This document provides an overview of evaluating and treating migraines through a case study of a patient named Peter. It begins by introducing Peter and categorizing his headaches as migraines without aura based on the diagnostic criteria. It then discusses differentiating between primary and secondary headaches, classifying primary headaches, and diagnosing the specific disorder. The document outlines considerations for developing a treatment plan, including non-pharmacological and pharmacological acute and preventive options. It emphasizes the importance of individualizing treatment based on a patient's needs and goals of therapy.

1. The Art and Science
of Evaluating and
Treating Migraine
Ryan J Punambolam MD, FRCPC
Neurology
Abbotsford Regional Hospital
!
!
Medicine Grand Rounds
April 9, 2014.

2. Disclosure
Advisory Board or
Similar Committee
None
Clinical Trials or
Studies
None
Honoraria or Other
Fees
Bayer, Sanofi-Aventis, Allergan, Tribute
Phamaceuticals
Research Grants No conflicts

3. Migraine
Backgrounder
The Art and Science of Evaluating and Treating Migraine

4. Case Vignette (Peter)
Initial Consult • 25-year-old obese (BMI=35) man who
presents to his primary care doctor with a
four year history of headache
Frequency • Two attacks per month
Prodrome • Dysphoric mood
Aura • Zig-zag lines and a graying of vision in a
visual field
Pain • Unilateral (R>L) throbbing severe pain
lasting 24 hours untreated
Symptoms • Nausea, photophobia, unable to function
Treatment • Excedrin Migraine up to six per day
Exam • WNL (within normal limits)
Diagnosis • ?

5. Primary or Secondary Headache?
Detailed History and Examination
No
Yes
Any
unusualfeatures?
Evaluate for Secondary Headache
Red Flags? Diagnose Primary
Headache Disorder
Step 1

6. S Systemic signs or symptoms Fever, weight loss, malignancy,
HIV, meningismus, pregnancy
N Neurologic signs or symptoms Papilledema, hemiparesis, hemi-
sensory loss, diplopia, dysarthria
O Onset “Worst headache of
life” (thunderclap)
O Older New headache at age ≥50
P Progression of existing
headache disorder
Change in quality, frequency, or
location
13. Dodick DW. Adv Stud Med 2003;3:S550-S555.
Red Flags in Headache: “SNOOP”

8. Peter has a Primary Headache Disorder
• Peter has no headache alarms
• Four year history, lack of alarms and
normal exam, additional work-up is not
necessary
Categorize Primary Headache Disorder
Step 2

9. Divide into headache syndromes
Short Duration
< 4hr duration
Recurrent
(Long Duration)
≥ 4hr duration
≤ 15 days/month
Chronic Daily
Headache
≥ 4hr duration
≥ 15 days/month
1 2 3
Categorize Into One of Three Groups
Primary Headaches
Assess frequency and duration for each
headache type
Step 2

10. Diagnose the Specific Disorder
Within the Category
Differential Diagnosis
Step 3
te example of inherited migraine
on of missense mutations in the
he gene for the P/Q type, voltage
nel on chromosome 19 in families
legic migraine.w1
Since then, other
miplegic migraine have been found
ations in the ATP1A2 gene, which
unit of the Na+
/K+
pump,w2
and in
for the neuronal voltage-gated
age is of migraine as an ionopathy,
n abnormal ion channels whose
nd anatomical distribution in the
clinical phenotype. If genetics can
have headaches and what the bio-
may be, then we can ask the
the problem?” or, framed in the
rology, “Where is the lesion?”
y of headache—where is
s promulgated by Gowers, sought
cal answers to clinical questions.
een successful, but the problems of
e will need a physiological
ome extent, human functional
this.
d ’70s migraine was considered a
on and is still often referred to
cular headache. Wolff summarised
the referral patterns of structures
on ≥ 15 days a month for more than six months,3
the
same area of the dorsolateral pons is activated,16
suggesting that infrequent and frequent migraine are
ends of a shared spectrum. Use of blood oxygen level
dependent (BOLD) contrast functional magnetic reso-
nance imaging holds the promise of studying single
patients and determining the site of abnormal
activation.w7
Moreover, magnetic resonance angiogra-
phy has shown that the blood flow changes seen in
migraine14
and cluster headache10
are simply a result of
ophthalmic division pain,17 18
not a cause of the
syndrome.
Table 1 Differentiating migraine from tension-type headache
Characteristics Migraine Tension-type headache
Pain features
of acute
attacks
Throbbing Boring or squashing
Unilateral Bilateral
Worsening of pain with
movement
No effect of head
movement
Associated
features
Nausea or vomiting None
Photophobia and phonophobia
Triggering
factors
Altered sleep patterns (too little
or too much)
Psychological stress
Skipping meals
Overexertion
Change in stress level (too much
or relaxation)
Excess afferent stimuli (such as
bright lights)
Weather change
Chemical (delayed headache after
alcohol or glyceryl trinitrate)
Menstruation
27NUARY 2006 bmj.com

11. Peter has Migraine without Aura
Migraine without Aura:
"
A. At least five attacks fulfilling criteria B-D
B. Headache attacks lasting 4-72 hr
C. Headache has ≥2 of the following characteristics:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by or causing avoidance of routine physical activity (e.g.,
walking, climbing stairs)
D. During headache ≥1 of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
E. Not attributed to another disorder
22. International Headache Society,2nd edition. Cephalalgia 2004;24 Suppl 1:1-160.
24. Kriegler JS. In: Tepper SJ and Tepper DE, eds. The Cleveland Clinic Manual of Headache Therapy (New York, NY: Springer), 2011.

12. Three-Item ID Migraine Screener *
During the last three months, did you have any of the following
with your headaches:
"
28. Lipton RB et al. Neurology 2003;61(3):375–382.
* An affirmative response on 2 of 3 questions yields a sensitivity and specificity of 81% and 75%,
respectively.
Item Yes / No
""
You felt nauseated or sick to your stomach when you had a
headache?
Yes □ No □
Light bothered you (a lot more than when you don’t have
headaches?)
Yes □ No □
Your headaches limited your ability to work, study or do
what you need to do for at least one day?
Yes □ No □

13. Migraine: A Common Episodic Headache
Disorder
Neurologic disorder
• Strong genetic component (up to 50%)
"
Global prevalence in women: >10%
• Women: 15%–17%
• Men: 6%–9%
"
Two major subtypes
• Without aura (~75%)
• With aura (~25%)
"
Burden
• Among the world’s 20 most disabling diseases (WHO)
• Affects 3 million women and 1 million men in Canada
➢An Angus Reid poll suggests that the cost of migraine in the workplace is
approximately $500 million annually
"35. Pietrobon D. Neuroscientist. 2005;11(4):373–386. 41. Stovner LJ et al. Cephalalgia. 2007;27(3):193–210. 26. Linde M. Acta Neurol Scand. 2006;114(2):
71–83. 22. ICHD. Cephalalgia. 2004;24 Suppl 1:1-160. 24. Kriegler JS. In: Tepper SJ and Tepper DE, eds. The Cleveland Clinic Manual of
Headache Therapy. (New York, NY: Springer), 2011. 20. Hu XH. et al Arch Intern Med. 1999;159(8):813–818.

14. Pain Pathways in the Head
18. Goadsby PJ. et al. J Clin Neurosci 2000 Jul; 7(4):377.

15. Peter also has “Classic Migraine”
Migraine with Aura"
"
"

16. Prevalence of Migraine and
Tension-type Headache in Various Settings
0
20
40
60
80
Population Waiting Room
16
40
75
12
Migraine Tension-Type Headache
"28. Lipton RB et al. Neurology 2003;61(3):375–382.
Percent

17. Migraine is Often Misdiagnosed
27. Lipton RB et al. Headache 2001; 41(7):638-645.
† Inaccurate diagnosis received by migraine patients
Tension-type
Headaches
Sinus
Headaches
Cluster
Headaches
% MISDIAGNOSIS†
44%
43%
18%

18. Why is Migraine Frequently Mistaken
for Sinus Headache?
• Pain is often located over
the sinuses
• Migraine is frequently
triggered by weather
changes
• Tearing and nasal
congestion are common
during attacks
• Sinus medication may help
migraine

19. Planning and Management
Strategies
The Art and Science of Evaluating and Treating Migraine
Step 4

20. What might be your preliminary
treatment recommendation for Peter?
Back to Peter…

22. Formulate a Specific Treatment Plan
Non-pharmacologic approaches
• Trigger identification and management
➢Identify triggers by history
➢Headache diaries
• Education and enhance self-efficacy
• Biofeedback and cognitive behavioural treatment
Specific Treatment Plan
Step 4

24. Principles of Acute Treatments
• Stratified care
"
• Early intervention
"
• Use correct dose and formulation
"
• Treat at least two or three attacks before judging acute
medications
"
• Use a maximum of 2-3 days / week
"
• Use preventive therapy in selected patients
38. Silberstein SD. Neurology 2000; Sep 26;55(6):754-62.
32. Lipton RB, et al. JAMA 2000;284(20):2599-2605.

25. Goals of Migraine Treatment
Terminate the attack without
increasing the risk for
subsequent attacks
• Address the potential peripheral and central
mechanisms of migraine pathogenesis
• Initiate treatment early to reduce risk of central
sensitization
• Reduce the risks of long-lasting latent central
sensitization and progression to chronic migraine
Consider the clinical aspects
• Rapid onset of analgesic effect with low rate of
recurrence
• Minimal interaction with other migraine treatments
• Significant efficacy across multiple end points
Address patient"
considerations
• Well-tolerated adverse event (AE) profile
• Improved function
• Convenient and flexible administration
34. Matchar DB, et al. Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management of Acute Attacks. http://www.aan.com/professionals/practice/pdfs/
gl0087.pdf 6. Brandes JL, et al. JAMA. 2007;297(13):1443-1454. 4. Bigal ME, et al. Headache. 2008;48(8):1157-1168. 40. Silberstein SD and Ruoff G. Postgrad Med. 2006 April;Spec No:20-6. 9.
CAMBIA Product Monograph. Tribute Pharmaceuticals Canada Ltd. March 9, 2012. 12. Diener HC, et al. Cephalalgia. 2006;26(5):537-547.
29. Lipton RB, et al. Cephalalgia. 2010;30(11):1336-1345.

26. Acute Pharmacotherapy:
What Do Patients Want?
Patients Rating Attribute as
Important or Very Important (%)
78 80 83 85 87
87
86
83
79
30. Lipton RB, Stewart WF. Headache 1999;39(Suppl 2):S20-S26.
No Side
Effects
Rapid
Relief
No
Recurrence
Complete
Relief
Treatment Attributes
Patients Choosing Route of
Administration as 1st Choice (%)
0 20 40 60 80
2.6
73
15
8.3
Nasal
Spray
Rapidly
Dissolving Tablet
Tablet or
Capsule
SC Injection
Route of Administration

27. Medication Classes
in Migraine Treatment
24. Kriegler JS. In: Tepper SJ and Tepper DE, eds. The Cleveland Clinic Manual of Headache Therapy. (New York, NY: Springer), 2011.
9. CAMBIA Product Monograph. Tribute Pharmaceuticals Canada Ltd. March 9, 2012.

28. Goals of Acute Migraine Therapy
Restore the patient’s ability to function normally by:
"
• Rapidly and consistently alleviating pain and the
associated symptoms of nausea and vomiting
• Remaining pain – free for 24 hours
• Minimal or no adverse events
16. Gladstone J and Dodick DW. Practical Neurology 2004;4:6-19.

29. SO … Ask About
Headache-related Disability
"
• Missed work/school (absenteeism)
• Unproductive work (presenteeism)
• Cancelled/missed family events
• Need to cancel/miss social/recreational events
• Inability to do house hold chores

30. Considerations in Treating
Early in the Attack
39. Silberstein SD et al. Wolff’s Headache And Other Head Pain, Seventh Edition (New York: Oxford University Press Inc), 2001.
ADVANTAGES • May prevent disability
• May reduce headache recurrence and decrease
number of doses used per attack
• May prevent sensitization and allodynia
DISADVANTAGES • Treating early pain may lead to over treatment
• To avoid overuse: limit use of acute treatment to
no more than three days/week

31. Follow-up Visits
39. Silberstein SD et al. Wolff’s Headache And Other Head Pain, Seventh Edition (New York: Oxford University Press Inc), 2001 .
Review outcome measures (diaries, MIDAS, etc.)
Assess efficacy, adverse effects, and satisfaction with current regimen
If treatment is not working, find out why?
Consider:
"
•Primary failure
•Effects take to long
•Poor consistency
•Recurrence
"
•Adverse events
•Interfering medications
•Expectations unrealistically high

32. Case Vignette Continued
• Peter was started on sumatriptan 50 mg po
"
• Returned to his PCP saying that the
treatment “does not work”
Now What?

33. “It Doesn’t Work”
Primary failure • Treat earlier" " "
• Increase the dose" " "
• Switch drug or route
Effect takes too long or poor consistency • Treat earlier"
• Increase the dose"
• Switch drug or route"
• Add adjunctive therapy
Recurrence • Treat earlier"
• Switch to a low recurrence drug"
• Increase the dose"
• Add adjunctive therapy
Adverse events • Treat earlier"
• Lower the dose"
• Switch drug or route
Interfering medication • Limit frequency of use of medication"
• Consider using preventatives

34. For Peter
"
• Acute treatment inconsistent because he
was treated late
• Peter lapsed from medical care
• He has risk for progression
"
Instead:
"
✓ Earlier treatment should have been provided
✓ Switch triptans or switch to a different class
of medication
✓ Avoid medication overuse

36. Treatment Options
In Migraine
The Art and Science of Evaluating and Treating Migraine

37. MILD: NSAIDS +/- METOCLOPRAMIDE
MOD-SEVERE: TRIPTANS +/- NSAIDS

39. riptan
linical
prefer
erence
both.
. It is
ts are
riptan
vidual
he one
o have
extent
ore be
of pain
dache
tential
l be to
* Adapted from: Bandolier (http://www.medicine.ox.ac.uk/bandolier)
except as noted; ** Note: Migraine attacks were treated at moderate or
severe intensity. NNTs may be lower for individual drugs when treat-
Drug and dosage Route NNT (for 2-h pain-free
vs. placebo)**
Sumatriptan 6 mg subcutaneous 2.3158
Sumatriptan 20 mg intranasal 4.7159
Zolmitriptan 5 mg intranasal 4.631
Almotriptan 12.5 oral 4.3160
Eletriptan 20 mg oral 10
Eletriptan 40 mg oral 4.5
Frovatriptan 2.5 mg oral 8.5161
Naratriptan 2.5 mg oral 8.2
Rizatriptan 10 mg oral 3.1
Sumatriptan 50 mg oral 6.1162
Sumatriptan 100 mg oral 4.7162
Zolmitriptan 2.5 mg oral 5.9
Migraine attacks were treated at moderate or severe intensity. NNTs may be lower for individual
Table 7: Triptans – Number Needed to Treat (NNT) for pain-
free response at 2 h in migraine*31,158-162

40. Pain Pathways in the Head
18. Goadsby PJ. et al. J Clin Neurosci 2000 Jul; 7(4):377.

41. Treatment of Migraine: Triptans
24. Kriegler JS. In: Tepper SJ and Tepper DE, eds. The Cleveland Clinic Manual of Headache Therapy. (New York, NY: Springer), 2011.

42. Triptans: Summary
Triptans are:
• Effective in many patients
• Generally safe and well tolerated
➢Small vascular liability in terms of coronary and cerebral
ischemia
However, there is still a need for
additional treatment options

43. Are all NSAIDs Created Equal?
• Varying degrees of efficacy were seen with aspirin, ibuprofen, naproxen, and tolfenamic acid for the treatment of
migraine24
• Two Phase III studies support diclofenac potassium for oral solution for acute treatment of episodic migraine 12, 29
9. CAMBIA Product Monograph. Tribute Pharmaceuticals Canada Ltd. March 9, 2012 . 24. Kriegler JS. In: Tepper SJ and Tepper DE, eds. The Cleveland Clinic Manual of
Headache Therapy. (New York, NY: Springer), 2011. 23. Kahn K. US Neurology. 2011;7(2):139-143.
12.Diener HC, et al. Cephalalgia. 2006;26(5):537-547. 29. Lipton RB, et al. Cephalalgia. 2010;30(11):1336-1345.

44. Pathophysiologic Consequence:
Gastroparesis
25. Krymchantowski AV, et al. Cephalalgia. 2006;26(7):871-874. 2. Aurora SK, et al. Headache. 2006;46(1):57-63. 3. Aurora S, et al. Headache. 2007;47(10):1443-1446. 5.
Boyle R, et al. Br J Clin Pharmacol. 1990;30(3):405-409. 46. Thomsen LL, et al. Cephalalgia. 1996;16(4):270-275. 48. Volans GN. Br J Clin Pharmacol. 1975;2(1):57-63. 47.
Tokola RA and Neuvonen PJ. Br J Clin Pharmacol. 1984;18(6):867-871. 43. Tfelt-Hansen P. Headache. 2007;47(6):929-930.
Gastroparesis is an important pathophysiological consequence
of migraine that may intensify symptoms such as headache,
nausea, and photophobia, and should be a consideration when
selecting migraine therapy.25, 2, 3, 5
"
•Gastroparesis has long been associated with migraines.
➢The absorption of oral drugs has been shown to be delayed by
gastroparesis, which also delays their onset of action. 25, 46, 48, 47
➢ Liquid preparations and those that act like liquids are thought to be
unaffected by gastroparesis.43

45. diclofenac
• diclofenac is available as either sodium or potassium
salts
"
• diclofenac anion (active ingredient) → exerts its effects
as a cyclo-oxygenase enzyme inhibitor
"
• Potassium salt is more rapidly absorbed and appears to
be more effective as a migraine treatment compared to
sodium salt

46. Pharmacokinetics
11.Data on file. Nautilus Neurosciences, Inc.
.
0 1 2 3 4
0
200
400
600
800
1000
1200
1400
1600
Time (hours)
DiclofenacPlasmaConcentration(ng/mL)
diclofenac potassium for
oral solution
diclofenac potassium
immediate release tablets
15 minutes: diclofenac potassium for
oral solution
15 minutes tablets
• Tmax: measurable plasma levels within 5 minutes of dosing, with a peak at 15 minutes
• Cmax: approximately 4-fold higher concentration at ~15 minutes
• AUC: similar total systemic drug exposure
• Minimally impacted by gastroparesis

47. NSAID Pharmacokinetics‡
All NSAIDs are not Created Equal
‡ All doses used were immediate-release.
11. Data on file. Nautilus Neurosciences, Inc. 21. Idkaidek N and Arafat T. J Clin Pharmacol. 2011;51(12):1685-1689. 19. Haberer LJ, et al. Headache.
2010;50(3):357-373.
diclofenac potassium for oral solution 50 mg 11
ibupfrofen 600 mg 21
naproxen sodium 500 mg 19
Achievement of Peak Absorption for Tablets can take up to Two Hours vs. 15 Minutes for CAMBIA

48. New Treatment for Migraine Sufferers
24. Kriegler JS. In: Tepper SJ and Tepper DE, eds. The Cleveland Clinic Manual of Headache Therapy. (New York, NY: Springer), 2011.
23. Kahn K. US Neurology. 2011;7(2):139-143. 9. CAMBIA Product Monograph. Tribute Pharmaceuticals Canada Ltd. March 9, 2012.

49. PercentageofPatients
Column1
0%
7%
13%
20%
26%
CAMBIA placebo
P<.001
Pain Free at Two Hours
29. Lipton, RB, Grosberg, B, Singer, RP, et al. Cephalalgia 2010;30(11):1336-45.
15. Ferrari MD, et al. Lancet 2001; 358(9294):1668-75.
Therapeutic Gain: 15%
suma 100 mg15
Therapeutic Gain: 19%
Absolute: 29%

50. Column1
6%
25%
43%
62%
80%
CAMBIA placebo
7.2%
19.0%
PercentageofPatients
P<.001
Sustained Pain Free through 24 Hours
29. Lipton, RB, Grosberg, B, Singer, RP, et al. Cephalalgia 2010;30(11):1336-45.
15. Ferrari MD, et al. Lancet 2001; 358(9294):1668-75.
suma 100 mg15
Absolute: 20%

51. 15. Ferrari MD, et al. Cephalalgia 2002;22(8):633-658.
12. Diener, HC, Montagna, P, Gács, G et al. Cephalalgia 2006;26(5):537- 47.
headache recurrence rate (2-24 hours)
mean=30%;
95% CI; 27-33
n=24,089 Few patients
experienced
recurrence at
24 and 48 hours12
diclofenac potassium for oral solution
recurrence rates12

52. EU Study: Onset Of Analgesic Effect
60
50
40
30
20
10
0
diclofenac potassium tablets diclofenac potassium for
oral solution
15 minutes
60 minutes
12. Diener, HC, Montagna, P, Gács, G et al. Cephalalgia 2006;26(5):537- 47.
Postdosetimeinminutes

53. Summary
The Art and Science of Evaluating and Treating Migraine

54. General Summary
• Many migraine patients remain undiagnosed and/or under-
treated
"
• It is important to:
➢ Thoroughly understand diagnostic criteria of migraine
➢ Identify warning signs of serious secondary headache
"
• Patients respond individually to different migraine medications
➢Triptans and NSAIDs
"
• Vary migraine treatment (medications and combinations) when
therapy is unsuccessful for a patient

55. CAMBIA for rapid onset pain, severe nausea
recommended when an anti-nauseant is needed, as more
evidence is available for efficacy for this drug than for the related
medication, domperidone. Domperidone can also be used, and
may have fewer side effects; however, domperidone may be
associated with QT prolongation in some patients.
1. Mild to moderate attack strategies
For patients with attacks that are not disabling (i.e., attacks do
not require bed rest, and do not stop participation in activities,
although it may be somewhat difficult for the patient to
continue), the following two strategies may be most appropriate:
a. Acetaminophen strategy
This strategy simply involves the use of acetaminophen 1,000
mg, as needed. It can be used alone, or in combination with
metoclopramide 10 mg (or domperidone 10 mg).
Acetaminophen has the advantage of fewer gastrointestinal side
effects than NSAIDs, and has been shown to be superior to
placebo in the acute treatment of migraine attacks.2,3
Acetaminophen is considered to be less effective than NSAIDs
for acute migraine treatment; and there is some limited
randomized controlled data to support this in pediatric patients4,
and in adults.5
Acetaminophen is thought to act primarily centrally, and
inhibits prostaglandin synthesis is neurons. Because it is unable
to inhibit prostaglandin synthesis in leukocytes and platelets, it
does not have anti-inflammatory or anti-platelet activity.
Acetaminophen-induced analgesia is blocked by CB1 receptor
antagonists, suggesting that it also acts through cannabinoid
ough
y be
It is
o the
drug
erred
aking
erity,
ld be
remains
eatment
) should
triptan-
casional
dication.
l, rectal,
ne (oral,
adol or
refully).
ly to an
e (nasal
amide (if
use in
codeine
sfactory
tored
ment
associated with QT prolongation in some patients.
1. Mild to moderate attack strategies
For patients with attacks that are not disabling (i.e., attacks do
not require bed rest, and do not stop participation in activities,
although it may be somewhat difficult for the patient to
continue), the following two strategies may be most appropriate:
a. Acetaminophen strategy
This strategy simply involves the use of acetaminophen 1,000
mg, as needed. It can be used alone, or in combination with
metoclopramide 10 mg (or domperidone 10 mg).
Acetaminophen has the advantage of fewer gastrointestinal side
effects than NSAIDs, and has been shown to be superior to
placebo in the acute treatment of migraine attacks.2,3
Acetaminophen is considered to be less effective than NSAIDs
for acute migraine treatment; and there is some limited
randomized controlled data to support this in pediatric patients4,
and in adults.5
Acetaminophen is thought to act primarily centrally, and
inhibits prostaglandin synthesis is neurons. Because it is unable
to inhibit prostaglandin synthesis in leukocytes and platelets, it
does not have anti-inflammatory or anti-platelet activity.
Acetaminophen-induced analgesia is blocked by CB1 receptor
antagonists, suggesting that it also acts through cannabinoid
receptors.6
It has a relatively short elimination half-life of 2 - 3 h,
so repeated dosing may be necessary for a sustained analgesic
effect. Maximum plasma concentrations of acetaminophen are
reached within 30 - 60 minutes. The usual recommended dose
for analgesia is 650 - 1,000 mg (a dose of 1,000 mg is
recommended for migraine). This can be repeated every four to
six hours, with a maximum of 4,000 mg per 24 hours.
monitored
treatment
option for
ctor drugs
ne treatment.
ent clinical
priately. The
reached within 30 - 60 minutes. The usual recommended dose
for analgesia is 650 - 1,000 mg (a dose of 1,000 mg is
recommended for migraine). This can be repeated every four to
six hours, with a maximum of 4,000 mg per 24 hours.
EXPERT CONSENSUS
i. Acetaminophen is an effective option for acute migraine
therapy for some patients with attacks of mild to moderate
intensity.
b. NSAID strategy
A number of commonly used NSAIDs have high quality
evidence for efficacy for acute migraine treatment. These include
ASA, ibuprofen, naproxen sodium, and diclofenac potassium.
Suppl. 3 - S37
for oral solution may be especially useful because of more rapid
oral absorption (see Table 4).
Supp
Analgesic or NSAID (tablets) NN
Acetaminophen 1,000 mg154
5.0
ASA 900-1,000 mg14
4.9
ASA 900 mg + metoclopramide 10 mg14
3.3
Ibuprofen 400 mg9
3.2
Naproxen sodium 500-825 mg11
7.0
Diclofenac potassium (tablet)12
6.2
Diclofenac potassium powder for oral solution13,155
4.5
Table 5:Number needed to treat (NNT) for sim
migraine9,11,14,154,155
solution has a more rapid oral absorption than tablets).
iv. The long plasma half-life of naproxen sodium may make it
particularly helpful for patients with prolonged migraine
attacks.
2. Moderate-severe attack or NSAID failure strategies
a. NSAID with triptan rescue strategy
Clinical trials indicate that NSAIDs may be helpful for
patients with migraine of any severity, although many of the
NSAID clinical trials excluded patients who frequently required
bed rest for their attacks. For the patient with relatively severe
migraine attacks, when an NSAID is tried, it may be useful to
provide a triptan as a rescue medication, should the NSAID
prove unsatisfactory. The triptan in this “step-care within attack”
mode of use may also not prove entirely satisfactory as it will be
taken relatively late in the attack, but nevertheless it should give
the patient some relief, and perhaps help avoid the patient
becoming a “lapsed consulter”. Patients can then decide over
LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
he
om
nt)
en
or
<
lly
ll-
hs
a
ng
is
ry,
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in
ate
ter
al)
.11
solution has a more rapid oral absorption than tablets).
iv. The long plasma half-life of naproxen sodium may make it
particularly helpful for patients with prolonged migraine
attacks.
2. Moderate-severe attack or NSAID failure strategies
a. NSAID with triptan rescue strategy
Clinical trials indicate that NSAIDs may be helpful for
patients with migraine of any severity, although many of the
NSAID clinical trials excluded patients who frequently required
bed rest for their attacks. For the patient with relatively severe
migraine attacks, when an NSAID is tried, it may be useful to
provide a triptan as a rescue medication, should the NSAID
prove unsatisfactory. The triptan in this “step-care within attack”
mode of use may also not prove entirely satisfactory as it will be
taken relatively late in the attack, but nevertheless it should give
the patient some relief, and perhaps help avoid the patient
becoming a “lapsed consulter”. Patients can then decide over
time whether it is necessary to make the triptan their primary
LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
en
em
hat
wo
not
ng
a
to
not
80
er-
ng
nd
ng
%)
all,
all
ura
ree
all
as
ra,
en
he
of
as
ra,
patients take their triptan early at onset of the pain phase, but if
they find taking their triptan during their aura consistently
effective in preventing their headaches, there is no reason to
discourage this practice.
EXPERT CONSENSUS
i. Patients with migraine with aura should be advised to take
their triptan at the onset of the pain phase, although
triptan treatment during typical migraine aura is safe, and
if patients find that treatment during the aura is effective,
there is no reason to discourage this practice.
3. Refractory migraine strategies
a. Triptan-NSAID combination strategy
The use of sumatriptan and naproxen sodium simultaneously
to treat migraine attacks is based on several randomized
controlled trials which have shown that the combination is more
effective than either drug used alone.66,67 Naproxen sodium 500
mg was used in these trials, and was combined with several
different sumatriptan dosages.
A sumatriptan-naproxen sodium combination tablet (not
available in Canada) has also been compared to placebo in a
patient population that had discontinued a short-acting triptan in
the previous year because of poor effectiveness or intolerance.
In these randomized double-blind, placebo-controlled, two-
attack crossover trials the sumatriptan-naproxen combination
LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
is the only formulation which guarantees complete absorption of
the administered dose in the presence of vomiting. It also
produces peak serum levels more rapidly than the other triptan
formulations. It should be considered when patients awaken with
fully developed migraine attacks that do not respond to oral
triptans, when patients vomit early in the attack, or in general
when migraine attacks do not respond well to other triptan
formulations. Zolmitriptan nasal spray can also be considered in
these situations, particularly in patients who are reluctant to use
an injectable formulation. The triptan formulations available in
Canada are shown in Table 8. Because individual patients
respond differently in an unpredictable fashion, patients should if
necessary try several other triptans over time, if the response to
their current triptan is not optimal.
Patients with a history of sulfonamide (sulfa) allergies usually
tolerate triptans well, including those that contain a sulfonamide
moiety or sulfonyl group. If previous reactions to sulfa drugs
have been severe, there is the option of choosing triptans without
a sulfonamide or sulfonyl group in their chemical structure.
Zolmitriptan, rizatriptan, and frovatriptan do not have a
sulfonamide moiety or sulfonyl group, whereas almotriptan and
eletriptan both have a sulfonyl group, and naratriptan and
sumatriptan have a sulphonamide moiety.
Triptan use with an anti-emetic
Although the triptans will often treat associated symptoms
like nausea quite satisfactorily at the same time as they relieve
the headache, there are two situations where the addition of an
anti-emetic (metoclopramide or domperidone), to be taken
simultaneously with the triptan, can be helpful. The first is if
nausea is so pronounced that additional medication is required to
control this symptom. The second is if the response to the triptan
is not fully satisfactory, perhaps because of gastric stasis and
delayed absorption of the triptan. It has been demonstrated that
migraineurs suffer from gastric stasis during an acute migraine
effervescent ASA during migraine attacks is rela
gastro-intestinal motility with delayed gastric emp
impaired motility can be overcome b
metoclopramide.49 A clinical trial in which domp
was added to acetaminophen concluded that
shortens the duration of a migraine attack, and m
headache and associated symptoms compared to
alone.50 In a study involving patients who had f
adequate relief from a triptan used alone, it w
sumatriptan 50 mg plus metoclopramide 10 mg
relief than sumatriptan alone. It could not be
whether this was due to central dopamine receptor
to better sumatriptan absorption.51
Metoclopramide is a substituted benzamide
antagonist, and at higher doses also a 5-HT3
antag
a gastrointestinal pro-kinetic agent through mech
not fully understood. In addition to metocl
domperidone, other anti-emetics that have been u
include prochlorperazine (a phenothiazine dopam
antagonist), and ondansetron (a 5-HT3
Prochlorperazine intravenously is widely used in
room setting for migraine treatment. It is also u
mg) and rectally (10 - 25 mg) as an anti-emetic i
the evidence base for its use is much smaller
metoclopramide, and it is more likely to cause e
side effects. The evidence base for use of ondanse
emetic in migraine is very limited.
Dimenhydrinate is widely available and o
patients for nausea. It is a complex formulat
diphenhydramine (an H1
antagonist that mediates
effect), and a theophylline derivative (a CNS stim
caffeine). Dimenhydrinate has some abuse poten
lack of evidence for its efficacy in migraine, m
domperidone, and possibly prochlorperazine wou
better choices for treatment of migraine-related n
patients take their triptan early at onset of the pain phase, but if
they find taking their triptan during their aura consistently
effective in preventing their headaches, there is no reason to
discourage this practice.
EXPERT CONSENSUS
i. Patients with migraine with aura should be advised to take
their triptan at the onset of the pain phase, although
triptan treatment during typical migraine aura is safe, and
if patients find that treatment during the aura is effective,
there is no reason to discourage this practice.
3. Refractory migraine strategies
a. Triptan-NSAID combination strategy
The use of sumatriptan and naproxen sodium simultaneously
LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
ketorolac 60 mg by IM self-injectio
indomethacin
b. Dopamine antagonists including pro
suppositories
c. Oral dexamethasone or another steroi
single dose or a short steroid taper over se
Potential rescue medic
c
Medication
NSAIDs:
Oral naproxen sodium, ibuprofen, o
(all may be combined with oral met
oral/rectal prochlorperazine)
Ketorolac (60 mg) IM
Indomethacin oral or rectal with or
prochlorperazine
Dopamine antagonists:
Table 10: Potential rescue m
triptan-NSAID combinati
hough the response rate is clearly much lower than has been
und in other studies when zolmitriptan is taken early in the
in phase of the headache. In summary, although all three of
ese small randomized studies showed no significant benefit as
mpared to placebo when a triptan is taken during the aura,
ne showed any adverse effects of the triptan on the aura.
Patients do anecdotally report success with taking a triptan
ring their migraine aura. These observations are difficult to
terpret, given that in the eletriptan study, 54% of patients given
acebo did not develop a headache afterwards, and similarly in
e sumatriptan study 25% did not develop a headache after
acebo. The randomized clinical studies would suggest that
ptan treatment during the aura is not beneficial, and that
tients should be advised to take their triptan after the aura
ring the initial part of the pain phase of their migraine. A small
cent open label study, however, has suggested that at least for
me patients, treatment during the aura may be advantageous.
sing sumatriptan RT (fast dissolving formulation), treatment
ring the aura prevented the development of headache in 89%
attacks, while treatment during the pain phase within one hour
pain onset in the same patients rendered 79% of attacks pain
ee.63
Triptan product monographs typically state that they are
ntraindicated in patients with hemiplegic, ophthalmoplegic,
d basilar migraine. These contraindications are theoretical and
esumably based on the vasoconstrictor actions of triptans,
ther than on data. Given that migraine auras appear related to
urophysiological factors and not direct vasoconstriction and
e lack of evidence regarding triptan use in these syndromes, the
k which triptans pose is unclear. Clinicians need to be aware
these contraindications. Anecdotally, where they have been
ed, patients with hemiplegic migraine do seem to tolerate
A sumatriptan-naproxen sodium combination
available in Canada) has also been compared to p
patient population that had discontinued a short-actin
the previous year because of poor effectiveness or
In these randomized double-blind, placebo-contr
attack crossover trials the sumatriptan-naproxen c
tablet provided 2-h pain free results in 40 and 44% o
the two trials, versus 17 and 14% for placebo.68
It would appear reasonable to apply the principl
treatment during a migraine attack increases effectiv
sumatriptan-naproxen combination. In pooled data
placebo-controlled trials, sumatriptan 85 mg com
naproxen sodium 500 mg taken early in the attack p
pain free results in 51.5% of patients, versus 16% fo
The sumatriptan-naproxen sodium combination h
shown to reduce the headache recurrence rate as c
sumatriptan taken alone.70
Although the evidence available is largely c
sumatriptan-naproxen sodium combinations, it w
reasonable to generalize from this evidence to ot
NSAID combinations. Among NSAIDs, naproxen s
be particularly suited for combining with most tripta
long half-life and duration of action, but other trip
combinations may also be effective. Table 9
information (doses, cautions, etc) for many medicatio
acute migraine treatment.
b. Triptan-NSAID combination with rescue
strategy
For some patients, triptans are effective for virt
attack, particularly if they are taken early when the pa
mild intensity. When patients do experience occasi

56. The Art and Science of
Evaluating and
Treating Migraine
THANK YOU

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62. REFERENCES 8. Suthisisang C, Poolsup N, Kittikulsuth W, Pudchakan P,
THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
Acute migraine treatment strategies and medication summary: Special Strategies
Clinical phenotype / strategy Medication options
Vasoconstrictor unresponsive
or contraindicated
strategy
1. One of: acetaminophen, ibuprofen, diclofenac potassium, naproxen sodium , or ASA, all ±
metoclopramide
2. Combinations of acetaminophen, ASA, and caffeine (note: combination product not available in
Canada but can use individual components) ± metoclopramide
3. One or more of:
! ketorolac IM (self-injection)
! indomethacin (oral or rectal)
! prochlorperazine (oral or rectal)
! chlorpromazine (oral)
! dexamethasone or prednisone (short course)
! opioid (including tramadol) combination analgesics (monitor use closely)
4. One of: butalbital-containing analgesics, or butorphanol nasal spray (both: exceptional
circumstances only – monitor use closely)
Menstrual migraine strategy
1. Acute therapy: General strategies 1 through 3c
2. Short term prophylaxis with one of: frovatriptan, zolmitriptan, naratriptan, or naproxen
(frovatriptan recommended)
3. Short term prophylaxis with percutaneous estrogen
4. Continuous oral contraceptives (observe contraindications)
5. Less proven options for short term prophylaxis: magnesium, mefenamic acid
Migraine during pregnancy
strategy
Avoid medication where possible
1. acetaminophen ± metoclopramide
2. acetaminophen with codeine ± metoclopramide
3. ibuprofen (avoid 1st
trimester and at /after 32nd
week gestation) ± metoclopramide
4. sumatriptan (if benefits outweigh risks – limited data but relatively safe) ± metoclopramide
Migraine during lactation
strategy
Avoid medication where possible
1. acetaminophen ± metoclopramide
2. ibuprofen ± metoclopramide
3. sumatriptan ± metoclopramide
4. morphine (exceptional circumstances only - avoid high doses, maternal sedation, avoid when
infant is premature, and use caution if infant under 1 month of age)
Table 11B: Acute migraine treatment strategies and medication summary: Special Strategies
The official Journal of: The Canadian Neurological Society, The Canadian Neurosurgical Society, The
Canadian Society of Clinical Neurophysiologists, The Canadian Association of Child Neurology
PM40007777R9824
AN INTERNATIONAL JOURNAL PUBLISHED BY THE CANADIAN NEUROLOGICAL SCIENCES FEDERATION
Canadian Headache Society Guideline
Acute Drug Therapy for Migraine Headache
A Peer-reviewed SUPPLEMENT to
The Canadian Journal of Neurological Sciences