Download Topiramate in Migraine Prevention

Migraine Prophylaxis 2009
Dr Richard Peatfield. MD FRCP
Princess Margaret Migraine Clinic
Charing Cross Hospital
London W6 8RF
[email protected]
Prevalence of headache in the previous year
Rasmussen et al J. Clin.Epidemiol. 44 1147 1991
Age group
n
Migraine
Men
Women
387
353
Tension-type headache
Men
Women
387
353
25-34
35-44
45-54
55-64
All ages
5%
7%
6%
7%
6%
68%
63%
70%
49%
63%
18%
14%
12%
19%
15%
93%
92%
82%
74%
86%
Functional impact of migraine by self-reported physician
diagnosis of migraine.
Lipton et al Headache 41 638 2001
INDICATIONS FOR MIGRAINE PROPHYLAXIS
Two attacks monthly.
Less frequent attacks proving intractable.
Note
 Cost benefit.
 Abolition of the first hour or so of each
headache if successful.
 Persistent symptoms after 2 hours, eg:



Mild Headache
Nausea
Photophobia
Disability
Quality of life can be impaired despite ‘effective’ treatment.
Migraine prophylactic medication
Amine Modulation
1. b-blockers: Propranolol, Atenolol
2. 5-HT Blockers: Pizotifen, Methysergide
3. Tricyclics
Channel Modulation
4. Anti-epileptics: Valproate, Topiramate
5. Calcium channel blockers: Flunarizine
Others
6. Metabolic enhancers: Riboflavin, Nicotinamide
7. ACE Inhibitors: Lisinopril
8. Also: NSAID’s, Magnesium, Feverfew
Prophylactic Agents: Europe v USA
North America
G5 EUROPE
(France, Germany, Italy, Spain, and UK)
Total others
(26)
propranolol
33%
Propranolol
22%
Amitriptyline
10%
!0%
Valproic
acid
1%
Amitriptyline
17%
Nortriptyline
6%
Other
β-blockers
Total others
(33)
15%
7%
Verapamil
8%
Gabapentin
4%
Valproate
Topiramate
14%
sodium
12%
Other
β-blockers
9%
Pizotifen
17%
Flunarizine
15%
Source: IMS MIDAS; 2002 RXs; N2C Migraine Products + top products used for G43 diagnosis code
(which includes off-label products).
Migraine - Preventive Treatment
First choice
• betablockers
• antiepileptic drugs
Second choice
• antidepressants
• calcium-antagonists
• serotonin antagonists
Third choice
• riboflavin, coenzyme Q10, magnesium
“Special cases“
• menstrual migraine:
• exercise induced:
NSAIDs, continuous contraceptive pill,
naratriptan, frovatriptan
betablockers, indomethacin
Sandor 2004
Conventional migraine prophylactic drugs
Daily dose (adult) mg.
Propranolol
Atenolol
Pizotifen
Methysergide
Valproate
Naproxen
Amitriptyline
Start
Max.
80
50
0.5
1
400
250
10-25
320
150
1.5
6
1600
1000
100
b 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 placebo
Flunarizine = Propranolol
[Cephalalgia 2001]
b Blockers
Diener
Propranolol since 1964; very cheap
26 drugs now available:-
Effective
Perhaps not
Propranolol
Metoprolol
Timolol
Bisoprolol
Nadolol
Atenolol
Acebutolol
Alprenolol
Oxprenolol
Pindolol
?? Differences due to trial design
Propranolol
http://www.cochrane.org/reviews/en/ab003225.html
Antidepressants
Bendtsen
Migraine Widely used – second only to b-blockers.
No DBXO trials following IHS guidelines
Three small trials of amitriptyline 1973-1987
21-42% reduction in attacks
Effect independent of depressive state
Trials of fluoxetine- benefit modest if any
Tension-type headache
Most trials of amitriptyline (1964-1996) show benefit
Pfaffenrath’s trial had a tough endpoint
Bendtsen’s own trial:- (1996)
Amitriptyline effective; Citalopram had no effect
Holroyd 2001 144 patients 30% reduction
Antidepressants
Discordant results with SSRI’s:-
Patients do not care any more
Headache continues unaltered
Not evidence based!!
Valproate in Migraine
Prevention: Efficacy—ITT
45
*
38
40
*
42
*
36
35
Mean 30
Reduction
25
in 4-Week
Migraine 20
Frequency15
(%)
10
8
5
0
Placebo
500 mg
1000 mg
1500 mg
*P<.05.
Valproate
ITT=intent to treat.
Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.
Valproate in Migraine
Prevention: Overall Responder
Rate—ITT
60
*
50
44
40
≥50%
Responder 30
Rate (%)
21
20
10
0
Placebo
Valproate
(vs placebo).
ITT=intent to treat.
Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.
*P≤.05
Divalproex in Migraine. Cochrane reviews 2006
http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html
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
Methysergide in Migraine Prophylaxis
60 patients, double blind cross over.
6 mg daily.
Placebo
No attacks
Over 50% fewer
Unchanged
4
12
44
Methysergide
16
18
26
p<0.01
Petersen & Moller: Clin.Pharm.Ther. 1966 7 520.
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.
Methysergide: fibrotic side effects
Continuous use ( ?Dose)
Stopping for 1 month annually
n
1000
cases
36
300
Nil
(Bala Am Ht J 1974 88 640)
Worth regular auscultation, and checking a renal
ultrasound and echocardiogram annually
What to do in the ‘Holidays’?
• Topiramate
• Prednisolone ( 50mg, reducing by 5mg/day)
Topiramate in Migraine Prevention
Response to Topiramate Therapy
(50% Responder Rate)
60
MIGR-001
MIGR-002
50
% of
patients with
>50%
reduction in
Migraine
Frequency
40
30
54‡
49
36*
23
‡
52‡
47‡
39†
23
20
10
0
Placebo
50 mg/d
100 mg/d
200 mg/d
Topiramate
*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
MIGR-001 / MIGR-002
Topiramate in Migraine Prevention:
Onset of Action
Month
0
1
2
3
4
5
6
0.0
-0.5
Cumulative
Reduction in -1.0
Mean
Migraine
-1.5
Frequency
-2.0
*
†
†
†
†
‡
‡
‡
‡
†
‡
†
‡
-2.5
Placebo (n=115)
Topiramate 100 mg/d (n=125)
Topiramate 50 mg/d (n=117)
Topiramate 200 mg/d (n=112)
*P=.032; †P≤.015; ‡P<.001.
Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;29198):965-973
Topiramate in Migraine. Cochrane reviews 2006
http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html
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
‘Therapeutic gain’ compared to placebo
proportion of patients with  50% reduction in attack frequency (verum – placebo)
valproate
45
betablockers
40
amitriptyline
therapeutic
gain
20
Mg (24 mM)
18
riboflavin (Vit B2)
37
33
coenzyme Q10
gabapentin
22
topiramate
40
flunarizine
1st choice (EBM) 0
42
5
10
15
20
25
30
well tolerated substances, mechanism: energy metabolism
new antiepileptics
35
40
45
50
[Sandor 2004]
55
Levetiracetam in Headache
Co-sponsored prospective multicentre trial of 1.5G
- No benefit. Unpublished. ?? Suppressed
(? Dose too low)
Young (Philadelphia) Open study 3G
35% >50% reduction in attacks
No control series
Personality change problems
Headache 2004 44 2238
Clin J Pain 2004 20 198
All retrospective
Angiotensin :Converting enzyme inhibitors and receptor antagonists
Lisinopril
20mg is an effective prophylactic
20% 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 patients
32-46% had headache reduced by 50%
No significant adverse events
[Tronvik. JAMA 2003 289 65-9].
Tronvik. JAMA 2003 289 65-9
Binding of 5-HT2B receptors
Botulinum Toxin
Zinc dependent Metalloproteinases
Cleaves proteins responsible for exocytosis of transmitter vesicles
Acts on sensory afferents too
Inhibits 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 separate
injection 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.
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
Sensory effects of botulinum toxin
In cervical dystonia low doses relieve pain before the motor
effects
Relja 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 neurones
Gazer~~ Pain 122 315 2006
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 month
Those not on prophylaxis [H 45 315 2005]
Botulinum Toxin
NO effect in tension-type headache
Possible effect in Migraine
High Placebo response rates
Greatest potential role in ‘Chronic Migraine’
Blinding
Aesthetic change
Less Sweating
Incidental effect in cosmetic patients
In the trials the number of patients guessing correctly
fell from 65% to 55% as they improved!
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)
Differences in Migraine Features for Botulinum
Toxin-A Responders and Nonresponders
Responders
100
Non-responders
92
89
90
88
80
71
52
60
40
20
2.5
0
0
100
% of study participants
% improvement over pre-treatment phase
Responders
Non-responders
80
70
60
50
40
30
20
10
-2
8
11
0
-20
Frequency
Duration
Pain Severity
Headache Characteristics
N=35 responders
N=24 nonresponders
Exploding
Imploding
Description of Headache Pain
Burstein et al., Neurology 2006
Expensive!
£129 for a 100 unit ampoule
4 patients at low dose – 25 units per patient
Trial used 150-190 units per patient
USA different from UK!
Vertical integration of costs and savings in the USA
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.
If you don’t have Botox…
USA
UK
Emergency
$600
Multiple
Opinions
Someone
Analgesics
Scans
Else’s
Cost of
Botox
Budget!
Prophylaxis in real life
MIGRAINE
PROPHYLACTIC MEDICATION
Dose used in trials
Propranolol
Atenolol
Pizotifen
Methysergide
Valproate
Amitriptyline
Topiramate
Cost / 28 days
mg
£
240
100
3
6
1000
c100
100
1.44
0.95
8.28
37.68
7.84
2.41
32.07
Percent of patiens likely
to make a 50% improvement compared to placebo
34
33
28
30
34
32
31
Revised prices 27 November 2005
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
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.
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.
DRUGS ACTING ON SEROTONIN RECEPTORS
(Adapted from Saxena)
Sumatriptan
5HTID Agonist
Pizotifen
Methysergide Ergotamine
Inactive
Agonist
5HT2A Inactive
Partial
Agonist
Antagonist Antagonist
5HT2C Inactive
5HT3 Inactive
Antagonist Antagonist
Inactive
Inactive
Agonist
Inactive
Agonist
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
Long Q-T interval
Upper limit 450msec, less in women
Long QT interval
Measure from the beginning of Q to the end of T
Resting ECG can be normal –need an exercise test
Patients may collapse during exercise
QTc is corrected for the heart rate
>460msec in women; 440msec in men
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 b-blockers may lower this risk
Drugs prolonging the Q-T interval
Withdrawn Terfenadine, Astemazole, Cisapride.
Hazardous
Amiodarone, Sotalol. Quinidine
Care!
Erythromycin, Chlorpromazine,
Haloperidol, Tricyclics, Domperidone,
Amantadine.
www.longqt.org
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.
Topiramate in Migraine Prevention
75% and 95% Responder Rate
30
6%
25
6%
20
% of
Patients
6%
6%
17%
17%
15
24%
10
19%
>95%
 75%-94% Reduction
5
0
Topiramate
100 mg/d
(MIGR-001)
Topiramate
100 mg/d
(MIGR-002)
Topiramate
100 mg/d
(MIGR-003)
Propranolol
160 mg/d
(MIGR-003)
Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL et al.
JAMA. 2004;291(8):965-973
MIGR-001 / MIGR-002 / MIGR-003