migraine prophylaxis 2009 dr richard peatfield. md frcp princess margaret migraine clinic charing...
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Migraine Prophylaxis 2009
Dr Richard Peatfield. MD FRCP Princess Margaret Migraine ClinicCharing Cross HospitalLondon W6 8RF
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Prevalence of headache in the previous yearRasmussen et al J. Clin.Epidemiol. 44 1147 1991
Migraine Tension-type headache
Age group Men Women Men Womenn 387 353 387 353
25-34 5% 18% 68% 93%
35-44 7% 14% 63% 92%
45-54 6% 12% 70% 82%
55-64 7% 19% 49% 74%
All ages 6% 15% 63% 86%
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Functional impact of migraine by self-reported physician diagnosis of migraine. Lipton et al Headache 41 638 2001
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INDICATIONS FOR MIGRAINE PROPHYLAXIS
Two attacks monthly.Less frequent attacks proving intractable.
Note
Mild Headache Nausea Photophobia Disability
Cost benefit. Abolition of the first hour or so of each headache if successful.
Persistent symptoms after 2 hours, eg:-
Quality of life can be impaired despite ‘effective’ treatment.
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Migraine prophylactic medication
1. -blockers: Propranolol, Atenolol2. 5-HT Blockers: Pizotifen, Methysergide3. Tricyclics 4. Anti-epileptics: Valproate, Topiramate5. Calcium channel blockers: Flunarizine
6. Metabolic enhancers: Riboflavin, Nicotinamide7. ACE Inhibitors: Lisinopril8. Also: NSAID’s, Magnesium, Feverfew
Amine Modulation
Channel Modulation
Others
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Prophylactic Agents: Europe v USA
Source: IMS MIDAS; 2002 RXs; N2C Migraine Products + top products used for G43 diagnosis code (which includes off-label products).
North America G5 EUROPE(France, Germany, Italy, Spain, and UK)
6%
Total others (26)
!0%
Other
β-blockers7%
Verapamil8%
Amitriptyline17%
Valproate sodium
12%Topiramate
14%
Gabapentin4%
Propranolol22%
Total others (33)15%
Otherβ-blockers
9%
Flunarizine
15%
Amitriptyline10%
Valproic acid1%
propranolol33%
Pizotifen17%
Nortriptyline
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Migraine - Preventive TreatmentFirst choice
• betablockers• antiepileptic drugs
Second choice• antidepressants• calcium-antagonists • serotonin antagonists
Third choice• riboflavin, coenzyme Q10, magnesium
“Special cases“• menstrual migraine: NSAIDs, continuous contraceptive
pill, naratriptan, frovatriptan
• exercise induced: betablockers, indomethacinSandor 2004
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Daily dose (adult) mg.
Start Max.
Propranolol 80 320Atenolol 50 150Pizotifen 0.5 1.5Methysergide 1 6Valproate 400 1600Naproxen 250 1000Amitriptyline 10-25 100
Conventional migraine prophylactic drugs
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Blockers Diener
Mode of action unknown; no animal models No proper dose finding studies of propranolol
160=80mg, or 160>80? Short titration times, never over 12 weeks Metoprolol second greatest number of trials, again for a short time Bisoprolol largest, best designed trial 226 patients. All seem of equal efficacy ~ 50% response rate. No correlation between plasma levels and efficacy
16 comparative trials Metoprolol > aspirin Propranolol > Nifedipine
Neither trial with placeboFlunarizine = Propranolol [Cephalalgia 2001]
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Blockers Diener
Propranolol since 1964; very cheap26 drugs now available:-
Effective Perhaps not
Propranolol AcebutololMetoprolol AlprenololTimolol OxprenololBisoprolol PindololNadololAtenolol
?? Differences due to trial design
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http://www.cochrane.org/reviews/en/ab003225.htmlPropranolol
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Antidepressants Bendtsen
Migraine Widely used – second only to -blockers.No DBXO trials following IHS guidelinesThree small trials of amitriptyline 1973-1987
21-42% reduction in attacksEffect independent of depressive state
Trials of fluoxetine- benefit modest if any
Tension-type headache Most trials of amitriptyline (1964-1996) show benefitPfaffenrath’s trial had a tough endpointBendtsen’s own trial:- (1996)
Amitriptyline effective; Citalopram had no effectHolroyd 2001 144 patients 30% reduction
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Antidepressants
Discordant results with SSRI’s:-
Patients do not care any moreHeadache continues unaltered
Not evidence based!!
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Valproate in Migraine Prevention: Efficacy—ITT
8
3842
36
0
5
10
15
20
25
30
35
40
45
Placebo 500 mg 1000 mg 1500 mg
*P<.05.ITT=intent to treat.
Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.
Mean Reductionin 4-WeekMigraine
Frequency(%)
Mean Reductionin 4-WeekMigraine
Frequency(%)
Valproate
* *
*
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Valproate in Migraine Prevention: Overall Responder
Rate—ITT
*P≤.05 (vs placebo).ITT=intent to treat.
Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.
21
44
0
10
20
30
40
50
60
Placebo Valproate
≥50%
ResponderRate (%)
≥50%
ResponderRate (%)
*
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Divalproex in Migraine. Cochrane reviews 2006
http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html
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Methysergide
• 5HT2 A,B&C receptor antagonist(But mianserin, ketanserin and ICI 169369 do not work)
• Metabolised to Methylergometrine, an agonist at 5HT1 B
receptors.- Greater bioavailability- Longer half-life.
• Antagonist at 5HT7 receptors.
• Increases Neuropeptide Y levels in the hypothalamus – appetite stimulant
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Methysergide in Migraine Prophylaxis
60 patients, double blind cross over.6 mg daily.
Placebo Methysergide
No attacks 4 16Over 50% fewer 12 18Unchanged 44 26
p<0.01
Petersen & Moller: Clin.Pharm.Ther. 1966 7 520.
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Methysergide: side effects
Less severe than the publicity!
Pain in the legs (?vasospasm) is less likely if the drug dose is
increased slowly ( 0.5mg daily for a few days- etc etc).
Retroperitoneal and cardiac fibrosis.
Rare; commoner with larger doses.
In one series 11/19 affected patients had received > 8mg/day
Seen after 6mg/day or less.
Reversible if the drug is stopped.
The risk of retroperitoneal fibrosis is lessened if the
drug is stopped for 1 month every 6 months.
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Worth regular auscultation, and checking a renal ultrasound and echocardiogram annually
Methysergide: fibrotic side effects
What to do in the ‘Holidays’? • Topiramate • Prednisolone ( 50mg, reducing by 5mg/day)
n cases
Continuous use ( ?Dose) 1000 36
Stopping for 1 month annually 300 Nil
(Bala Am Ht J 1974 88 640)
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Topiramate in Migraine Prevention
Response to Topiramate Therapy(50% Responder Rate)
*P<.05; †P<.01; ‡P<.001.
Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;291(8):965-973
23 23
52‡54‡
36*
47‡49‡
39†
0
10
20
30
40
50
60
Placebo 50 mg/d 100 mg/d 200 mg/d
MIGR-001
MIGR-002
% of patients % of patients with with >>50% 50%
reduction in reduction in Migraine Migraine
FrequencyFrequency
% of patients % of patients with with >>50% 50%
reduction in reduction in Migraine Migraine
FrequencyFrequency
TopiramateTopiramateTopiramateTopiramate
MIGR-001 / MIGR-002
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Topiramate in Migraine Prevention: Onset of Action
-2.5
-2.0
-1.5
-1.0
-0.5
0.00 1 2 3 4 5 6
Placebo (n=115) Topiramate 50 mg/d (n=117)
Topiramate 100 mg/d (n=125) Topiramate 200 mg/d (n=112)
*P=.032; †P≤.015; ‡P<.001.
††
†
†
†
†
*Cumulative Cumulative Reduction in Reduction in
Mean Mean Migraine Migraine
FrequencyFrequency
‡‡
‡‡
‡
‡
MonthMonth
Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;29198):965-973
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Topiramate in Migraine. Cochrane reviews 2006
http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html
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Topiramate side-effects 50% get paraesthesiae –
carbonic anhydrase inhibition - try K+
20% Cognitive – concentration, memory, speech unpredictable ? K+
1½% Kidney stones Calcium oxalate Fatigue Anorexia; weight loss Diarrhoea Taste change Glaucoma
Brandes JAMA 2004 291 965; Silberstein Arch N. 2004 61 490
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‘Therapeutic gain’ compared to placebo proportion of patients with 50% reduction in attack frequency (verum – placebo)
1st choice (EBM)
well tolerated substances, mechanism: energy metabolism
new antiepileptics
42flunarizine
gabapentin 22
topiramate 40
0 5 10 15 20 25 30 35 40 45 50 55
20amitriptyline
40betablockers
45valproate
therapeutic gain
37riboflavin (Vit B2)
18Mg (24 mM)
33coenzyme Q10
[Sandor 2004]
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Levetiracetam in Headache
Co-sponsored prospective multicentre trial of 1.5G- No benefit. Unpublished. ?? Suppressed (? Dose too low)
Young (Philadelphia) Open study 3G35% >50% reduction in attacksNo control seriesPersonality change problems
Headache 2004 44 2238Clin J Pain 2004 20 198All retrospective
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Angiotensin :- Converting enzyme inhibitors and receptor antagonists
Lisinopril 20mg is an effective prophylactic20% improvement above placebo in a DBXO trial in 47 patients[Schrader BMJ 2001 322 19-22].
Fewer headaches in patients on ACE inhibitors[Etminan Am J Med 2002 112 642-6]
Candesartan Trial of 16mg daily in 57 migraine patients32-46% had headache reduced by 50%No significant adverse events[Tronvik. JAMA 2003 289 65-9].
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Tronvik. JAMA 2003 289 65-9
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Binding of 5-HT2B receptors
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Botulinum ToxinZinc dependent Metalloproteinases
Cleaves proteins responsible for exocytosis of transmitter vesiclesActs on sensory afferents tooInhibits release of all neurotransmitters, including SP, CGRP etc, in doses comparable to those used in man.
Consensus is that is does work, so long as there are enough separateinjection sites – 15-20 per patient.Sites of action are not confined to the neuromuscular junction
In published trials most patients are unaware of the treatment used.Some trials are biased; placebo patients less severe.
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Type A – Most potent and lasting effect
Light Chain cleaves SNAP 25 protein inside membrane - 1 of the 3 proteins in SNARE complex that leads to Ach release
Collateral axonal sprouts lead to early recovery, until original terminal recovers
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Sensory effects of botulinum toxin
In cervical dystonia low doses relieve pain before the motor effectsRelja 2006
Suppresses secondary inflammatory pain after formalin injection Release of Substance P, CGRP, etc.Cui Pain 107 125 2004
Less c-fos expression in cervical neuronesGazer~~ Pain 122 315 2006
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Botulinum Toxin in Chronic Daily Headache
Mathew Headache 45 293 2005. 355 subjects
47% met criteria for analgesic abuse; slightly more in the active group Side effects in 2.3% only (usually neck pain from weakness)
Primary end-point (change in the number of headache free days) not met --6.7 cf 5.2.in placebo non-responders Doubtful clinical significance
Significant improvement in:-Headache frequency The proportion with >50% decrease of headache days per monthThose not on prophylaxis [H 45 315 2005]
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Botulinum Toxin
NO effect in tension-type headache
Possible effect in Migraine High Placebo response rates
Greatest potential role in ‘Chronic Migraine’
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Blinding
Aesthetic changeLess Sweating
Incidental effect in cosmetic patients
In the trials the number of patients guessing correctly fell from 65% to 55% as they improved!
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Exploding vs Imploding Headaches Burstein Kyoto, Dodick AAN 2006
Exploding Bursting 12% responded
Imploding Tightening 92% responded
Ocular 100% responded
? Related to fine extracranial c-fibres passing through the skull to innervate the dura (in the rat)
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Differences in Migraine Features for Botulinum Toxin-A Responders and Nonresponders
92
8 11
89
0
10
20
30
40
50
60
70
80
90
100
Exploding Imploding
Responders Non-responders
Burstein et al., Neurology 2006
88
-2
71
0
52
2.5
-20
0
20
40
60
80
100
Frequency Duration Pain Severity
Responders Non-responders
% o
f st
udy
part
icip
ants
Description of Headache Pain
% im
prov
emen
t o
ver
pre-
trea
tmen
t ph
ase
Headache Characteristics
N=35 respondersN=24 nonresponders
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Expensive!
£129 for a 100 unit ampoule4 patients at low dose – 25 units per patient
Trial used 150-190 units per patient
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USA different from UK!
Chronic migraine sufferers are already costing insurers a lot of money by the time they are referred for Botox treatment, and the additional costs are seen as marginal and the potential gains large.
Vertical integration of costs and savings in the USA
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Scans
Multiple Opinions
Analgesics
Emergency $600
If you don’t have Botox…
USA UK
Someone
Else’s
Budget! Cost Botox
of
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Prophylaxis in real life
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MIGRAINEPROPHYLACTIC MEDICATION
Dose used in trials Cost / 28 days Percent of patiens likely mg £ to make a 50% improve- ment compared to
placebo
Propranolol 240 1.44 34
Atenolol 100 0.95 33
Pizotifen 3 8.28 28
Methysergide 6 37.68 30
Valproate 1000 7.84 34
Amitriptyline c100 2.41 32
Topiramate 100 32.07 31
Revised prices 27 November 2005
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Consensus view on migraine prophylaxis
Offered :- Patients with 6 or more headache days per month; 4 or more days with some impairment; or 3 or more days with severe impairment.
Considered:- Patients with 4 or 5 headache days per month with normal functioning; 3 days with some impairment; or 2 days with severe impairment.
Not indicated:- Patients with <4 headache days per month with normal functioning; or no more than 1 day per
month regardless of impairment.
Lipton Neurology 2007 68 343
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Principles of Preventative Pharmacotherapy Goadsby
Clarify Diagnosis:- History is taken, not given. Explain what it means to the patient. Assess the burden to the patient. Establish what the patient expects. Be clear what the Physician can offer; limited! Advise on areas where the patient can intervene. Optimise the treatment of acute attacks. Plan preventative treatment.
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Migraine: Prophylactic trials Small trials in single centres Some crossover and some parallel group designs Variety of endpoints used:-
- Percentage of patients improving in categories
- Overall percentage improvement Not a comprehensive metaanalysis:-
results from individual selected trials.
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DRUGS ACTING ON SEROTONIN RECEPTORS(Adapted from Saxena)
Sumatriptan Pizotifen Methysergide Ergotamine
5HTID Agonist Inactive Partial AgonistAgonist
5HT2A Inactive Antagonist Antagonist Agonist
5HT2C Inactive Antagonist Antagonist Agonist5HT3 Inactive Inactive Inactive Inactive
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Select for positive side effects, e.g.
• anxiety → betablocker
• insomnia → sedating tricyclic at night (amitriptyline)
• constipation → magnesium
• obesity → topiramate
• comorbid depression → antidepressant in sufficient dosage
Sandor 2004
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Long Q-T interval
Upper limit 450msec, less in women
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Long QT interval
Measure from the beginning of Q to the end of TResting ECG can be normal –need an exercise testPatients may collapse during exercise
QTc is corrected for the heart rate
>460msec in women; 440msec in men
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Congenital long Q-T interval
• 7 identified genes; 300 mutations
• Mostly related to K+ Channels
• Risk of sudden death,
especially during sudden arousal or exercise
• Prophylactic -blockers may lower this risk
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Drugs prolonging the Q-T interval
Withdrawn Terfenadine, Astemazole, Cisapride.
Hazardous Amiodarone, Sotalol. Quinidine
Care! Erythromycin, Chlorpromazine,
Haloperidol, Tricyclics, Domperidone,
Amantadine.
www.longqt.org
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Valproate in Migraine Prevention
• 16-week double-blind, placebo-controlled trial of valproate; N=171
• Study design
– 4-week placebo run-in
– Patients randomized to receive 500, 1000, or 1500 mg/d valproate or placebo for 12 weeks
• Initial dose, 250 mg/d
• Titration every 4 d (8 d for 500 mg/d group) of 250 mg/d to maintenance dose
• 8-week maintenance phase
– Efficacy evaluations every 4 weeks
Klapper J et al. Cephalagia. 1997;17:103-108.
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Topiramate in Migraine Prevention
MIGR-001 / MIGR-002 / MIGR-003
19%24%
17% 17%
6%
6%
6% 6%
0
5
10
15
20
25
30
Topiramate100 mg/d
(MIGR-001)
Topiramate100 mg/d
(MIGR-002)
Topiramate100 mg/d
(MIGR-003)
Propranolol160 mg/d
(MIGR-003)
>95%
75%-94% Reduction
% of% ofPatients Patients
75% and 95% Responder Rate75% and 95% Responder Rate
Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL et al. JAMA. 2004;291(8):965-973