1. The Dark Side: Pitfalls of therapy Migraine www.pneuro.com
Charles Yanofsky M.D.
PA Neurological Assocs.

2. World prevalence of migraine: A disorder of First World
USA 12%
Chile 7%
Japan 8%
Italy 16%
Denmark 10%
France 8%†
Switzerland 13%
Rasmussen and Olesen (1994); Rasmussen (1995); Lipton et al (1994); Lavados and Tenhamm (1997); Sakai and Igarashi (1997)
†Prevalence measured over a few years
1-year prevalence rates
Population-based studies
IHS criteria (or modified)

3. Prevalence of migraine by sex and age
Migraine prevalence (%)
Females 30
Males 25 20 15 10 5 20 30 40 50 60 70 80
100
Age (years)
The American Migraine Study (n=2479 migraine sufferers)
Lipton and Stewart (1993)

4. 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

5. 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)

6. 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

7. Migraine Pathophysiology
Collusion between trigeminal and afferent tracts and blood vessel reactivity
Goadsby NEJM 346
:257-70,2002

8. Mechanisms for treatment
CGRP NK SP
5-HT1F
5-HT1D
5-HT1B
Blood vessel
Trigeminal nerve
Adapted from Goadsby (1997)
CGRP calcitonin gene related peptide
NK neurokinin A
SP substance P
triptan
CONSTRICTION
INHIBITION

9. 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)

11. 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

12. TRIPTANS Selective 5-HT1B/1D/1F agonists
Silberstein SD. Neurology
As a class, relative to nonspecific therapies, triptans provide
Rapid onset of action
High efficacy
Favorable side effect profile
Triptans, as a class, represent a significant advancement in the therapeutic management of migraine. These agents have been described as receptor-specific agonists toward serotonin or 5-HT receptors. Specifically, they are selective 5-HT1B/1D agonists having the greatest affinity for these receptors. Blockade of 5-HT1 receptors has been shown to result in acute migraine relief.
Triptans, relative to nonspecific therapies, including analgesics and NSAIDs, provide rapid onset of action (between 15 minutes and 1 hour, depending on the formulation), are highly effective in relieving migraine pain symptoms, and have a favorable side effect profile. All agents in this class have proven therapeutic efficacy.
In the majority of patients, the intensity of adverse effects is mild and of short duration. Adverse effects can include chest pressure, flushing, dizziness, drowsiness, and nausea. Patients who are at risk for coronary heart disease, diabetes, obesity, severe uncontrolled hypertension, or hypercholesterolemia should be screened prior to administration of triptans.
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):
Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. Oxford, England: Isis Medical Media; 1998.
Adverse events and contraindications

13. TRIPTANS: TREATMENT CHOICES
Almotriptan
Tablet (6.25, 12.5 mg)
Sumatriptan
Tablet (25, 50, 100 mg)
Injection (6 mg)
Nasal spray (5, 20 mg*)
* Pediatric efficacy shown
Ferrari MD et al. Lancet
Frovatriptan
Tablet (2.5 mg)
Zolmitriptan
Tablet (2.5, 5 mg)
Nasal spray (5 mg)
Eletriptan
Tablet (20, 40 mg)
There are several triptans currently available in the United States. The first is sumatriptan (Imitrex®), which is considered to be the “gold standard” in the class. The oral formulation is available in 25-mg, 50-mg and 100-mg doses. Since its introduction in the early 1990s, over 400 million doses of sumatriptan have been given.
Zolmitriptan (Zomig®), the second product in the triptan class, has a longer half-life than sumatriptan and a more rapid Tmax. It is available as a tablet, orally disintegrating tablet, and as a nasal spray.
Naratriptan (Amerge®) has a longer half-life than sumatriptan, and lower recurrence rate. Naratriptan is considered to have lower efficacy than sumatriptan with minimal adverse events.
Rizatriptan (Maxalt®) has a rapid onset of action and a shorter Tmax of 1 hour compared to oral sumatriptan. This product is available as a tablet and in a dissolvable wafer form.
Almotriptan (Axert®) is available as an oral tablet and has a good adverse event profile.
Frovatriptan (Frova®) is available as a tablet. It, like naratriptan, has a long half-life, low rate of adverse events, and a low recurrence rate.
Eletriptan (Relpax®) will be available as an oral tablet.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):
Worldwide Product Safety and Pharmacovigilance Document. December 1999.
Question and Answer
Naratriptan
Tablet (1, 2.5 mg)
Are there differences between the triptans?
If one triptan fails, will another triptan work?
Rizatriptan
Tablet (5, 10 mg)

16. Individual eletriptan–sumatriptan comparison trials: Headache response at 2 h
Placebo
(n=126)
24%
Mild or no pain
Eletriptan
20 mg
(n=129)
54% *
*P<0.01 vs placebo
†P<0.05 vs sumatriptan
% Patients with response
100 mg
(n=115)
55%
Pain-free
29%
37%
23% 6% * *†
19%
100 80 60 40 20
Study 314
80 mg
(n=118)
77% *†
n=605
40 mg
(n=117)
65% * * *
Sumatriptan
Goadsby et al (2000)

19. 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,

22. Pharmacokinetic parameters for eletriptan and sumatriptan
Eletriptan1,2 Sumatriptan3
Oral absorption (Tmax) Consistent, 1.5 h† Variable, 0.75–5 h
Half-life (t1/2) 5 h 2 h
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)
†Tmax increases to 2.8 h during migraine attacks5
Intersubject variability 37% 60%
Oral bioavailability 50% 14%
Renal clearance 10% 20%
Metabolic pathway P450 MAO4

23. Relpax (Eletriptan) Advantages
Favorable pain free, 1 and 2 hour efficacy vs. Sumatriptan
Longer half life, quick absorption
Peak hrs, T1/2=4 hrs, 50% oral absorption
Cerebro (vs. Cardio) Selective
Avid binder to relevant receptors
Eletriptan (Relpax™)

24. 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

25. 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

31. After Triptans
Refractory Migraine

32. 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

33. Sinus Headache and Tension Headaches are almost always migraine headaches Tension headache pharmacologically is Migraine

34. “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

35. REASONS FOR MISDIAGNOSIS OF MIGRAINE AS TTH OR SINUS
Raskin NH. Headache. 2nd ed. 1988; Barbanti P, et.al. Cephalalgia. 2001;
Kaniecki R. Cephalalgia
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
The pain process is a combination of direct factors, such as activation of the nociceptors of pain-producing intracranial structures combined with reduced function of the endogenous pain-control pathways that normally gate the pain.
Raskin NH. Headache. 2nd ed. New York: Churchill Livingstone; 1988.
Barbanti P, Fabbrini G, Pesare M, Cerbo R. Neurovascular symptoms during migraine attacks. [abstract] Cephalalgia. 2001;21(4):295.
Kaniecki R. Migraine headache exacerbation with sumatriptan injection: a sign of supratherapeutic dosing? [abstract] Cephalalgia. 2001;21(4):413.
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

36. Differential diagnosis of primary headaches
Family history Yes
Sex More females
Onset Variable
Location Usually unilateral in adults
Character/severity Pulsatile Throbbing
Frequency/ 2–72 h/attack
duration 1 attack/year to >8 per month
Associated Visual aura
symptoms Phonophobia Photophobia Pallor Nausea/vomiting
Clinical feature Migraine No
More males
During sleep
Behind/around one eye
Excruciating/ sharp Steady
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
Cluster headache
Yes
More females
Under stress
Bilateral in band around head
Dull Persistent Tightening/pressing
30 min to 7 days
3–4 attacks/week to 1–2 attacks/year
Mild photophobia
Mild phonophobia Anorexia
Tension headache
Dubose et al (1995); Goadsby (1999); Marks and Rapoport (1997)

37. 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

38. 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

39. Chronic Daily HA

40. 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

41. Comorbidities

42. 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)
An attempt to elicit these worrisome features should be part of every new headache evaluation because their presence may signify an underlying pathological condition for which diagnostic testing is obligatory.
Systemic symptoms, such as fever, malaise, or weight loss, should suggest an underlying infectious or systemic inflammatory disorder. Newly acquired neurologic signs or symptoms should always raise concern.
The mode of onset is perhaps the most important characteristic of a headache to be delineated. Those patients who have a sudden or abrupt headache that peaks in seconds or minutes require careful assessment to exclude causes such as subarachnoid hemorrhage (SAH) venous sinus thrombosis, arterial dissection, or raised intracranial pressure.
Any new or progressive headache that begins in middle age or any headache that deviates significantly from a previous pattern should be investigated further.
If these features are addressed, the chance of overlooking a sinister cause for headache are greatly diminished.
Silberstein SD, Lipton RB, Dalessio DJ. Overview, diagnosis, and classification. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain. 7th ed. Oxford, England: Oxford University Press; 2001:20.
Previous headache history: first headache or different (change in attack frequency, severity, or clinical features)

43. 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

44. Children red flags AM headache Posterior Headache
Vomiting without nausea
Papilledema
Focal signs or ataxia
Consider tumor or pseudotumor

45. EVALUATION STRATEGIES
“Investigate
the
Atypical
and the
Laboratory testing is not routinely needed in the evaluation of a headache patient. The necessity for and extent to which laboratory tests are obtained will be determined by the clinical suspicion of a secondary headache disorder, for example, temporal arteritis. A practical suggestion in this setting is to appropriately investigate the atypical, as well as the red flags.
Occasionally, depending on the medications prescribed, a pertinent screening baseline laboratory assessment may be necessary, for example, divalproex sodium.
Evans RE, Rozen TD, Adelman JU. Neuroimaging and other diagnostic testing in headache. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain. 7th ed. New York: Oxford University Press; 2001:27-49.
Campbell JK, Sakai F. Diagnosis and differential diagnosis. In: Olesen J, Tfelt-Hansen P, Welch KMA. The Headaches. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:
Red Flags”

46. SUDDEN ONSET HEADACHE Primary Secondary
Idiopathic thunderclap headache (TCH)
Exertional headache
Cough headache
Sexual headache
deBruijn, SF, et al. Lancet. 1996; Lancet
SAH
Pituitary apoplexy
Venous sinus thrombosis
Arterial dissection
Meningoencephalitis
Acute hydrocephalus
Acute hypertension
Spontaneous intracranial hypotension
Although a number of primary headache syndromes exist that can present with sudden, severe headache, many underlying diseases that can be clinically indistinguishable from benign thunderclap headache (TCH) to SAH also occur. These include:
Venous sinus thrombosis
Pituitary apoplexy
Arterial dissection
Meningoencephalitis
Acute hydrocephalus
Acute hypertension
Some of these conditions may be very difficult to detect on CT scan, which underscores the need for MRI in patients with bloodless CT and CSF who present with a sudden-onset severe headache.
de Bruijn SF, Stam J, Kappelle LJ. For the Cerebral Venous Sinus Thrombosis Study Group. Thunderclap headache as first symptom of cerebral venous sinus thrombosis. Lancet.1996;348(9042):
de Bruijn SF, Stam J, Vandenbroucke JP. For the Cerebral Venous Sinus Thrombosis Study Group. Increased risk of cerebral venous sinus thrombosis with third-generation oral contraceptives. Lancet. 1998;351(9113):1404.

47. But the vast majority of these headaches turn out to be migraines!!

48. LUMBAR PUNCTURE The first unusually severe headache
Evans RE, Rozen TD, Adelman JU. In: Wolff’s Headache And Other Head Pain
Thunderclap headache with negative CT head
Subacute progressive headache
Headache associated with fever, confusion, meningism, or seizures
Although no formal guidelines exist on the use of lumbar puncture as a diagnostic test in headache, lumbar puncture is critical in a number of situations. Unless a patient is suspected of having an SAH, meningoencephalitis, or a high or low pressure syndrome, a lumbar puncture is unnecessary during a headache.
Nonetheless, patients who present with thunderclap headache or their first unusually severe headache should always be considered as having an acute neurologic event, even though a variety of benign headaches may present in this fashion. If the initial CT is negative, a lumbar puncture must be performed in this situation.
Patients with a subacute and progressive headache syndrome should have a lumbar puncture to exclude other disease conditions, including infections (fungal, Lyme), inflammation (vasculitis), or neoplasms (carcinomatous leptomeningeal disease).
Lumbar puncture is crucial in any patient suspected of having an acute intracranial infection, as well as in patients suspected of having raised or low intracranial pressure.
In patients suspected of having pseudotumor, a lumbar puncture should be performed, even in the absence of papilledema, since idiopathic intracranial hypertension has been well described in patients with normal fundoscopic examinations.
Evans RE, Rozen TD, Adelman JU. Neuroimaging and other diagnostic testing in headache. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain. 7th ed. New York: Oxford University Press; 2001:27-49.
High or low CSF pressure suspected (even if papilledema is absent)

49. 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
Although CT scans are very sensitive, with 92% to 95% probability in detecting acute SAH if performed within 24 hours after ictus, blood rapidly clears from the subarachnoid space. The sensitivity of CT scanning decreases to 80% at 3 days, 58% to 85% at 5 days, 50% at 1 week and 30% at 2 weeks. At 3 weeks after the hemorrhage, the CT scan will be negative.
Kassell NF, Torner JC, Haley EC Jr, et al. The International Cooperative Study on the timing of aneurysm surgery. Part 1: Overall management results. J Neurosurg. 1990;73(1):18-36.
van Gijn J, van Dongen KJ. The time course of aneurysmal haemorrhage on computed tomograms. Neuroradiology. 1982;23(3):
van Gijn J, van Dongen KJ. Neuroradiology
Kassell NF et al. J Neurosurg

50. Headache Crisis Rule out serious Cause DHE + Reglan i.v.
Toradol i.v. + Reglan
Depacon™ i.v mg.
Decadron
Morphine infusion
Consider outpatient Actiq™-saves trip to ER
Dependence

51. Medication Impersistence
Treatment

52. 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

53. 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

54. 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

55. 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

56. 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™

57. Our Armamentarium expands

58. Botox (from B. Todd Troost, m.d.)

59. Conquering Headache

60. That’s the Tale of the Comet
Fini