese), others; caffeine, chocolate, bananas, citrus fruits

• Environment • Smoke, perfume, paint

Migraine TriggersHyper-excitable cortex

Development of cortical spreading depression

Activation of unmyelinated nerve fibers supplying large cerebral vessels, the pial vessels, the

large venous sinuses, and the dura mater

Transient ↓ in neuronal activity and vasoconstriction

AURA Neuronal activation

PATHOPHYSIOLOGY

Release of CGRP, substance P, Nitric oxide, and cytokines

Acts on 5HT1B receptors

Vasodilation (meningeal vessels)

Pain produced by peripheral nociceptors

Activation of nerve fibers

PATHOPHYSIOLOGY

Activation of the TNC

Trigemino-cervical network

Superior salivatory nucleus

Referred pain both sides of head,

around eyes and sinus and post. neck and head

Chemoreceptor trigger zone

Hypothalamus

Nausea, vomiting

Rhinorrhea, lacrimation, nasal,

conjunctival congestion

Photophobia, phonophobia

PATHOPHYSIOLOGY: REFERRED PAIN AND MIGRAINE- ASSOCIATED SYMPTOMS

MIGRAINE ATTACK ONSET OVER TIME

MIGRAINE – NOT JUST A “HEADACHE”

Time

HeadacheAuraProdrome Postdrome

AssociatedFeatures

Intensity ofSymptomsor Phases

MIGRAINE – PRODROMAL PHASE

Excitatory – Irritability– Elation – Physical hyperactivity– Yawning– Food craving– Photophobia/ phonophobia– Bowel or bladder activity

Inhibitory– Mental / physical slowing – Poor concentration– Word finding difficulty– Weakness/ faculty– Chills, anorexia, constipation,

abdominal bloating

AURA• Complex focal neurological phenomenon• Accompanies 36% of migraine attacks • Develops over 5-20 minutes and lasts < 60 min• An aura not followed by a headache: migraine equivalent or acephalic migraine

– Most common in patients older than 40 years

AURAComplex focal neurological phenomenon

Visual Scotoma (64%), fortification spectra, scintillations

Auditory Temporary hearing loss, paracussis, tinnitus, Oscillocusis

Motor Hemiparesis, speech and language disturbance (17-20%)

Sensory Numbness, paresthesias (40%), olfactory illusions, gustatory illusions

AURA

MIGRAINE WITHOUT AURA (COMMON MIGRAINE)

A. Two of the following:• Headache—unilateral site• Headache—pulsating quality• Associated nausea• Associated photophobia and

phonophobiaB. Other criteria:

• History of similar headaches• No evidence of organic

disease

MIGRAINE WITH AURA (CLASSIC MIGRAINE)

A. Headache pain is preceded by any of the following symptoms:• Visual

—Flashing lights—Shimmering zigzag lines—Blind spots

• Neurological—Paresthesia —Numbness—Unilateral weakness—Speech disturbance

(aphasia)B. No evidence of organic

disease

THE IHS CRITERIA FOR MIGRAINE DIAGNOSIS

Migraine Criteria• ≥ 5 attacks lasting 4-72 hours (30 minutes – 7 days)• ≥ 2 of the following

• Unilateral (bilateral)• Pulsating ( not pulsating)• Moderate or severe intensity (mild or moderate)• Aggravation by routine physical activity (not)

• ≥ 1 of the following• Nausea and/or vomiting (no nausea/vomiting)• Photophobia and phonophobia (one or neither)

• No evidence on history or examination of disease that might cause headaches

Adapted from Headache Classification Committee of the HIS. Cephalalgia. 1988

RESOLUTION AND POSTDROMAL PHASE

• Resolution: during sleep

• Rapid resolution: vomiting or strong emotional stimulus

• Postdromal phase (migraine hangover)

• Symptoms:

• Anorexia, nausea, muscle tension, fatigue, cognitive impairment

MIGRAINE COMORBIDITIES• Neurological/psychiatric:

• Epilepsy, stroke, depression, bipolar disorder, anxiety disorders, impaired cognition

• Others:• Irritable bowel syndrome, asthma, mitral valve prolapse

MIGRAINE AND STROKE• Migraine is a risk factor for stroke• Stroke is associated with migraine with aura• Causal relationship complex:

• Migraine may coexist with stroke• Stroke may occur with clinical features of migraine• Stroke may be induced by migraine (true migrainous infarction)

MIGRAINE AND EPILEPSY• Patients with epilepsy are 2.4 times more likely to have migraine

than their relatives without epilepsy• 24% prevalence of migraine among people with epilepsy (Lipton

et al)• 5.9% prevalence of epilepsy among those with migraine (vs.

0.5% in general population) (Andermann)

MIGRAINE AND AFFECTIVE DISORDERS

• Odds ratios for patients with migraine (Merikangas et al):

• 2.2 for depression• 2.9 for bipolar disorder• 2.7 for generalized anxiety disorder• 3.3 for panic disorder• 2.4 for simple phobia• 3.4 for social phobia

ACUTE TREATMENT

THE GOALS OF MANAGING MIGRAINE

• reduce migraine frequency, severity and disability• reduce reliance on poorly tolerated, ineffective, or unwanted acute

pharmacotherapeutics• improve quality of life• reduce headache-related distress• educate patients and enable them to manage their disease• avoid dose escalation to acute medications

PREVENTATIVE MIGRAINE THERAPY

Favors greater use of preventative medicines

* Up to 2 days/week

Favors acute caremedicines only*

Rapoport AM, Adelman JU. Am J Managed Care. 1998:531-544.

PREVENTATIVE MIGRAINE THERAPY• Not disabling• Short duration• Good response to acute care

medications

• Disabling• Long duration headaches• Poor response to acute care

medicines

WHY MIGRAINE PREVENTION?• 60% of migraineurs have 1 or more severe attacks per

month• 25% experience 4 or more severe attacks per month

• Use of abortive treatments should be limited to 2 times per week

• Avoid development of rebound• Not all patients respond adequately or can tolerate

abortive treatments

WHY MIGRAINE PREVENTION? (CONT.)

• Abortive agents may not adequately control frequent or disabling auras

• Prolonged or frequent episodes of pain may lead to changes in pain generators and more frequent migraines

• Akin to “kindling” in seizure disorders• To decrease frequency, duration, and severity of

attacks• Improve function and decrease disability• To improve responsiveness and decrease use and related

costs of acute medications

NEED FOR PREVENTION• Recent studies suggest that habitual overuse of

acute medications, including triptans, ergots, and other analgesics, can lead to the development of chronic daily headaches

• Preventive medications can serve an important role in the treatment of migraine by reducing migraine frequency and by ameliorating dose escalation

TREATMENT STRATEGIES: WHEN TO CHOOSE MIGRAINE PROPHYLAXIS

• Headache frequency (> 2 days per week)• Degree and frequency of migraine-related disability• Amount of prescription and OTC medications used by patient• Presence of concomitant disorders (e.g., depression)• Willingness and ability of patient to comply with daily

medication given• Special circumstances, such as hemiplegic migraine or

headaches that risk permanent neurologic injury• Patient preference

The US Headache Consortium Evidence-Based Guidelines. May 2000.

TREATMENT STRATEGIES: WHEN TO CHOOSE MIGRAINE PROPHYLAXIS

• Recurring migraines that, in patient’s opinion, interfere with daily routines despite acute treatment

• Contraindication to, failure of, or overuse of acute therapies

• Adverse events with acute therapies• Cost of both acute and preventative therapies

The US Headache Consortium Evidence-Based Guidelines. May 2000.

GOALS OF MIGRAINE PREVENTION• Reduce attack

• Frequency• Severity• Duration

• Improve responsiveness to treatment of acute attacks• Improve function and reduce disability

PROPHYLACTIC DRUGS FOR MIGRAINE• Beta blockers (Propranolol 120 to 240 mg daily)

• Calcium channel blockers (Nimodipine, Nicardipine & Verapamil)• Hormone therapy (Estrogens and/or progestogens)• Antidepressants (Amitriptyline)• Anticonvulsants

• Vitamins & minerals (High dose of vit B12 [700 mg])

Am Fam Phy 2000 62 (11)

Role of Topiramate

TPM is currently considered a first-line migraine preventive drug and should especially be considered a preferred

treatment for all patients who are concerned about gaining weight, who are currently

overweight, or who have coexisting epilepsy.

TOPIRAMATE IN MIGRAINE PREVENTION

• Topiramate is a broad-spectrum antiepileptic drug indicated as adjunctive therapy and monotherapy for adults and pediatric patients

• Topiramate has shown efficacy in the treatment of several other neurologic and psychiatric diseases

• Topiramate has multiple mechanism of actions that could contribute to migraine prevention

• Clinical studies showed an approximately 50% responder rate in migraine for topiramate,

• This efficacy is comparable to drugs in IHS Class I for migraine prophylaxis (propranolol, migraine and valproate)

TOPIRAMATE TARGET - TRIGEMINOVASCULAR SIGNALING AFFECTING PATHOGENESIS

Recent research suggests that topiramate may modulate trigeminovascular signaling, which could affect migraine pathogenesis

MECHANISM OF ACTIONSite ActionVoltage-activated Na+ channels

Limits sustained repetitive firing via state-dependent blockade of Na+ channels

Ca++ channel subtypes Reduces slightly the amplitude of high voltage-activated CA++ currents

GABAA receptor Potentiates GABA-mediated inhibition at GABAA site not modulated by benzodiazepines or barbiturates

Glutamate receptor subtypes (kainate and AMPA)

Blocks glutamate-mediated neuroexcitation with no apparent effect on NMDA receptor activity

Carbonic anhydrase Inhibits type II and type IV carbonic anhydrase

TOPIRAMATE IN THE TREATMENT OF CHRONIC MIGRAINE

PIVOTAL STUDY (MIG 001)

Silberstein SD et al.

Cephalalgia 2003; 23(8):820-4.

No. of patients N = 487

Design Double-blind, randomized, placebo-controlled, multicenter study

Diagnosis Migraine with or without aura (IHS migraine criteria for at least 6 months.

Age 12-65 years

Severity 2-12 migraine periods/month

Dose; duration 50, 100 and 200 mg /day; 26 weeks of total treatment time with 18 weeks of maintenance

STUDY DESIGN

Cephalalgia 2003; 23(8):820-4.

REDUCTION IN MIGRAINE EPISODES WITH TOPIRAMATE VS PLACEBOPlacebo Topiramate 50 mg Topiramate 100 mg Topiramate 200 mg

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-1.5

-1

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-0.8

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-2.3

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P<0.001 P<0.001*Least squares meanCephalalgia 2003; 23(8):820-4.

200 mg dose was not significantly more effective than the 100 mg dose

Topiramate treatment was also associated with reduced consumption of acute treatment medications

PERCENTAGE OF PATIENTS ACHIEVING 50% REDUCTION IN MIGRAINE FREQUENCY

The onset of efficacy was observed by the end of the first month of treatment.

0

10

20

30

40

50

6052 54

36 Topiramate 200 mgTopiramate 100 mgTopiramate 50 mgPlacebo%

of P

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Cephalalgia 2003; 23(8):820-4.

TOPIRAMATE FOR MIGRAINE PREVENTION: A RANDOMIZED CONTROLLED TRIAL

PIVOTAL STUDY (MIG 002)

Brandes JL et al.

JAMA 2004; 291(8):965-73.

No. of patients N = 483

Design Double-blind, randomized, placebo-controlled, multicenter study

Diagnosis Migraine with or without aura (IHS migraine criteria for at least 6 months.

Age 12-65 years

Severity 3-12 migraine periods/month

Dose; duration 50, 100 and 200 mg /day; 26 weeks of total treatment time with 18 weeks of maintenance

STUDY DESIGN

JAMA 2004; 291(8):965-73.Brandes J L et al.

REDUCTION IN MIGRAINE EPISODES WITH TOPIRAMATE VS PLACEBOPlacebo Topiramate 50 mg Topiramate 100 mg Topiramate 200 mg

-3

-2.5

-2

-1.5

-1

-0.5

0

-1.1

-1.3

-2.1

-2.4

Mea

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asel

ine*

P<0.008 P<0.001*Least squares mean

Mean monthly migraine frequency decreased significantly for patients receiving topiramate at 100 or 200 mg/d

Rescue medication use was reduced in the 100-mg/d (p=0.01) and 200 mg/d (p=0.005)

JAMA 2004; 291(8):965-73.

PERCENTAGE OF PATIENTS ACHIEVING 50% REDUCTION IN MIGRAINE FREQUENCY

Statistically significant reductions (p<0.05) occurred within the first month with topiramate 100 and 200 mg/d

0

10

20

30

40

50

60

47 49

39Topiramate 200 mgTopiramate 100 mgTopiramate 50 mgPlacebo%

of P

atie

nts

JAMA 2004; 291(8):965-73.

MIG 002

P=0.01

P<0.001P<0.001

TPM MAY BE USEFUL FOR PEDIATRIC MIGRAINEURS

• TPM may be useful for pediatric migraineurs as well. Campistol and colleagues[1] evaluated 24 patients aged 6-14 years in a 4-month trial, observing efficacy and safety of TPM with a mean dose of 3.5 mg/kg/day after titration.

• A significant decline in severity and duration of attacks was shown with good/excellent impressions of efficiency. Two patients withdrew because of paresthesias or lack of efficacy.

1. Campistol J, Campos J, Casas C, Herranz JL. Topiramate in the prophylactic treatment of migraine in children. J Child Neurol. 2005;20:251-253.

DOSE• Start at a dose of 25 mg at bedtime• Increase by a dose of 25 mg /week• Do not increase the dose if bothersome AEs develop• wait until they resolve (they usually do)• if they do not resolve, decrease the drug to the last tolerable dose, then

increase by a lower dose more slowly• Attemp to reach a dose of 50-100 mg/day twice a day• The dose can be increased up to 600 mg/day

KEY POINTS• Clinical trials of topiramate in migraine

represent the largest controlled clinical trials of a migraine preventive drug

• Effective as monotherapy and adjuctive therapy

• Adverse events are mild and tend to decrease with time

• Weight loss is common and a major benefit

• Treatment with 100 or 200 mg/day of topiramate was associated with significant reduction in

• migraine frequency• migraine days• migraine duration• migration severity• use of acute medications

TIAGABINE (TGB)• TGB was initially studied in patients with refractory migraine,[1] with doses titrated

to 4 mg, 4 times daily. In an open-label study of 41 migraine patients who had been previously treated with divalproex and discontinued therapy because of adverse events or relative lack of efficacy, Freitag and colleagues[1] used a mean dose of 10 mg/day.

• In this study, 5 patients experienced a remission of their migraine attacks, and 33 of the 41 studied had at least a 50% reduction in their attacks.

• The reported side effects, usually mild to moderate in severity and almost always resolving without medical intervention, included dizziness, asthenia (fatigue or generalized muscle weakness), nervousness, tremor, trouble concentrating, mental lethargy, slowness of thought, depression, aphasia, and abdominal pain.[1]

• The drug is not a standard treatment for migraine and does not carry an FDA indication for migraine.

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

LEVETIRACETAM (LCT)• Levetiracetam (LCT) is a new AED of unknown mechanism of action,

although it has proved to be a broad-spectrum anticonvulsant in animal models.[1]

• It is rapidly and nearly completely absorbed after oral administration; peak serum concentrations are achieved within 2 hours, and daily doses are linearly related with plasma concentrations.

• LCT is metabolized primarily by hydrolysis of the acetamide group to the inactive carboxylic derivative and it is poorly protein-bound (< 10%).[2]

• The metabolic degradation of LCT is independent of the hepatic system of cytochrome P450, and therefore is not affected by the concomitant use of other AEDs. In children as well as in adults, steady state is achieved after 2 days of twice-daily dosing.1. Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent model of seizures and

epilepsy. Eur J Pharmacol. 1998;353:191.2. Nicolas J-M, Collart P, Gerin B, et al. In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic

agent. Drug Metab Disp. 1999;27:250-254.

LEVETIRACETAM (LCT)• Anecdotal evidence suggests the usefulness of LCT in the prevention of

migraine.[1,2] • A recent study assessed LCT as prophylaxis of transformed migraine.

Mean headache frequency per month at baseline was 24.9 and a significant reduction of headache frequency was obtained in 1 month (19.4, P < .001), 2 months (18.4, P < .001), and 3 months (18.0, P < .001).[3]

• The most common side effects reported in these initial clinical trials included fatigue or tiredness, somnolence, dizziness, and infection (common cold or upper respiratory tract infection).1. Drake ME, Greathouse NI, Armentbright AD, Renner JB. Levetiracetam for preventive treatment of migraine. Cephalalgia.

2001;21:373.2. Krusz JC. Levetiracetam as prophylaxis for resistant headaches. Cephalalgia. 2001;21:373.3. Rapoport AM, Sheftell FD, Tepper SJ, Bigal ME. Levetiracetam in the preventive treatment of transformed migraine. Curr Ther

Res. 2005;66:212-221.

LEVETIRACETAM (LCT)• The efficacy and safety of LCT for

pediatric migraine was evaluated in a population of 30 children or adolescents aged 6 to 19 years (mean 12.9 years).

• This was a 10-week, open-label study. • Among the 19 patients who completed

the study, • 6 patients experienced at least a 50%

reduction in headache frequency and severity;

• 8 had at least 75% improvement; • 3 became headache-free; and • 2 developed worsening headaches.

• In 16 of the participants, disability decreased and quality of life improved, evaluated by PedMIDAS.

• One patient reported delusions and violent behavior;

• 1 patient developed a seizure disorder;

• 5 patients did not comply; and • 4 withdrew because of lack of

efficacy.[1]

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

ZONISAMIDE• Zonisamide (ZNS) is a sulfonamide derivative that is structurally and

chemically unrelated to other AEDs. • It has been used for adjunctive therapy of partial seizures, and it is

rapidly and nearly completely absorbed after oral administration with negligible first-pass metabolism.[1]

• ZNS is unaffected by tightly protein-bound drugs, is binding to plasmatic proteins between 40% and 60%, and does not affect the protein binding of other drugs.

• The plasma half-life of ZNS in healthy volunteers after a single oral dose ranges from 50 hours to 68 hours, but in the presence of enzyme-inducing AEDs, it decreases by approximately 50%.[2-3]

1. Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: A European double-blind trial. Epilepsy Res. 1993;15:67-73. 2. Ito T, Hori M, Kadokawa T. Effects of zonizamide (AD-810) on tungistic acid gel-induce thalamic generalized seizures and conjugated estrogen-induced cortical spike-

wave discharge in cats. Epilepsia. 1986;27:367-374. 3. Yagi K, Seino M. Methodological requirements for clinical trials in refractory epilepsies: our experience with zonisamide. Prog Neuropsychopharmacol Biol Psychiatry.

1992;16:79-85.

ZONISAMIDE• ZNS presents a unique combination of pharmacologic actions:

• It blocks voltage-dependent sodium and T-type (but not L-type) calcium channels;

• reduces glutamate-mediated excitatory neurotransmission; inhibits excessive nitric oxide (NO) production,

• scavenging hydroxyl and NO radicals; and • inhibits carbonic anhydrase

• All of these mechanisms may play a role in headache and pain modulation, possibly via neuronal stabilization.[1]

1. Mimaki T. Clinical pharmacology and therapeutic drug monitoring of zonisamide. Ther Drug Monit. 1998;20:593-597.

ZONISAMIDE• ZNS was studied for migraine prevention in 2 open-label trials presented. The first

evaluated 33 patients with mixed headache disorders and refractory migraines.[1] • Most had not responded to at least 2 previous preventive agents. ZNS was started

at a dosage of 100 mg at bedtime every third day for 4-5 doses. • The dosage frequency was then increased to every other day for another 4-5

doses, followed by the same dosage on a daily regimen. • Dosage was adjusted upward every 2-3 weeks and in some cases reached as high

as 600 mg/day. • A total of 18% of the participants reported a 65% or better reduction in the

frequency of migraine attacks and other headaches; 24.2% reported a 25% to 50% decrease in the same parameter; and 27% did not respond or were noncompliant with the protocol.

1. Krusz JC. Zonisamide in the treatment of headache disorders. Cephalalgia. 2001;21:374-375.

ZONISAMIDE• In the second study,[1] 34 patients with migraine with and without aura

who were refractory to other preventive therapies received an initial dosage of 100 mg of ZNS daily, which was titrated as tolerated to 400 mg daily.

• Headache severity was significantly reduced as well as the other headache measures.

• The side effects reported included paresthesia, fatigue, anxiety, and weight loss.

• Agitated dysphoria and difficulty concentrating were also observed.• The tolerability of ZNS is favorable if titrated slowly.

1. Drake ME, Greathouse NI, Armentbright AD, Renner JB. Preventive treatment of migraine with zonisamide. Cephalalgia. 2001;21:374.

BETA BLOCKERS• The use of beta blockers for migraine prevention is not new. • The evidence for the use of this pharmacologic class was well established

with propranolol, timolol, atenolol, and nadolol. • The use of novel beta blockers, such as carvedilol, for the prophylactic

treatment of migraine is a new concept because it offers additional alpha-1 blocking and antioxidant properties.

• This nonselective alpha-1 and beta-1 antagonist reduces blood pressure by reducing peripheral vascular resistance with no alteration of heart frequency or cardiac debit.[1]

• The results are a very favorable adverse event profile, which may represent an appeal in migraine prevention because traditional beta blockers have limiting side effects.

1. Cleophus TJ, Zwinderman AH. Beta-blockers and heart failure: meta-analysis of mortality trials. Int J Clin Pharm Ther. 2001;39:383-387.

TIZANIDINE• The efficacy of tizanidine in headache was shown in a controlled study

involving the treatment of chronic daily headache, especially in chronic migraineurs.[1]

• In addition, an open study of 220 patients demonstrated efficacy in both migraine and chronic tension-type headache,[2] which makes this drug attractive as a possible prophylactic treatment of episodic migraine and tension-type headache.

1. Zaimis E, Hanington E. A possible pharmacological approach to migraine. Lancet. 1969;2:298-300.

2. Krusz JC, Belanger J, Mills C. Tizanidine: a novel effective agent for the treatment of chronic headaches. Headache. 2000;11:41-45.

Role of Memantine

NMDA RECEPTOR ANTAGONISTS IN MIGRAINE

• Blockage of glutamate release from NMDA and non-NMDA receptors has been shown to inhibit pain transmission to the trigeminal nucleus complex.[1]

• This inhibition of pain by NMDA receptor antagonists was a key discovery. • NMDA antagonists are being studied extensively for the prophylactic

treatment of migraines. • Older NMDA receptor antagonists, such as ketamine and

dextromethorphan, cause major CNS side effects• they are not used in a clinical setting for migraine prophylaxis.[2,3]

1. Fanciullacci M. Seeking the best care for acute migraine. J Headache Pain. 2002;3:1–5.2. Rogawski MA. Common pathophysiologic mechanisms in migraine and epilepsy. Arch Neurol. 2008;65:709–714.3. Smith TR, Stoneman J, Munson P. Memantine for the prophylaxis of migraine: a report of 3 cases and discussion of pharmacology. Headache. 2005;16:167–

170.

MEMANTINE• Memantine is a moderate-affinity uncompetitive NMDA receptor

antagonist that is approved in the U.S. for the treatment of Alzheimer's disease

• This antagonist, which has fewer side effects than other NMDA antagonists, is believed to work by competing with magnesium in the synapse, which inhibits the prolonged influx of calcium.[1,2]

• This inhibition blocks neuronal excitation or CSD and therefore is thought to inhibit migraine pain.[2]

• For this reason, memantine is now being prescribed as off-label prophylactic therapy for migraine.1. Smith TR, Stoneman J, Munson P. Memantine for the prophylaxis of migraine: a report of 3 cases and discussion of pharmacology. Headache. 2005;16:167–170.2. Krymchantowski A, Jevoux C. Memantine in the preventive treatment for migraine and refractory migraine. Headache. 2009;49:481–482.

PREVENTIVE THERAPY FOR MIGRAINE

• Clinical trial examined the use of memantine (5 mg, 10 mg, 15 mg, or 20 mg) as preventive therapy for migraine in patients at a headache clinic.[1]

• Of the 60 patients, 54 continued therapy for 2 months. Prior to therapy, headache frequency in these patients was 4 to 30 (mean 15.2, SD 8.8) per month.

• After therapy, headache frequency was 0 to 22 (mean 6.1, SD 6) per month. The majority of patients also experienced reduced headache severity, needed fewer migraine medications, and experienced improvements in level of functioning.[1]

• Forty-five patients reported no side effects.[13] Limitations of this trial are that it was retrospective and that patients continued taking their previous migraine medications.[1]

1. Charles A, Flippen C, Romero Reyes M, Brennan KC. Memantine for prevention of migraine: a retrospective study of 60 cases. J Headache Pain. 2007;8:248–250.

MEMANTINE FOR REFRACTORY MIGRAINES

• A different clinical study investigated memantine for refractory migraines.[1] Subjects received memantine 10 mg to 20 mg per day

• Twenty-three of 38 subjects completed the study. All subjects were taking other preventive medications, but had been on stable doses of these medications for a minimum of 3 months.[1]

• The mean number of days with severe pain decreased from 7.8 at baseline to 5.9 after 1 month, to 4.0 after 2 months, and to 3.2 after 3 months.[14] The mean headache frequency decreased from 21.5 at baseline to 14.3 days per month by the conclusion of the study.[1]

• Side effects were reported by 10 patients, and two patients dropped out because of tolerability issues.[1]

1. Bigal M, Rapoport A, Sheftell F, et al. Memantine in the preventive treatment of refractory migraine. Headache. 2008;48:1337–1342.

CASE STUDY• One case study describes a 75-year-old patient with a history of memory

deficits and daily chronic migraines in whom memantine therapy was initiated[1]

• While on a 10-mg dose, the patient reported cessation of her chronic daily migraines

• After 5 months, she reported an improved quality of life and claimed to be symptomfree[1]

1. Spengos K, Theleritis K, Paparrigopoulos T. Memantine and NMDA antagonism for chronic migraine: a potentially novel therapeutic approach? Headache. 2008;48:284–298.

CHRONIC MIGRAINES AND TENSION-TYPE HEADACHES

• Memantine was studied for the treatment of chronic migraines and tension-type headaches (TTH) in 20 patients who had failed all other prophylactic treatments[1]

• After 1 month of treatment with memantine 20 mg, migraine frequency decreased 56%—to 4.1 migraines per month—in 14 patients.[1]

• TTH frequency decreased 62%, and acute migraine medication use decreased by two-thirds.[1]

• All of the aforementioned studies have limitations. • Therefore, there is still a need for a prospective, double-blind, randomized

control study for migraine prophylaxis.[1] • Studies suggest that memantine may be useful for migraine prophylaxis

1. Krusz JC, Robert T. Preventing chronic THH and migraine with Namenda. http://headaches.about.com/od/medsarticlesandinfo/a/namenda_prev.htm. Accessed July 25, 2009.

MEMANTINE FOR PROPHYLAXIS OF CHRONIC TENSION-TYPE HEADACHE-A DOUBLE-BLIND,

RANDOMIZED, CROSSOVER CLINICAL• Treatment for chronic tension-type headache (CTTH) is unsatisfactory. • investigate the efficacy of the N-methyl D-aspartate (NMDA) antagonist memantine in the

prophylactic treatment of CTTH. • 40 patients in a randomized, double-blind, placebo-controlled, crossover trial. • Memantine 20-40 mg/day or placebo was each given for 10 weeks separated by a 2-week

wash-out period; • 29 patients completed the study• Headache intensity in both sexes was significantly lower on a 0-10 verbal rating scale with

memantine (3.8) than with placebo (4.1; P = 0.03). • In women, area-under-the-headache curve was significantly lower with memantine (1343 +/-

919) than with placebo (1555 +/- 1019; P = 0.01) • Beneficial effects of memantine were observed in women• Memantine was shown to reduce pain intensity in CTTH patients

Cephalalgia. 2009 Mar;29(3):314-21. doi: 10.1111/j.1468-2982.2008.01720.x

SUMMARY• The use of memantine for the prophylaxis of migraines could prove to be

an effective treatment• Although memantine is not the first NMDA antagonist used to target

migraines, it is one of the first with a low side-effect profile that has been shown to be efficacious

• Clinical trials have demonstrated that memantine is effective as add-on therapy

• Research needs to be conducted with memantine for monotherapy in migraine prophylaxis

Role of Amitriptyline

Amitriptyline is a first-line agent for migraine prophylaxis and is the only antidepressant

with consistent evidence supporting its effectiveness for this use.

MIGRAINE PROPHYLACTIC DRUGS

First-line• Beta-blockers (atenolol,metoprolol, propranolol, bisoprolol) if not contra-

indicated• Amitriptyline – when migraine co-exists with

• TTH• Another chronic pain condition• Disturbed sleep• Depression

AMITRIPTYLINE• One study involving 162 persons with migraines compared amitriptyline

therapy (50 to 100 mg daily) with placebo over four weeks. • Results showed an odds ratio (OR) of 2.4 (95% CI, 1.1 to 5.4) for the

number of patients reporting a 50 percent improvement in migraine index, and a moderate effect size of 0.62 (95% CI, 0.15 to 1.10) on a migraine index that included frequency and duration.2

• Results of a study1comparing amitriptyline with propranolol suggest that propranolol is more effective in patients with a single migraine type, whereas amitriptyline is more beneficial for patients with mixed migraine and tension features.

• Amitriptyline also is useful in patients with comorbid insomnia or, when used at higher dosages, depression.31. Snow V, Weiss K, Wall EM, Mottur-Pilson C, American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:840–9.2. Gray RN, Goslin RE, McCrory DC, Eberlein K, Tulsky J, Hasselblad V. Drug treatments for the prevention of migraine. Technical review 2.3. February 1999. Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025.3. Silberstein SD, Freitag FG. Preventive treatment of migraine. Neurology. 2003;60:S38–44.

BTX• BTX has been evaluated in open-label trials and large multicenter studies.[1, 2] • Silberstein and associates[2] examined the safety and efficacy of BTX in migraine

prevention with a double-blind, vehicle-controlled design. • A total of 123 patients from 12 headache centers were recruited in this double-

blind, randomized, placebo-controlled (vehicle-controlled), parallel-group prospective study. The requirements of the protocol included a 1-month baseline, an injection visit, 3 monthly postinjection visits, and completion of a daily headache diary.

• Patients with migraine (with or without aura) who had experienced an average of 2-8 moderate-to-severe migraines per month during the 3 previous months were eligible. Patients were randomized to 1 of 3 groups: BTX 25 U or 75 U, or vehicle.

• The sites of the injections were symmetric into the glabellar, frontalis, and temporalis muscles. Participants kept diaries for 3 months post injection.1. Evers S, Rahmann A, Vollmer-Haase J, Husstedt IW. Treatment of headache with botulinum toxin A -- a review according to evidence-based

medicine criteria. Cephalalgia. 2002;22:699-710. 2. Silberstein SD, Mathew NT, Saper J, Jenkins S; Botox Migraine Clinical Research Group. Botulinum toxin type A as a migraine preventive

treatment. Headache. 2000;40:445-450.

BTX• The group of patients that received 25 U of BTX received a significantly

better performance than the vehicle in all endpoints. • The 75-U BTX treatment group was significantly more improved than the

vehicle group on patient global assessment for days 31-60 but not other parameters.

• BTX was well tolerated, but the group that was injected with 75 U showed significantly more treatment-related adverse events than vehicle.

• The conclusion of the study was that pericranial injection of BTX, 25 U, is effective for the treatment of migraine.

• The adverse effects, usually transient and mild, included blepharoptosis, diplopia, and injection-site weakness, which is an expected drug effect.

BTX• In other study, BTX reduced the number of headache days 60 patients

with either chronic tension-type headache or chronic migraine compared with placebo, but this difference was not statistically significant.[1]

1. Ondo W, Vuong K, Derman H. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel-design study. Cephalalgia. 2004;24:6-15.

• NO is a small molecule gas synthesized from L-arginine with potent vasodilator properties.

• NO is found in endothelial cells, granulocytes, platelets, and the brain. • In the normal brain, endothelial and neuronal NO are expressed, but a third

isozyme that synthesizes NO appears to be inducible in response to tissue damage or following nitroglycerine administration.[86]

• The relationship of nitric oxide synthase (NOS) inhibition on neuronal activity in the trigeminal nucleus has been demonstrated in animal models.

• The infusion of a NOS inhibitor significantly reduced neuronal activity, suggesting that NO may play an important role in sensitized neurons in the trigeminal nucleus.

• CGRP is a neuropeptide found within cell bodies of the sensory terminals in the trigeminal nerve. Along with other neuropeptides, such as substance P and neurokinin A, it innervates the cerebral vasculature and may exert a counterbalance effect on cerebrovascular contraction. This action, which is induced by dilatation of cerebral vessels, increasing cerebral blood flow and mediating the trigeminal reflex, relates to CGRP receptors existing in various cerebral and cranial arteries.[74] In addition, in animal models, stimulation of trigeminal ganglion fibers results in release of CGRP leading to neurogenic vasodilation.[75]

• CGRP has an important role in migraine. • CGRP levels are increased in the external jugular venous blood during

spontaneous migraine attacks or following electrical or chemical stimulation, with normalization of levels after treatment with sumatriptan.[1,2]

• Furthermore, infusion of human CGRP in migraineurs induces migrainelike headache.[1]

• The investigation of the CGRP role in migraine has led to the development of CGRP antagonists, which are still in preclinical phase trials.Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology. 1993;43:S16-S20. Abstract Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183-187. Abstract

BIBN4096BS• BIBN4096BS is a small molecule with a high affinity and specificity for the

human CGRP receptor. It is a nonpeptide CGRP-receptor antagonist.[1]

• Fatigue and paresthesias were the most reported adverse events.[2]

• The first study in migraine was carried out with a multicenter, randomized, double-blind design.[3] The primary endpoint was headache efficacy (severe or moderate headache at baseline to mild or no headache at 2 hours). The 2.5-mg dose resulted in a response rate of 66%, compared with 27% for the placebo.

1. Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol. 2000;129:420-423.

2. Iovino M, Feifel U, Young CL, Wolters JM, Wallestein G. Safety, tolerability and pharmacokinetics of BIBN4096BS, the first selective small molecule calcitonin gene-related peptide receptor antagonist, following single intravenous administration in healthy volunteers. Cephalalgia. 2004;24:645-656.

3. Olesen J, Diener HC, Husstedt IW, et al. BIBN4096BS Clinical Proof of Concept Study. Calcitonin gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine. N Engl J Med. 2004;350:1104-1110.

NO IN MIGRAINE• In addition, the administration of the exogenous NO donor nitroglycerin in

rats induces delayed plasma protein extravasation in dura mater. • Furthermore, the cortical spreading depression, which releases CGRP from

nerve terminals triggering the migraine cascade, also releases NO.[1] • These observations along with the knowledge that intravenous

nitroglycerine infusion causes a migraine attack in migraineurs but not in nonmigraine controls suggests the important role of NO in migraine.[2]

1. Read SJ, Smith MI, Hunter AJ, Parsons AA. Enhanced nitric oxide release during cortical spreading depression following infusion of glyceryl trinitrate in the anesthetized cat. Cephalalgia. 1997;17:159-165.

2. Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity. A possible molecular mechanism of migraine pain. Neuroreport. 1993;4:1027-1030.

LNMAH 546C88• Thus far, LNMAH 546C88 is the only NOS inhibitor being studied. This agent was

administered intravenously to 15 patients with migraine, and compared with 14 subjects who received placebo.

• Ten of the 15 patients experienced relief 2 hours after the infusion compared with 2 of 14 in the placebo group.[89]

• Although well tolerated, LNMAH 546C88 did not alleviate histamine-induced migraine, but in a randomized, double-blind, crossover trial of 16 patients with chronic tension-type headache (patients were assigned intravenous infusion of 6 mg/kg L-NMMA or placebo for 2 days separated by at least 1 week in a randomized order), L-NMMA reduced pain intensity on the visual analog scale significantly more than placebo.

• These preliminary results suggest that NOS inhibition may represent a safe and effective way of treating acutely primary headache in which NO mechanisms may be involved.[90,91]

1. Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia. 1998;18:27-32.

2. Lassen LH, Christiansen I, Iversen HK, Jansen-Olesen I, Olesen J. The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs. Cephalalgia. 2003;23:877-886.

3. Ashina A, Lassen LH, Bendtsen L, Janssen R, Olesen J. Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial. Lancet. 1999;353:287-289.

CONCLUSION• Although many of the drugs presented here provide effective migraine

relief, they do not approach having the prerequisites of an ideal antimigraine medication.

• With the exception of sodium divalproex and TPM, most of the current prophylactic agents have not been studied in randomized controlled trials with an acceptable number of subjects.

• look forward to a drug, or at least a strategy of treatment, that can act on the glutamatergic-GABAergic transmission imbalance in addition to exerting a modulating effect on the serotonergic system.

CONCLUSION• Although effective, most of the current options for acute therapy do not offer

consistent and fast pain-free endpoints in all patients. • Acting simultaneously in different pathophysiologic mechanisms of a migraine

attack, such as inflammation and "low serotonin," is an attractive goal. In addition, developing a serotonergic agonist devoid of vasoconstrictor effects (ie, no 5-HT1B action) would represent a significant advance, as would an agent that acts on different targets as the CGRP receptor.

• The importance of rational polytherapy is indisputable. • Combining pharmacologic agents with actions on specific, different

neurotransmitter systems and targets is a necessary goal. • As a multifactorial disease, migraine should be managed through multimodal

pharmacotherapy, which currently cannot be provided by a single agent.

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