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 hormone-neurotransmitter 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 untreated2. At least two of the following characteristics: Unilateral locationPulsating qualityModerate or severe pain intensityAggravation by or causing avoidance of routine physical activity3. During the headache there must be at least one of the following

associated symptom clusters: Nausea and/or vomitingPhotophobia 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 untreated2. 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 anti-inflammatory 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 diseasemonoamine 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.

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