Migraine: A Paroxysmal Disorder

The malady known as migraine was identified thousands of years ago & is
known throughout all civilizations on the earth. Aretaeus of Cappadocia
(130-200 AD) coined first migraine as distinct entity because of its unilateral
occurrence associated with nausea, regular reoccurrence and paroxysm of pain,
separated by pain free intervals. Because the pain was unilateral, Aretaeua
called this HETEROCRANIA. We now use the term “HEMICRANIA” which literally
means “half a head”. Although several definitions of migraine have been proposed,
yet the world federation of neurology defines migraine as a “familial disorder
characterized by recurrent attacks of headache, widely variable in intensity,
frequency and duration. Attacks are usually unilateral (hemicrania) and are
usually associated with anorexia, nausea & vomiting. In some cases they
are preceded by or associated with neurological & mood disturbances.”(1)

Migraine is the most common cause of disabling headache in general population. Migraine occurs equally frequently in all countries & all races. They are slightly more common in male children, but after puberty are 2-3 times more common in women. (2) Over 80 % of migraineurs have their first attack before an age of 30 years. (3) Migraine variants occur in 5 % of the patients. (3) Migraine occurs in 12-15 of the total U K population, in women more than men in a ratio of 3: 1. (4)

CLASSIFICATION

On the basis of clinical manifestations migraine can be classified in
the following

Categories (5, 6, 7, 8)

1.  Classical migraine
   
2.  Common migraine
   
3.  Complicated migraine

a)Hemiplegic

b)Ophthalmic

c)Basilar

d) Status migrainosus

1. Classical Migraine (migraine with aura)

This type of migraine is preceded or accompanied by some visual symptoms known
as Aura (Prodromata). The aura consists of focal neurological symptoms such
as flashing light, zigzag lines, temporary loss of vision, and difficulty in
focusing, distorted perception, speech difficulty confusion and weakness. Aura
is characterized by a wave of oligemia that passes across the cortex (9, 10)
at the characteristic slow rate 2-6 mm/minute. (11) A short phase of hyperemia
precedes this oligemia (12) and is likely to be correlated to the symptoms such
as flashing, zigzag lines etc.

2.  Common Migraine (migraine with out aura)

As the term reflects itself that it is more frequent in general population
and is devoid of any aura. However, during the attack one may have abdominal
pain, diarrhea, increased irritation, nausea & vomiting. Some patients also
have vague premonitory symptoms (hyperactivity to sluggishness, extreme hunger
to anorexia, diarrhea to constipation, frequent urination to fluid retention)
that start from 12- 36 hours before actual attack. (8, 13, 26)

3. Hemiplegic Migraine

This is accompanied by a temporary paralysis of one side of body (a condition
known as hemiplegia). A gene has been identified for this type of migraine on
chromosome band 19p13. This gene encodes a subunit of a brain specific calcium
channel in the cell membrane. Pain is probably mediated through the trigeminal
nerve which releases a vasoactive peptide resulting in dilation of blood vessels.
(8,13)

4. Ophthalmic Migraine

This results in pain around eye and may evolve droopy eyelid and vision disturbance
such as double vision. This type of migraine is always preceded by oculomotor
defect by several hours or days.(7, 13)

5.Basilar Migraine

In this the episodes begins with total blindness accompanied by vertigo, ataxia,
dysarthria and tinnitus. These neurological symptoms are referable to disturbance
in brain stem function and usually followed by a throbbing occipital headache.
(13)

6. Status migrainosus

This is a rare, extreme and long lasting type of migraine which is usually
preceded by some behavioral symptoms (anxiety, depression) and often requires
hospitalization. (7, 13)

PATHOPHYSIOLOGY 

A Series of efforts over the last 15 years have led to the concept that migraine is the outcome of hyper excitable brain (14) and can be declared as a primary disorder of brain. (15) A cascade of events, beginning with cortical activation, followed by brainstem activation which in term leads to perimeningeal vasodilation and neurogenic inflammation. (16, 17) It is widely accepted that the headache phase in migraine is caused by extra cranial vasodilation & sterial inflammation surrounding the affected vessals. (18) Moskowitz (19) identified the trigeminal ganglion as a factor in inducing neurogenic dural inflammation & subsequent vascular pattern of migraine attack. Various causes of hyperexcitability of brains have been suggested as low cerebral magnesium level, mitochondrial abnormalities, dysfunctions related to increased nitric oxide or existence of P/Q type calcium channel channelopathy. (20, 21) .A growing biological, pharmacological bodies and genetic data support the role of Dopamine in the pathogenesis of certain subtypes of migraine. As most of migraine symptoms are simply dopaminergic stimulation as demonstrated by yawning, nausea, vomiting and hypotension. Moreover, dopamine receptor antagonists are effective therapeutic agent in migraine especially when given with other antimigraine drugs. (22). Work of Sicuteri & associates (23) and Curran & colleagues (24) confirmed the role of serotonins and its metabolites during all phases of migraine attack. These investigators demonstrated that serotonin releasing substances could induce migraine like attack. This is potentially substantiated by, Approximately 40 years ago; METHYL SERGIDE was found to antagonize certain peripheral actions of serotonin and was introduced as the first drug capable of preventing migraine attack.

DIAGNOSIS

Repeated severe headache lasting from few hours to few days with the
person feeling well between the episodes are likely migraine. An aura before
or during the early part of headache further supports the diagnosis of migraine.
In a recent large population study, 64 % patients with migraine had migraine
without aura, 18 % had only migraine with aura, 13 % had both and remaining
5% had aura without migraine. Thus up to 13 % patients with migraine have aura
on some occasions. (25) Thus an aura is not the sole criteria to judge migraine.
According to International Headache Society (26) when a patient’s headache meets
the following criteria (see Table 1), migraine can be diagnosed and computer
tomographic scanning or magnetic resonance imaging is unnecessary. (27) Table
1 (26)

Headache lasts from few hours to few days.

■ Headache have at least two of the following features.

•  Moderate or severe intensity
  
•  Worsening with physical activity
  
•  Unilateral location
  
•  Pulsating pain

■ Headache is associated with at least one of the following

•  Nausea & vomiting
  
•  Aversion to noise & light

■ No other causes of headache is evident in medical history or physical
examination.

 

FACTORS PROVOKING MIGRAINE (28)

 

■ Environmental

♦ Temperature (heat or cold) ♦ Head or Neck injury ♦ Odor (smoke/perfume)

♦ Bright lights ♦ Weather change ♦ Motion

♦ Flying/high attitude ♦ Noise ♦ Physical strain

 

■ Lifestyle

♦ High stress level ♦ Skipping meals ♦ Disturbed sleep

♦ Smoke

 

■ Hormonal

♦ Puberty ♦ Menopause ♦Menstruation

♦ Ovulations ♦Pregnancy

 

■ Emotional

 

♦ Anxiety ♦ Depression ♦ Excitement ♦ Anger

 

■ Medication

♦ Nitroglycerine ♦ Nifedipine ♦ Oral Contraceptives

 

■ Dietary

♦ Citrus fruits ♦ Caffeine ♦ Chocolate

♦Alcohol ♦ Food containing monosodium glutamate

♦ Aged cheese

 

MANAGEMENT OF MIGRAINE

Objectives of management of migraine should be I) reducing the pain
if already exists II) preventing attacks of migraine. The migraine management
can be classified as

Non pharmacological management

Patient must be educated about disorder, its mechanism, changes in lifestyle
(to avoid migraine triggers). Patient should be approached for regular sleep,
meals and exercise, avoidance of crust of stress & trough of relaxation
and avoidance of dietary triggers. (29)

Pharmacological management

• Treatment of acute attack
  
•  Preventative therapy
  
• Treatment of acute attack

This can further be divided in to treatment with migraine non specific drugs
(NSAIDS, Opiates) and migraine specific drugs (ergotamine, dihydroergotamine
and triptans) (30)

Ø Demonstrated efficacy & favorable tolerability makes NSAIDS a drug of
choice as first line treatment in all types of migraine attacks. Among the NSAIDS
the most consistent evidence exists for Aspirin (31, 32), Ibuprofen
(33, 34), Naproxen Sod. (35 36), Tolfenamic acid (31, 37) and
the combination of Acetaminophen + Aspirin + Caffeine (38) for
acute migraine treatment. The evidence demonstrates that Acetaminophen is
ineffective alone (39). The dose of the drug should be adequate; For exp: 900
mg of Aspirin (40. 32), 1000 mg of Acetaminophen (41), 500 to
1000 mg of Naproxen (42), 800 mg of Ibuprofen (43) or appropriate
combination of these drugs (38, 44). The administration of anti-emetic drugs
those increase the gastric motility is likely to facilitate the absorption of
the primary drug & thus help to ameliorate the attack (40, 45, 46). Overuse
of these drugs should be avoided; for example intake should be restricted to
not more than two or three days a week.

Ø      It is patent to all that opiates are good analgesics
but there is evidence only for the efficacy of Butorphanol (47) nasal
spray. Because few studies of opioids use in headache has been documented, until
further data is available, these drugs may be better secured for use as last
line therapy.

ØThere is a good number of evidence for the efficacy & safety of intranasal
Dihydroergotamine as monotherapy of acute migraine (48, 49). There
merits are low cost and long experience with their use (50, 51) while their
demerits are lack of evidence for effective doses, their potency, sustained
vasoconstriction effect resulting in rebound attack (51).

Ø Triptans are specific & selective 5-HT IB/ID agonist (52). They
were discovered (53) as a result of studies of serotonin and migraine (23, 54)
that lead to identification of an atypical 5-HT receptor. Three potential mechanism
of action of triptans have been proposed I) Cranial Vasoconstriction (53), II)
Peripheral neuronal inhibition (55), III) inhibition of transmission through
second order neuron of trigeminocervical complex (52). Which mechanism is most
important is yet unclear (52). These actions inhibit the effect of activated
nociceptive trigeminal afferents and thereby potentially control acute migraine
attack. There are five commonly used triptans; Sumatriptan, Naratriptan,
Rizatriptan, Zolmitriptan and Almotriptan. Eletriptan is recently
approved in Europe, Frovatriptan is waiting for approval and Donitriptan
is in preclinical development. (56) In a study as compared to 100 mg of
Sumatriptan, 10 mg of Rizatriptan and 80 mg of Eletriptan was
found to be more effective. (29) The main disadvantages of triptans are there
high cost & restriction of their use in a patient with cardiovascular disorder.
The most important side effects with triptans are tingling, paresthesias, sensation
of warmth in head, neck, chest and limbs. They may constrict coronary arteries
and may cause chest symptoms, sometime mimicking angina pectoris.

Preventative or Prophylactic Therapy

Once the patient and his health care workers have decided how to treat acute
migraine attack, preventative therapy should be considered if headache occurs
three or four days a months and if headache occurs five days or more than preventative
therapy must be considered (29). Each drug should be started at low dose and
dose should be gradually increased up to required therapeutic level. Various
options available for prophylactic management of migraine are

Ø There are a number of evidences in support of efficacy of β blockers
such as; Propranolol 80 to 240 mg /d (57, 58) and Timolo 20
to 30 mg/d (58, 59) for the prevention of migraine. One trial comparing Propranolol
& Amitriptyline suggested that Propranolol is more efficacious
in patients with migraine alone & Amitriptyline was superior for
the patient with migraine & tension type of headache (60). Adverse effects
associated with β blockers are fatigue, depression, nausea, digginess &
insomnia.

Ø Amitriptyline is the only drug among Anti-depressants that
holds consistent support for efficacy in migraine prevention (61, 62) at the
dose of 25-75 mg at bed time (29). Drowsiness, wt gain and anti-cholinergic
symptoms are frequently reported with Amitriptyline.

Ø Among Anticonvulsants, there is good evidence for the efficacy of Divalproex
Sodium (63, 64) and Sodium Valporate (65, 66). Recommended doses
of Divalporex (valporate) is 400-600 mg twice a day (29). Adverse
events with these therapies include weight gain, hair loss, tremor and teratogenic
potential such as neural tube defect.

Ø  In Serotonergic agents, Methylsergide (67, 68) and Pizotifen
(69, 70) have consistent evidence to support their efficacy at the dose
of 1-6 mg/d and 0.5-3 mg/d respectively (29) in the prophylaxis o migraine.
Weight gain and drowsiness are the reported adverse effects.

Ø Flunarizine, 10 mg/d, a Calcium Channel Blocker, has been proven
effective in the prevention of migraine (71, 72). Depression & extra pyramidal
symptoms can be observed in elderly persons.

Ø A mitochondrial dysfunction resulting in impairment of oxygen metabolism
& low cellular energy levels may play a role in migraine pathogenesis (73).
Riboflavin (Vitamin B2) is the precursor of flavin mononucleotide &
flavin adenosine dinucleotide, which are required for the activity of flavoenzyme
involved in the electron transport chain in the mitochondria of a cell (74).
A double blind study of large doses of Riboflavin (400 mg/d) compared
with placebo in migraine, showed that Riboflavin was significantly superior
at reducing the attack frequency, headache intensity and other indexes after
three months of therapy (75).

Ø Some studies have demonstrated low intracellular magnesium in the
migrainous brain (76, 77). In a study with 81 patients, the attack frequency
was reduced by 41.6% in magnesium group and 15.8 % in placebo groups. Adverse
effects were diarrhea and gastric irritation (78).

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*Sumit Khanna

Department of Pharmaceutical Sciences, G. J. University, Hisar-125 001                                                                                 

*Author for correspondence

397,Sec-13, Hisar, Haryana, India  

GSM: +919416045445 

E-mail: sumkhanna@hotmail.com 

Sunil Sirohi

College of Pharma Sciences

St. John University

New York, USA 

E-mail: sunilmsus@yahoo.co.in