HOVEDPINE

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Preventive treatment of migraine
Lars Bendtsen, MD, Dr Med Sci Department of
Neurology, Danish Headache Center Glostrup
Hospital, University of Copenhagen, Denmark The
European Headache Summer School Baku, May, 2008
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Preventive treatment of migraine

• Why should we use preventive treatment?
• Who should be treated?
• Scientific evidence for efficacy
• Which doses should be used?
• How to monitor?
• Side effects
• Treat for how long time?
• Feel free to ask questions

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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days
• What to do?

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Diagnosis

• Headache diary for diagnosis

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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days. Triptan
  partly effective, often recurrence. No medication
  overuse. What to do?

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Treatment
Patient education
Acute pharmacological treatment
Non-pharmacological treatment
Prophylactic pharmacological treatment
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Education and other non-pharmacological treatment

• Patient education
• Information about mechanisms
• Identification and treatment of comorbid
  disorders, e.g., depression and astma
• Avoidance of trigger factors

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Trigger factors

• Stress
• Hormones
• Alcohol
• Medication
• Lack of sleep
• Food, hunger
• Weather, strong light
• Non-physiological working positions

Trigger factors
Protective factors
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Protective factors

• Proper sleep
• Regular food intake
• Regular exercise
• Knowledge

Protective factors
Trigger factors
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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days. Triptan
  partly effective, often recurrence. No MOH
• Information, avoidance of trigger factors no
  effect. What to do?

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Non-pharmacological preventive treatment

• Physical therapy
• Relaxation and exercise programs
• Improvement of posture
• Cognitive-behavioral therapy (stress
  management)
• Relaxation training
• Biofeedback
• Cognitive restructuring
• Problem solving methods
• Acupuncture

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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days. Triptan
  partly effective, often recurrence. No MOH
• Information, avoidance of trigger factors no
  effect
• Increased pericranial tenderness no effect of
  physiotherapy
• No effect of cognitive-behavioral therapy (stress
  management)
• What to do?

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Treatment
Patient education
Acute pharmacological treatment
Non-pharmacological treatment
Prophylactic pharmacological treatment
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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days. Triptan
  partly effective, often recurrence. No MOH. What
  to do?
• Information, avoidance of trigger factors no
  effect
• Non-pharmacological management no effect
• Optimization of acute treatment
• Change of triptan and earlier intake improved
  acute treatment by 25
• Treatment still unsatisfactory. What to do?

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Why prophylactic pharmacotherapy?

• To reduce
• Frequency and/or intensity of migraine attacks
• Anxiety and speculations about next attack
• Use of acute medications
• Requirement for success
• Improvement of migraine has to outweigh adverse
  effects
• To increase quality of life

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When should prophylactic treatment be given?

• When flowers is not enough

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Who should be treated?

• 2-3 severe attacks per month in spite of
• optimal non-pharmacological treatment
• optimal pharmacological acute treatment
• no medication-overuse
• EFNS Guidelines 2006 Prophylactic drug treatment
  when
• quality of life, business duties, or school
  attendance are severely impaired
• frequency of attacks per month is two or higher
• attacks do not respond to acute drug treatment
• frequent, very long or uncomfortable auras occur
• Basilar-type migraine, hemiplegic migraine

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When is prophylactic treatment a success?

• Frequency or intensity reduced by at least 50
• Acceptable adverse effects
• Monitor with calendar

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Headache calendar
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Which drugs to choose?

• Previous treatments
• Sufficient dose?
• Sufficient duration?
• Concomitant medication overuse?
• Consider co-morbidity
• E.g. depression, overweight, cardiac problems

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Prophylactic treatment

• 3 most important points to consider

Information
Information
Information

• Information
• Mechanisms
• Aim
• Adverse effects
• Duration of treatment

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Prophylactic treatment

• Start low, go slow
• Sufficient dose and duration
• Follow-up
• Monitor with calendar
• Treat for up to 3 months
• Taper off every 6-12 months
• Follow EFNS Guidelines

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EFNS Guidelines 2006
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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days, triptans
  partly effective, no MOH, no effect of
  information, avoidance of trigger factors,
  physiotherapy or stress management, acute
  treatment is optimized
• Prophylactic treatment, which drug is first
  choice?

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Beta-blockers

• Propranolol and metoprolol
• 16 and 5 positive placebo-controlled trials
  respectively
• Bisoprolol, timolol and atenolol
• Each 2 placebo-controlled positive trials
• Common mechanism
• Lack of partial agonist activity
• Mechanisms in migraine
• Stabilizes vessels?
• Modulation of central catecholaminergic system?
• Efficacy
• Approximately 50 reduction of attack frequency

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Beta-blockers, dosing

• Propranolol
• 40 mg bid increasing after 1 week to 80 mg bid
• Maintenance dose 40-240 mg daily
• Often efficacy at 120-160 mg daily
• When optimal dose has been found change to
  long-acting formulation
• Metoprolol
• 50 mg once daily increasing after 1 week to 100
  mg once daily
• Maintenance dose 50-200 mg daily
• Often efficacy at 100 mg daily

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Beta-blockers

• Side effects Fatigue, cold extremities,
  gastrointestinal symptoms, dizziness, sleep
  disturbances (vivid dreams, nightmares,
  insomnia), depression, memory disturbances,
  impotence
• Caution Asthma, diabetes, depression, conduction
  defects
• Taper off over 1-2 weeks

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Case 1

• Forty-three year old woman, 4 severe migraine
  attacks per month each lasting 3 days, triptans
  partly effective, no MOH, no effect of
  information, avoidance of trigger factors,
  physiotherapy or stress management
• Metoprolol 100 mg daily reduced migraine to 2
  attacks of moderate severity per month

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Case 2

• Thirty-four year old woman, 5 migraine attacks of
  moderate intensity per month each lasting 2 days.
  Frequency reduced to 4 attacks after
  non-pharmacological treatment (stress
  management). Acute pharmacological management is
  optimized
• Severe asthma and depression. Which prophylactic
  drug?

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Anti-epileptics

• Topiramate and valproate
• Mechanisms
• Modulation of central hyperexcitability?

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Topiramate

• 3 large, placebo-controlled trials
• Efficacy
• At least 50 reduction in attack frequency in 46
  of patients
• 48 reduction in frequency

Bussone et al. Int J Clin Pract, 2006
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Topiramate, efficacy
Silberstein et al. Arch Neurol, 2004
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Topiramate, long-term efficacy
Diener et al. Lancet Neurol, 2007
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Topiramate

• Dosing
• 25 mg once daily increasing by 25 mg every 2nd
  week up to 50 mg twice daily
• Maintenance dose 25-200 mg daily
• Usually efficacy at 100 mg daily
• Taper off with 100 mg per week
• Adverse events
• Paresthesia, weight loss, somnolence, taste
  perversion, sedation and difficulties with
  concentration, language and memory

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Topimax dosing chart
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Valproate

• 5 placebo-controlled trials
• Efficacy
• At least 50 reduction in attack frequency in
  43-50 of the patients

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Valproate

• Dosing
• 1000 mg once daily
• Maintenance dose 500-1800 mg daily
• Adverse events
• Dyspepsia, weight gain, hair loss, tremor,
  hepatitis

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Case 2

• Thirty-four year old woman, 5 migraine attacks of
  moderate intensity per month each lasting 2 days.
  Non-pharmacological and acute pharmacological
  management is optimized
• Severe asthma and depression
• Overweight. Which kind of prophylactic treatment?
• Topiramate 150 mg daily reduced frequency to 3
  attacks per month (and lost 3 kg)

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Case 3

• Thirty-nine year old man, 3 migraine attacks of
  moderate intensity per month each lasting 3 days.
  Non-pharmacological and acute pharmacological
  management is optimized. Which kind of
  prophylactic treatment?
• No effect of beta-blockers and anti-epileptics.
  Which drug?

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Flunarizine

• Calcium antagonist
• 7 placebo-controlled trials
• Efficacy comparable to propranolol
• Dosing
• 10 mg once daily, 5 mg to elderly
• Adverse effects
• Sedation, weight gain, depression, extrapyramidal
  symptoms (parkinsonism)

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Case 3

• Thirty-nine year old man, 3 migraine attacks of
  moderate intensity per month each lasting 3 days.
  Non-pharmacological and acute pharmacological
  management is optimized.
• No effect of beta-blockers and anti-epileptics
• Flunarizine 10 mg daily gave slight reduction to
  2 attacks per month, moderate sedation

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Prophylactic treatment

• First choices
• Beta-blockers (propranolol and metoprolol)
• Anti-epileptics (topiramate and valproate)
• Calcium antagonist (flunarizine)
• Choose on basis of co-morbidity and side effects
• Combination therapy?

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Prophylactic treatment, first choice
EFNS Guidelines 2006
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Prophylactic treatment, second choice
EFNS Guidelines 2006
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Prophylactic treatment, third choice
EFNS Guidelines 2006
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Case 4

• Twenty-nine year old woman, 1 severe migraine
  attack lasting 4 days with each menstruation and
  2 mild attacks at other times of menstrual cycle.
  Only limited efficacy of acute treatment for the
  menstrual related attack. Good prophylactic
  effect of propranolol 160 mg daily
• How to improve treatment of the menstrually
  related attack?

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Menstrually related migraine

• Cyclic treatment perimenstrually (e.g. for 6 days
  starting 3 days before expected menstruation)
  with
• NSAIDs e.g. naproxen 500 mg twice daily
• Increase dose of usual prophylactic treatment
• Estrogen, e.g. estradiol gel 1.5 mg daily

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MacGregor et al., Neurology 2006
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Menstrually related migraine

• Cyclic treatment perimenstrually (e.g. for 6 days
  starting 3 days before expected menstruation)
  with
• NSAIDs e.g. naproxen 500 mg twice daily
• Increase dose of usual prophylactic treatment
• Estrogen, e.g. estradiol gel 1.5 mg daily
• Continuous hormonal treatment, e.g. continuous
  treatment with estrogencontaining contraceptive
  pills (provided no contraindications)
• Magnesium, triptans?

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Preventive treatment of migraineSummary

• Headache diary for correct diagnosis
• Information, avoidance of trigger factors
• Optimize acute treatment
• Non-pharmacological preventive treatment
• Physiotherapy
• Cognitive-behavioural treatment
  (stress-management)

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Preventive treatment of migraineSummary

• Pharmacological preventive treatment
• Inform patient
• Choose between 1st line drugs (propranolol,
  metoprolol, topiramate, valproate, flunarizine)
  on basis of adverse effects and previous
  treatment
• Sufficient dose and duration
• Monitor with headache calendar
• Taper off every 6-12 months
• Does it help?

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Treatment outcome, Danish Headache Center


Days/month
plt0.001 plt0.01 plt0.05



Frequent episodic tension-type headache(N 51)
Chronic tension-type headache(N 87)
Migraine(N 136)
Cluster headache(N 21)
Posttraumatic headache(N 10)
Other headaches(N 22)
Zeeberg et al. Cephalalgia 2005