Transcript drugs used in migraine

DRUGS USED IN MIGRAINE
Md. Amran Howlader
• Migraine is a neurological syndrome that can
cause a wide range of symptoms during an
attack. The most commonly thought of
symptom is headache.
• It is widespread in the population. In the U.S.,
18% of women and 6% of men report having
had at least one migraine episode in the
previous year, with seriousness ranging from
an annoyance to a life-threatening and/or
daily experience.
Overview
• Usually migraine causes episodes of severe or
moderate headache (which is often one-sided
and pulsating) lasting from four to 72 hours,
accompanied by gastrointestinal upsets, such
as nausea and vomiting, and a heightened
sensitivity to bright lights (photophobia) and
noise (phonophobia). Approximately one third
of people who experience migraine get a
preceding aura, in which a patient senses a
strange light or unpleasant smell.
• The word migraine is French in origin and
comes from the Greek hemicrania, as does
the Old English term megrim. Literally,
hemicrania means "half (the) head".
• Migraines' secondary characteristics are
inconsistent. Triggers precipitating a particular
episode of migraine vary widely. The efficacy of
the simplest treatment, applying warmth or
coolness to the affected area of the head, varies
between persons, sometimes worsening the
migraine. A particular migraine rescue drug may
sometimes work and sometimes not work in the
same patient. Some migraine types don't have
pain or may manifest symptoms in parts of the
body other than the head.
• Available evidence suggests that migraine pain is one
symptom of several to many disorders of the
serotonergic control system, a dual hormoneneurotransmitter with numerous types of receptors.
Two disorders — classic migraine with aura (MA, STG)
and common migraine without aura (MO, STG) —
have been shown to have a genetic factor. Studies on
twins show that genes have a 60 to 65% influence on
the development of migraine. Additional migraine
types are suspected and could be proven to be genetic.
Migraine understood as several or many disorders
could explain the inconsistencies, especially if a single
patient has more than one genetic type.
Classification
• Migraines have been classified by the
International Headache Society which
periodically revises their classification.
• Defining severity of pain
• In addition to classifying the type of headache, the
International Headache Society defines intensity of
pain on a verbal 4 point scale:
– 0 no pain
– 1 mild pain 'does not interfere with usual
activities'
– 2 moderate pain 'inhibits, but does not wholly
prevent usual activities'
– 3 severe pain 'prevents all activities'
Migraine without aura
• This is the most commonly seen form of migraine;
patients who primarily suffer from migraine without
aura may also have attacks of migraine with aura.
According to the International Classification of
Headache Disorders it is a recurrent headache disorder
manifesting in attacks lasting 4–72 hours. Typical
characteristics of the headache are unilateral location,
pulsating quality, moderate or severe intensity,
aggravation by routine physical activity and association
with nausea and/or photophobia and phonophobia.
• In order to diagnose migraine without aura, there must
have been at least five attacks not attributable to another
cause that fulfill the following criteria:
1. Headache attacks lasting 4–72 hours when untreated
2. At least two of the following characteristics:
Unilateral location
Pulsating quality
Moderate or severe pain intensity
Aggravation by or causing avoidance of routine physical activity
3. During the headache there must be at least one of the following
associated symptom clusters:
Nausea and/or vomiting
Photophobia and phonophobia
• Where these criteria are not fully met, the problem may be
classified as "probable migraine without aura" but other
diagnoses such as "episodic tension type headache" must
also be excluded.
Migraine with aura
• This is the second most commonly seen form of
migraine: patients who primarily suffer from migraine
with aura may also have attacks of migraine without
aura. According to the International Classification of
Headache Disorders it is a recurrent disorder
manifesting in attacks of reversible focal neurological
symptoms that usually develop gradually over 5–20
minutes and last for less than 60 minutes. Headache
with the features of "migraine without aura" usually
follows the aura symptoms. Less commonly, the aura
may occur without a subsequent headache or the
headache may be non-migrainous in type.
• In order to diagnose migraine with aura, there must
have been at least two attacks not attributable to
another cause that fulfill the following criteria:
1. Aura consisting of at least one of the following, but no
muscle weakness or paralysis:
• Fully reversible visual symptoms (e.g. flickering lights, spots, lines,
loss of vision)
• Fully reversible sensory symptoms (e.g. pins and needles,
numbness)
Fully reversible dysphasia (speech disturbance)
2. Aura has at least two of the following characteristics:
• Visual symptoms affecting just one side of the field of vision
and/or sensory symptoms affecting just one side of the body
• At least one aura symptom develops gradually over more than 5
minutes and/or different aura symptoms occur one after the other
over more than 5 minutes
Each symptom lasts from 5–60 minutes
• Where these criteria are not fully met, a
diagnosis of "probable migraine with aura"
may be considered, although other
neurological causes must also be excluded. If
the picture complies with the criteria but
includes one-sided muscular weakness or
paralysis, a diagnosis of "sporadic hemiplegic
migraine" or "familial hemiplegic migraine"
should be considered.
Basilar type migraine
• Basilar type migraine (BTM), formerly known as basilar
artery migraine (BAM) or basilar migraine (BM), is an
uncommon type of complicated migraine with
symptoms that result from brainstem dysfunction.
Serious episodes of BTM can lead to stroke, coma, or
even death. The use of triptans and other
vasoconstrictors as abortive treatments in BTM is
contraindicated. Abortive treatments for BTM often
focus on vasodilation and restoration of normal blood
flow to the vertebrobasilar territory and subsequent
return of normal brainstem function.
Familial hemiplegic migraine
• Familial hemiplegic migraine 'FHM' is a type of migraine with a
possible polygenetic component. These migraine attacks may last
4–72 hours and are apparently caused by ion channel mutations,
three types of which have been identified until now. Patients who
experience this syndrome have relatively typical migraine
headaches preceded and/or accompanied by reversible limb
weakness on one side as well as visual, sensory or speech
difficulties. A non-familial form exists as well, "sporadic hemiplegic
migraine" (SHM). It is often difficult to make the diagnosis between
basilar-type migraine and hemiplegic migraine. When making the
differential diagnosis is difficult, the deciding symptom is often the
motor weakness or unilateral paralysis which can occur in FHM or
SHM. While basilar-type migraine can present with tingling or
numbness, true motor weakness and/or paralysis occur only in
hemiplegic migraine.
Abdominal migraine
• According to the International Classification of
Headache Disorders abdominal migraine is a
recurrent disorder of unknown origin which
occurs mainly in children. It is characterised by
episodes of moderate to severe central
abdominal pain lasting 1–72 hours. There is
usually associated nausea and vomiting but the
child is entirely well between attacks.
• In order to diagnose abdominal migraine, there
must be at least five attacks, not attributable to
another cause, fulfilling the following criteria:
1. Attacks lasting 1–72 hours when untreated
2. Pain must have ALL of the following characteristics:
• Location in the midline, around the umbilicus or poorly localised
• Dull or 'just sore' quality
• Moderate or severe intensity
3. During an attack there must be at least two of the following:
•
•
•
•
Loss of appetite
Nausea
Vomiting
Pallor
• Most children with abdominal migraine will develop
migraine headache later in life and the two may co-exist
during adolescence.
Acephalgic migraine
• Acephalgic migraine is a neurological syndrome.
It is a variant of migraine in which the patient
may experience aura symptoms such as
scintillating scotoma, nausea, photophobia,
hemiparesis and other migraine symptoms but
does not experience headache. Acephalgic
migraine is also referred to as amigrainous
migraine, ocular migraine, or optical migraine.
• Sufferers of acephalgic migraine are more likely
than the general population to develop classical
migraine with headache.
Menstrual migraine
• Menstrual migraine is distinct from other
migraines. Approximately 21 million women in
the US suffer from migraines, and about 60%
of them suffer from menstrual migraines.
• The exact causes of menstrual migraine are
uncertain but evidence suggest there may be
a link between menstruation and migraine
due to the drop in estrogen levels that
normally occurs right before the period starts.
Signs and symptoms
• The signs and symptoms of migraine vary among
patients. Therefore, what a patient experiences before,
during and after an attack cannot be defined exactly.
The four phases of a migraine attack listed below are
common but not necessarily experienced by all
migraine sufferers. Additionally, the phases
experienced and the symptoms experienced during
them can vary from one migraine attack to another in
the same migraineur:
– The prodrome, which occurs hours or days before the
headache.
– The aura, which immediately precedes the headache.
– The pain phase, also known as headache phase.
– The postdrome.
Diagnosis
• Migraines are underdiagnosed and misdiagnosed. The
diagnosis of migraine without aura, according to the
International Headache Society, can be made according to
the following criteria,
• the "5, 4, 3, 2, 1 criteria":
– 5 or more attacks
– 4 hours to 3 days in duration
– 2 or more of - unilateral location, pulsating quality, moderate to
severe pain, aggravation by or avoidance of routine physical
activity
– 1 or more accompanying symptoms - nausea and/or vomiting,
photophobia, phonophobia
Pathophysiology
•
Migraines were once thought to be initiated by
exclusively by problems with blood vessels. The
vascular theory of migraines is now considered
secondary to brain dysfunction and claimed to have
been discredited by others.
• The effects of migraine may persist for some days after
the main headache has ended. Many sufferers report a
sore feeling in the area where the migraine was, and
some report impaired thinking for a few days after the
headache has passed.
• Migraine headaches can be a symptom of
hypothyroidism.
Depolarization theory
• A phenomenon known as cortical spreading
depression can cause migraines. In cortical
spreading depression, neurological activity is
depressed over an area of the cortex of the
brain. This situation results in the release of
inflammatory mediators leading to irritation
of cranial nerve roots, most particularly the
trigeminal nerve, which conveys the sensory
information for the face and much of the
head.
• This view is supported by neuroimaging
techniques, which appear to show that migraine
is primarily a disorder of the brain (neurological),
not of the blood vessels (vascular). A spreading
depolarization (electrical change) may begin 24
hours before the attack, with onset of the
headache occurring around the time when the
largest area of the brain is depolarized. A French
study in 2007, using the Positron Emission
Tomography (PET) technique identified the
hypothalamus as being critically involved in the
early stages.
Vascular theory
•
Migraines can begin when blood vessels in the brain contract and
expand inappropriately. This may start in the occipital lobe, in the
back of the brain, as arteries spasm. The reduced flow of blood
from the occipital lobe triggers the aura that some individuals who
have migraines experience because the visual cortex is in the
occipital area.
• When the constriction stops and the blood vessels dilate, they
become too wide. The once solid walls of the blood vessels
become permeable, some fluid leaks out. This leakage is
recognized by pain receptors in the blood vessels of surrounding
tissue. In response, the body supplies the area with chemicals
which cause inflammation. With each heart beat, blood passes
through this sensetive area causing a throb of pain.
• The vascular theory of migraines is now seen as secondary to brain
dysfunction.
Serotonin theory
• Serotonin is a type of neurotransmitter, or
"communication chemical" which passes
messages between nerve cells. It helps to control
mood, pain sensation, sexual behaviour, sleep, as
well as dilation and constriction of the blood
vessels among other things. Serotonin levels in
the brain may lead to a process of constriction
and dilation of the blood vessels which trigger a
migraine.
• Triptans activate serotonin receptors to stop a
migraine attack.
Neural theory
• When certain nerves or an area in the brain stem
become irritated, a migraine begins. In response
to the irritation, the body releases chemicals
which cause inflammation of the blood vessels.
These chemicals cause further irritation of the
nerves and blood vessels and results in pain.
Substance P is one of the substances released
with first irritation. Pain then increases because
substance P aids in sending pain signals to the
brain.
Unifying theory
• Both vascular and neural influences cause
migraines.
– stress triggers changes in the brain
– these changes cause serotonin to be released
– blood vessels constrict
– chemicals including substance P irritate nerves
and blood vessels causing pain
Treatment
• Conventional treatment focuses on three areas: trigger
avoidance, symptomatic control, and preventive
drugs. Patients who experience migraines often find
that the recommended treatments are not 100%
effective at preventing migraines, and sometimes may
not be effective at all.
• Children and adolescents, are often first given drug
treatment, but the value of diet modification should
not be overlooked. The simple task of starting a diet
journal to help modify the intake of trigger foods like
hot dogs, chocolate, cheese and ice cream could help
alleviate symptoms
Abortive treatment
• Migraine sufferers usually develop their own
coping mechanisms for the pain of a migraine
attack. Hot or cold water applied to the head,
resting in a dark and silent room or a cup of
coffee at an appropriate time may be as
helpful as medication for some patients.
Paracetamol or Non-steroidal antiinflammatory drug (NSAIDs)
• The first line of treatment is over-the-counter
abortive medication.
• Regarding non-steroidal anti-inflammatory
drugs, a randomized controlled trial found
that naproxen can abort about one third of
migraine attacks, which was 5% less than the
benefit of sumatriptan.
Serotonin agonists
• Sumatriptan and related selective serotonin
receptor agonists are excellent for severe
migraines or those that do not respond to
NSAIDs or other over-the-counter drugs.
Triptans are a mid-line treatment suitable for
many migraineurs with typical migraines.
Ergot alkaloids
• Until the introduction of sumatriptan in 1991, ergot
derivatives (see ergoline) were the primary oral drugs
available to abort a migraine once it is established.
• Ergot drugs can be used either as a preventive or
abortive therapy, though their relative expense and
cumulative side effects suggest reserving them as an
abortive rescue medicine. However, ergotamine
tartrate tablets (usually with caffeine), though highly
effective, and long lasting (unlike triptans), have fallen
out of favour due to the problem of ergotism
Other agents
• Fioricet or Fiorinal, which is a combination of
butalbital (a barbiturate), Paracetamol (in
Fioricet) or acetylsalicylic acid
• Narcotic pain killers (for example, codeine,
morphine or other opiates) provide variable relief
• Amidrine
• Anti-emetics by suppository or injection may be
needed in cases where vomiting dominates the
symptoms
• Anti-emetics by suppository or injection may be
needed in cases where vomiting dominates the
symptoms
• feverfew
Preventative treatment
•
Preventative (also called prophylactic)
treatment of migraines can be an important
component of migraine management. Such
treatments can take many forms, including
everything from taking certain drugs or
nutritional
supplements,
to
lifestyle
alterations such as increased exercise and
avoidance of migraine triggers.
Prescription Drugs
• A 2006 review article by S. Modi and D.
Lowder offers some general guidelines on
when a physician should consider prescribing
drugs for migraine prevention:
• Following appropriate management of acute migraine, patients should be
evaluated for initiation of preventive therapy. Factors that should prompt
consideration of preventive therapy include- the occurrence of two or
more migraines per month with disability lasting three or more days per
month; failure of, contraindication for, or adverse events from acute
treatments; use of abortive medication more than twice per week; and
uncommon migraine conditions (e.g., hemiplegic migraine, migraine with
prolonged aura, migrainous infarction). Patient preference and cost also
should be considered.
Other drugs:
• Sansert was withdrawn from the US market by
Novartis, but is available in Canadian
pharmacies. Although highly effective, it has
rare but serious side effects, including
retroperitoneal fibrosis.
• Namenda, memantine HCI tablets, which is
used in the treatment of Alzheimer's Disease,
is beginning to be used off label for the
treatment of migraines. It has not yet been
approved by the FDA for the treatment of
migraines.
• ASA or Asprin can be taken daily in low doses
such as 80 to 81 mg, the blood thinners in ASA
has been shown to help some migrainures,
especially those who have an aura.
Trigger avoidance
• Patients can attempt to identify and avoid
factors that promote or precipitate migraine
episodes. Moderation in alcohol and caffeine
intake, consistency in sleep habits, and regular
meals may be helpful.
• General dietary restriction has not been
demonstrated to be an effective approach to
treating migraine.
Herbal and nutritional
supplements:
•
•
•
•
Cannabis
Coenzyme Q10
Magnesium Citrate
Vitamin B12
Behavioral treatments
• Many physicians believe that exercise for 15–20
minutes per day is helpful for reducing the
frequency of migraines.
• Sleep is often a good solution if a migraine is not
so severe as to prevent it, as when a person
awakes the symptoms will have most likely
subsided.
• Diet, visualization, and self-hypnosis are also
alternative treatments and prevention
approaches.
Alternative medicine
• Incense and scents
• acupuncture
• Massage therapy and physical therapy
Rizatriptan
• Rizatriptan (Maxalt®) is a triptan drug
developed by Merck & Co. for the treatment
of migraine headaches.
Mechanism of action:
•
Rizatriptan or Maxalt is a "triptan" like
zolmitriptan and sumatriptan and works in
the same fashion - it constricts blood vessels
in the cerebral or head area. It is thought that
migraine headaches involve dilation of these
blood vessels. These drugs may also reduce
inflammation in the nerves that sense the
pain of a migraine headache.
Cautions for People:
• Rizatriptan or Maxalt can cause chest pain like sumatriptan and zolmitriptan. Thus people
with heart disease, prior heart attack, or even
high blood pressure that is difficult to control
should not use it because it may complicate
their condition.
Drug Interactions:
Rizatriptan or Maxalt should not be taken with either
zolmitriptan or sumatriptan - they are the same type of drug.
Indicated for:
migraine headache with or without aura
Contraindications:
coronary artery disease
monoamine oxidase inhibitors
Butorphanol
• Butorphanol (INN) is a morphinan-type
synthetic opioid analgesic marketed in the U.S.
under the trade name Stadol. It is most closely
structurally related to dextromethorphan.
Mechanism of action
• Butorphanol exhibits partial agonist and antagonist
activity at the μ opioid receptor and agonist activity
at the κ opioid receptor. Stimulation of these
receptors on central nervous system neurons causes
an intracellular inhibition of adenylate cyclase,
closing of influx membrane calcium channels, and
opening of membrane potassium channels. This
leads to hyperpolarization of the cell membrane
potential and suppression of action potential
transmission of ascending pain pathways.
Place in therapy
• The most common indication for butorphanol
is management of migraine using the
intranasal spray formulation. It may also be
used parenterally for management of
moderate-to-severe pain, as a supplement for
balanced general anesthesia, and
management of pain during labor.
Butorphanol is more effective in reducing pain
in women than in men.
Adverse effects
• As with other opioid analgesics, central
nervous system effects (such as sedation,
confusion, and dizziness) are considerations
with butorphanol. Nausea and vomiting are
common. Less common are the
gastrointestinal effects of other opioids
(mostly constipation).
Side effects, overdose, and
precautions
• Overdosing may result in seizures, falling, salivation,
consitipation, and muscle twitching. If an overdose
occurs, a narcotic antagonist, such as naloxone, may
be given. Caution should be used if Butorphanol is
administered in addition to other narcotics,
sedatives, depressants, or antihistamines as it will
cause an additive effect.
• Butorphanol can cross the placenta, and it will be
present in the milk of lactating mares who are given
the drug.
Thank You