Transcript Slide 1

Stuart Weatherby
Consultant Neurologist
Derriford Hospital. Plymouth
David Hartley, Treaty
of Paris
William Wilberforce
John Venn
Amy Johnson
When should I give
prophylaxis?
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What prophylaxis
should I give?
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What benefit
should my patient
expect?
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Factors that may affect use, or
apparent efficacy of migraine
prophylaxis
Factors predicting chronic pain
The patient. The doctor
Principles of prophylaxis
How to choose
First line, Second line, third line
Magnitude of effects
Herbal
Psychological
Injection- Acupuncture and Botox
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Fear -central role in the duration of pain
 Through medial prefrontal region, ventral lateral frontal
region, and cingulate regions
Anxiety and depression may also be markers for CNS
chemical changes that play a significant role in the duration of
pain.
Between 30-50% of people with chronic daily headache can
become depressed
Catastrophizing more than 7 times more powerful a predictor
than any other predictor or clinical variable among acute back
pain patients in determining the risk of subsequent chronic
pain
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‘Its all part of a ‘chronic pain syndrome’’
‘They have pain because they are depressed’
‘They don’t respond to anything’
‘Analgesic overuse’
‘Cold feet’
or is it secondary headache
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Prophylaxis is used to reduce the
number of attacks in circumstances
when acute therapy, used
appropriately, gives inadequate
symptom control.
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Frequent headaches (more than 2 per week)
Attack duration > 48 hours
Severity is extreme
Migraine attacks with prolonged aura
Unacceptable adverse effects occur with acute
treatment
Substantially interferes with the patient’s daily
routine, despite acute treatment
Special circumstances such as hemiplegic migraine
or attacks with a risk of permanent neurologic injury
Patient preference
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Most prophylactics are used within a dose range, and
in general must be up-titrated slowly to an effective
dose (or to the maximum dose) in order to avoid sideeffects that will precipitate premature discontinuation.
This can lead to a delay in efficacy which itself,
unfortunately, sometimes triggers discontinuation
Tell patient it takes ages to get to a therapeutic dose
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Migraine is cyclical: treatment is required for periods
of exacerbation.
Uninterrupted prophylaxis over very long periods is
rarely appropriate.
If effective continue for 4-6 months, then gradual
withdrawal to establish continued need.
In absence in the absence of unacceptable sideeffects, 6-8 weeks is a reasonable trial
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The criteria for preferring
one prophylactic drug to
another
are based upon:
• evidence of efficacy;
• comorbidity
• contraindications,
including risks in
pregnancy;
Also good evidence that poor
compliance is a major
factor and that once-daily
dosing is preferable.
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The formal evidence-base
for efficacy is good for:Betablockers,
Topiramate
Valproate
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Adequate for amitriptyline
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Poor for other
prophylactics
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Cardioselectivity and hydrophilicity both improve
the side-effect profile
On this basis, atenolol 25-100mg bd might be
preferred over metoprolol 50-100mg bd and over
propranolol LA 80mg od-160mg bd.
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First-line when migraine coexists with:
• Tension-type headache
• Another chronic pain condition;
• Disturbed sleep;
• Depression
Desipramine*, nortriptyline* and
protriptyline* are less sedative alternatives
Valproate 300-1000mg bd
Topiramate 25mg od-50mg bd
(can go 100mg bd)
Does not affect hormonal
contraception.
Enzyme-inducer and can reduce the
efficacy of COCP
Adverse events
50% ‘pins and needles’,
Usually resolve with continued use.
25% relative anorexia and loss of 10% of
body weight,
15% cognitive dysfunction.
Kidney stones
Depression
Secondary angle-closure glaucoma has
been reported
Discontinuation 22% topiramate vs 11%
placebo
Weight gain and alopecia.
Blood cell count, platelet count, bleeding
time and
coagulation tests are recommended prior to
starting
treatment and in case of spontaneous
bruising or bleeding.
Liver dysfunction is reported rarely.
Pretend they have epilepsy
MigraineSubclinical structural brain changes and persistent
alteration of pain perception
In some cases correlated with the duration of the disease
Frequency of attacks might play a role in the
transformation of episodic migraine to chronic
Anticonvulsants Increase activation threshold resulting in neuronal
stabilisation and cortical neurons hyperexcitability,
electrophysiological feature underlying the pathogenesis
of epilepsy and migraine.
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Gabapentin* 300mg od-800mg tds
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Betablockers and Amitryptiline together
Flunarizine
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Methysergide 1-2mg tds
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Beware retroperitoneal fibrosis, 5HT agonist
activity/rebound headache/drug holidays
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(Verapamil)
Flunarizine
808 pts Flunarizine vs Propranolol
Responders (50% reduction), 5mg:46%. 10mg:53%. Propranolol:48%
Drop out due to adverse effects
5mg:16.7%. 10mg: 19.3%. Propranolol:16.7%
HC Deiner et al Cephalalgia 2002;22:209-221
Flunarizine blocks voltage-gated Na(+) and Ca(2+) currents in cultured
rat cortical neurons: A possible locus of action in the prevention of
migraine.
Neurosci Lett. 2011 Jan 10;487(3):394-9.
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Pizotifen- little
Clonidine- little
Pregabalin
Verapamil* MR 120-240mg bd has limited clinicaltrials. Headache is sometimes a side-effect.
Lisinopril montelukast
Candesartan riboflavin and co-enzyme Q10 some evidence
Lamotrigine
Zonisamide
Levetiracetam
Placebo controlled trial 96 pts, Resistant pts. Median duration 20 yrs.
Poss trend to effect. Small subpopulation who benefit? Worse mental
health on keppra.
Beran Cephalalgia November 8, 2010-
Compared with placebo or other drugs in 58 trials. 5072 participants
26 placebo controlled trials
Unclear whether effects persist after stopping propranolol.
Drug comparisons did not yield any clear-cut differences. Sample size was,
however, insufficient in most trials to establish equivalence.
50% resp
No. Studies
Participants
OR
CI
First crossover
4
205
1.72
1.23, 2.40
Pooled crossover
9
668
1.94
1.61, 2.35
Cochrane Database of Systematic Reviews 2004, Issue 2
70
No. of attacks reduced by more than 50%
% of Patients
60
50
48
50
Flunarizine (p<0.01)
Propranolol (p<0.0005)
40
30
20
10
0
Headache 1989; 29: 218-223
Chronicle E, Mulleners Cochrane Database Syst Rev. 2004;(3)
Anticonvulsants, (cf placebo) as a class:- Data from 2024 patients
-Reduce migraine frequency- 8 trials (n = 841),
1.4 attacks per 28 days (CI -0.93 to -0.26).
No. of pts reduced migraine freq by 50% or more (cf placebo)- 10 trials (n = 1341)
OR 3.90; 95% CI 2.61 to 5.82;
NNT 3.8; 95% CI 3.2 to 4.6
NNHs for various clinically important adverse events:Valproate from 6.6 to 16.3.
Topiramate from 2.4 to 32.9.
Drug
No. studies
No pt
OR
CI
Valpr
4
454
3.34
1.46, 7.67
Gabapentin
1
87
4.67
1.54, 14.14
Topiramate
6
898
3.34
2.36, 4.73
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Topiramate significantly reduced the mean number of
monthly migraine days (±SD) by 3.5 ± 6.3, compared
with placebo (−0.2 ± 4.7, P < 0.05)
78% analgesic overuse at baseline
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Bussone... Goadsby TOP CHROME study 2007 Cephalagia , 27 (7) , 814 – 823
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Diener, Dodick, Goadsby et al Cephalalgia October 2009 vol. 29 no. 10 1021-1027
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Feverfew
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5 trials, 343 pts. Can contain carcinogens. Not conclusive
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Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane database of systematic
reviews 2004: CD002286.5
170 pts placebo control. Logistic regression of responder
rates OR 3.4, P = 0.0049, in favour of feverfew extract Diener et
al Cephalalgia 2005 vol. 25 no. 11 1031-1041
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Butterbur
245 pts Proportion with ≥50% reduction 68% for 75-mg and
49% for the placebo arm (p < 0.05). Burping and ?carcinogens in
european preparations?
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Lipton RB, et al Neurology 2004; 63:2240–2244.
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Melatonin.
Open label 3mg at night helps Neurology 2004; 63:757.
Placebo control 46 pts negative. Neurology 2010 vol. 75 no.
17 1527-1532
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Co Q 10
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Riboflavin, Magesium- some class B evidence
Grade A evidence:
 Relaxation training
 Biofeedback combined with relaxation training
 Electromyographic biofeedback
 Cognitive-behavioral therapy.
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Silberstein SD for the US Headache Consortium. (2000)
www.neurology.org/cgi/reprint/55/6/754.pdf.
Psychological therapies for the management of chronic
pain (excluding headache) in adults
40 studies (4781 pts).
‘Weak effects in improving pain.
Minimal effects on disability associated with chronic pain.
Effective in altering mood outcomes, and evidence these
changes maintained at six months
Cochrane Database of Systematic Reviews 2009, Issue 2.
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Psychological therapies for the management of chronic
and recurrent pain in children and adolescents
29 studies 1432 pts. 20 were for headache.
(OR) of 5.51 (CI 3.28 to 9.24, P < 0.05)
NNT = 2.57 (CI 2.2 to 3.13)
At follow-up, the OR was 9.91 (95% CI 3.73 to 26.33), P <
0.05)
NNT = 1.99 (CI 1.63 to 2.72.
‘Psychological treatments are effective in pain control for
children with headache and benefits appear to be
maintained’
Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD003968
22 trials, 4419 pts
Benefit to treatment of
acute migraine attacks
only or to routine care.
No evidence for an
effect of 'true'
acupuncture over sham
interventions.
Cochrane Database Syst Rev. 2009
Jan 21;(1):CD001218.
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GONI/operations- covered later
Medication overuse- covered later
Menstrual migraine- covered later
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Men or women aged 18 to 65 years1
Headache occurring 15 days/4 weeks,3 with
each day consisting of 4 hours of continuous
headache and 50% of baseline headache days
being migraine days1*
≥4 distinct headache episodes/4 weeks, with
each episode consisting of 4 hours of
continuous headache1
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Patients overusing acute medications were not
excluded
*Migraine days or probable migraine days. Migraine defined by ICHD-II 1.1, 1.2, and 1.6.
OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial
Cephalalgia July 1, 2010 30: 793-803
OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial
Cephalalgia July 1, 2010 30: 804-814
Double-blind phase:
BOTOX® vs. placebo
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Open-label phase:
All patients on BOTOX®
Mean change in frequency migraine days
(days/28-day
baseline
period)
from
of migraine
in frequency
change
Mean
days from baseline (days/28-day period)
Study week
0
4
8
0
12
16
20
24
28
32
36
40
44
48
52
56
BOTOX® (n=688)
Placebo (n=696)
-2
-4
-6
-8
-10
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
-12
p<0.001
p=0.006
p=0.024
p=0.003
p=0.003
p=0.018
p=0.013
p=0.01
-14
Mean ± standard error.
The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group.
Migraine days at baseline: 19.1 BOTOX® group vs 18.9 placebo group, p=0.328.
1. Dodick DW et al. Headache 2010;50:921–936.
2. Aurora SK et al. Presented at IHC 2009.
3. Allergan Data on File – 50% responder rate at Week 56.
Nearly 70% of patients
treated with BOTOX®
throughout the entire
study experienced
≥50% reduction in
migraine days from
baseline at Week 56
(67.8% vs. 59.6% for
placebo; p=0.018)3
Double-blind phase:
BOTOX® vs. placebo
Open-label phase:
All patients on BOTOX®
Weeks
0
4
0
12
16
20
24
28
36
48
56
BOTOX®
Placebo
-1
Change from baseline in
total HIT-6 score
8
-2
-3
2.4*
-4
-5
-6
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001 p<0.001
-7
-8
p=0.002 p=0.022
p=0.002
p=0.069
-9
*Between-group difference exceeded the minimally important difference (MID) for HIT-6 (2.3 units) indicating a clinically significant effect of
BOTOX® treatment.1 The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group.
Total HIT-6 scores at baseline: 65.5 BOTOX® group vs 65.4 placebo group; p=0.638.
1. Coeytaux RR et al. J Clin Epidemiol 2006;59:374–380.
2. Dodick DW et al. Headache 2010;50:921–936.
3. Allergan Data on File – HIT-6 Scores (56 weeks).
When should I give
prophylaxis?
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What prophylaxis
should I give?
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What benefit
should my patient
expect?

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


Factors that may affect use, or
apparent efficacy of migraine
prophylaxis
Factors predicting chronic pain
The patient. The doctor
Principles of prophylaxis
How to choose
First line, Second line, third line
Magnitude of effects
Herbal
Psychological
Injection- Acupuncture and Botox
High rates of FMS in chronic migraine
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Peres (Neurology 2001)
FMS in 36% of patients with primary headache
Those with comorbid FMS had highest level of migraine
severity
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DeTommaso et al (Cephalagia 2008)
Patients with FMS show increased sensitivity to various stimuli,
with abnormal central pain mechanism and augmented pain
experience.
Suggestion episodic migraine, chronic daily headache and FMS
are continuum of the same disorder
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Peres (Current Neurol Neuroscience Rep 2003) and Centonze
(Neurol Sci 2004)
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Reduction in attack frequency
Reduction in attack intensity / severity
Decrease in migraine-induced disability
% of patients with >50% reduction in attack
frequency