Acute migraine treatment arh

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

Transcript of Acute migraine treatment arh

Page 1: Acute migraine treatment   arh

The Art and Science of Evaluating and Treating Migraine

Ryan J Punambolam MD, FRCPC Neurology

Abbotsford Regional Hospital !!

Medicine Grand Rounds April 9, 2014.

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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

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Migraine Backgrounder

The Art and Science of Evaluating and Treating Migraine

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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 • ?

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Primary or Secondary Headache?

Detailed History and Examination

No

Yes

Any un

usua

l featu

res?

Evaluate for Secondary Headache

Red Flags? Diagnose Primary Headache Disorder

Step 1

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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”

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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

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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

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Diagnose the Specific Disorder Within the Category

Differential Diagnosis Step 3

Genetics of migraine—explaining topatients why they have the problemIt seems logical to suppose that all sufferers of primaryheadaches have a genetic predisposition that is in someway activated by physiological and other life events,such as puberty, although the only genetic associationsyet identified are for migraine. Migraine genetics offera useful tool in clinical practice for helping to explainto patients that they were born with a tendency toheadache—by establishing that their parents also hadheadaches, or by pointing out that the triggers listed intable 1 do not produce headache universally, thedoctor can explain the cause. This is useful in allayingfear and setting the groundwork for improving theproblem.

The first concrete example of inherited migrainewas the identification of missense mutations in theCav2.1 subunit of the gene for the P/Q type, voltagegated, calcium channel on chromosome 19 in familieswith familial hemiplegic migraine.w1 Since then, othercases of familial hemiplegic migraine have been foundto be caused by mutations in the ATP1A2 gene, whichencodes the !2 subunit of the Na+/K+ pump,w2 and inthe SCN1A gene for the neuronal voltage-gatedsodium channel.w3

The overall message is of migraine as an ionopathy,a disorder based on abnormal ion channels whosestrategic function and anatomical distribution in thebrain determine the clinical phenotype. If genetics canexplain why patients have headaches and what the bio-chemical disorder may be, then we can ask thequestion, “Where is the problem?” or, framed in theterms of classic neurology, “Where is the lesion?”

Pathophysiology of headache—where isthe lesion?Classic neurology, as promulgated by Gowers, soughtto provide anatomical answers to clinical questions.This approach has been successful, but the problems ofprimary headache will need a physiologicalapproach.w4 To some extent, human functionalimaging starts to do this.

In the 1960s and ’70s migraine was considered avascular phenomenon and is still often referred toincorrectly as a vascular headache. Wolff summarisedin his classic book the referral patterns of structures

that produced intracranial pain, taking a view thatmigraine aura was due to vasoconstriction and that thesubsequent headache was due to a reactive vasodilata-tion. Olesen debunked this link. The spreading depres-sion theory points out that the changes in blood flowfollow metabolic demand—vasoneuronal coupling.w5

Considering features of the attack that do not occur inall cases (such as nausea, photophobia, and phonopho-bia) or of the premonitory phase (such as yawning ordiuresis), the vascular hypothesis seems unattractive.

The lesion should be considered a functional con-cept. What structure or network of structures wouldproduce a syndrome whose core features are unilateralhead pain and sensitivity to light, sound, smells, andhead movement, as well as have the potential to alterbrain blood flow, be influenced by sleep or changingsleep patterns, and alter broadly cortical function interms of attention and concentration. Brainstem amin-ergic neurones, such as the noradrenergic neurones ofthe locus coeruleus, could potentially have these broadeffects,w6 so the hypothesis would predict functionalimaging changes in the brainstem, indeed in the pons.

Functional brain imaging in migrainePositron emission tomography in acute migraine hasshown activations in the rostral brainstem thatpersisted after successful treatment of the attack butare not present interictally.8 These changes are notseen in experimentally induced ophthalmic divisionpain9 or in other primary headaches, such as clusterheadache10 or paroxysmal hemicrania (fig).11 Indeed,we and others have consistently observed activation inthe dorsolateral pons in both spontaneous andtriggered episodic migraine.12–15 Moreover, in chronicmigraine, defined as migraine without aura that occurson ≥ 15 days a month for more than six months,3 thesame area of the dorsolateral pons is activated,16

suggesting that infrequent and frequent migraine areends of a shared spectrum. Use of blood oxygen leveldependent (BOLD) contrast functional magnetic reso-nance imaging holds the promise of studying singlepatients and determining the site of abnormalactivation.w7 Moreover, magnetic resonance angiogra-phy has shown that the blood flow changes seen inmigraine14 and cluster headache10 are simply a result ofophthalmic division pain,17 18 not a cause of thesyndrome.

Box 3: Chronic migraine (modified criteria ofthe ICHD-II3)

A: Current or prior headache fulfils criteria formigraine without aura (see box 1)B: Headache on ≥ 15 days a monthC: At least 8 headache days a month for the previous 3months fulfilling at least one of the following:

Criteria C and D for migraine without aura (see box1)Criteria C and D for migraine without aura with theexception of a single sub-criterion, and not meetingcriteria for tension-type headache (see table 2)Headache that the patient believes to be migraineand is relieved by a 5-HT1B/1D receptor agonist

D: Not attributable to another disorder, includingmedication overuse headache

Table 1 Differentiating migraine from tension-type headache

Characteristics Migraine Tension-type headachePain features

of acuteattacks

Throbbing Boring or squashingUnilateral Bilateral

Worsening of pain withmovement

No effect of headmovement

Associatedfeatures

Nausea or vomiting NonePhotophobia and phonophobia

Triggeringfactors

Altered sleep patterns (too littleor too much)

Psychological stress

Skipping mealsOverexertion

Change in stress level (too muchor relaxation)

Excess afferent stimuli (such asbright lights)

Weather changeChemical (delayed headache after

alcohol or glyceryl trinitrate)Menstruation

Clincal review

27BMJ VOLUME 332 7 JANUARY 2006 bmj.com

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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.

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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 □

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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.

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Pain Pathways in the Head

18. Goadsby PJ. et al. J Clin Neurosci 2000 Jul; 7(4):377.

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Peter also has “Classic Migraine”

Migraine with Aura """

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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.

Perc

ent

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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%

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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

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Planning and Management Strategies

The Art and Science of Evaluating and Treating Migraine

Step 4

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What might be your preliminary treatment recommendation for Peter?

Back to Peter…

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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 PlanStep 4

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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.

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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.

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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

RapidRelief

NoRecurrence

Complete Relief

Treatment Attributes

Patients Choosing Route of Administration as 1st Choice (%)

0 20 40 60 80

2.6

73

15

8.3NasalSpray

RapidlyDissolving Tablet

Tablet or Capsule

SC Injection

Route of Administration

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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.

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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.

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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

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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

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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

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Case Vignette Continued

• Peter was started on sumatriptan 50 mg po "

• Returned to his PCP saying that the treatment “does not work”

Now What?

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“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

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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

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Treatment Options In Migraine

The Art and Science of Evaluating and Treating Migraine

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MILD: NSAIDS +/- METOCLOPRAMIDE

MOD-SEVERE: TRIPTANS +/- NSAIDS

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vomiting. Patients may need access to more than one triptanformulation, based on attack characteristics.25,26

Triptan choice and patient preferenceAlthough the triptans are chemically related drugs, in clinical

practice it is a common experience that some patients will preferone triptan to another. This may relate to a perceived differencein efficacy, differences in the side effects experienced, or both.Which triptan a patient will prefer cannot be predicted. It isgenerally accepted that the differences between patients aregreater than the differences between triptans, and no one triptanis superior to the others for all patients. With regard to individualpatients this has led to the adage that the best triptan “is the onethat works best for the patient”. The different triptans do havedifferent pharmacokinetic properties, and also to some extentshow differences in side effects. Triptan choice can therefore betailored to some extent to the individual patient. Rapidity of painrelief, the probability of pain relief, the probability of headacherecurrence, and the probability of adverse events all are potentialcontributors to how satisfactory the patient’s response will be toany given triptan.17,27,28

Pharmacokinetic differences among triptans and onset of painrelief

The pharmacokinetic differences among the triptans (Table 6)may be clinically relevant for individual patients.19,23,28,29

Subcutaneous sumatriptan has the most rapid onset of action(approximately 10 min) compared to oral or intranasal triptans.30

Intranasal zolmitriptan also has a relatively rapid onset of action(10-15 min).29,31 Of the oral triptans, rizatriptan and eletriptanhave a relatively fast onset of action (approximately 30 min).Naratriptan and frovatriptan have the slowest onset of action (upto 4 h). There is no evidence that orally dissolving tablets/wafersact more quickly than regular tablets.

Subcutaneous sumatriptan with its rapid absorption and onsetof action, coupled with no interference with absorption due tonausea or vomiting, gives it a unique therapeutic role. Althoughit is not as widely used as the oral triptans because of the needfor an injection and also because of increased side effects, itshould be considered where other formulations have proven lesseffective than desired, or where early vomiting in the attackrenders other formulations ineffective.

Among the oral tablets, frovatriptan and naratriptan stand outas having a slower absorption, and a longer time to Tmax. Theremaining triptans show less differentiation, with rizatriptanhaving perhaps the fastest time to Tmax, indicating the potentialfor a rapid onset of action.

The probability of pain reliefTable 7 shows the number needed to treat (NNT) for the “pain

free at two hours” endpoint. This is the number of patients thatneed to be treated to render one patient pain free at two hoursover and above the placebo response. Subcutaneous sumatriptan(6 mg) has the lowest NNT, indication the best efficacy for thisendpoint. Among the oral triptans, rizatriptan provides the lowestNNT.

Adverse eventsAdverse events also vary greatly from patient to patient, with

one patient tolerating one triptan much better than another, whilea second patient may show the reverse. Although the differencesbetween the oral triptans are not large, almotriptan appears tohave the lowest absolute adverse event rate.32 Triptan safetyduring pregnancy and lactation has not been established, butavailable information on triptan use during pregnancy andlactation is discussed below under the “Migraine duringpregnancy strategy” and the “Migraine during lactationstrategy”.

a) Cardiovascular safetyConcerns about the cardiovascular safety of triptans are due,

in part, to adverse effects experienced by some patients, whichare referred to as “triptan sensations”. These effects, includingburning, tingling or tightness in the face, neck, limbs or chest,have been reported in approximately 1-7% of patients in clinicaltrials. Triptan-associated chest symptoms are generally mild andtransient, and are not associated with electrocardiographic orenzymatic evidence of myocardial ischemia. However, because5-HT1B receptors are located on coronary arteries, triptans canconstrict coronary arteries to a small extent, which isinsignificant in patients without underlying coronary arterydisease. Triptans do not appear to differ from one another in thisregard.23 The Triptan Cardiovascular Safety Expert Panel, amultidisciplinary panel convened by the American HeadacheSociety, concluded that while serious cardiovascular adverseevents have occurred after the use of triptans, the frequency inboth clinical trials and in clinical practice appeared to be verylow (less than one per one million exposed).33 All triptans exhibita similar safety profile when prescribed appropriately.

LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

Suppl. 3 - S41

* Adapted from: Bandolier (http://www.medicine.ox.ac.uk/bandolier)except as noted; ** Note: Migraine attacks were treated at moderate orsevere intensity. NNTs may be lower for individual drugs when treat-ment is taken early in the migraine attack.

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 drugs w

Table 7: Triptans – Number Needed to Treat (NNT) for pain-free response at 2 h in migraine*31,158-162

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Pain Pathways in the Head

18. Goadsby PJ. et al. J Clin Neurosci 2000 Jul; 7(4):377.

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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.

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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

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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.

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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

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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

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Pharmacokinetics

11.Data on file. Nautilus Neurosciences, Inc. .

0 1 2 3 40

200

400

600

800

1000

1200

1400

1600

Time (hours)

Dic

lofe

nac

Plas

ma

Con

cent

ratio

n (n

g/m

L)

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

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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

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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.

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Perc

enta

ge o

f Pat

ient

s

Column1

0%

7%

13%

20%

26%

CAMBIA placebo

P<.001Pain 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%

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Column1

6%

25%

43%

62%

80%

CAMBIA placebo

7.2%

19.0%

Perc

enta

ge o

f Pat

ient

s

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%

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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 experiencedrecurrence at 24 and 48 hours12

diclofenac potassium for oral solution recurrence rates12

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EU Study: Onset Of Analgesic Effect

60

50

40

30

20

10

0diclofenac 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.

Post

dos

e tim

e in

min

utes

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Summary

The Art and Science of Evaluating and Treating Migraine

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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

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CAMBIA for rapid onset pain, severe nausea

prescribed at the same time. The triptan can be used as a rescuemedication by the patient as necessary if the NSAID oracetaminophen occasionally fails, or can be adopted as thepatient’s primary acute migraine medication if the NSAID oracetaminophen proves unhelpful (see step 2 below).

Step 2: For patients not responding well to NSAIDs, use atriptan as the primary medication for acute migraine therapy: a. At least three different triptans should be tried (in different

attacks) if the response to the first triptan is not excellent.An excellent response is defined as pain free or almostpain free with the ability to resume usual activities at 2 hpost-dose, and no significant side effects.

b. A triptan should be used to treat approximately threeseparate migraine attacks before being judged effective orineffective.

c. Intranasal triptans which are partially absorbed throughthe nasal mucosa (e.g., zolmitriptan 5 mg) may bepreferred to oral triptans for patients with nausea. It isimportant that patients administer them according to theproduct monograph to allow for maximum nasal drugabsorption.

d. Orally dissolving tablets (wafers) may be the preferredoral triptan for patients with nausea exacerbated by takingfluids.

e. For patients with more than one migraine attack severity,providing medications from two different classes should beconsidered (e.g., a triptan and NSAID).Step 3: For patients whose response to triptans remains

inadequate because of incomplete relief or frequent treatmentfailure, an NSAID (e.g., naproxen sodium 500 - 550 mg) shouldbe used simultaneously with their triptan.

Step 4: For patients with a good response to their triptan-NSAID combination therapy but who experience occasionaltreatment failure, consider the need for a rescue medication.Rescue medications can include additional NSAIDs (oral, rectal,or injectable with oral metoclopramide), prochlorperazine (oral,rectal), corticosteroids, and acetaminophen with tramadol orcodeine (not for routine use; monitor frequency of use carefully).

Step 5: For patients who do not respond satisfactorily to anNSAID-triptan combination, the use of dihydroergotamine (nasalspray or self-injection), combined with oral meto-clopramide (ifneeded), can be considered.

Step 6: Although not recommended for routine use inmigraine, opioid analgesics (e.g., acetaminophen with codeineor tramadol) remain an option for patients without a satisfactoryresponse to earlier treatment steps, but:

a. their frequency of use should be closely monitored(using a headache diary).b. behavioural and pharmacological preventive treatmentoptions should be explored. c. these medications are also a treatment option forpatients with contraindications to vasoconstrictor drugsand who do not respond to NSAIDs.

Acute Migraine Treatment StrategiesThere are many drugs available for acute migraine treatment.

These need to be chosen based upon patient clinicalcharacteristics, and each needs to be used appropriately. The

medications are organized here into a number of treatmentstrategies, and are discussed below. Once the clinical data on aspecific patient has been gathered, including past medication useand response, an appropriate strategy should be chosen andimplemented. Depending upon the patient’s response to thechosen pharmacological treatment strategy, the same strategycan be continued, or a new strategy can be implemented.

The primary drugs for acute migraine attack treatment are theNSAIDs (including ASA) and the triptans. Acetaminophen iswidely used, but is considered less effective than the NSAIDs,and suitable mainly for attacks of mild to moderate severity. Inthe treatment strategies discussed below, metoclopramide isrecommended when an anti-nauseant is needed, as moreevidence is available for efficacy for this drug than for the relatedmedication, domperidone. Domperidone can also be used, andmay have fewer side effects; however, domperidone may beassociated with QT prolongation in some patients.

1. Mild to moderate attack strategiesFor 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 tocontinue), the following two strategies may be most appropriate:

a. Acetaminophen strategyThis strategy simply involves the use of acetaminophen 1,000

mg, as needed. It can be used alone, or in combination withmetoclopramide 10 mg (or domperidone 10 mg).Acetaminophen has the advantage of fewer gastrointestinal sideeffects than NSAIDs, and has been shown to be superior toplacebo in the acute treatment of migraine attacks.2,3

Acetaminophen is considered to be less effective than NSAIDsfor acute migraine treatment; and there is some limitedrandomized controlled data to support this in pediatric patients4,and in adults.5

Acetaminophen is thought to act primarily centrally, andinhibits prostaglandin synthesis is neurons. Because it is unableto inhibit prostaglandin synthesis in leukocytes and platelets, itdoes not have anti-inflammatory or anti-platelet activity.Acetaminophen-induced analgesia is blocked by CB1 receptorantagonists, suggesting that it also acts through cannabinoidreceptors.6 It has a relatively short elimination half-life of 2 - 3 h,so repeated dosing may be necessary for a sustained analgesiceffect. Maximum plasma concentrations of acetaminophen arereached within 30 - 60 minutes. The usual recommended dosefor analgesia is 650 - 1,000 mg (a dose of 1,000 mg isrecommended for migraine). This can be repeated every four tosix hours, with a maximum of 4,000 mg per 24 hours.

EXPERT CONSENSUSi. Acetaminophen is an effective option for acute migraine

therapy for some patients with attacks of mild to moderateintensity.

b. NSAID strategy A number of commonly used NSAIDs have high quality

evidence for efficacy for acute migraine treatment. These includeASA, ibuprofen, naproxen sodium, and diclofenac potassium.

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LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUESprescribed at the same time. The triptan can be used as a rescuemedication by the patient as necessary if the NSAID oracetaminophen occasionally fails, or can be adopted as thepatient’s primary acute migraine medication if the NSAID oracetaminophen proves unhelpful (see step 2 below).

Step 2: For patients not responding well to NSAIDs, use atriptan as the primary medication for acute migraine therapy: a. At least three different triptans should be tried (in different

attacks) if the response to the first triptan is not excellent.An excellent response is defined as pain free or almostpain free with the ability to resume usual activities at 2 hpost-dose, and no significant side effects.

b. A triptan should be used to treat approximately threeseparate migraine attacks before being judged effective orineffective.

c. Intranasal triptans which are partially absorbed throughthe nasal mucosa (e.g., zolmitriptan 5 mg) may bepreferred to oral triptans for patients with nausea. It isimportant that patients administer them according to theproduct monograph to allow for maximum nasal drugabsorption.

d. Orally dissolving tablets (wafers) may be the preferredoral triptan for patients with nausea exacerbated by takingfluids.

e. For patients with more than one migraine attack severity,providing medications from two different classes should beconsidered (e.g., a triptan and NSAID).Step 3: For patients whose response to triptans remains

inadequate because of incomplete relief or frequent treatmentfailure, an NSAID (e.g., naproxen sodium 500 - 550 mg) shouldbe used simultaneously with their triptan.

Step 4: For patients with a good response to their triptan-NSAID combination therapy but who experience occasionaltreatment failure, consider the need for a rescue medication.Rescue medications can include additional NSAIDs (oral, rectal,or injectable with oral metoclopramide), prochlorperazine (oral,rectal), corticosteroids, and acetaminophen with tramadol orcodeine (not for routine use; monitor frequency of use carefully).

Step 5: For patients who do not respond satisfactorily to anNSAID-triptan combination, the use of dihydroergotamine (nasalspray or self-injection), combined with oral meto-clopramide (ifneeded), can be considered.

Step 6: Although not recommended for routine use inmigraine, opioid analgesics (e.g., acetaminophen with codeineor tramadol) remain an option for patients without a satisfactoryresponse to earlier treatment steps, but:

a. their frequency of use should be closely monitored(using a headache diary).b. behavioural and pharmacological preventive treatmentoptions should be explored. c. these medications are also a treatment option forpatients with contraindications to vasoconstrictor drugsand who do not respond to NSAIDs.

Acute Migraine Treatment StrategiesThere are many drugs available for acute migraine treatment.

These need to be chosen based upon patient clinicalcharacteristics, and each needs to be used appropriately. The

medications are organized here into a number of treatmentstrategies, and are discussed below. Once the clinical data on aspecific patient has been gathered, including past medication useand response, an appropriate strategy should be chosen andimplemented. Depending upon the patient’s response to thechosen pharmacological treatment strategy, the same strategycan be continued, or a new strategy can be implemented.

The primary drugs for acute migraine attack treatment are theNSAIDs (including ASA) and the triptans. Acetaminophen iswidely used, but is considered less effective than the NSAIDs,and suitable mainly for attacks of mild to moderate severity. Inthe treatment strategies discussed below, metoclopramide isrecommended when an anti-nauseant is needed, as moreevidence is available for efficacy for this drug than for the relatedmedication, domperidone. Domperidone can also be used, andmay have fewer side effects; however, domperidone may beassociated with QT prolongation in some patients.

1. Mild to moderate attack strategiesFor 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 tocontinue), the following two strategies may be most appropriate:

a. Acetaminophen strategyThis strategy simply involves the use of acetaminophen 1,000

mg, as needed. It can be used alone, or in combination withmetoclopramide 10 mg (or domperidone 10 mg).Acetaminophen has the advantage of fewer gastrointestinal sideeffects than NSAIDs, and has been shown to be superior toplacebo in the acute treatment of migraine attacks.2,3

Acetaminophen is considered to be less effective than NSAIDsfor acute migraine treatment; and there is some limitedrandomized controlled data to support this in pediatric patients4,and in adults.5

Acetaminophen is thought to act primarily centrally, andinhibits prostaglandin synthesis is neurons. Because it is unableto inhibit prostaglandin synthesis in leukocytes and platelets, itdoes not have anti-inflammatory or anti-platelet activity.Acetaminophen-induced analgesia is blocked by CB1 receptorantagonists, suggesting that it also acts through cannabinoidreceptors.6 It has a relatively short elimination half-life of 2 - 3 h,so repeated dosing may be necessary for a sustained analgesiceffect. Maximum plasma concentrations of acetaminophen arereached within 30 - 60 minutes. The usual recommended dosefor analgesia is 650 - 1,000 mg (a dose of 1,000 mg isrecommended for migraine). This can be repeated every four tosix hours, with a maximum of 4,000 mg per 24 hours.

EXPERT CONSENSUSi. Acetaminophen is an effective option for acute migraine

therapy for some patients with attacks of mild to moderateintensity.

b. NSAID strategy A number of commonly used NSAIDs have high quality

evidence for efficacy for acute migraine treatment. These includeASA, ibuprofen, naproxen sodium, and diclofenac potassium.

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LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

prescribed at the same time. The triptan can be used as a rescuemedication by the patient as necessary if the NSAID oracetaminophen occasionally fails, or can be adopted as thepatient’s primary acute migraine medication if the NSAID oracetaminophen proves unhelpful (see step 2 below).

Step 2: For patients not responding well to NSAIDs, use atriptan as the primary medication for acute migraine therapy: a. At least three different triptans should be tried (in different

attacks) if the response to the first triptan is not excellent.An excellent response is defined as pain free or almostpain free with the ability to resume usual activities at 2 hpost-dose, and no significant side effects.

b. A triptan should be used to treat approximately threeseparate migraine attacks before being judged effective orineffective.

c. Intranasal triptans which are partially absorbed throughthe nasal mucosa (e.g., zolmitriptan 5 mg) may bepreferred to oral triptans for patients with nausea. It isimportant that patients administer them according to theproduct monograph to allow for maximum nasal drugabsorption.

d. Orally dissolving tablets (wafers) may be the preferredoral triptan for patients with nausea exacerbated by takingfluids.

e. For patients with more than one migraine attack severity,providing medications from two different classes should beconsidered (e.g., a triptan and NSAID).Step 3: For patients whose response to triptans remains

inadequate because of incomplete relief or frequent treatmentfailure, an NSAID (e.g., naproxen sodium 500 - 550 mg) shouldbe used simultaneously with their triptan.

Step 4: For patients with a good response to their triptan-NSAID combination therapy but who experience occasionaltreatment failure, consider the need for a rescue medication.Rescue medications can include additional NSAIDs (oral, rectal,or injectable with oral metoclopramide), prochlorperazine (oral,rectal), corticosteroids, and acetaminophen with tramadol orcodeine (not for routine use; monitor frequency of use carefully).

Step 5: For patients who do not respond satisfactorily to anNSAID-triptan combination, the use of dihydroergotamine (nasalspray or self-injection), combined with oral meto-clopramide (ifneeded), can be considered.

Step 6: Although not recommended for routine use inmigraine, opioid analgesics (e.g., acetaminophen with codeineor tramadol) remain an option for patients without a satisfactoryresponse to earlier treatment steps, but:

a. their frequency of use should be closely monitored(using a headache diary).b. behavioural and pharmacological preventive treatmentoptions should be explored. c. these medications are also a treatment option forpatients with contraindications to vasoconstrictor drugsand who do not respond to NSAIDs.

Acute Migraine Treatment StrategiesThere are many drugs available for acute migraine treatment.

These need to be chosen based upon patient clinicalcharacteristics, and each needs to be used appropriately. The

medications are organized here into a number of treatmentstrategies, and are discussed below. Once the clinical data on aspecific patient has been gathered, including past medication useand response, an appropriate strategy should be chosen andimplemented. Depending upon the patient’s response to thechosen pharmacological treatment strategy, the same strategycan be continued, or a new strategy can be implemented.

The primary drugs for acute migraine attack treatment are theNSAIDs (including ASA) and the triptans. Acetaminophen iswidely used, but is considered less effective than the NSAIDs,and suitable mainly for attacks of mild to moderate severity. Inthe treatment strategies discussed below, metoclopramide isrecommended when an anti-nauseant is needed, as moreevidence is available for efficacy for this drug than for the relatedmedication, domperidone. Domperidone can also be used, andmay have fewer side effects; however, domperidone may beassociated with QT prolongation in some patients.

1. Mild to moderate attack strategiesFor 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 tocontinue), the following two strategies may be most appropriate:

a. Acetaminophen strategyThis strategy simply involves the use of acetaminophen 1,000

mg, as needed. It can be used alone, or in combination withmetoclopramide 10 mg (or domperidone 10 mg).Acetaminophen has the advantage of fewer gastrointestinal sideeffects than NSAIDs, and has been shown to be superior toplacebo in the acute treatment of migraine attacks.2,3

Acetaminophen is considered to be less effective than NSAIDsfor acute migraine treatment; and there is some limitedrandomized controlled data to support this in pediatric patients4,and in adults.5

Acetaminophen is thought to act primarily centrally, andinhibits prostaglandin synthesis is neurons. Because it is unableto inhibit prostaglandin synthesis in leukocytes and platelets, itdoes not have anti-inflammatory or anti-platelet activity.Acetaminophen-induced analgesia is blocked by CB1 receptorantagonists, suggesting that it also acts through cannabinoidreceptors.6 It has a relatively short elimination half-life of 2 - 3 h,so repeated dosing may be necessary for a sustained analgesiceffect. Maximum plasma concentrations of acetaminophen arereached within 30 - 60 minutes. The usual recommended dosefor analgesia is 650 - 1,000 mg (a dose of 1,000 mg isrecommended for migraine). This can be repeated every four tosix hours, with a maximum of 4,000 mg per 24 hours.

EXPERT CONSENSUSi. Acetaminophen is an effective option for acute migraine

therapy for some patients with attacks of mild to moderateintensity.

b. NSAID strategy A number of commonly used NSAIDs have high quality

evidence for efficacy for acute migraine treatment. These includeASA, ibuprofen, naproxen sodium, and diclofenac potassium.

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LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

Other NSAIDs (e.g., oral ketorolac) lack randomized controlledtrial studies in migraine. It would appear most prudent to utilizeNSAIDs with good evidence for efficacy, although it is possiblethat other NSAIDs might be more effective in selected patients.The NSAID can be used alone or with metoclopramide.

In choosing an NSAID, the pharmacokinetic properties of thedrug should be considered. Rapid absorption provides theopportunity for a rapid onset of action for quick migraine relief,and this may be important for patients with migraine attacks thatincrease rapidly in intensity. For patients with relativelyprolonged migraine attacks, an NSAID with a longer half-life(e.g., naproxen) may reduce the likelihood of headacherecurrence. NSAIDs currently used for migraine have quitedifferent pharmacokinetic properties (Table 4).

Rapidity of absorption of NSAIDs does depend in part ontablet dissolution times, and solubilized formulations ofibuprofen, effervescent ASA, and diclofenac potassium powderfor oral solution may be especially useful because of more rapidoral absorption (see Table 4).

There is probably no ideal NSAID for migraine, and it isoften worthwhile for patients to try several if their response totheir initial NSAID is not ideal. Numbers needed to treat (NNTs)for various NSAIDs (the number of patients who will need to betreated to achieve a pain relief endpoint in one patient over andabove the placebo response) as available are given in Table 5.

Ibuprofen appears to be the most commonly used NSAID formigraine in Canada, perhaps in part because it is widelyavailable without prescription.7 Its relatively short eliminationhalf-life (2 h) may result in the need for repeated dosing in manypatients. Ibuprofen is preferred by many patients, perhapsbecause of its rapid onset of action. It may produce less gastricirritation than ASA, and the NNT for a positive response ascompared to placebo is at least as good if not better than for ASAin migraine. In controlled clinical trials, doses greater than 400mg were no more effective than the 400 mg dose for acutemigraine attacks.

Ibuprofen has shown good efficacy in acute migraine8,9, andappears to have similar efficacy compared to other acute

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Tmax = time to maximum plasma concentration; *Note: for acute migraine treatment, only one or two doses are usually recom-mended; doses are for adults; **Absorbed more quickly than naproxen; ***No controlled trial evidence for efficacy in migraine

Non-Steroidal Anti-Inflammatory Drugs: Pharmacokinetics and Dosage

Drug

Tmax (hours)

Elimination half-

life (hours)

Dose (mg)*

Dosage interval (if repeated)

& maximum daily dose* Acetylsalicylic acid (ASA) (tablet)

1 - 2 ASA: 0.25 Salicylate (active): 5-6 (after 1 g dose)

975 - 1,000 every 4-6 h; max: 5.4 g/day (varies depending on indication)

Acetylsalicylic acid (ASA)(effervescent)

~20 min as above 975 - 1,000 every 4 h; max: 8 (325 mg) tablets

Ibuprofen (tablet) 1 - 2 2 400 every 4 h; max: 2,400 mg

Ibuprofen (solubilized) < 1 2 400 every 4 h; max: 2,400 mg

Naproxen sodium** 2 14 500 - 550 (up to 825 mg)

twice a day; max: 1,375 mg

Diclofenac potassium (tablet)

< 1 2 50 3-4 times a day; max: 150 mg

Diclofenac potassium (powder for oral solution)

15 min 2 50 single dose recommended for migraine attack

Ketorolac (tablet)*** < 1 5 10 3-4 times a day; max: 40 mg

Table 4: Non-Steroidal Anti-Inflammatory Drugs: Pharmacokinetics and Dosage

Analgesic or NSAID (tablets)

NNT (2-h headache relief)

NNT (2-h pain-free)

Acetaminophen 1,000 mg154 5.0 12.0 ASA 900-1,000 mg14 4.9 8.1 ASA 900 mg + metoclopramide 10 mg14 3.3 8.8 Ibuprofen 400 mg9 3.2 7.2 Naproxen sodium 500-825 mg11 7.0 15.0 Diclofenac potassium (tablet)12 6.2 8.9 Diclofenac potassium powder for oral solution13,155 4.5 7.1

Table 5:Number needed to treat (NNT) for simple analgesics/NSAIDs in the acute treatment ofmigraine9,11,14,154,155

migraine drugs. In one large, double-blind, cross-over trial, thepercentage of patients with a reduction in headache severity frommoderate or severe to mild or no pain at 2 h (primary endpoint)was 52.5% for effervescent ASA 1,000 mg, 60.2% for ibuprofentablets 400 mg, 55.8% for sumatriptan 50 mg, and 30.6% forplacebo. All active treatments were superior to placebo (p <0.0001), whereas the active treatments were not statisticallydifferent from one another.10 Ibuprofen is, therefore, a well-established acute migraine headache treatment. Its strengthsinclude a short time to maximal plasma concentrations and arapid onset of action, with the solubilized formulation beingsomewhat faster than the regular tablets. Its main shortcoming isits relatively short half-life. When repeated dosing is necessary,the patient may respond better to an NSAID with a longerduration of action (e.g., naproxen sodium).

Naproxen sodium also has good evidence for efficacy inmigraine11, and is widely used. Naproxen sodium (immediaterelease formulation) is preferred to naproxen due to its fasteronset of action, and there is some evidence (one clinical trial)that the 825 mg dose is more effective than the 500 mg dose.11

Naproxen sodium may be used up to twice daily, if necessary,and its long half-life may be an advantage over other NSAIDs insome patients.

There is good evidence supporting the use of diclofenacpotassium for the acute treatment of migraine.12 As the sodiumsalt of diclofenac is only available in Canada as enteric-coated orsustained release tablets, diclofenac potassium should be used inmigraine because of a faster onset of action. Although dosesgreater than 50 mg (i.e., 100 mg) have not been shown to besuperior to the 50 mg dose, it is possible that higher doses maybenefit individual patients. Diclofenac potassium has recentlybecome available as a powder (50 mg) for oral solution. It has aTmax of 15 minutes, and has shown superiority over the regulartablet at the same dose for the pain-free at two hours endpoint inone study (p=0.0035).13 The plasma half-life for diclofenacpotassium is relatively short and similar to that of ibuprofen.

ASA in doses of 975 to 1,000 mg with or withoutmetoclopramide also has good evidence for efficacy in acutemigraine; addition of metoclopramide 10 mg improves relief ofnausea.14 Effervescent ASA has a faster onset of action thanregular tablets (Table 4), and has shown similar efficacy tosumatriptan 50 mg for the treatment of acute migraine attacks(including severe attacks).15

EXPERT CONSENSUSi. NSAIDs (including ASA) are helpful for many patients

with migraine. Although it cannot be predicted whichNSAID will be best for a specific patient, pharmacokineticdifferences between them should be considered whentreatment recommendations are made.

ii. For patients with migraine attacks that increase inintensity rapidly, diclofenac potassium powder for oralsolution, effervescent ASA, and solubilized ibuprofencapsules have a rapid onset of action and may beparticularly helpful.

iii. For patients with migraine attacks that increase inintensity rapidly, diclofenac potassium tablets have themost rapid onset of action for tablet formulations ofNSAIDs (note: diclofenac potassium powder for oral

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 migraineattacks.

2. Moderate-severe attack or NSAID failure strategiesa. NSAID with triptan rescue strategy

Clinical trials indicate that NSAIDs may be helpful forpatients with migraine of any severity, although many of theNSAID clinical trials excluded patients who frequently requiredbed rest for their attacks. For the patient with relatively severemigraine attacks, when an NSAID is tried, it may be useful toprovide a triptan as a rescue medication, should the NSAIDprove unsatisfactory. The triptan in this “step-care within attack”mode of use may also not prove entirely satisfactory as it will betaken relatively late in the attack, but nevertheless it should givethe patient some relief, and perhaps help avoid the patientbecoming a “lapsed consulter”. Patients can then decide overtime whether it is necessary to make the triptan their primaryacute medication rather than the NSAID, in which case they canstart to take it early in the attack.

Another situation where the “NSAID with triptan rescue”strategy can be useful is if the patient’s attacks usually dorespond well to an NSAID, but the NSAID occasionally fails.The patient will then use the triptan for only a relatively smallproportion of attacks. If patients have attacks of varying severityand are able to predict the eventual intensity of a developingmigraine attack, they may choose to take a triptan early only forthose attacks that they think will become severe, and an NSAIDfor those that will likely be of mild or moderate intensity. If theyare unable to predict the intensity of the developing migraineattack, the “NSAID with triptan rescue” strategy may be moresatisfactory for them.

More details on triptan use are provided in the next sectionbelow.

b. Triptan strategy This section will provide a detailed description of triptan

pharmacology and adverse events, as the triptans are veryimportant acute migraine medications and many physicians arenot as familiar with them as they are with NSAIDs. Clinical useof the triptan strategy will then be summarized. Triptans can beused with or without metoclopramide.

Triptan pharmacologyTriptans are serotonin agonists with high affinity for 5-HT1Band 5-HT1D receptors, and act on the trigeminovascular system.

Through activation of the 5-HT1D receptor, they may block therelease of vasoactive peptides from perivascular trigeminalnociceptive nerve terminals, and also inhibit synaptictransmission from primary to secondary sensory neurons in thetrigeminocervical complex. Selective vasoconstrictor effects onintracranial blood vessels through activation of 5-HT1B receptorson vascular smooth muscle also may be important in theirmigraine-abortive efficacy. Triptans may also facilitatedescending pain inhibitory systems.16,17 Almotriptan is also anagonist at the 5-HT1F receptor (shown to be effective in abortingmigraine)18, and frovatriptan at the 5-HT7 receptor (clinical

LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

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migraine drugs. In one large, double-blind, cross-over trial, thepercentage of patients with a reduction in headache severity frommoderate or severe to mild or no pain at 2 h (primary endpoint)was 52.5% for effervescent ASA 1,000 mg, 60.2% for ibuprofentablets 400 mg, 55.8% for sumatriptan 50 mg, and 30.6% forplacebo. All active treatments were superior to placebo (p <0.0001), whereas the active treatments were not statisticallydifferent from one another.10 Ibuprofen is, therefore, a well-established acute migraine headache treatment. Its strengthsinclude a short time to maximal plasma concentrations and arapid onset of action, with the solubilized formulation beingsomewhat faster than the regular tablets. Its main shortcoming isits relatively short half-life. When repeated dosing is necessary,the patient may respond better to an NSAID with a longerduration of action (e.g., naproxen sodium).

Naproxen sodium also has good evidence for efficacy inmigraine11, and is widely used. Naproxen sodium (immediaterelease formulation) is preferred to naproxen due to its fasteronset of action, and there is some evidence (one clinical trial)that the 825 mg dose is more effective than the 500 mg dose.11

Naproxen sodium may be used up to twice daily, if necessary,and its long half-life may be an advantage over other NSAIDs insome patients.

There is good evidence supporting the use of diclofenacpotassium for the acute treatment of migraine.12 As the sodiumsalt of diclofenac is only available in Canada as enteric-coated orsustained release tablets, diclofenac potassium should be used inmigraine because of a faster onset of action. Although dosesgreater than 50 mg (i.e., 100 mg) have not been shown to besuperior to the 50 mg dose, it is possible that higher doses maybenefit individual patients. Diclofenac potassium has recentlybecome available as a powder (50 mg) for oral solution. It has aTmax of 15 minutes, and has shown superiority over the regulartablet at the same dose for the pain-free at two hours endpoint inone study (p=0.0035).13 The plasma half-life for diclofenacpotassium is relatively short and similar to that of ibuprofen.

ASA in doses of 975 to 1,000 mg with or withoutmetoclopramide also has good evidence for efficacy in acutemigraine; addition of metoclopramide 10 mg improves relief ofnausea.14 Effervescent ASA has a faster onset of action thanregular tablets (Table 4), and has shown similar efficacy tosumatriptan 50 mg for the treatment of acute migraine attacks(including severe attacks).15

EXPERT CONSENSUSi. NSAIDs (including ASA) are helpful for many patients

with migraine. Although it cannot be predicted whichNSAID will be best for a specific patient, pharmacokineticdifferences between them should be considered whentreatment recommendations are made.

ii. For patients with migraine attacks that increase inintensity rapidly, diclofenac potassium powder for oralsolution, effervescent ASA, and solubilized ibuprofencapsules have a rapid onset of action and may beparticularly helpful.

iii. For patients with migraine attacks that increase inintensity rapidly, diclofenac potassium tablets have themost rapid onset of action for tablet formulations ofNSAIDs (note: diclofenac potassium powder for oral

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 migraineattacks.

2. Moderate-severe attack or NSAID failure strategiesa. NSAID with triptan rescue strategy

Clinical trials indicate that NSAIDs may be helpful forpatients with migraine of any severity, although many of theNSAID clinical trials excluded patients who frequently requiredbed rest for their attacks. For the patient with relatively severemigraine attacks, when an NSAID is tried, it may be useful toprovide a triptan as a rescue medication, should the NSAIDprove unsatisfactory. The triptan in this “step-care within attack”mode of use may also not prove entirely satisfactory as it will betaken relatively late in the attack, but nevertheless it should givethe patient some relief, and perhaps help avoid the patientbecoming a “lapsed consulter”. Patients can then decide overtime whether it is necessary to make the triptan their primaryacute medication rather than the NSAID, in which case they canstart to take it early in the attack.

Another situation where the “NSAID with triptan rescue”strategy can be useful is if the patient’s attacks usually dorespond well to an NSAID, but the NSAID occasionally fails.The patient will then use the triptan for only a relatively smallproportion of attacks. If patients have attacks of varying severityand are able to predict the eventual intensity of a developingmigraine attack, they may choose to take a triptan early only forthose attacks that they think will become severe, and an NSAIDfor those that will likely be of mild or moderate intensity. If theyare unable to predict the intensity of the developing migraineattack, the “NSAID with triptan rescue” strategy may be moresatisfactory for them.

More details on triptan use are provided in the next sectionbelow.

b. Triptan strategy This section will provide a detailed description of triptan

pharmacology and adverse events, as the triptans are veryimportant acute migraine medications and many physicians arenot as familiar with them as they are with NSAIDs. Clinical useof the triptan strategy will then be summarized. Triptans can beused with or without metoclopramide.

Triptan pharmacologyTriptans are serotonin agonists with high affinity for 5-HT1Band 5-HT1D receptors, and act on the trigeminovascular system.

Through activation of the 5-HT1D receptor, they may block therelease of vasoactive peptides from perivascular trigeminalnociceptive nerve terminals, and also inhibit synaptictransmission from primary to secondary sensory neurons in thetrigeminocervical complex. Selective vasoconstrictor effects onintracranial blood vessels through activation of 5-HT1B receptorson vascular smooth muscle also may be important in theirmigraine-abortive efficacy. Triptans may also facilitatedescending pain inhibitory systems.16,17 Almotriptan is also anagonist at the 5-HT1F receptor (shown to be effective in abortingmigraine)18, and frovatriptan at the 5-HT7 receptor (clinical

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A number of clinical trials have shown greater efficacy whena triptan is taken early in the migraine attack. It would seemlogical, therefore, to extend this observation and recommend thatpatients take their triptan during the migraine aura. Tworandomized controlled trials, however, suggest that this is notadvantageous. When subcutaneous sumatriptan was given duringthe migraine aura, 68% of patients went on to develop amoderate or severe headache within six hours, as compared to75% of patients with placebo.60 This difference was notstatistically significant, although the study had only just over 80patients in each group, and may therefore have been under-powered to detect a difference. Similarly, a study comparingeletriptan 80 mg given during the aura phase with placebo foundno significant difference in the proportion of patients developingmoderate-to-severe headache within six hours (eletriptan (61%)versus placebo (46%).61 This study was also relatively small,with just over 40 patients in each patient group. A third smallcrossover study using zolmitriptan 20 mg given during the aurafound that a migraine headache did not follow the aura in threeout of 16 patients, whereas the headache followed the aura in allpatients who took placebo.62 This small study was interpreted asshowing some promise for taking a triptan during the aura,although the response rate is clearly much lower than has beenfound in other studies when zolmitriptan is taken early in thepain phase of the headache. In summary, although all three ofthese small randomized studies showed no significant benefit ascompared to placebo when a triptan is taken during the aura,none showed any adverse effects of the triptan on the aura.

Patients do anecdotally report success with taking a triptanduring their migraine aura. These observations are difficult tointerpret, given that in the eletriptan study, 54% of patients givenplacebo did not develop a headache afterwards, and similarly inthe sumatriptan study 25% did not develop a headache afterplacebo. The randomized clinical studies would suggest thattriptan treatment during the aura is not beneficial, and thatpatients should be advised to take their triptan after the auraduring the initial part of the pain phase of their migraine. A smallrecent open label study, however, has suggested that at least forsome patients, treatment during the aura may be advantageous.Using sumatriptan RT (fast dissolving formulation), treatmentduring the aura prevented the development of headache in 89%of attacks, while treatment during the pain phase within one hourof pain onset in the same patients rendered 79% of attacks painfree.63

Triptan product monographs typically state that they arecontraindicated in patients with hemiplegic, ophthalmoplegic,and basilar migraine. These contraindications are theoretical andpresumably based on the vasoconstrictor actions of triptans,rather than on data. Given that migraine auras appear related toneurophysiological factors and not direct vasoconstriction andthe lack of evidence regarding triptan use in these syndromes, therisk which triptans pose is unclear. Clinicians need to be awareof these contraindications. Anecdotally, where they have beentried, patients with hemiplegic migraine do seem to toleratetriptans safely and find them effective.64,65

In summary, although small randomized double-blindplacebo controlled trials have given no support for triptan useduring the migraine aura, this practice appears safe in patientswith a typical aura. It would seem appropriate to recommend that

patients take their triptan early at onset of the pain phase, but ifthey find taking their triptan during their aura consistentlyeffective in preventing their headaches, there is no reason todiscourage this practice.

EXPERT CONSENSUSi. Patients with migraine with aura should be advised to take

their triptan at the onset of the pain phase, althoughtriptan treatment during typical migraine aura is safe, andif patients find that treatment during the aura is effective,there is no reason to discourage this practice.

3. Refractory migraine strategiesa. Triptan-NSAID combination strategy

The use of sumatriptan and naproxen sodium simultaneouslyto treat migraine attacks is based on several randomizedcontrolled trials which have shown that the combination is moreeffective than either drug used alone.66,67 Naproxen sodium 500mg was used in these trials, and was combined with severaldifferent sumatriptan dosages.

A sumatriptan-naproxen sodium combination tablet (notavailable in Canada) has also been compared to placebo in apatient population that had discontinued a short-acting triptan inthe previous year because of poor effectiveness or intolerance.In these randomized double-blind, placebo-controlled, two-attack crossover trials the sumatriptan-naproxen combinationtablet provided 2-h pain free results in 40 and 44% of patients inthe two trials, versus 17 and 14% for placebo.68

It would appear reasonable to apply the principle that earlytreatment during a migraine attack increases effectiveness of thesumatriptan-naproxen combination. In pooled data from twoplacebo-controlled trials, sumatriptan 85 mg combined withnaproxen sodium 500 mg taken early in the attack provided 2-hpain free results in 51.5% of patients, versus 16% for placebo.69

The sumatriptan-naproxen sodium combination has also beenshown to reduce the headache recurrence rate as compared tosumatriptan taken alone.70

Although the evidence available is largely confined tosumatriptan-naproxen sodium combinations, it would seemreasonable to generalize from this evidence to other triptan-NSAID combinations. Among NSAIDs, naproxen sodium maybe particularly suited for combining with most triptans, given itslong half-life and duration of action, but other triptan-NSAIDcombinations may also be effective. Table 9 providesinformation (doses, cautions, etc) for many medications used foracute migraine treatment.

b. Triptan-NSAID combination with rescue medicationstrategy

For some patients, triptans are effective for virtually everyattack, particularly if they are taken early when the pain is still ofmild intensity. When patients do experience occasional triptanfailure, a rescue medication can be helpful and may in somecases prevent emergency department visits. For most patients, itwould appear best to use the triptan-NSAID combinationstrategy before resorting to other rescue medications, althoughthere may be exceptions if patients have only the very occasionaltriptan failure.

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equivalent to the corresponding oral tablets except that water isnot required for ingestion.42

Sumatriptan (6 mg) by SC self-injection remains the triptanformulation with the highest overall headache response rate, andis the only formulation which guarantees complete absorption ofthe administered dose in the presence of vomiting. It alsoproduces peak serum levels more rapidly than the other triptanformulations. It should be considered when patients awaken withfully developed migraine attacks that do not respond to oraltriptans, when patients vomit early in the attack, or in generalwhen migraine attacks do not respond well to other triptanformulations. Zolmitriptan nasal spray can also be considered inthese situations, particularly in patients who are reluctant to usean injectable formulation. The triptan formulations available inCanada are shown in Table 8. Because individual patientsrespond differently in an unpredictable fashion, patients should ifnecessary try several other triptans over time, if the response totheir current triptan is not optimal.

Patients with a history of sulfonamide (sulfa) allergies usuallytolerate triptans well, including those that contain a sulfonamidemoiety or sulfonyl group. If previous reactions to sulfa drugshave been severe, there is the option of choosing triptans withouta sulfonamide or sulfonyl group in their chemical structure.Zolmitriptan, rizatriptan, and frovatriptan do not have asulfonamide moiety or sulfonyl group, whereas almotriptan andeletriptan both have a sulfonyl group, and naratriptan andsumatriptan have a sulphonamide moiety.

Triptan use with an anti-emeticAlthough the triptans will often treat associated symptoms

like nausea quite satisfactorily at the same time as they relievethe headache, there are two situations where the addition of ananti-emetic (metoclopramide or domperidone), to be takensimultaneously with the triptan, can be helpful. The first is ifnausea is so pronounced that additional medication is required tocontrol this symptom. The second is if the response to the triptanis not fully satisfactory, perhaps because of gastric stasis anddelayed absorption of the triptan. It has been demonstrated thatmigraineurs suffer from gastric stasis during an acute migraineattack, and also interictally between migraine attacks.43,44

Although parenteral metoclopramide is used to treat theheadache component of the migraine attack in the emergencydepartment, metoclopramide in oral form seems much lesseffective for that purpose, and is used primarily to treat migraine-related nausea and to improve gastric motility. Eithermetoclopramide or domperidone can be used. Metoclopramideis used much more widely in migraine, and has more evidencefor efficacy. Domperidone penetrates the CNS less, and thereforehas less potential for extrapyramidal side effects. Domperidonein high doses, particularly in older individuals, has been linkedto QT prolongation and serious cardiac arrhythmias.45,46

Does metoclopramide increase the rapidity of drug absorptionin migraine? In a small study involving ten patients, the time toreach peak plasma concentration of effervescent acetaminophenand the peak concentration reached were not changed bymetoclopramide.47 However, other studies have shown an effecton drug absorption. Metoclopramide pre-treatment in migraineattacks increased the serum concentration of tolfenamic acid at

1.5 h, but its peak concentration, time to peak concentration andthe AUC0-5 h remained unchanged as compared with the valuesobtained with tolfenamic acid alone.48

Another study concluded that the impairment of absorption ofeffervescent ASA during migraine attacks is related to impairedgastro-intestinal motility with delayed gastric emptying, and thisimpaired motility can be overcome by parenteralmetoclopramide.49 A clinical trial in which domperidone 20 mgwas added to acetaminophen concluded that domperidoneshortens the duration of a migraine attack, and may help reduceheadache and associated symptoms compared to acetaminophenalone.50 In a study involving patients who had failed to obtainadequate relief from a triptan used alone, it was found thatsumatriptan 50 mg plus metoclopramide 10 mg provided betterrelief than sumatriptan alone. It could not be differentiatedwhether this was due to central dopamine receptor antagonism orto better sumatriptan absorption.51

Metoclopramide is a substituted benzamide dopamine D2antagonist, and at higher doses also a 5-HT3 antagonist. It is alsoa gastrointestinal pro-kinetic agent through mechanisms that arenot fully understood. In addition to metoclopramide anddomperidone, other anti-emetics that have been used in migraineinclude prochlorperazine (a phenothiazine dopamine D2 receptorantagonist), and ondansetron (a 5-HT3 antagonist).Prochlorperazine intravenously is widely used in the emergencyroom setting for migraine treatment. It is also used orally (10mg) and rectally (10 - 25 mg) as an anti-emetic in migraine, butthe evidence base for its use is much smaller than that formetoclopramide, and it is more likely to cause extra-pyramidalside effects. The evidence base for use of ondansetron as an anti-emetic in migraine is very limited.

Dimenhydrinate is widely available and often used bypatients for nausea. It is a complex formulation containingdiphenhydramine (an H1 antagonist that mediates the anti-emeticeffect), and a theophylline derivative (a CNS stimulant related tocaffeine). Dimenhydrinate has some abuse potential. Given thelack of evidence for its efficacy in migraine, metoclopramide,domperidone, and possibly prochlorperazine would appear to bebetter choices for treatment of migraine-related nausea.

EXPERT CONSENSUSi. It should be recognized that the response of an individual

patient to a specific triptan cannot be predicted withaccuracy. Patients with a less than optimal response totheir current triptan should be encouraged to try severalother triptans in different migraine attacks to determine ifthey will obtain better relief.

ii. Patients should be encouraged to take their triptan earlyin their attacks while pain is still mild, although cautionmay need to be exercised in patients with frequent attacksto avoid medication overuse.

iii. For severe migraine attacks with early vomiting, the useof subcutaneous sumatriptan 6 mg should be considered.Zolmitriptan nasal spray 5 mg may be an alternativechoice for some patients. These formulations should alsobe considered for all patients with severe nausea,particularly those who have nausea early in their attacks,and for attacks not responsive to oral triptan medications.

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A number of clinical trials have shown greater efficacy whena triptan is taken early in the migraine attack. It would seemlogical, therefore, to extend this observation and recommend thatpatients take their triptan during the migraine aura. Tworandomized controlled trials, however, suggest that this is notadvantageous. When subcutaneous sumatriptan was given duringthe migraine aura, 68% of patients went on to develop amoderate or severe headache within six hours, as compared to75% of patients with placebo.60 This difference was notstatistically significant, although the study had only just over 80patients in each group, and may therefore have been under-powered to detect a difference. Similarly, a study comparingeletriptan 80 mg given during the aura phase with placebo foundno significant difference in the proportion of patients developingmoderate-to-severe headache within six hours (eletriptan (61%)versus placebo (46%).61 This study was also relatively small,with just over 40 patients in each patient group. A third smallcrossover study using zolmitriptan 20 mg given during the aurafound that a migraine headache did not follow the aura in threeout of 16 patients, whereas the headache followed the aura in allpatients who took placebo.62 This small study was interpreted asshowing some promise for taking a triptan during the aura,although the response rate is clearly much lower than has beenfound in other studies when zolmitriptan is taken early in thepain phase of the headache. In summary, although all three ofthese small randomized studies showed no significant benefit ascompared to placebo when a triptan is taken during the aura,none showed any adverse effects of the triptan on the aura.

Patients do anecdotally report success with taking a triptanduring their migraine aura. These observations are difficult tointerpret, given that in the eletriptan study, 54% of patients givenplacebo did not develop a headache afterwards, and similarly inthe sumatriptan study 25% did not develop a headache afterplacebo. The randomized clinical studies would suggest thattriptan treatment during the aura is not beneficial, and thatpatients should be advised to take their triptan after the auraduring the initial part of the pain phase of their migraine. A smallrecent open label study, however, has suggested that at least forsome patients, treatment during the aura may be advantageous.Using sumatriptan RT (fast dissolving formulation), treatmentduring the aura prevented the development of headache in 89%of attacks, while treatment during the pain phase within one hourof pain onset in the same patients rendered 79% of attacks painfree.63

Triptan product monographs typically state that they arecontraindicated in patients with hemiplegic, ophthalmoplegic,and basilar migraine. These contraindications are theoretical andpresumably based on the vasoconstrictor actions of triptans,rather than on data. Given that migraine auras appear related toneurophysiological factors and not direct vasoconstriction andthe lack of evidence regarding triptan use in these syndromes, therisk which triptans pose is unclear. Clinicians need to be awareof these contraindications. Anecdotally, where they have beentried, patients with hemiplegic migraine do seem to toleratetriptans safely and find them effective.64,65

In summary, although small randomized double-blindplacebo controlled trials have given no support for triptan useduring the migraine aura, this practice appears safe in patientswith a typical aura. It would seem appropriate to recommend that

patients take their triptan early at onset of the pain phase, but ifthey find taking their triptan during their aura consistentlyeffective in preventing their headaches, there is no reason todiscourage this practice.

EXPERT CONSENSUSi. Patients with migraine with aura should be advised to take

their triptan at the onset of the pain phase, althoughtriptan treatment during typical migraine aura is safe, andif patients find that treatment during the aura is effective,there is no reason to discourage this practice.

3. Refractory migraine strategiesa. Triptan-NSAID combination strategy

The use of sumatriptan and naproxen sodium simultaneouslyto treat migraine attacks is based on several randomizedcontrolled trials which have shown that the combination is moreeffective than either drug used alone.66,67 Naproxen sodium 500mg was used in these trials, and was combined with severaldifferent sumatriptan dosages.

A sumatriptan-naproxen sodium combination tablet (notavailable in Canada) has also been compared to placebo in apatient population that had discontinued a short-acting triptan inthe previous year because of poor effectiveness or intolerance.In these randomized double-blind, placebo-controlled, two-attack crossover trials the sumatriptan-naproxen combinationtablet provided 2-h pain free results in 40 and 44% of patients inthe two trials, versus 17 and 14% for placebo.68

It would appear reasonable to apply the principle that earlytreatment during a migraine attack increases effectiveness of thesumatriptan-naproxen combination. In pooled data from twoplacebo-controlled trials, sumatriptan 85 mg combined withnaproxen sodium 500 mg taken early in the attack provided 2-hpain free results in 51.5% of patients, versus 16% for placebo.69

The sumatriptan-naproxen sodium combination has also beenshown to reduce the headache recurrence rate as compared tosumatriptan taken alone.70

Although the evidence available is largely confined tosumatriptan-naproxen sodium combinations, it would seemreasonable to generalize from this evidence to other triptan-NSAID combinations. Among NSAIDs, naproxen sodium maybe particularly suited for combining with most triptans, given itslong half-life and duration of action, but other triptan-NSAIDcombinations may also be effective. Table 9 providesinformation (doses, cautions, etc) for many medications used foracute migraine treatment.

b. Triptan-NSAID combination with rescue medicationstrategy

For some patients, triptans are effective for virtually everyattack, particularly if they are taken early when the pain is still ofmild intensity. When patients do experience occasional triptanfailure, a rescue medication can be helpful and may in somecases prevent emergency department visits. For most patients, itwould appear best to use the triptan-NSAID combinationstrategy before resorting to other rescue medications, althoughthere may be exceptions if patients have only the very occasionaltriptan failure.

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discussed with the patient. This may include a rescuemedication to be taken at home when their usualmedication fails.

iv. In providing a rescue medication, the patient needs to becarefully assessed, and the medication tailored as much aspossible to the patient’s needs. For parenteralformulations, careful patient training is essential, andconsideration should be given as to whether the patientcan safely administer the medication.

v. For many rescue medications, in particular opioids anddexamethasone, frequency of use should be carefullymonitored to ensure patient safety, and in the case ofopioids to avoid medication overuse headache, abuse,dependence and possible addiction.

vi. Rescue medications that can be considered, either aloneor in combination, include:a. NSAIDs with or without an anti-emetic, includingketorolac 60 mg by IM self-injection and rectalindomethacin b. Dopamine antagonists including prochlorperazinesuppositoriesc. Oral dexamethasone or another steroid, either as asingle dose or a short steroid taper over several days

d. Tramadol or codeine-containing combinationanalgesics (limit use to not more than 9 days a month)e. Other opioids (suggest limiting use to not more thanseven days per month)

vii.Migraine attack preventive management options, bothpharmacological and behavioural, should be consideredfor all patients where acute therapy is not adequatelysuccessful or the patient is at risk of medication overuseheadache.

c. Dihydroergotamine strategyDihydroergotamine (DHE)

Dihydroergotamine (DHE) has a similar mode of action to thetriptans, and is a 5HT1B and 5HT1D agonist. Unlike the triptans,it also acts on a number of other receptor subtypes, and this maybe why some patients who do not respond well to the triptansrespond to DHE. Dihydroergotamine is also associated with alower headache recurrence rate than most triptans. BecauseDHE, like other ergotamines, is a vasoconstrictor, it is not anoption as a rescue medication for triptan failure unless 24 hourshave elapsed since the triptan was last taken.93-95

Dihydroergotamine is an option for primary therapy forpatients without contraindications who do not respond well to

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*For additional information on drug dosages, etc, see discussion of Strategy 3b: Triptan-NSAID combinationwith rescue medication strategy.

Potential rescue medications in patients with occasional triptan failure (or failure of triptan-NSAID

c

Medication

Comments

NSAIDs:

Oral naproxen sodium, ibuprofen, or diclofenac potassium

(all may be combined with oral metoclopramide or

oral/rectal prochlorperazine)

Less likely to be effective as a rescue medication

Ketorolac (60 mg) IM Requires patient training in safe injection technique

Indomethacin oral or rectal with or without

prochlorperazine

Limited evidence

Dopamine antagonists:

Prochlorperazine oral or rectal May be used in combination with NSAIDs

Chlorpromazine oral Sedation and anti-emetic properties may be useful

Steroids:

Dexamethasone / prednisone oral Limited evidence. Limit to short courses (single dose or

several days), and limit frequency of use.

Opioids:

Combination analgesics with tramadol Monitor use – risk of medication overuse – limit to 9

days a month or less

Combination analgesics with codeine Monitor use – risk of medication overuse – limit to 9

days a month or less

Intranasal butorphanol Best avoided - monitor frequency of use closely – high

risk of addiction, medication overuse – select patients

carefully, limit use to no more than 7 days a month

Combination analgesics with barbiturates Best avoided, use only in exceptional circumstances –

monitor use – high risk of addiction, medication overuse

Strong opioids (morphine, hydromorphone, oxycodone) Best avoided, use only in exceptional circumstances –

monitor use – high risk of addiction, medication overuse,

limit to no more than 7 days a month

Triptan-NSAID combination with

r

Table 10: Potential rescue medications in patients with occasional triptan failure (or failure oftriptan-NSAID combination therapy)*

A number of clinical trials have shown greater efficacy whena triptan is taken early in the migraine attack. It would seemlogical, therefore, to extend this observation and recommend thatpatients take their triptan during the migraine aura. Tworandomized controlled trials, however, suggest that this is notadvantageous. When subcutaneous sumatriptan was given duringthe migraine aura, 68% of patients went on to develop amoderate or severe headache within six hours, as compared to75% of patients with placebo.60 This difference was notstatistically significant, although the study had only just over 80patients in each group, and may therefore have been under-powered to detect a difference. Similarly, a study comparingeletriptan 80 mg given during the aura phase with placebo foundno significant difference in the proportion of patients developingmoderate-to-severe headache within six hours (eletriptan (61%)versus placebo (46%).61 This study was also relatively small,with just over 40 patients in each patient group. A third smallcrossover study using zolmitriptan 20 mg given during the aurafound that a migraine headache did not follow the aura in threeout of 16 patients, whereas the headache followed the aura in allpatients who took placebo.62 This small study was interpreted asshowing some promise for taking a triptan during the aura,although the response rate is clearly much lower than has beenfound in other studies when zolmitriptan is taken early in thepain phase of the headache. In summary, although all three ofthese small randomized studies showed no significant benefit ascompared to placebo when a triptan is taken during the aura,none showed any adverse effects of the triptan on the aura.

Patients do anecdotally report success with taking a triptanduring their migraine aura. These observations are difficult tointerpret, given that in the eletriptan study, 54% of patients givenplacebo did not develop a headache afterwards, and similarly inthe sumatriptan study 25% did not develop a headache afterplacebo. The randomized clinical studies would suggest thattriptan treatment during the aura is not beneficial, and thatpatients should be advised to take their triptan after the auraduring the initial part of the pain phase of their migraine. A smallrecent open label study, however, has suggested that at least forsome patients, treatment during the aura may be advantageous.Using sumatriptan RT (fast dissolving formulation), treatmentduring the aura prevented the development of headache in 89%of attacks, while treatment during the pain phase within one hourof pain onset in the same patients rendered 79% of attacks painfree.63

Triptan product monographs typically state that they arecontraindicated in patients with hemiplegic, ophthalmoplegic,and basilar migraine. These contraindications are theoretical andpresumably based on the vasoconstrictor actions of triptans,rather than on data. Given that migraine auras appear related toneurophysiological factors and not direct vasoconstriction andthe lack of evidence regarding triptan use in these syndromes, therisk which triptans pose is unclear. Clinicians need to be awareof these contraindications. Anecdotally, where they have beentried, patients with hemiplegic migraine do seem to toleratetriptans safely and find them effective.64,65

In summary, although small randomized double-blindplacebo controlled trials have given no support for triptan useduring the migraine aura, this practice appears safe in patientswith a typical aura. It would seem appropriate to recommend that

patients take their triptan early at onset of the pain phase, but ifthey find taking their triptan during their aura consistentlyeffective in preventing their headaches, there is no reason todiscourage this practice.

EXPERT CONSENSUSi. Patients with migraine with aura should be advised to take

their triptan at the onset of the pain phase, althoughtriptan treatment during typical migraine aura is safe, andif patients find that treatment during the aura is effective,there is no reason to discourage this practice.

3. Refractory migraine strategiesa. Triptan-NSAID combination strategy

The use of sumatriptan and naproxen sodium simultaneouslyto treat migraine attacks is based on several randomizedcontrolled trials which have shown that the combination is moreeffective than either drug used alone.66,67 Naproxen sodium 500mg was used in these trials, and was combined with severaldifferent sumatriptan dosages.

A sumatriptan-naproxen sodium combination tablet (notavailable in Canada) has also been compared to placebo in apatient population that had discontinued a short-acting triptan inthe previous year because of poor effectiveness or intolerance.In these randomized double-blind, placebo-controlled, two-attack crossover trials the sumatriptan-naproxen combinationtablet provided 2-h pain free results in 40 and 44% of patients inthe two trials, versus 17 and 14% for placebo.68

It would appear reasonable to apply the principle that earlytreatment during a migraine attack increases effectiveness of thesumatriptan-naproxen combination. In pooled data from twoplacebo-controlled trials, sumatriptan 85 mg combined withnaproxen sodium 500 mg taken early in the attack provided 2-hpain free results in 51.5% of patients, versus 16% for placebo.69

The sumatriptan-naproxen sodium combination has also beenshown to reduce the headache recurrence rate as compared tosumatriptan taken alone.70

Although the evidence available is largely confined tosumatriptan-naproxen sodium combinations, it would seemreasonable to generalize from this evidence to other triptan-NSAID combinations. Among NSAIDs, naproxen sodium maybe particularly suited for combining with most triptans, given itslong half-life and duration of action, but other triptan-NSAIDcombinations may also be effective. Table 9 providesinformation (doses, cautions, etc) for many medications used foracute migraine treatment.

b. Triptan-NSAID combination with rescue medicationstrategy

For some patients, triptans are effective for virtually everyattack, particularly if they are taken early when the pain is still ofmild intensity. When patients do experience occasional triptanfailure, a rescue medication can be helpful and may in somecases prevent emergency department visits. For most patients, itwould appear best to use the triptan-NSAID combinationstrategy before resorting to other rescue medications, althoughthere may be exceptions if patients have only the very occasionaltriptan failure.

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The Art and Science of Evaluating and

Treating Migraine

THANK YOU

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THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

Suppl. 3 - S58

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 32

nd 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

Fédérationdes sciencesneurologiquesdu Canada

canadianneurologicalsciencesFederation

Thejournal

Canadian Journal of Neurological Sciences

The official Journal of: The Canadian Neurological Society, The Canadian Neurosurgical Society, TheCanadian Society of Clinical Neurophysiologists, The Canadian Association of Child Neurology

PM 40007777 R 9824

AN INTERNATIONAL JOURNAL PUBLISHED BY THE CANADIAN NEUROLOGICAL SCIENCES FEDERATION

Volume 40 Number 5 (Supplement 3) September 2013

Canadian Headache Society GuidelineAcute Drug Therapy for Migraine Headache

A Peer-reviewed SUPPLEMENT to The Canadian Journal of Neurological Sciences