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  • 1. The Art and Science of Evaluating and Treating Migraine Ryan J Punambolam MD, FRCPC Neurology Abbotsford Regional Hospital ! ! Medicine Grand Rounds April 9, 2014.
  • 2. Disclosure Advisory Board or Similar Committee None Clinical Trials or Studies None Honoraria or Other Fees Bayer, Sanofi-Aventis, Allergan, Tribute Phamaceuticals Research Grants No conflicts
  • 3. Migraine Backgrounder The Art and Science of Evaluating and Treating Migraine
  • 4. Case Vignette (Peter) Initial Consult • 25-year-old obese (BMI=35) man who presents to his primary care doctor with a four year history of headache Frequency • Two attacks per month Prodrome • Dysphoric mood Aura • Zig-zag lines and a graying of vision in a visual field Pain • Unilateral (R>L) throbbing severe pain lasting 24 hours untreated Symptoms • Nausea, photophobia, unable to function Treatment • Excedrin Migraine up to six per day Exam • WNL (within normal limits) Diagnosis • ?
  • 5. Primary or Secondary Headache? Detailed History and Examination No Yes Any unusualfeatures? Evaluate for Secondary Headache Red Flags? Diagnose Primary Headache Disorder Step 1
  • 6. S Systemic signs or symptoms Fever, weight loss, malignancy, HIV, meningismus, pregnancy N Neurologic signs or symptoms Papilledema, hemiparesis, hemi- sensory loss, diplopia, dysarthria O Onset “Worst headache of life” (thunderclap) O Older New headache at age ≥50 P Progression of existing headache disorder Change in quality, frequency, or location 13. Dodick DW. Adv Stud Med 2003;3:S550-S555. Red Flags in Headache: “SNOOP”
  • 7. 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
  • 8. 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
  • 9. Diagnose the Specific Disorder 
 Within the Category Differential Diagnosis Step 3 te example of inherited migraine on of missense mutations in the he gene for the P/Q type, voltage nel on chromosome 19 in families legic migraine.w1 Since then, other miplegic migraine have been found ations in the ATP1A2 gene, which unit of the Na+ /K+ pump,w2 and in for the neuronal voltage-gated age is of migraine as an ionopathy, n abnormal ion channels whose nd anatomical distribution in the clinical phenotype. If genetics can have headaches and what the bio- may be, then we can ask the the problem?” or, framed in the rology, “Where is the lesion?” y of headache—where is s promulgated by Gowers, sought cal answers to clinical questions. een successful, but the problems of e will need a physiological ome extent, human functional this. d ’70s migraine was considered a on and is still often referred to cular headache. Wolff summarised the referral patterns of structures on ≥ 15 days a month for more than six months,3 the same area of the dorsolateral pons is activated,16 suggesting that infrequent and frequent migraine are ends of a shared spectrum. Use of blood oxygen level dependent (BOLD) contrast functional magnetic reso- nance imaging holds the promise of studying single patients and determining the site of abnormal activation.w7 Moreover, magnetic resonance angiogra- phy has shown that the blood flow changes seen in migraine14 and cluster headache10 are simply a result of ophthalmic division pain,17 18 not a cause of the syndrome. Table 1 Differentiating migraine from tension-type headache Characteristics Migraine Tension-type headache Pain features of acute attacks Throbbing Boring or squashing Unilateral Bilateral Worsening of pain with movement No effect of head movement Associated features Nausea or vomiting None Photophobia and phonophobia Triggering factors Altered sleep patterns (too little or too much) Psychological stress Skipping meals Overexertion Change in stress level (too much or relaxation) Excess afferent stimuli (such as bright lights) Weather change Chemical (delayed headache after alcohol or glyceryl trinitrate) Menstruation 27NUARY 2006 bmj.com
  • 10. 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.
  • 11. 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 □
  • 12. 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.
  • 13. Pain Pathways in the Head 18. Goadsby PJ. et al. J Clin Neurosci 2000 Jul; 7(4):377.
  • 14. Peter also has “Classic Migraine” Migraine with Aura" " "
  • 15. Prevalence of Migraine and 
 Tension-type Headache in Various Settings 0 20 40 60 80 Population Waiting Room 16 40 75 12 Migraine Tension-Type Headache "28. Lipton RB et al. Neurology 2003;61(3):375–382. Percent
  • 16. 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%
  • 17. 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
  • 18. Planning and Management Strategies The Art and Science of Evaluating and Treating Migraine Step 4
  • 19. What might be your preliminary treatment recommendation for Peter? Back to Peter…
  • 20. Formulate a Specific Treatment Plan Non-pharmacologic approaches • Trigger identification and management ➢Identify triggers by history ➢Headache diaries • Education and enhance self-efficacy • Biofeedback and cognitive behavioural treatment Specific Treatment Plan Step 4
  • 21. 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.
  • 22. 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.
  • 23. Acute Pharmacotherapy:
 What Do Patients Want? Patients Rating Attribute as Important or Very Important (%) 78 80 83 85 87 87 86 83 79 30. Lipton RB, Stewart WF. Headache 1999;39(Suppl 2):S20-S26. No Side
 Effects Rapid
 Relief No
 Recurrence Complete
 Relief Treatment Attributes Patients Choosing Route of Administration as 1st Choice (%) 0 20 40 60 80 2.6 73 15 8.3 Nasal
 Spray Rapidly
 Dissolving Tablet Tablet or
 Capsule SC Injection Route of Administration
  • 24. 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.
  • 25. 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.
  • 26. 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
  • 27. 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
  • 28. 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
  • 29. Case Vignette Continued • Peter was started on sumatriptan 50 mg po " • Returned to his PCP saying that the treatment “does not work” Now What?
  • 30. “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
  • 31. 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
  • 32. Treatment Options In Migraine The Art and Science of Evaluating and Treating Migraine
  • 33. MILD: NSAIDS +/- METOCLOPRAMIDE MOD-SEVERE: TRIPTANS +/- NSAIDS
  • 34. riptan linical prefer erence both. . It is ts are riptan vidual he one o have extent ore be of pain dache tential l be to * Adapted from: Bandolier (http://www.medicine.ox.ac.uk/bandolier) except as noted; ** Note: Migraine attacks were treated at moderate or severe intensity. NNTs may be lower for individual drugs when treat- Drug and dosage Route NNT (for 2-h pain-free vs. placebo)** Sumatriptan 6 mg subcutaneous 2.3158 Sumatriptan 20 mg intranasal 4.7159 Zolmitriptan 5 mg intranasal 4.631 Almotriptan 12.5 oral 4.3160 Eletriptan 20 mg oral 10 Eletriptan 40 mg oral 4.5 Frovatriptan 2.5 mg oral 8.5161 Naratriptan 2.5 mg oral 8.2 Rizatriptan 10 mg oral 3.1 Sumatriptan 50 mg oral 6.1162 Sumatriptan 100 mg oral 4.7162 Zolmitriptan 2.5 mg oral 5.9 Migraine attacks were treated at moderate or severe intensity. NNTs may be lower for individual Table 7: Triptans – Number Needed to Treat (NNT) for pain- free response at 2 h in migraine*31,158-162
  • 35. Pain Pathways in the Head 18. Goadsby PJ. et al. J Clin Neurosci 2000 Jul; 7(4):377.
  • 36. 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.
  • 37. 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
  • 38. 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.
  • 39. 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
  • 40. 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
  • 41. Pharmacokinetics 11.Data on file. Nautilus Neurosciences, Inc. .
 0 1 2 3 4 0 200 400 600 800 1000 1200 1400 1600 Time (hours) DiclofenacPlasmaConcentration(ng/mL) diclofenac potassium for oral solution diclofenac potassium immediate release tablets 15 minutes: diclofenac potassium for oral solution 15 minutes tablets • Tmax: measurable plasma levels within 5 minutes of dosing, with a peak at 15 minutes • Cmax: approximately 4-fold higher concentration at ~15 minutes • AUC: similar total systemic drug exposure • Minimally impacted by gastroparesis
  • 42. 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
  • 43. 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.
  • 44. PercentageofPatients Column1 0% 7% 13% 20% 26% CAMBIA placebo P<.001 Pain Free at Two Hours 29. Lipton, RB, Grosberg, B, Singer, RP, et al. Cephalalgia 2010;30(11):1336-45. 15. Ferrari MD, et al. Lancet 2001; 358(9294):1668-75. Therapeutic Gain: 15% suma 100 mg15 Therapeutic Gain: 19% Absolute: 29%
  • 45. Column1 6% 25% 43% 62% 80% CAMBIA placebo 7.2% 19.0% PercentageofPatients P<.001 Sustained Pain Free through 24 Hours 29. Lipton, RB, Grosberg, B, Singer, RP, et al. Cephalalgia 2010;30(11):1336-45. 15. Ferrari MD, et al. Lancet 2001; 358(9294):1668-75. suma 100 mg15 Absolute: 20%
  • 46. 15. Ferrari MD, et al. Cephalalgia 2002;22(8):633-658. 12. Diener, HC, Montagna, P, Gács, G et al. Cephalalgia 2006;26(5):537- 47. headache recurrence rate (2-24 hours) mean=30%; 
 95% CI; 27-33 n=24,089 Few patients
 experienced
 recurrence at 
 24 and 48 hours12 diclofenac potassium for oral solution recurrence rates12
  • 47. EU Study: Onset Of Analgesic Effect 60 50 40 30 20 10 0 diclofenac potassium tablets diclofenac potassium for oral solution 15 minutes 60 minutes 12. Diener, HC, Montagna, P, Gács, G et al. Cephalalgia 2006;26(5):537- 47. Postdosetimeinminutes
  • 48. Summary The Art and Science of Evaluating and Treating Migraine
  • 49. 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
  • 50. CAMBIA for rapid onset pain, severe nausea recommended when an anti-nauseant is needed, as more evidence is available for efficacy for this drug than for the related medication, domperidone. Domperidone can also be used, and may have fewer side effects; however, domperidone may be associated with QT prolongation in some patients. 1. Mild to moderate attack strategies For patients with attacks that are not disabling (i.e., attacks do not require bed rest, and do not stop participation in activities, although it may be somewhat difficult for the patient to continue), the following two strategies may be most appropriate: a. Acetaminophen strategy This strategy simply involves the use of acetaminophen 1,000 mg, as needed. It can be used alone, or in combination with metoclopramide 10 mg (or domperidone 10 mg). Acetaminophen has the advantage of fewer gastrointestinal side effects than NSAIDs, and has been shown to be superior to placebo in the acute treatment of migraine attacks.2,3 Acetaminophen is considered to be less effective than NSAIDs for acute migraine treatment; and there is some limited randomized controlled data to support this in pediatric patients4, and in adults.5 Acetaminophen is thought to act primarily centrally, and inhibits prostaglandin synthesis is neurons. Because it is unable to inhibit prostaglandin synthesis in leukocytes and platelets, it does not have anti-inflammatory or anti-platelet activity. Acetaminophen-induced analgesia is blocked by CB1 receptor antagonists, suggesting that it also acts through cannabinoid ough y be It is o the drug erred aking erity, ld be remains eatment ) should triptan- casional dication. l, rectal, ne (oral, adol or refully). ly to an e (nasal amide (if use in codeine sfactory tored ment associated with QT prolongation in some patients. 1. Mild to moderate attack strategies For patients with attacks that are not disabling (i.e., attacks do not require bed rest, and do not stop participation in activities, although it may be somewhat difficult for the patient to continue), the following two strategies may be most appropriate: a. Acetaminophen strategy This strategy simply involves the use of acetaminophen 1,000 mg, as needed. It can be used alone, or in combination with metoclopramide 10 mg (or domperidone 10 mg). Acetaminophen has the advantage of fewer gastrointestinal side effects than NSAIDs, and has been shown to be superior to placebo in the acute treatment of migraine attacks.2,3 Acetaminophen is considered to be less effective than NSAIDs for acute migraine treatment; and there is some limited randomized controlled data to support this in pediatric patients4, and in adults.5 Acetaminophen is thought to act primarily centrally, and inhibits prostaglandin synthesis is neurons. Because it is unable to inhibit prostaglandin synthesis in leukocytes and platelets, it does not have anti-inflammatory or anti-platelet activity. Acetaminophen-induced analgesia is blocked by CB1 receptor antagonists, suggesting that it also acts through cannabinoid receptors.6 It has a relatively short elimination half-life of 2 - 3 h, so repeated dosing may be necessary for a sustained analgesic effect. Maximum plasma concentrations of acetaminophen are reached within 30 - 60 minutes. The usual recommended dose for analgesia is 650 - 1,000 mg (a dose of 1,000 mg is recommended for migraine). This can be repeated every four to six hours, with a maximum of 4,000 mg per 24 hours. monitored treatment option for ctor drugs ne treatment. ent clinical priately. The reached within 30 - 60 minutes. The usual recommended dose for analgesia is 650 - 1,000 mg (a dose of 1,000 mg is recommended for migraine). This can be repeated every four to six hours, with a maximum of 4,000 mg per 24 hours. EXPERT CONSENSUS i. Acetaminophen is an effective option for acute migraine therapy for some patients with attacks of mild to moderate intensity. b. NSAID strategy A number of commonly used NSAIDs have high quality evidence for efficacy for acute migraine treatment. These include ASA, ibuprofen, naproxen sodium, and diclofenac potassium. Suppl. 3 - S37 for oral solution may be especially useful because of more rapid oral absorption (see Table 4). Supp Analgesic or NSAID (tablets) NN Acetaminophen 1,000 mg154 5.0 ASA 900-1,000 mg14 4.9 ASA 900 mg + metoclopramide 10 mg14 3.3 Ibuprofen 400 mg9 3.2 Naproxen sodium 500-825 mg11 7.0 Diclofenac potassium (tablet)12 6.2 Diclofenac potassium powder for oral solution13,155 4.5 Table 5:Number needed to treat (NNT) for sim migraine9,11,14,154,155 solution has a more rapid oral absorption than tablets). iv. The long plasma half-life of naproxen sodium may make it particularly helpful for patients with prolonged migraine attacks. 2. Moderate-severe attack or NSAID failure strategies a. NSAID with triptan rescue strategy Clinical trials indicate that NSAIDs may be helpful for patients with migraine of any severity, although many of the NSAID clinical trials excluded patients who frequently required bed rest for their attacks. For the patient with relatively severe migraine attacks, when an NSAID is tried, it may be useful to provide a triptan as a rescue medication, should the NSAID prove unsatisfactory. The triptan in this “step-care within attack” mode of use may also not prove entirely satisfactory as it will be taken relatively late in the attack, but nevertheless it should give the patient some relief, and perhaps help avoid the patient becoming a “lapsed consulter”. Patients can then decide over LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES he om nt) en or < lly ll- hs a ng is ry, ger in ate ter al) .11 solution has a more rapid oral absorption than tablets). iv. The long plasma half-life of naproxen sodium may make it particularly helpful for patients with prolonged migraine attacks. 2. Moderate-severe attack or NSAID failure strategies a. NSAID with triptan rescue strategy Clinical trials indicate that NSAIDs may be helpful for patients with migraine of any severity, although many of the NSAID clinical trials excluded patients who frequently required bed rest for their attacks. For the patient with relatively severe migraine attacks, when an NSAID is tried, it may be useful to provide a triptan as a rescue medication, should the NSAID prove unsatisfactory. The triptan in this “step-care within attack” mode of use may also not prove entirely satisfactory as it will be taken relatively late in the attack, but nevertheless it should give the patient some relief, and perhaps help avoid the patient becoming a “lapsed consulter”. Patients can then decide over time whether it is necessary to make the triptan their primary LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES en em hat wo not ng a to not 80 er- ng nd ng %) all, all ura ree all as ra, en he of as ra, patients take their triptan early at onset of the pain phase, but if they find taking their triptan during their aura consistently effective in preventing their headaches, there is no reason to discourage this practice. EXPERT CONSENSUS i. Patients with migraine with aura should be advised to take their triptan at the onset of the pain phase, although triptan treatment during typical migraine aura is safe, and if patients find that treatment during the aura is effective, there is no reason to discourage this practice. 3. Refractory migraine strategies a. Triptan-NSAID combination strategy The use of sumatriptan and naproxen sodium simultaneously to treat migraine attacks is based on several randomized controlled trials which have shown that the combination is more effective than either drug used alone.66,67 Naproxen sodium 500 mg was used in these trials, and was combined with several different sumatriptan dosages. A sumatriptan-naproxen sodium combination tablet (not available in Canada) has also been compared to placebo in a patient population that had discontinued a short-acting triptan in the previous year because of poor effectiveness or intolerance. In these randomized double-blind, placebo-controlled, two- attack crossover trials the sumatriptan-naproxen combination LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES is the only formulation which guarantees complete absorption of the administered dose in the presence of vomiting. It also produces peak serum levels more rapidly than the other triptan formulations. It should be considered when patients awaken with fully developed migraine attacks that do not respond to oral triptans, when patients vomit early in the attack, or in general when migraine attacks do not respond well to other triptan formulations. Zolmitriptan nasal spray can also be considered in these situations, particularly in patients who are reluctant to use an injectable formulation. The triptan formulations available in Canada are shown in Table 8. Because individual patients respond differently in an unpredictable fashion, patients should if necessary try several other triptans over time, if the response to their current triptan is not optimal. Patients with a history of sulfonamide (sulfa) allergies usually tolerate triptans well, including those that contain a sulfonamide moiety or sulfonyl group. If previous reactions to sulfa drugs have been severe, there is the option of choosing triptans without a sulfonamide or sulfonyl group in their chemical structure. Zolmitriptan, rizatriptan, and frovatriptan do not have a sulfonamide moiety or sulfonyl group, whereas almotriptan and eletriptan both have a sulfonyl group, and naratriptan and sumatriptan have a sulphonamide moiety. Triptan use with an anti-emetic Although the triptans will often treat associated symptoms like nausea quite satisfactorily at the same time as they relieve the headache, there are two situations where the addition of an anti-emetic (metoclopramide or domperidone), to be taken simultaneously with the triptan, can be helpful. The first is if nausea is so pronounced that additional medication is required to control this symptom. The second is if the response to the triptan is not fully satisfactory, perhaps because of gastric stasis and delayed absorption of the triptan. It has been demonstrated that migraineurs suffer from gastric stasis during an acute migraine effervescent ASA during migraine attacks is rela gastro-intestinal motility with delayed gastric emp impaired motility can be overcome b metoclopramide.49 A clinical trial in which domp was added to acetaminophen concluded that shortens the duration of a migraine attack, and m headache and associated symptoms compared to alone.50 In a study involving patients who had f adequate relief from a triptan used alone, it w sumatriptan 50 mg plus metoclopramide 10 mg relief than sumatriptan alone. It could not be whether this was due to central dopamine receptor to better sumatriptan absorption.51 Metoclopramide is a substituted benzamide antagonist, and at higher doses also a 5-HT3 antag a gastrointestinal pro-kinetic agent through mech not fully understood. In addition to metocl domperidone, other anti-emetics that have been u include prochlorperazine (a phenothiazine dopam antagonist), and ondansetron (a 5-HT3 Prochlorperazine intravenously is widely used in room setting for migraine treatment. It is also u mg) and rectally (10 - 25 mg) as an anti-emetic i the evidence base for its use is much smaller metoclopramide, and it is more likely to cause e side effects. The evidence base for use of ondanse emetic in migraine is very limited. Dimenhydrinate is widely available and o patients for nausea. It is a complex formulat diphenhydramine (an H1 antagonist that mediates effect), and a theophylline derivative (a CNS stim caffeine). Dimenhydrinate has some abuse poten lack of evidence for its efficacy in migraine, m domperidone, and possibly prochlorperazine wou better choices for treatment of migraine-related n patients take their triptan early at onset of the pain phase, but if they find taking their triptan during their aura consistently effective in preventing their headaches, there is no reason to discourage this practice. EXPERT CONSENSUS i. Patients with migraine with aura should be advised to take their triptan at the onset of the pain phase, although triptan treatment during typical migraine aura is safe, and if patients find that treatment during the aura is effective, there is no reason to discourage this practice. 3. Refractory migraine strategies a. Triptan-NSAID combination strategy The use of sumatriptan and naproxen sodium simultaneously LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES ketorolac 60 mg by IM self-injectio indomethacin b. Dopamine antagonists including pro suppositories c. Oral dexamethasone or another steroi single dose or a short steroid taper over se Potential rescue medic c Medication NSAIDs: Oral naproxen sodium, ibuprofen, o (all may be combined with oral met oral/rectal prochlorperazine) Ketorolac (60 mg) IM Indomethacin oral or rectal with or prochlorperazine Dopamine antagonists: Table 10: Potential rescue m triptan-NSAID combinati hough the response rate is clearly much lower than has been und in other studies when zolmitriptan is taken early in the in phase of the headache. In summary, although all three of ese small randomized studies showed no significant benefit as mpared to placebo when a triptan is taken during the aura, ne showed any adverse effects of the triptan on the aura. Patients do anecdotally report success with taking a triptan ring their migraine aura. These observations are difficult to terpret, given that in the eletriptan study, 54% of patients given acebo did not develop a headache afterwards, and similarly in e sumatriptan study 25% did not develop a headache after acebo. The randomized clinical studies would suggest that ptan treatment during the aura is not beneficial, and that tients should be advised to take their triptan after the aura ring the initial part of the pain phase of their migraine. A small cent open label study, however, has suggested that at least for me patients, treatment during the aura may be advantageous. sing sumatriptan RT (fast dissolving formulation), treatment ring the aura prevented the development of headache in 89% attacks, while treatment during the pain phase within one hour pain onset in the same patients rendered 79% of attacks pain ee.63 Triptan product monographs typically state that they are ntraindicated in patients with hemiplegic, ophthalmoplegic, d basilar migraine. These contraindications are theoretical and esumably based on the vasoconstrictor actions of triptans, ther than on data. Given that migraine auras appear related to urophysiological factors and not direct vasoconstriction and e lack of evidence regarding triptan use in these syndromes, the k which triptans pose is unclear. Clinicians need to be aware these contraindications. Anecdotally, where they have been ed, patients with hemiplegic migraine do seem to tolerate A sumatriptan-naproxen sodium combination available in Canada) has also been compared to p patient population that had discontinued a short-actin the previous year because of poor effectiveness or In these randomized double-blind, placebo-contr attack crossover trials the sumatriptan-naproxen c tablet provided 2-h pain free results in 40 and 44% o the two trials, versus 17 and 14% for placebo.68 It would appear reasonable to apply the principl treatment during a migraine attack increases effectiv sumatriptan-naproxen combination. In pooled data placebo-controlled trials, sumatriptan 85 mg com naproxen sodium 500 mg taken early in the attack p pain free results in 51.5% of patients, versus 16% fo The sumatriptan-naproxen sodium combination h shown to reduce the headache recurrence rate as c sumatriptan taken alone.70 Although the evidence available is largely c sumatriptan-naproxen sodium combinations, it w reasonable to generalize from this evidence to ot NSAID combinations. Among NSAIDs, naproxen s be particularly suited for combining with most tripta long half-life and duration of action, but other trip combinations may also be effective. Table 9 information (doses, cautions, etc) for many medicatio acute migraine treatment. b. Triptan-NSAID combination with rescue strategy For some patients, triptans are effective for virt attack, particularly if they are taken early when the pa mild intensity. When patients do experience occasi
  • 51. The Art and Science of Evaluating and Treating Migraine THANK YOU
  • 52. Bibliography References: 1. Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison to oral sumatriptan and placebo. The Diclofenac-K/Sumatriptan Migraine Study Group. Cephalalgia 1999;19(4):232-240. 2. Aurora SK, Kori SH, Barrodale P, et al. Gastric stasis in migraine: more than just a paroxysmal abnormality during a migraine attack. Gastric stasis in migraine: more than just a paroxysmal abnormality during a migraine attack. Headache 2006;46(1):57-63. 3. Aurora SK, Kori SH, Barrodale P, et al . Gastric stasis occurs in spontaneous, visually induced, and interictal migraine. Headache 2007;47(10):1443-1446. 4. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48(8):1157-1168. 5. Boyle R, Behan PO, Sutton JA. A correlation between severity of migraine and delayed gastric emptying measured by an epigastric impedance method. Br J Clin Pharmacol 1990;30(3):405-409. 6. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA 2007;297(13): 1443-1454. 7. Burstein R, Collins B, Bajwa Z, et al. Triptan therapy can abort migraine attacks if given before the establishment or in the absence of cutaneous allodynia and central sensitization: clinical and preclinical evidence. Headache 2002, 42:390–391. 8. Burstein R, Yarnitsky D, Goor-Aryeh I, et al. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47(5): 614-624. 9. Pr CAMBIA®. Product Monograph. Tribute Pharmaceuticals Canada Ltd. March 9, 2012. 10.Dahlöf C. Integrating the triptans into clinical practice. Curr Opin Neurol 2002;15:317-322.
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  • 57. REFERENCES 8. Suthisisang C, Poolsup N, Kittikulsuth W, Pudchakan P, THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Acute migraine treatment strategies and medication summary: Special Strategies Clinical phenotype / strategy Medication options Vasoconstrictor unresponsive or contraindicated strategy 1. One of: acetaminophen, ibuprofen, diclofenac potassium, naproxen sodium , or ASA, all ± metoclopramide 2. Combinations of acetaminophen, ASA, and caffeine (note: combination product not available in Canada but can use individual components) ± metoclopramide 3. One or more of: ! ketorolac IM (self-injection) ! indomethacin (oral or rectal) ! prochlorperazine (oral or rectal) ! chlorpromazine (oral) ! dexamethasone or prednisone (short course) ! opioid (including tramadol) combination analgesics (monitor use closely) 4. One of: butalbital-containing analgesics, or butorphanol nasal spray (both: exceptional circumstances only – monitor use closely) Menstrual migraine strategy 1. Acute therapy: General strategies 1 through 3c 2. Short term prophylaxis with one of: frovatriptan, zolmitriptan, naratriptan, or naproxen (frovatriptan recommended) 3. Short term prophylaxis with percutaneous estrogen 4. Continuous oral contraceptives (observe contraindications) 5. Less proven options for short term prophylaxis: magnesium, mefenamic acid Migraine during pregnancy strategy Avoid medication where possible 1. acetaminophen ± metoclopramide 2. acetaminophen with codeine ± metoclopramide 3. ibuprofen (avoid 1st trimester and at /after 32nd week gestation) ± metoclopramide 4. sumatriptan (if benefits outweigh risks – limited data but relatively safe) ± metoclopramide Migraine during lactation strategy Avoid medication where possible 1. acetaminophen ± metoclopramide 2. ibuprofen ± metoclopramide 3. sumatriptan ± metoclopramide 4. morphine (exceptional circumstances only - avoid high doses, maternal sedation, avoid when infant is premature, and use caution if infant under 1 month of age) Table 11B: Acute migraine treatment strategies and medication summary: Special Strategies The official Journal of: The Canadian Neurological Society, The Canadian Neurosurgical Society, The Canadian Society of Clinical Neurophysiologists, The Canadian Association of Child Neurology PM40007777R9824 AN INTERNATIONAL JOURNAL PUBLISHED BY THE CANADIAN NEUROLOGICAL SCIENCES FEDERATION Canadian Headache Society Guideline Acute Drug Therapy for Migraine Headache A Peer-reviewed SUPPLEMENT to The Canadian Journal of Neurological Sciences