Migraine
The Dark Side:
Pitfalls of therapy
www.pneuro.com
Charles Yanofsky M.D.
PA Neurological Assocs.
World prevalence of migraine:
A disorder of First
World
Switzerland 13%
Denmark 10%
France 8%†
USA 12%
Italy 16%
Chile 7%
†Prevalence measured over a few years
Japan 8%
 1-year prevalence rates
 Population-based studies
 IHS criteria (or modified)
Rasmussen and Olesen (1994); Rasmussen (1995);
Lipton et al (1994); Lavados and Tenhamm (1997);
Sakai and Igarashi (1997)
Prevalence of migraine by
sex and age
Migraine prevalence (%)
30
Females
Males
25
20
15
10
5
0
20
30
40
50
60
Age (years)
70
The American Migraine Study (n=2479 migraine sufferers)
80
100
Lipton and Stewart (1993)
How Common is Migraine?
30,000,000 Americans
20% of women
7% of men at any given time
Most of us have some migraine
manifestations occasionally
Diagnosis of migraine
Diagnosis depends on patient history
No specific tests or clinical markers for migraine
Positive diagnosis if attack history fulfils IHS
criteria for migraine
Other pointers include:
–
–
–
–
family history of migraine
age of onset <45
presence of aura
menstrual association
Organic disease must be excluded
Cady (1999); Warshaw et al (1998)
Migraine Without Aura
Diagnostic Criteria
– A. At least 5 attacks fulfilling criteria B-D
– B. HA attacks lasting 4-72 hours
– C. HA has at least 2 of following:
1. Unilateral location
2. pulsatile quality
3. moderate to severe pain
4. aggravation by routine physical activity
– D. During attack at least one of foll’g
1. Nausea and/or vomitting
2. photophobia and/or phonophobia
Migraine Pathophysiology
Goadsby NEJM 346
:257-70,2002
Mechanisms for treatment
Trigeminal
nerve
INHIBITION
5-HT1D
5-HT1F
CGRP triptan
NK
SP
CGRP
calcitonin gene
related peptide
NK
neurokinin A
SP
substance P
CONSTRICTION
5-HT1B
Blood vessel
Adapted from Goadsby (1997)
What is Central Sensitization?
Central Sensitization is a time-dependent
physiological event
During a migraine attack, neuronal
pathways become sensitized in stages
– Peripheral neurons are activated early in the
attack (mild pain phase throbbing)
– Central neurons are activated later in the
attack (full-blown migraine)
Triptans
Major Advance in treatment of migraines
Useful for Occasional Highly paroxysmal
headaches
Oral administration: Newer agents may be
more effective than Imitrex (sumatriptan)
Imitrex: Nasal and SQ form available
Triptans: Partial answer
serotonin
TRIPTANS
Selective 5-HT1B/1D/1F agonists
As a class, relative to nonspecific therapies,
triptans provide
 Rapid
onset of action
 High efficacy
 Favorable side effect profile
Adverse events and contraindications
Silberstein SD. Neurology. 2000.
TRIPTANS:
TREATMENT CHOICES
Almotriptan
Sumatriptan



Tablet
Tablet (25, 50, 100 mg)
Injection (6 mg)
Nasal spray (5, 20 mg*)
Frovatriptan
Tablet


Tablet (1, 2.5 mg)
Rizatriptan

Tablet
Tablet (2.5, 5 mg)
Nasal spray (5 mg)
Naratriptan
Tablet (5, 10 mg)
* Pediatric efficacy shown
(2.5 mg)
Eletriptan
Zolmitriptan

(6.25, 12.5 mg)
(20, 40 mg)
Question and Answer

Are there differences
between the triptans?

If one triptan fails, will
another triptan work?
Ferrari MD et al. Lancet. 2001.
Eletriptan: Key Clinical Trials
Double-blind, Placebo-controlled, Randomized Trials
Phase II/III/III-b
clinical program
8 trials; N=8105
Placebo
8 trials; n=1508
25 mg
1 trial;
n=180
50 mg
2 trials;
n=362
Sumatriptan
4 trials; n=1690
100 mg
3 trials;
n=1148
Eletriptan
8 trials; n=4704
20 mg
2 trials;
n=434
40 mg
8 trials;
n=2797
Cafergot®
1 trial; n=203
80 mg
6 trials;
n=1473
The maximum recommended single dose of eletriptan is 40 mg.
Data on file. Pfizer Inc., New York, NY.
Efficacy of Eletriptan:
Comprehensive Relief at 2 Hours
Placebo
Sumatriptan 100 mg
Eletriptan 40 mg
Headache response, %
80
*†
60 *
Pain-free response, %
*†
40
Relief of Nausea, %
40
*
30
†
* * 80
20
20
10
0
40
20
60
20 20
40
Relief of Photophobia, %
*†
* 60
80
40
60
*
*†
Relief of Phonophobia, %
80
Sumatriptan was blinded using encapsulation. Encapsulated sumatriptan was bioequivalent to commercial tablets.
*P<.001 vs placebo. †P<.05 vs sumatriptan.
Adapted from Mathew et al. Headache. 2003.
Individual eletriptan–sumatriptan comparison trials:
Headache response at 2 h
Mild or no pain
% Patients with response
100
Study 314
80
n=605
60
Pain-free
*
65%
*†
77%
*
55%
*
54%
*
23%
*
19%
*
29%
*†
37%
100 mg
(n=115)
20 mg
(n=129)
40 mg
(n=117)
80 mg
(n=118)
40
24%
20
0
6%
Placebo
(n=126)
*P<0.01 vs placebo
†P<0.05 vs sumatriptan
Sumatriptan
Eletriptan
Goadsby et al (2000)
Elitriptan in Pts poorly tolerance or
response to Sumatriptan
446 pts, 40 or 80 mg v placebo
2 hr ha response up to 70% for 80mg,
59% for 40 mg
2 hr pain free 35% E40, 42% E80
Farkkila et al, Cephalalgia 2003,23,463-471
Incidence of Adverse Events*
Placebo
20 mg
Eletriptan
40 mg
80 mg
(n=988)
(n=431)
(n=1774)
(n=1932)
Asthenia
3%
4%
5%
10%
Nausea
5%
4%
5%
8%
Somnolence
4%
3%
6%
7%
Dizziness
3%
3%
6%
7%
Headache
3%
4%
3%
4%
Paresthesia
2%
3%
3%
4%
Dry mouth
2%
2%
3%
4%
Chest tightness/pain/pressure
1%
1%
2%
4%
*Events experienced by 2% of patients. Incidence following a single dose of study medication.
The maximum recommended single dose of eletriptan is 40 mg.
Relpax® (eletriptan HBr) Prescribing Information. Data on file. Pfizer Inc., New York, NY.
Eletriptan Dosing and Administration
• RELPAX should be taken at the onset of a migraine
headache.
• RELPAX can be taken with or without food.
• RELPAX should not be used within at least 72 hours
of treatment with the following potent CYP3A4
inhibitors: ketoconazole, itraconazole, nefazodone,
troleandomycin, clarithromycin, ritonavir and
nelfinavir.
• Studies have shown that the pharmacokinetics of
eletriptan are generally unaffected by age, gender, or
menstrual cycle.
Relpax® (eletriptan HBr) Prescribing Information. Pfizer Inc., New York, NY.
Pharmacokinetic parameters for
eletriptan and sumatriptan
Eletriptan1,2
Sumatriptan3
Consistent, 1.5 h†
Variable, 0.75–5 h
Half-life (t1/2)
5h
2h
Intersubject variability
37%
60%
Oral bioavailability
50%
14%
Renal clearance
10%
20%
Metabolic pathway
P450
MAO4
Oral absorption (Tmax)
†T
max
increases to 2.8 h during migraine attacks5
1 Milton et al (1997)
2 Pfizer data on file
3 Lacey et al (1995)
4 Dixon et al (1994)
5 Johnson et al (1997)
Relpax (Eletriptan) Advantages
Favorable pain free, 1
and 2 hour efficacy
vs. Sumatriptan
Longer half life, quick
absorption
– Peak 1.5-2 hrs, T1/2=4
hrs, 50% oral
absorption
Cerebro (vs. Cardio)
Selective
– Avid binder to relevant
receptors
Eletriptan (Relpax™)
Relpax Cautions
Available only in oral form
CYP 3A4
– Do not give within 72 hours of: Ketoconazole,
Nefazadone, clarithromycin, rotonavir, nelfinavir,
others. caution with verapamil, erythromycin.
Contraindications (all triptans)
–
–
–
–
–
–
Suspected Coronary disease
Basilar or hemiplegic, ophthalmoplegic migraine
Uncontrolled hypertension
<18 or >65
Within a day of any other triptan
Hypersensitivity to the drug
Relpax Dosing
40 mg. May repeat X1 in 2 hours
Max dose in 24 hours is 80 mg
Repeating dose most efficacious if
headache returns
After Triptans
Refractory Migraine
Why we fail (and what to do about
it)
Misdiagnosis – exclusion, inclusion
Unrealistic expectations
Chronic Daily headache and rebound
Logic and Persistence
Ignoring psychological factors
Missing Red Flags
Sinus Headache and Tension
Headaches are almost always
migraine headaches
Tension headache
pharmacologically is Migraine
“Sinus” Headache Fallacy
Paroxysmal headaches are migraine until
proved otherwise.
Most “Sinus headaches” are migraines
Sinus headaches are rare in comparison to
migraine.
Patients commonly present years or decades
after failed treatment for sinus headaches
ENT’s among our most frequent referrers for
head pain
REASONS FOR
MISDIAGNOSIS OF MIGRAINE
Sinus AS TTH OR SINUS
Migraine is a referred pain syndrome (V1, C1-C3)
Up to 50% of migraine patients report their headaches are
influenced by weather
45% of migraine patients report attack related ‘sinus’ symptoms
including lacrimation, rhinorrhea, nasal congestion
Tension-Type Headache
75% of migraine patients report posterior neck pain/tightness/stiffness
during attacks
Stress/anxiety frequent migraine trigger
Migraine is bilateral in up to 40% of patients
Raskin NH. Headache. 2nd ed. 1988; Barbanti P, et.al. Cephalalgia. 2001;
Kaniecki R. Cephalalgia. 2001.
Differential diagnosis of
primary headaches
Clinical feature
Migraine
Cluster headache
Tension headache
Family history
Yes
No
Yes
Sex
More females
More males
More females
Onset
Variable
During sleep
Under stress
Location
Usually unilateral
in adults
Behind/around
one eye
Bilateral in band
around head
Character/severity
Pulsatile
Throbbing
Excruciating/
sharp
Steady
Dull
Persistent Tightening/pressing
Frequency/
duration
Associated
symptoms
2–72 h/attack
1 attack/year to
>8 per month
Visual aura
Phonophobia
Photophobia
Pallor
Nausea/vomiting
15–90 min/attack
1–8 attacks/day
for 3–16 weeks
1–2 bouts/year
Sweating
Facial flushing
Nasal congestion
Ptosis
Lacrimation
Conjunctival injection
Pupillary changes
30 min to 7 days
3–4 attacks/week
to 1–2 attacks/year
Mild photophobia
Mild phonophobia
Anorexia
Dubose et al (1995); Goadsby (1999); Marks and Rapoport (1997)
Expectations
Two thirds of patients will have a 50% reduction
of headaches
Migraine is a Chronic Disease
No Preventive therapy will eliminate all
headaches
Patients should expect “breakthrough headache”
Give patient some means of escape
You can’t kill every headache with medicine
“Rules of the game” have to be explained
Morphed Migraine
Conversion from headache attacks to
chronic headache.
Paroxysmal headache becomes chronic
headache
Patients describe multiple headache types
– All of them are migraine variants
Migraine natural history:
– Asthma becomes COPD
– RR MS becomes secondary progressive MS
Chronic Daily HA
Treating Morphed Migraine
Cut prn meds
– Tough to convince pts to give up prn meds
Emphasize preventive meds
Treat psychosocial comorbidities
– Psychotherapy, counseling
– Medicine
Ancillary modalities
– Relaxation, biofeedback, exercise, healthtful
habits
Comorbidities
WORRISOME HEADACHE RED
FLAGS
“SNOOP”
Systemic symptoms (fever, weight loss) or
Secondary risk factors (HIV, systemic cancer)
Neurologic symptoms or abnormal signs (confusion,
impaired alertness, or consciousness)
Onset: sudden, abrupt, or split-second
Older: new onset and progressive headache, especially
in middle-age >50 (giant cell arteritis)
Previous headache history: first headache or different
(change in attack frequency, severity, or clinical features)
Headache “Red Flags”
First or worst headache
Significant change from previous headache
pattern
New onset headache in middle age or later
New progressive headache lasting for days
Precipitation by cough, sneeze, bending down
Systemic symptoms: fever, myalgia, malaise, wt
loss, scalp tenderness, jaw claudication
Focal symptoms or altered sensorium, seizures
Pryce-Phillips et al, 1997
Children red flags
AM headache
Posterior Headache
Vomiting without nausea
Papilledema
Focal signs or ataxia
Consider tumor or pseudotumor
EVALUATION STRATEGIES
“Investigate
the
Atypical
and the
Red Flags”
SUDDEN ONSET HEADACHE
Primary
Idiopathic thunderclap
headache (TCH)
Sexual headache
Exertional headache
Cough headache
Secondary
SAH
Venous sinus thrombosis
Pituitary apoplexy
Arterial dissection
Meningoencephalitis
Acute hydrocephalus
Acute hypertension
deBruijn, SF, et al. Lancet. 1996; Lancet. 1998.
Spontaneous intracranial
hypotension
But the vast majority of these
headaches turn out to be
migraines!!
LUMBAR PUNCTURE
The first unusually severe headache
Thunderclap headache with negative CT head
Subacute progressive headache
Headache associated with fever, confusion,
meningism, or seizures
High or low CSF pressure suspected (even if
papilledema is absent)
Evans RE, Rozen TD, Adelman JU. In: Wolff’s Headache And Other Head
Pain. 2001.
SENSITIVITY OF CT SCAN IN
SUBARACHNOID HEMORRHAGE
(SAH)
TIME AFTER
HEADACHE
ONSET
PROBABILITY
(%)
DAY 0
95
DAY 3
80
1 WEEK
50
2 WEEKS
30
3 WEEKS
~0
van Gijn J, van Dongen KJ. Neuroradiology. 1982.
Kassell NF et al. J Neurosurg. 1990.
Headache Crisis
Rule out serious Cause
DHE + Reglan i.v.
Toradol i.v. + Reglan
Depacon™ i.v. 1000 mg.
Decadron
Morphine infusion
Consider outpatient Actiq™-saves trip to ER
– Dependence
Medication Impersistence
Treatment
Changing Meds
Most preventives req’r 1-2 month trial
Long lists of meds
Inadequate trial
Inadequate dosage
“I want relief now!!”
2 headache (for PRN’s), 2 month (for
prophylaxis) rule
Inadequate trials
Pick a medication
– Good track record Type IA evidence
– Treat comorbidities
Sleep disturbance
Depression
Hypertension
Use it long enough for reasonable trial
– 2 months – No medicine works immediately
– Headache calendar
– Give patient an “out’ for breakthru headache
Ignoring psychological factors
Underlying migraine diathesis (history)
Very frequent gnawing headache or
Screamingly urgent headache frequently
State of being overwhelmed
Sub-optimal life strategies
– Ennui vs. pointless moto-perpetuo pattern
When Ψ paramount
Don’t abandon patient
Give her an “out”
Continue to treat headaches
Get Help!!
Don’t just keep trying medicines and throwing
SSRI’s at patient
“Therapy” in guise in non-drug treatment
– Exercise, getting away, regularization of sleep, diet,
Counseling
Surprisingly, some few patients respond
dramatically, sadly, most don’t
HA prophylaxis
Anti-convulsants are “in”
– Topamax, Depakote ER and i.v., Zonegran,
Neurontin, Keppra
Tricyclics, not SSRI’s for headache and
sleep, depression comorbidity
ACE inhibitors: Prinivil™, Atacand™
Botox™, Myobloc™
Our Armamentarium expands
Botox (from B. Todd Troost, m.d.)
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