Migraine, Contraception and Stroke
Definitions
|
Migraine with/without aura |
Defined by presence of aura |
|
Episodic migraine |
Intermittent attacks with recovery in
between |
|
High frequency migraine |
≥8 migraine headaches/month |
|
Chronic migraine |
≥15 headache days/month with ≥8 migraine headaches For at least 3 months ? Better defined as “High frequency
headache” |
|
Basilar migraine “Migraine with brainstem aura” |
Dysarthria, vertigo, diplopia, ataxia |
|
Hemiplegic migraine |
Aura contains motor weakness (Familial/genetic forms) |
|
“Aura without headache” Acephalgic migraine Retinal migraine Late life/onset migraine accompaniments |
Aura symptoms without associated
headache (or mild headache) Visual most common |
Epidemiology
- Lifetime
prevalence: Women 33%, Men 18%
- Active migraine
(i.e. one attack in last year) 8-15% (~15% of women and 6% of men)
- Equal M=F
prior to puberty after which it is more frequent in females
- Age of onset
median 23-25yrs with another peak between 15-19yrs
- Peak
prevalence 30-40yrs
- Significant
decrease with age (5% in male and female after age 50yrs)
- Atack
frequency
- Median monthly
migraine 1.5
- Weekly
attacks in 25%
- Chronic
migraine 5%
Pathogenesis
- Not thought to
be primary vascular phenomenon
- Abnormal
activation of cells in trigeminal nucleus
- increased
release of CGRP (calcitonin gene related peptide), substance P and
neurokinin A
- Results in
neurogenic inflammation
- CGRP results
in vasodilation
- Agents also
result in sensitization of other neural pathways – including pain
pathways.
- Cortical
spreading depression
- A phenomenon
that is observed in association with aura
- Self-propagating
wave of neuronal and glial depolarization that spreads across the
cerebral cortex.
- May activate
trigeminal nerve afferents and trigger headache
- 5-HT
involvement
- Exact role
unclear – may act on vasculature and or central pain pathways.
- Dopamine
receptor hypersensitivity
- Rare genetic
forms – familial hemiplegic migraine
- FHM1 –
Calcium channel mutation (gene implicated in SCA)
- FHM2 – Na/K
ATPase
- FHM3 – Na
channel
- Menstrual
migraine
- Thought to
be related to decreased oestrogen levels during menstruation
- Aura is rare
Clinical
manifestations
- Traditional
division
- Migraine
with aura (classic migraine)
- Migraine
without aura (common migraine) 80%
- Atypical
migraine
- Acephalgic
migraine - Migraine without headache – episodic neurological features
often associated with vomiting
- Triggers
- Menstrual
cycle (plus heightened sensitivity to other triggers)
- Usually 2 days before to 3 days after onset of
menstruation
- Usually not
associated with aura
- Glare,
bright lights
- Sounds
- Hunger
- Stress
(common)
- Exertion
- Changing
weather
- Lack of
sleep
- Alcohol
- Medications
- GTN,
histamine, resperpine, oestrogens, steroid
withdrawal, hydralazine
- 5 factors
identified as predictive of migraine:
- Pulsating
- Duration
4-72hours
- Unilateral
(60-70%)
- Nausea
- Disabling
Ferrari MD, Goadsby PJ, Burstein R, et al.
Migraine. Nat Rev Dis Primers. 2022;8(1):2. Published 2022 Jan 13.
- Aura
- Usually just
precedes migraine, rarely there can be up to an hours
gap
- Very rarely
aura starts with headache or comes after it (~4%)
- Aura
symptoms can persist during headache but majority resolve within one
hour, motor symptoms resolve more slowly.
- Side of
headache does not relate to side of aura symptoms
- Possible
symptoms
- Visual
disturbances
- Of
patients who get aura – 99% will get some visual change
- Fortification
spectra ~60%
- Mean
duration ~30min
- Sensory
symptom
- ~31% of
patients with aura
- Often
unilateral affecting hand then progressing to face
- Progress
over ~30min and last ~1hour on average
- Motor
weakness
- ~18%
- Unilateral
weakness, most often affecting upper limb
- Onset over
~30min and on average last 7hours
- Dysphasia
- ~18%
- Expressive
75%, Receptive 38%
- Average
duration 45min
- Basilar
type aura
- 10%
- Dysarthria/vertigo/tinnitus/Diplopia/Ataxia
- Decreased
consciousness can rarely occur
- Bilateral
paraesthesia can also occur rarely
- Average
duration 1hour
- Symptoms
- Headache
- Median untreated
duration is one day (range from 2 hours to 3 days)
- Can wake at
night – although more commonly cluster headache or think of tumour etc.
- Cutaneous Allodynia
is probably very common
- Autonomic
features – classically associated with cluster headaches but can occur
with migraine
|
Symptom |
Patients
Affected, % |
|
Nausea |
87 |
|
Photophobia |
82 |
|
Lightheadedness |
72 |
|
Scalp
tenderness |
65 |
|
Vomiting |
56 |
|
Visual
disturbances |
36 |
|
Photopsia |
26 |
|
Fortification
spectra |
10 |
|
Paresthesias |
33 |
|
Vertigo |
33 |
|
Alteration
of consciousness |
18 |
|
Syncope |
10 |
|
Seizure |
4 |
|
Confusional
state |
4 |
|
Diarrhoea |
16 |
- Migraine
variants
- Hemiplegic
migraine
- Unilateral motor
symptoms that may take a long time to resolve
- Permanent
weakness may occur after multiple attacks
- Familial
hemiplegic migraine – rare AD condition (see pathogenesis)
- 100-200
families identified and another 200 patients with de-novo mutations
known.
- Prevalence
?3/100,000 at most
- Many
different mutations in the affected genes make testing difficult –
however may be achievable.
- See
references for paper.
- Basilar-type
migraine
- Affects
young women and children
- Dysarthria,
vertigo, diplopia, tinnitus, decreased hearing, ataxia, bilateral paresthesias, altered conciousness
- Opthalmoplegic migraine
- Affects 3rd,
4th and 6th cranial nerves
- ? Recurrent
demyelinating neuropathy
- Retinal
(ocular) migraine
- Repeat attacks
of monocular scotoma or blindness lasting less than one hour
- Irreversible
visual loss may occur
- MUMS –
Migraine with unilateral motor symptoms
- Complications
- Chronic
migraine - >15 days per month
- Status migrainosus – headache lasting >72hours
- Migraine
with
- prolonged
aura - >1hr to 1 week
- Persistent
aura - >1 week
- Migrainous infarction
- Migraine
triggered seizures
- Cardiovascular
risk
- Complex
association has been noted
- Correlation
is generally only in patients with migraine with aura
- Increasing
frequency of migraine with aura was associated with increased risk of
ischaemic stroke HR ~4 (Neurology 2009;73;581-588)
- Found that
general cardiovascular risk was elevated in patients with aura who had
infrequent migraines (but not frequent).
- OCP and
smoking possibly increase the risk of stroke in patients with aura.
- Cognitive
decline
o
Womens health study found no association between
migraine and cognitive decline over 3.5yrs (BMJ 2012;345:e5027)
Diagnosis
- Classification
criteria
- Repeated
attacks 4-72hours with 2 of the following
- Unilateral
- Throbbing
- Aggravation
by movement
- Moderate or
severe intensity
- Plus at
least one
- N+V
- Photophobia
and phonophobia
- CSF
- Aseptic meningitis
picture can be seen in patients with hemiplegic migraine – raised WCC,
mainly lymphocytes, raised protein.
- MRI
- Cerebral
oedema with swelling of the cortical ribbon may be seen
- EEG
- May be
abnormal in hemiplegic migraine
- Diffuse
slow waves contralateral to the motor deficit can persist for weeks
Treatment
Prevention
·
Avoid triggers
o Regular sleep
o Avoid excess caffeine or alcohol
o Avoid changes in stress levels
o Regular exercise
o Change or avoid OCP
Acute
Simple analgesia
- NSAIDS –
effective
- Paracetamol/aspirin/caffeine
combination proven effectiveness
5HT agonists - Ergotamine and dihydroergotamine
· These medications stimulate a number of 5-HT subclasses, the most important is felt to be 5-HT 1b/1d
· Ergotamine and dihydroergotamine
- Mixed
results of trials – overall in balance of some efficacy
5HT agonists - Triptans
· Designed to be more selective for 5-HT 1b/1d subclass
· Effective – avg. NNT 5 (to have one patient pain-free at 2 hours)
· Intranasal route faster, but maybe less effective
· Best taken when headache is mild, not effective if taken earlier during aura
· Should allow 24hours before using ergotamine agents
· 15-40% relapse rate the following day
· Rebound/medication overuse headaches have been linked to use >3x/week (>10 days/month)
· Contraindication:
o Patients with cerebrovascular or CVS disease,
§ This is controversial with studies both confirming and refuting.
§ E.g. Mayo database study compared rate of cardiovascular events in patients with CV risk factors and triptan use vs matched controls – CV events higher in triptan group (1.48% vs 0.37%) Wang Z, et al. Mayo Clin Proc. 2024;99(11):1722-1731.
o CI in raynauds.
o Often stated to avoid in familial hemiplegic or basilar type migraine, however evidence suggests likely safe.
o No definite issues in pregnancy (cases of atonic uterus, haemorrhage) – CAT B1, suggest limit use if possible.
· Side effects:
o Tingling/paraesthesia, flushing, chest pain or heaviness (probably muscle/oesophageal spasm vs angina), dizziness, ?drowsiness.
· Serotonin syndrome
o In the past concern about use with SSRIs has been raised. Subsequent studies have suggested low risk (1/10,000 with co-use)
o Headache society does not view it as a contraindication
|
Generic name |
Formulation |
Dosing (maximum dose) |
Initial 2-hour relief |
Sustained pain free |
Tolerability |
Comments (courtesy of Dr Stark) |
|
Sumatriptan (Imigran) |
Tablet or fast disintegrating tablet
(50mg) |
50–100 mg (300 mg/day) |
= |
= |
= |
Tablet form has
variable absorption |
|
|
|
Discontinued |
||||
|
Subcutaneous injection* |
6 mg
autoinjector (12 mg/day) |
|||||
|
Rizatriptan (Maxalt, Rixalt) |
Tablet or wafer (10mg) |
10 mg (30 mg/day) |
+ |
+ |
= |
Potent, more reliable absorption |
|
Eletriptan (Relpax) |
Tablet (40 mg) Tablet (80 mg) |
40–80 mg (160 mg/day) |
=/+ + |
=/+ + |
= – |
Very potent (at
80mg dose) |
|
Zolmitriptan (Zomig) |
Tablet (2.5mg) |
2.5–5 mg (10 mg/day) |
= |
=/+ |
= |
Quicker onset |
|
Naratriptan (Naramig) |
Tablet (2.5mg) *Required Authority |
2.5 mg (5 mg/day) |
– |
– |
++ |
Gentle, long
half life |
* sumatriptan injection not subsidised
on Pharmaceutical Benefits Scheme Using 100 mg sumatriptan as the comparator:
= indicates no difference
+ indicates better
– indicates inferior, when compared with sumatriptan
Dopamine antagonists
- May be
helpful in decreasing symptoms and helping with absorption of other drugs
- Maxalon, chlorperazine,
chlorpromazine
Telcagepant
- CGRP
receptor antagonist
- Some efficacy in early trials
- Not yet
approved anywhere
From: NEJM Migraine review 2020
Prophylaxis
• Used
for patients with 5+ attacks per month
• Overall probably good effectiveness in 1/3 of patients
- B-Blockers
- Evidence
that propranolol reduces migraine in 60-80% of people
- Other
b-blockers used but less evidence
- Calcium
channel blockers
- Often used,
some small trials show beneficial effect however overall
no convincing evidence of effect
- Antidepressants
- Evidence
exists for efficacy of amitriptyline however side effects are often
problematic
- Anti-convulsants
- Valproate –
probably as effective as propranolol
- Gabapentin –
proven effective
- Topiramate
- 2 large
RCTs
- No effect
found until dose at least 100mg/day
- 50% had a
50% decrease in migraines
• Menstrual migraine
o Naratriptan prophylaxis
o Naproxen 500mg bd prophylaxis
Prophylaxis Guidelines
|
|
AAN 2012 |
EFNS |
|
|
Valproate |
A |
A |
|
|
Metoprolol |
A |
A |
|
|
Propranolol |
A |
A |
|
|
Timolol |
A |
|
|
|
Topiramate |
A |
A |
|
|
Amitriptyline |
B |
B |
|
|
Venlafaxine |
B |
|
|
|
Atenolol |
B |
|
|
|
Riboflavin |
B |
C |
|
|
Magnesium |
B |
|
|
|
Flunarazine |
C |
A |
|
|
Candesartan |
C |
C |
|
|
Gabapentin |
U |
C |
|
|
Verapamil |
U |
No data |
|
U – unknown, probably not
effective
Anti-CGRP Treatment
|
|
Dose |
Formulation |
|
|
|
Erenumab (Aimovig) |
70mg monthly Patients with
partial response can trial 140mg dose |
70mg pre-filled
syringe 140mg
pre-filled syringe |
Antibody to cGRP receptor |
No longer
available |
|
Galcanezumab (Emgality) |
240mg loading
dose then 120mg/month |
120mg
pre-filled syringe |
Antibody to cGRP (ligand) |
|
|
Fremanezumab (Ajovy) |
225mg monthly OR 675mg every 3
months |
225mg pre-filled
syringe |
Antibody to cGRP (ligand) |
|
|
Epitinezumab (Vyepti) |
IV infusion
every 3 months |
|
Antibody to cGRP (ligand) |
|
Gepants
|
|
|
|
|
|
|
Rimegepant (Nurtec) |
Oral, dissolves
under tongue (75mg tablets, $31 per tablet 2024) Acute treatment
or prevention |
Similar
efficacy to ibuprofen. Less effective
than triptans |
Safe in cardiovascular and
cerebrovascular disease Rare side
effects Does not have rebound
effect |
|
|
Ubrogepant |
Not available
in Australia |
|
|
|
TRIALS
|
|
|
Dose |
Mean MMD Change (days) |
>50% MMD Change rate% |
Absolute difference/NNT |
Side effects |
|
Erenumab (Aimovig) |
|
|
|
|
|
|
|
STRIVE |
Episodic migraine Ages 18-65, 4-14 MD/month, <15 HD/month, onset <50 y/o. Exclude Botox in 4 months, failed >2 preventive categories, allows 1 stable preventive |
140 mg/M (N = 318) 70 mg/M (N = 312) Placebo (N = 316) |
-3.7 -3.2 -1.8 |
50 43 27 |
23% (4.3) 16% (6.25) |
Nasopharyngitis, URI, injection site pain, arthralgia, fatigue, nausea, constipation, UTI |
|
ARISE |
Similar to STRIVE |
70mg Placebo |
-2.9 -1.8 |
40 30 |
10% (10) |
|
|
LIBERTY |
Similar to above |
|
|
|
|
|
|
NCT020… |
Chronic migraine by ICHD3β, 18-65 y/o. Exclude continuous
headache, Botox within 4 months, on preventive, failed >3 preventive categories, opioid >12 days/3month, barbiturate >6 days/3months, device use |
140mg/month 70mg/month Placebo |
-6.6 -6.6 -4.2 |
41 40 23 |
18% 17% |
|
|
|
|
|
|
|
|
|
|
Galcanezumab (Emgality) |
|
|
|
|
|
|
|
EVOLVE I (see graph below) |
Ages 18-65, 4-14 migraine or probable migraine days/month, onset <50 y/o. Exclude failure ≥3 preventive classes, ≥2 days opioid or barbiturate |
240 mg/M (N = 208) 120 mg/M (N = 210) Placebo (N = 425) |
-4.6 -4.7 -2.8 |
61 62 39 |
22% 23% |
Injection site pain, nasopharyngitis, URI |
|
EVOLVE II |
Same as above |
Similar to above |
Similar to above |
Similar to above |
Similar to above |
Similar to above |
|
REGAIN |
Chronic Migraine CM by ICHD3β, 18-65 y/o. Exclude <1 headache free day, Botox
<4 months, on >1 preventive other than topiramate or propranolol |
240mg/M 120mg/month |
-4.6 -4.8 -2.7 |
28 28 15 |
13% 13% |
|
|
Fremanezumab (Ajovy) |
|
|
|
|
|
|
|
HALO (episodic) |
Ages 18-70, ≥4MD/month, 6-14 HD/month, onset <50 y/o. Exclude Botox use in 4 months. Exclude failure of ≥2 classes of preventives, ≥4 days opioid or barbiturates, Botox in 4 months |
675 mg/Q (N = 291 225 mg/M (N = 290) Placebo (N = 294) |
-3.4 -3.7 -2.2 |
44 48 30 |
14% 18% |
Injection site reaction, nausea, sinusitis, dizziness, URI |
|
HALO (Chronic) |
CM by ICHD3β, 18-70 y/o. Exclude any preventive use (70%), >1 preventive use (30%). failed >1 preventive category, Botox within 4 months, <4 headache free days, opioid or barbiturate >4 days/month, device use |
675,225 x2 mg/M 675mg/month Placebo |
-4.6 -4.3 -2.5 |
41 38 18 |
23% 20% |
|
|
Epitinezumab |
|
|
|
|
|
|
|
PROMISE 1 |
|
|
|
|
|
|
From: NEJM Migraine review 2020
Botulinum toxin
PBS Criteria
• Average of 15 headache days/month
• At least 8 days of migraine
• Symptoms meeting above criteria present for at least 6 months
• Experienced inadequate response, intolerance or contraindication to at least 3 prophylactic migraine medications (propranolol, amitriptyline, pizotifen, cyproheptadine, topiramate)
• Must be appropriately managed for medication overuse headache prior to initiation
• Must achieve a 50% or greater reduction from baseline in the number of headache days/month after 2 treatment cycles.
Trials
PREEMPT 1 and 2
• Two similar trials run in parallel and published in 2010
• Blinded phase 24 weeks
• Open label phase out to 54weeks
Pooled results:
|
|
Botox |
Placebo |
Difference |
|
Baseline migraine days/month |
19 |
19 |
|
|
Baseline headache days/month |
20 |
20 |
|
|
%overusing acute medication |
65 |
66 |
|
|
Week 24 |
|
|
|
|
Reduction in HA days/month |
-8.4 |
-6.6 |
-1.8 |
|
Reduction in migraine days/month |
-8.2 |
-6.2 |
-2.0 |
|
>50% reduction in headache days |
47.1 |
35.1 |
12% |
|
Adverse effects |
|
|
|
|
Neck pain |
6.7 |
2.2 |
|
|
Muscular weakness |
5.5 |
0.3 |
|
|
Eyelid ptosis |
3.3 |
0.3 |
|
|
Musculoskeletal pain |
2.2 |
0.7 |
|
|
Myalgia |
2.6 |
0.3 |
|
|
Musculoskeletal stiffness |
2.3 |
0.7 |
|
Treatment in Pregnancy
Acute treatment
• Safe
o Paracetamol
o Codeine
o Cefaly
• Probably safe
o Triptans (B1)
- ?Some reports of atonic uterus and haemorrhage
- No overall increase in malformations, however ?some increase in subgroups
Prevention
• Safe
o Propranolol (Cat C)
o Amitriptyline (Cat C)
o Verapamil (Cat C)
o Cefaly
o ?Riboflavin
• Uncertain/Low risk
o Lamotrigine
o Pizotifen (Cat B1, but limited data)
o BOTOX
o Anti-CGRP AB (Cat B1, limited data)
• Unsafe
o Topiramate,
o Valproate
o Candesartan
Migraine, Contraception and Stroke
Risk of stroke with migraine
• Without aura
o Conflicting evidence with several studies showing no elevated risk
o Meta-analysis (BMJ 2005) – suggested OR 1.83 (just significant)
• With aura
o Most studies support elevated risk of stroke
o Meta-analysis – OR 2.27 (significant)
Risk of stroke with migraine, OCP and smoking
• Migraine and OCP use
o Highly variable results – some studies show no increased risk
o Meta-analysis (BMJ 2009) – suggested stroke risk of migraine RR 3.6 increased to RR 7.2 with COCP
o There is insufficient data to separate out risk for patient with migraine with aura specifically
• Type of OCP
o Combined COCP – the risk is considered higher for 50mcg preparations, no known difference between 30mcg and very low dose perparations
o Progesterone only pill – not considered to increase risk
o Other forms of contraception also considered safe
• Migraine and smoking
o ?RR 2x
• Migraine, smoking and OCP
o Most studies suggest a significantly elevated risk
o Generally considered to be RR of at least 10x risk compared to non-migraine, non-ocp, nonsmokers.
o RR at least 7x risk compared to patients with migraine with aura who do not smoke or use OCP
o Some risk estimates up to RR 34x
• Context
o Risk of stroke in young women is 5-10/100,000 women years (WY)
o Assuming risk at upper limit of this range (1/10,000 WY = 0.01%/year) and RR with OCP 7x (=7/10,000 or 1/1429 = 0.07%/year)
- ARR = 0.06%/year
- NNH (to cause one stroke) – 1667
• Reference: Edlow and Bartz, Reviews in Obseterics and Gynecology Vol 3, No 2 2010
References
- Sporadic and
familial hemiplegic migraine. Lancet Neurology 2011; 10;457-70.