Text Books Reading

“Neuroemergency Clinical Trials: Migraine ”

Oleh :
Lailatul Masruroh G4A018011

Pembimbing :
dr. Untung Gunarto, Sp. S

SMF ILMU SARAF RSUD PROF. DR. MARGONO SOEKARJO

FAKULTAS KEDOKTERAN
UNIVERSITAS JENDERAL SOEDIRMAN
PURWOKERTO
2019
Neuroemergency Clinical Trials:
Migraine
Migraine is a common, debilitating neurological
disease characterized by moderate-to-severe
headache with associated symptoms including
nausea, photophobia, and phonophobia.

The early and effective treatment of migraine is

essential to treat an individual attack as well as
to decrease the risk of migraine recurrence and
chronification
 Optional Treatment
ERGOTS

TRIPTAN
NEUROLEPTICS

NSAID

OPIATES&BARBITURATES

OTHER TREATMENT
 ERGOTS

• Ergot extracts have been used for the

treatment of acute headache
• The vasconstrictive properties of ergotamines
were thought to be the mechanism of action
for migraine
• Ergot derivates:
1. Ergotamine Tartrate-ET
2. Dihydroergotamine- DHE
1. Ergotamine Tartrate—ET was found to have a very erratic
pharmacokinetic profile. ET was found to be more effective
than aspirin and equal to ketoprofen, naproxen and
metoclopramide. ET plus caffeine was reported as less
effective than oral sumatriptan
2. Dihydroergotamine—intravenous (IV) has a higher and
more consistent bioavailability than any of other DHE
formulations (intramuscular (IM), subcutaneous (SC), or
nasal spray (NS)).
• DHE NS was found to be less effective than sumatriptan
injection and equal to ET plus caffeine.
• Subcutanous DHE had a lower headache recurrence rate
than SC sumatriptan and IM administration was equal to IM
meperidine
• Dihydroergotamine mesylate (DHE) has a more potent
inhibitory effect on alpha-adrenergic receptor, less potent
inhibitory effect on an arterial vasoconstrictor, less emetic
and weaker effect on uterine ton
 TRIPTANS
• Triptans are a group of selective 5HT 1B/1D agonists.
Triptans are safe and very effective for the acute treatment
of migraine; BUT not useful in the treatment of aura.
Derivates of Triptans:
1. Sumatriptan
2. Almotriptan
3. Eletriptan
4. Frovatriptan
5. Naratriptan
6. Rizatriptan
7. Zolmitriptan
• Sumatriptan available as a SC injection, oral tablet, NS, and
ionophoretic patch.
• When compared to the oral administration, the SC formulation
was found to be more effective at 2 and 4 h and when
compared to SC and intranasal (IN) DHE,
• Sumatriptan was found to be more beneficial regard short-term
headache relief however, DHE had a lower 24-h recurrence
rate. When administered during aura but before the onset of
headache, sumatriptan was found to be no more effective at
preventing the development of moderate-to-severe pain.
• A dose of 100 mg is effective for 2 and 4 h headache .
Subsequent second dose of oral sumatriptan did not show
additional benefit in further headache relief or prevention of
headache recurrence.
• Almotriptan is an oral triptan with a slightly prolonged half-life
compared to sumatriptan (3.1 vs. 2 h). Headache relief was achieved
at all doses above 6.25 mg, and the doses of 6.25 and 12.5 mg were
superior and better tolerated than 100 mg oral sumatriptan.
• Eletriptan is another oral formulated for higher bioavailability,
longer half-life, and more rapid absorption than sumatriptan. Doses
of eletriptan (20, 40, and 80 mg) all of which were superior When
compared to oral sumatriptan (50–100 mg). Eletriptan was found to
have a lower recurrence rate and it provided better relief of the
associated migrainous symptoms of nausea, photophobia, and
phonophobia, as well as migraine-related disability
• Frovatriptan has the highest affinity for the 5HT-1B/1D receptor and
has selectivity for the cerebral vascular system with limited coronary
artery vasoconstrictive activity. It has the longest half of all triptans
(26 h). Frovatriptan have a significant benefit in 2 h headache relief
at doses over 2.5 mg
• Naratriptan has a longer half-life and higher bioavailability than
sumatriptan; however, the response rate was lower than all other triptans.
Naratriptan when compared to sumatriptan in patients prone to headache
recurrence found that naratriptan had a lower recurrence rate after 4 h, but
that the two were equal after 24 h.
• Rizatriptan was found to be superior in both headache relief and pain
freedom after 2 h in doses ranging from 5–40 mg. High-dose rizatriptan (40
mg) was found to be superior to 100 mg oral sumatriptan when compared
directly; however, lower doses were found to be equal.
• Zolmitriptan is available in both oral and IN formulations. Doses 2.5 and 5
mg and was seen to be superior for both headache relief and headache
freedom at 2 and 4 h. The headache response rate was superior to most
triptans (with the exception of sumatriptan) and when compared to 100 mg
oral sumatriptan, no significant benefit was seen. It was only slightly better
in recurrent headache relief and was not beneficial when during aura and
prior to headache.
 NEUROLEPTICS
• The neuroleptic class of medications are useful
both as an adjunct to migraine-specific
medication and as primary therapy. Neuroleptics
can be administered in a variety of oral and
parenteral and can be especially useful to treat
the associated symptoms of migraine including
nausea and vomiting.
• The neuroleptics are antidopaminergic and
include metoclopramide, prochlorperazine,
chlorpromazine, haloperidol, and droperidol
• Metoclopramide is available in oral and IV formulations. IV
metoclopramide revealed it as superior to ibuprofen.
Metoclopramide IV plus dimenhydrate IM in repeated doses was
found to be as effective as SC sumatriptan in emergency settings.
Oral metoclopramide has been studied extensively as an adjuvant
therapy in acute migraine with NSAIDs or a migraine-specific drug
as primary therapy; however, as monotherapy for acute migraine, it
has not been proven effective. Metoclopramide should be dosed as
10 mg IV or 10–20 mg as an oral tablet or syrup, up to every 8 h.
• Prochlorperazine is available in oral, IV, and PR formulations. IV
prochlorperazine has been shown to significantly reduce headache
pain and was also found to be superior to IV divalproex in relieving
acute pain and nausea in an emergency setting. Prochlorperazine
can be dosed from 7.5 to 15 mg IV over 5–10 h, rectally 25 mg or
orally 5–10 mg up to every 8 h
• Chlorpromazine is available in oral and IV formulations and found
to be effective in achieving pain freedom and improvement in
nausea after 30 min. This was found to be true in both migraine
with and without aura. Oral chlorpromazine has not been studied
as primary migraine therapy but similar to other neuroleptics, it
has been useful as an adjuvant. It is dosed 25–50 mg orally or 10–
25 IV up to every 6 h.
• Droperidol is only available parenterally and statistically significant
in reducing nausea and headache relief at 2 h. Droperidol was seen
to be effective in status migrainosus, refractory migraine, and
moderate-to-severe acute migraine
• Atypical Antipsychotics- are serotonergic and
adrenergic compounds that share a number of
chemical properties with neuroleptic medications
and can be helpful in both the acute setting in
addition to being an adjunctive preventive
medication. Some examples:
• Olanzapine decreased headache days and
headache intensity. Doses 5 and 10 mg were
taken as a daily preventive.
• Quetiapine was showed a decreased frequency of
migraine days
NONSTEROIDAL ANTIINFLAMMATORY
DRUGS
• Although as a class nonsteroidal antiinflammatory
drugs (NSAIDs) are nonspecific analgesic treatments
and are not specific for migraine treatment, a number
of disparate NSAIDs have been studied in the acute
treatment of migraine.
• NSAIDs are primarily prostaglandin synthesis inhibitors
via activity on two subtypes of the enzyme
cyclooxygenase (COX1 and COX2); however, some
NSAIDs (namely indomethacin and diclofenac) inhibit
leukotriene synthesis through action on 5-lipoxegynase
and direct antagonistic effect on prostaglandin.
• Aspirin in low doses is a selective COX 1 inhibitor and mainly
affects platelet aggregation and only at intermediate and higher
doses does the active metabolite salicylate contribute a
significant antiinflammatory effect. When 1000 mg Aspirin was
compared to 50 mg oral sumatriptan or 400 mg ibuprofen,
aspirin was as effective as the other drug at headache relief and
relief of associated migrainous symptoms but not pain freedom
at 2 h. However Aspirin was inferior to ergotamine
• Ibuprofen in doses of 200 and 400 mg was superior for 2-h pain
relief of mild and moderate headache. The 400 mg dose was the
only effective dose for severe headache. Low-dose ibuprofen
(200 mg) was found to be inferior to acetaminophen, aspirin, and
caffeine combination. Higher doses of ibuprofen can contribute
to more side effects, particularly gastrointestinal distress.
• Ketoprofen at doses of 75 and 150 mg was equal to 2.5 mg of
oral zolmitriptan
• Diclofenac is available in oral, IM, and IV formulations, all of which
are superior acetaminophen in 1 and 2 h headache relief.
 OPIATES AND BARBITURATES
• Opiates are made endogenously in the brain and
are commercially synthesized for the treatment of
acute pain In migraine, the use of opiates is
associated with tolerance, dependence, and the
chronification of headache
1. Acetaminophen/codeine was found to be equal to aspirin
2. Butorphanol is a K-receptor agonist available in IN and IM
formulations with a decreased risk of respiratory suppression
as compared to morphine or other u-receptor agonists. The
risk of dependence and tolerance of the parenteral opiate
formulations is not decreased relative to oral opiates, as is the
risk of withdrawal
3. Butalbital is the only barbiturate compound studied for the
treatment of migraine and is commercially available in
combination with APAP and caffeine, aspirin and caffeine. It
was found to be equal for headache relief at 4 h. Although
butorphanol was superior in efficacy at 2 h, the butalbital
combination had fewer adverse effects. However,
Sumatriptan and naproxen in combination was studied in
comparison to butalbital and was found to be superior
 OTHER ACUTE MIGRAINE
TREATMENTS
1. Antiepileptic drugs are common migraine preventive
medications and a number of drugs have been studied as
well for acute migraine treatment. The infusion of valproic
acid has been studied both in combination with
ergotamines and neuroleptic drugs, as well as
independent of other drugs for acute migraine. IV
valproate at a dose of 15 mg/kg had Complete pain relief
was seen as quickly as 10 min.
• Comparison of 500 mg IV valproate to 10 mg
metoclopramide and 1 mg IV DHE or SC sumatriptan
showed valproate to more beneficial for headache relief at
1, 2, and 4 h as well as improvement in the associated
symptoms of photophobia, phonophobia, and nausea
2. Corticosteroids are thought to decrease neurogenic
inflammation related to migraine, likely due to their effect on the
hypothalamic–pituitary access. Prednisone, methylprednisolone,
and dexamethasone are common treatments for acute migraine
in both IV and oral formulations. IV dexamethasone has been
studied in comparison to IV valproate,where it was found to be
ineffective for aura and equal for pain reduction.

6 mg of IV dexamethasone preceded by 10 mg metoclopramide found this combination to

be effective
 Treatment migrain
• Early treatment of acute migraine is essential as most abortive
medications, especially triptans, are significantly more
effective early in an attack
• A stratified approach for Migrain:
1. stratified approach considers the severity of the migraine
attack first
2. step-care-across-attacks considers side effect and cost
effectiveness first
3. step-care-within-attacks
1. A stratified approach considers the severity of the migraine attack
first, for example, a mild or moderate headache would be treated
best with over-the-counter analgesics or NSAIDs, while a more
severe headache would be first treated with a triptan or DHE
2. Another approach, called step-care-across-attacks considers side effect
and cost effectiveness first. In this approach, first recommend a simple
analgesic such as an NSAID as the first option and if it fails, then a
neuroleptic, a generically available triptan, and then a potentially more
costly but more effective triptan or DHE. In this approach, the choice of
drug is “stepped up” in a hierarchical manner until the appropriate drug is
found.
Potent Triptan or DHE
Generically Triptan
Neuroleptic
NSAID

3. The last approach is known as step-care-within-attacks. The patient is

given instructions to follow for each attack—to start with the most benign
medication and then “step up” while the headache is ongoing to more
potent medications if the first medication fails to be effective
• Each patient may have a unique response to
any of these acute medications. The clinical
trials reviewed above provide the scientific
basis regarding these decisions; however, each
individual patient will likely have their own
experience, and it is the provider’s
responsibility to tailor an effective plan based
on the patient’s feedback and the scientific
evidence.