A Report on Migraine

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A Report on Migraine


Headache is one of man’s most common afflictions. It has been estimated that one person out of three experiences severe headaches at some stage of life (Boes et.al. 2008). A large percentage of headache patients will be diagnosed as having migraine, a specific sub-type of headache affecting approximately 10-20 percent of the population. The morbidity associated with the millions of migraine sufferers is staggering; approximately 64 million workdays each year are estimated to be lost in the United States due to migraine. Pharmacology have advanced for modern therapeutic approaches for many diseases but that in case of headache is minimum throughout the century (Peroutka 1996).

Migraine is a ubiquitous familial disorder. Its onset is usually noted in childhood or in early adult life. The nature of headache in migraine is usually unilateral having history of recurrence. The frequency of recurrences diminish with advancing age (Ropper and Brown 2005). Over two-thirds of patients neither consult with a physician nor attempt to do so due to the fatalistic belief that migraine is not a curable disease. Moreover, physician’s empathy about migraine as an only headache or poor experiences with older drugs has created a bit reluctance among the young researchers. But recent progresses on pathophysiology and modern diagnosis have opened up an area for expanding and advancing therapeutic options (Ferrari 1998).

Recurrent migraines can be disabling: the cost of missed work-days and impaired performance associated with migraines in the United States totals around $ 13 billion each year. Preventive therapy, which can reduce the frequency of migraines by 50 percent or more, is used by less than one half of persons with migraine headache (Modi and Lowder 2006).

The pharmacological treatment of migraine can be acute (abortive) or preventive. Patients with frequent severe headaches often require both approaches. Preventive treatment is used to reduce the frequency, duration or severity of attacks. Additional benefits include improvement of responsiveness to abortive treatment, improvement of function and reduction in disability(Silberstein 2006). Preventive treatment might preclude the progression of episodic migraine to chronic migraine and result in reductions in the cost of healthcare(Silberstein 2003).

Many medication groups are used for preventive treatment of migraine. The choice of preventive medication is empiric; it is influenced by efficacy, adverse effects and patient’s coexistent and comorbid conditions (Silberstein 2002).

Amitriptyline was first mentioned as an antimigraine agent in 1968. Subsequently its effectiveness in migraine prophylaxis was reported in 1973. A double blind study was presented in 1979 in which up to four 25 mg tablets of amitriptyline were given to each of 47 subjects and identical placebo to 53 subjects per day for 4 to 8 weeks. In this study, the conditions of 55.3% of amitriptyline subjects as opposed to 34.0% of placebo subjects were > 50% improved and the difference between amitriptyline and placebo response rates was significant (P < 0.05), (Couch and Hassanein 1979).

Linde and Rossnagel analyzed a total of 58 trials on propranolol in migraine prophylaxis with 5072 participants. The trials were published between 1966 to 2003. Propranolol was studied with placebo and in comparison with other drugs like calcium antagonists, other beta-blockers, amitriptyline and divalproex. The analysis showed clear short-term benefit of propranolol over placebo but no difference in efficacy over other migraine prophylactic drugs (Linde and Rossnagel 2005).

Pizotifen, a serotonin antagonist, has proven efficacy in randomized controlled trials (Ramadan et.al. 2000).It can be used as an alternative when other drugs have failed to be effective(Pierangeli et.al. 2006).


Migraine is an important cause of headache and headache related disabilities. The impact of migraine on the sufferer and his productivity in national level is immense. This not only affects lost labour but also results in leisure time loss, inability to carry out daily activities, disruption of family and social lives. The pathophysiology of migraine is still poorly understood. No effective and curative medicine has yet been discovered. Abortive therapies have different options and are more or less successful. But prevention is a difficult task. The purpose of migraine-preventive therapy is to reduce migraine attack frequency, severity and its impact on the sufferer. Moreover, preventive therapy acts synergistically with abortive therapy to improve its effectiveness.

Amtriptyline ,pizotifen and propranolol are the most common drugs used as preventive therapy in migraine. These drugs are also cheap in comparison to other drugs used in migraine prophylaxis. These drugs are not free from contraindications, in that case we can use them interchangeably. In this respect, this study will help in choosing the best alternative for migraine prophylaxis.

So far my knowledge goes, in Bangladesh no study has yet been conducted on migraine prophylaxis with amitriptyline, pizotifen and propranolol.


Efficacy of amitriptyline, pizotifen and propranolol in prophylaxis of migraine is similar.


General objective

To compare efficacy of amitriptyline, pizotifen and propranolol in the prophylaxis of migraine.

Specific objectives

  1. To evaluate amitriptyline, pizotifen and propranolol seperately in the prophylaxis of migraine in respect of efficacy among Bangladeshi people.
  2. To assess tolerability of amitriptyline, pizotifen and propranolol.
  3. To observe recurrence of migraine attack in different groups of study population.



Migraine had afflicted humankind for centuries. Description of acute migraine attacks appear as early as the second century AD in the writings of Aretaeus of Cappadocia. The term migraine is derived from the ancient Greek word hemikranios which means “half head “, underscoring the unilateral distribution of head pain in many sufferers. The Roman translated the word to the Latin hemicranium, later corrupted to hemigranea and hence migranea. These terms were in turn modified to the Middle English megrim. The current name migraine, the French translation, gained acceptance in eighteenth century and finally given this term migraineur for a sufferer of this type of headache (Campbell and Caselli 1996).


In fact, there are so many cases of headache that special headache clinics have been established in many medical centers. Most people with mild recurrent or isolated headache do not consult a physician and therefore the true incidence is unknown. A survey showed that among 25 – 64 years old men and women in Denmark, a life-time prevalence of any type of headache was 93 percent in men and 99 percent in women (Rasmussen, Jensen and Schroll 1991).Migraine patients are defined as individuals who have had at least two attacks of headache with aura or at least five attacks of headache without aura (Olesen 1988).

Migraine is a common condition and its prevalence is worldwide. Although attacks of migraine may start at any age, the incidence peaks in early to mid adolescence. Although many countries have their own epidemiologic data from a large number of population, such data in Bangladesh is lacking. A cross-sectional and observational randomized study was conducted amongst the outpatients attending the Headache clinic of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU) from November 1999 to September 2002. A total of 3440 patients were studied. Of them 552 (16.05%) had migraine. Among 552 migraineurs, 391 patients (70.83%) had migraine without aura and 161 patients( 29.17%) had migraine with aura. Female to male ratio was 2.441(Hannan et. al. 2007). In the United States and Western Europe, the one-year prevalence of migraine is 11 percent overall; 6 percent among men and 15 to 18 percent among women. The median frequency of attacks is 1.5 per month, and the median duration of an attack is 24 hours; at least 10 percent of patients have weekly attacks, and 20 percent have attacks lasting 2 to 3 days(Stewart et. al. 1992).Thus 5 percent of the general population have at least 18 days of migraine per year, and at least 1 percent-that is, more than 2.5 million persons in North America-have at least 1 day of migraine per week. The lifetime prevalence of migraine is at least 18 percent(Rasmussen and Olesen 1992),although among older subjects the figures are deflated by recall bias. In the United States, most patients with migraine have not seen a physician for headache during the previous year; have never received a medical diagnosis of migraine, and use over the counter medications to the exclusion of prescription drugs(Lipton and Stewart 1997).

A survey by the World Health Organization (WHO) rates severe migraine, along with quadriplegia, psychosis, and dementia, as one of the most disabling chronic disorders. This ranking suggests that in the judgment of the WHO, a day with severe migraine is as disabling as a day with quadriplegia (Murray and Lopez 1997).

Three neuropsychiatric disorders showed increased co-morbidity with migraine. Epilepsy, major affective and anxiety disorders and in young female migraineurs only, ischemic stroke(Rasmussen and Olesen 1992).The coincidence of migraine and stroke in MELAS and CADASIL (cerebral aurtosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) suggests common pathogenic pathways(Ferrari 1998).

In community studies, tension headache is five times more common than migraine. However, although 50 percent of migraine sufferers consults their general practitioners each year, only 16 percent of tension headache sufferers do so. Figures from the United Kingdom suggest that loss of work due to migraine is about 270 days/ 1000/ year and tension headache 820 days/1000/year(Pearce 1996).


PAIN SENSITIVE STRUCTURES OF CRANIUM Headache arises from activation of pain-sensitive intracranial structures. In the 1930s, Ray and Wolfe identified which intracranial components were pain-sensitive and mapped the pattern of pain referral based on studies in which various intracranial structures were stimulated during intracranial surgery performed during local anesthesia. The pain-sensitive structures of cranium include-

(1) Skin, subcutaneous tissue, muscles, extracranial arteries, and periosteum of the skull;

(2) Delicate structures of the eye, ear, nasal cavities, and paranasal sinuses;

(3) Intracranial venous sinuses and their large tributaries, especially pericavernous structures.

(4) Parts of the dura at the base of the brain and the arteries within the dura and pia-arachnoid, particularly the proximal parts of the anterior and middle cerebral arteries and the intracranial segment of the internal carotid artery;

(5) Middle meningeal and superficial temporal arteries, and

(6) The optic, oculomotor, trigeminal, glossopharyngeal, vagus and first three cervical nerves (Ropper and Brown 2005).

Pain from supratentorial structures is referred to the anterior two-thirds of the head, i.e., to the territory of sensory supply of the first and second divisions of the trigeminal nerve; pain from infratentorial structures is referred to the vertex and back of the head and neck by the upper three cervical roots. The seventh, ninth, and tenth cranial nerves refer pain to the naso-orbital region, ear and throat (Ropper and Brown 2005).

Headache can occur as the result of –

(a) Distension, traction or dilatation of intracranial or extracranial arteries.

(b) Traction or displacement of large intracranial veins or their dural envelope

(c) Compression, traction or inflammation of cranial or spinal veins

(d) Spasm, inflammation or trauma to cranial and cervical nerves

(e) Meningeal irritation and raised intracranial pressure; or

(f) Other possible mechanisms such as activation of brainstem structures(Raskin 2005).

3.4. CLASSIFICATION OF HEADACHE In 1988, the Headache Classification Committee of the International Headache Society introduced a detailed classification of headaches, which was revised in 2004 (Headache Classification Committee,2004). The 14 main headache types are as follows-

The Primary Headaches:

  1. Migraine.
  2. Tension-type headache.
  3. Cluster headache and other trigeminal-autonomic cephalalgias.
  4. Other primary headache disorders.

The Secondary Headaches:

  1. Headache attributed to head and /or neck trauma.
  2. Headache attributed to cranial and/or cervical vascular disorder.
  3. Headache attributed to non- vascular, non- infectious intracranial disorder.
  4. Headache attributed to a substance or its withdrawal.
  5. Headache attributed to infection.
  6. Headache attributed to disturbance of homeostasis.
  7. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structures.
  8. Headache attributed to psychiatric disorder.
  9. Cranial neuralgias and central causes of facial pain.
  10. Other headache, cranial neuralgia, central or primary facial pain.(Boes et. al. 2008).

Diagnostic criteria for migraine (Olesen 1988)

A. Migraine without aura

1) At least 5 attacks fulfilling 2 – 4

2) Headache attacks lasting 4 – 72 hours (untreated or unsuccessfully treated)

3) Headache has at least two of the following characteristics

a) Unilateral location

b) Pulsating quality

c) Moderate or severe intensity

d) Aggravation by walking stairs or similar routine physical activity

4) During headache, at least one of the following

a) Nausea and /or vomiting

b) Photophobia and phonophobia

B. Migraine with aura

1) At least two attacks fulfilling 2

2) At least three of the following four characteristics:

a) One or more fully reversible aura symptoms indicating focal cerebral cortical and / or brainstem dysfunction

b) At least one aura symptoms develops gradually over more than 4 minutes or two or more symptoms occur in succession.

c) No aura symptoms last more than 60 minutes; if more than one aura symptom is present, accepted duration is proportionally increased

d) Headache follows aura with a free interval of less than 60 minutes (it may also being before simultaneously with the aura)


Current concepts of pathogenesis of migraine focus on three mechanisms and anatomic regions. First there is a vasomotor component mediated by constriction or dilation of arteries within and outside the brain. Second, there is a midbrain trigger, perhaps in serotonergic neurons of dorsal raphe. Third, there is activation of trigeminal vascular system consisting of medullary neurons in trigeminal nucleus caudalis that terminates on walls of arteries and release of vasoactive neuropeptides. The role of each of these systems in the production of specific symptoms of migraine is unknown. It is possible that any of these three may be sufficient for headache production and that one mechanism may dominate in a particular migrainous syndrome. Such as, the evaluation of the fortification spectrum may be entirely neurogenic requiring only activation of the dorsal raphe system (Raskin 1998).

Migraine triggers:

Any one can have a migraine attack occasionally without being a migraine patient. It is not the attack but repeated recurrence that is abnormal(Ferrari 1998). Attacks seem to involve physiological mechanisms, initiated by migraine specific triggers. Attack recurs only when threshold is reduced or when triggers are particularly strong and frequent. Genetic factors, possibly involving ion?channel function appear to set individual threshold; internal and environmental factor such as hormonal fluctuations, fatigue, relaxation after stress, meteorological change and substance misuse may modulate the set point (Haan et. al. 1996).

Cortical hyperexcitability

Neurophysiological, magnetic resonance spectroscopic, biochemical and epidemiological data suggest that migraineur have an interictal state of cortical hyperexcitability, characterized by a reduced threshold and increased responses(Welch and Ramadan 1995; Van Der Kamp et. al. 1996; Schoenen 1997).The excitability level is proportional to the attack frequency. Its physiological basis may be defective mitochondrial oxidative phosphorylation(Welch and Ramadan 1995), low intracellular magnesium, increased level of neurotoxic amino acids, inherited dysfunction of calcium channels or a combination of these factors (Ophoff et. al.1996).

Migraine generator

During attacks, positron emission tomography has identified an area of increased cerebral blood flow in upper brainstem, opposite the headache side. This area of activation persisted after pain relief with sumatriptan, while activation of cortical areas associated with pain perception had disappeared (Weiller et. al. 1995).

Thus, the brainstem may be important? for initiating the attack and acute anti?migraine drugs may merely suppress symptoms rather than inhibit the central “migraine generator” (Ferrari 1998).

No NO, no migraine?

Nitric oxide (NO) may be pivotal to be initiation and maintenance of migraine headache (Olesen et. al. 1995).Compared with non -migraineurs, migraneurs who received placebo?controlled intravenous infusion of the NO donor nitroglycerine showed greater dilation of middle cerebral artery and were more likely to develop migraine?like headache (but no aura). The migraine response only appeared after 3 -10 hours, suggesting that an intermediate pathway had to be activated first. However, an uncontrolled trial with an NO synthase inhibitor produced antimigranous results(Lassen et. al 1997).

Migraine aura

The traditional view aura is caused by vasoconstriction, headache by vasodilatation is to simplistic. The current view is that the aura is caused by cortical spreading depression” (CSD)(Lauritzen 1994),a depolarization wave that propagates across the brain cortex at 2?3 mm/min and is associated with transient depression of spontaneous and evoked neuronal activity. The depression wave lasts several ‘minutes, preceded by a front of brief neuronal activity. During CSD, there is dramatic failure of brain ion homeostasis and efflux of excitatory amino acids from nerve cells. In laboratory animals, CSD can be elicited by local electrical, mechanical and biochemical (high concentrations of K+) stimulation. Impaired clearance of brain K + (by glial cells) predisposes to CSD. The human visual cortex has the lowest ratio of glial to neuronal cells, suggesting a reduced threshold for CSD (Ferrari 1998).

Vasomotor Component

Regional cerebral blood flow studies have shown that in patients with classic migraine, there is, during attack, a modest cortical hypoperfusion that begins in the visual cortex and spreads forward at a rate of 2?3 mm/min. The decrease in blood flow averages 25?30 percent (insufficient to explain symptoms on the basis of ischemia) and progresses anteriorly in a wave?like fashion independent of topography of cerebral arteries. The wave of hypoperfusion persists for 4?6 hours, appears to follow the convolutions of the cortex and does not cross the central or lateral sulcus, progressing to frontal lobe via insula. Perfusion of subcortical structure is normal. Contralateral neurologic symptoms appear during temporoparietal hypoperfusion; at times, hypoperfusion persists in these regions after symptoms cease. More often, frontal spread continues as the headache phase begins. A few patients with classic migraine show no flow abnormalities; an occasional patient has developed focal ischemia sufficient to cause symptoms. However, focal ischemia does not appear to be necessary for focal symptoms to occur. During common migraine no?flow abnormalities usually seen (Raskin 2005).

Serotonergic projections and the dorsal raphe

Taken together, the pharmacologic data on migraine point to involvement of serotonin receptors. About 35 years ago methysergide was found to antagonize certain peripheral actions of serotonin [5 – hydroxy tryptamine (5HT)] and was introduced as the first drug capable of preventing migraine attack. Subsequently it was found that platelet levels of serotonin fall consistently at the onset of headache and that migrainous episodes may be triggered by drugs that cause serotonin to be released. Such changes in circulating levels proved to be pharmacologically trivial, however, interest in the humoral role of serotonin in migraine declined. Currently, there is a renewed interest due almost entirely to introduction of the drug sumatriptan, which remarkably effective in migraine attacks. Of still greater interest is the fact that sumatriptan is a designer drug synthesized to activate selectively a particular subpopulation of serotonin receptors.

There are four main families of 5 HT receptors: type 1, 2, 3 and 4; receptor subtypes have been found for each type. Many of the drugs effective in migraine prophylaxis are type 2 antagonists, whereas abortive agents are type -1 agonists. Sumatriptan is most potent as an agonist of 5 HT ID receptor and is less potent at 5 HT IA and 5 HT IB receptor. By contrast, dihydroergotamine, another drug that is highly effective in aborting migraine attacks is most potent as an agonist of 5 HT IA receptors and, is an orders of magnitude less potent at 5 HT ID receptors. After systemic administration, dihydroergotamine in the brain is found in highest concentrations in midbrain dorsal raphe. The dorsal raphe is a good candidate as a generation of migraine and as a site of antirnigraine drug action. The highest concentration of serotonin receptors in brain tissue is found there. They are mainly of the 5 HT IA variety but 5 HT ID receptors also are present.

Electrical stimulation in dorsal raphe neurons can result in migraine-like headache. Bloodflow in pons and midbrain increases focally during migraine headache episodes. This alteration probably results from activity of cells in dorsal raphe and locus ceruleus. There are projections from dorsal raphe that terminate on cerebral arteries and alter cerebral bloodflow. There are also major projections from dorsal raphe to important visual centre, including the lateral geniculate body; superior colliculus, retina and visual cortex. These various serotonergic projections may represent the neural substrate for the circulating and visual characteristic of migraine. The dorsal raphe cells stop firing during sleep and sleep is known as ameliorate migraine. The antimigraine prophylactic drugs also inhibit activity of the dorsal raphe cells through a direct or indirect agonist effect.

Trigeminal vascular system

Activation of cells in trigeminal nucleus caudalis in medulla (a pain, processing centre in medulla for head and face region) results in release of vasoactive neuropeptides including substance P and calcitonin gene related peptide, at vascular terminations of trigeminal nerve. Moskowitz et al. proposed that these peptide neurotransmitters induce a sterile inflammation that activates trigeminal nociceptive afferents originating on the vessel wall further contributing to the production of pain. This mechanism also provides a potential way for the soft tissue swelling and tenderness of blood vessels that occurs during migraine attacks(Moskowtitz 1991).

Genetic basis

The genetic basis of migraine is largely unknown. Family studies indicate that genetic heterogeneity i.e. independent migraine genesis likely to be present. Genetic linkage analysis has been successful in one rare migraine syndrome, autosomal dominant familial hemiplegic migraine. About one?half of families have mutations in CACNA1, a gene located on chromosome 19p13 that codes for the ??1 subunit of a brain-specific voltage-gated P/Q-type calcium channel (Boes et. al. 2008).

Mitochondrial dysfunction

Mitochondrial dysfunction resulting in impaired oxygen metabolism may play role in migraine pathogenesis(Welch et. al. 1989; Montagna et. al. 1994; Watanabe et. al. 1996). Migraineous headache can be a prominent feature in patients affected by the syndrome of mitochondrial encephalopathy, lactic acidosis and stroke?like episodes (MELAS)(Montagna et. al. 1988). A reduction in phosphorylation potential in brain and muscle mitochondria has recently been reported between attacks in migraine with and without aura(Barbirali et. al. 1992). Although this finding is in the line, with previous observations of reduced phosphocreatine-inorganic phosphate ratio in the brain of migraineurs, it requires confirmation because it could represent the link between biochemical factors(Welch 1986), imbalance of brain oxygen metabolism and secondary activation of trigeminal vascular system(Olesen 1988).



The international Headache Society has considerably improved the diagnosis of migraine and other headache syndrome(Olesen 1988).Different types of headache rather than patients are diagnosed. Patients may have concurrent types (e.g. migraine and tension type headache), which should be treated separately. The main two types of migraines are migraine without aura (common migraine), occurring in 75 Percent of migraineurs and migraine with aura (classic migraine), occurring in one?third of patients. Up to 33 percent of migraineurs experience both types of attack during their lifetime(Olesen1988; Russel et. al. 1995; Bille 1997).

Aura symptoms nearly always include visual (99% of patients), together with sensory (31%) or aphasic (18%) symptoms and rarely motor ones (6%). Aura symptoms typically progress over minutes or different symptoms succeed one another. They usually occur at alternative body sites in different attacks, nearly always precede the headache and usually last between 5 to 60 minutes. Motor symptoms may last longer. Up to 42 percent of patients may have attacks of migraine aura without headache. Basilar migraine is a subtype of migraine with aura, characterized by at least two aura symptoms originating from the brainstem or both occipital lobes(Welch and Ramadan 1995).


Migraine or migraine-like symptoms may sometimes be caused by arteriovenous malformations, internal carotid dissection, epilepsy, mitochondrial DNA disorders e.g. mitochondrial encephalopathy with lactic acidosis and stroke?like episodes (MELAS)(Welch and Ramadan 1995),by cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL).Thus, like epilepsy, migraine is a syndrome that can be caused by a wide range of cerebral disorders (Chabriat and Vahedi 1995).


WITHOUT AURA (Olesen 1988).

Migraine with aura

  1. Attack? lasting 4?72 hours (duration applies to untreated or unsuccessfully treated attacks)
  2. At least two of the following four headache characteristics:
    1. Unilateral
    2. Pulsating
    3. Moderate to severe (disturbing or precluding daily activities)
    4. Aggravated by movement
  3. At least one associated symptom:
    1. Nausea or vomiting
    2. Photophobia
    3. Phonophobia

Migraine with aura

  1. One or more transient focal neurological aura symptoms (referring to focal cortical or brainstem dysfunction)
  2. Gradual development of aura symptoms over > 4 minutes or several symptoms in succession
  3. Aura symptoms last 4 – 60 minutes
  4. Headache follows or accompanies aura within 60 minutes


After a complete clinical examination and after appropriate investigations have been performed, the nature of migraine should be explained to the patient and reassurance should be given that it is a painful but generally a benign condition that can in most instances be controlled or alleviated. The lack of a cure for migraine should not be underemphasized. It is important that patients be made to feel that the physician understands their complain of headache and will not simply dismiss them as having a headache for psychological reasons. A normal CT or MRI scan offers considerable reassurance. Many patients are more interested in knowing that they do not have brain tumour or other potentially lethal condition than they are in obtaining relief from pain.

Avoidance of trigger factors is important in the management of migraine but simply advising a patient to avoid stress and relax more is usually meaningless.

Advice to reduce excessive caffeine intake, to stop smoking and to reduce alcohol intake may be more useful. Current medication use should be reviewed and modified. If necessary, the use of drugs known to cause headache, such as reserpine, indomethacin, nifedipine, theophylline derivative, caffeine, vasodilators, including long?acting nitrates and alcohol should be discontinued or other agents should be substituted. If possible, use of oestrogens, and oral contraceptives should be discontinued if they are suspected of contributing to headache.

Excessive programmes to promote wellbeing, correction of dietary excess and avoidance of prolonged fasts and irregular sleeping habits can be helpful.

The topic of dietary factors in migraine is difficult. Radical alterations in diet are rarely justified, but there are exceptions. Avoidance of’ foods containing nitrites, such as hot?dogs and preserved cold?nuts and or prepared foods containing monosodium glutamate can be helpful. Ripened cheeses, fermented food items, red wine, chocolate, chicken liver, pork, and many other foods have been suspected for precipitating migraine attacks. They mostly contain tyramine, phenyl?ethylamine and octopamine. Some migraines have some attacks precipitated by strong odours, especially of the perfumes of aromatic type. Avoiding the use of strongly smelling soaps, shampoos, perfumes and other items as fabric softeners and after?shaving lotion can be helpful for some individuals.

Everyone is under stress at sometime as part of living. Migraine sufferers are not under more stress than any other group of population, although their responses to stress may be different on the basis of their personality makeup and the efficacy of their defense mechanisms that increase the blood pressure, increase the production of gastric acid or produce symptoms of increased gastrointestinal motility; others develop various dermatological conditions. The migraineur seems to react with the cerebral and cranial circulations, by mechanisms that are far more complex than this statement would imply.

Helping the patient deal with or avoid stress is difficult. It may be helpful to use a minor tranquilizer or sedative if the response to stress is overwhelming and if the source of the stress is temporary. Long?term stress management requires the help of psychologist or other appropriately trained professionally. Many techniques are used including biofeedback relaxation training and hypnosis. Evidence that these techniques are helpful is difficult to evaluate because double blind trials are impractical(Campbell and Caselli 1996).


Migraine can be treated pharmacologically using an acute, prophylactic or combined medication programme. The choice of approach should include a number of factors such as headache frequency and severity, age of patient, previous history of medication response, contraindications and potential side?effects. In addition, the presence of other types of headache (e.g. muscle contraction, cluster, etc) should be evaluated to determine the optimal therapeutic approach.

Selection of appropriate therapeutic approach should be guided by a detailed assessment of migraine frequency and severity.

The major decisions to be made by the physician include the following:

1. The migraine to be treated solely with nonprescription medications, such as aspirin and nonsteriodal anti? inflammatory agents (NSAIDs).

2. When acute medication is needed, which drug would provide the highest efficacy with minimum side-effects.

3. Whether the patient needs a prophylactic agent.

Attack treatment or abortive treatment

Specific and nonspecific symptomatic anti?migraine drugs treat the headache and associated symptoms only, not the aura. Nonspecific drugs include analgesic rapidly absorbable NSAIDs, prokinetic and antiemetic compounds, such as metoclopramide and domperidone (Ferrari 1998).

In migraine attacks, oral drug absorption is impaired even in non?nauseated patients and parenteral administration is usually preferred. Use of metoclopramidc or domperidone 30 minutes before analgesic improves oral absorption and combats the nausea but there is no evidence that analgesic efficacy is improved. The choice of treatment depends on the severity and frequency of the attack, associated symptoms, coexistent disorders, previous treatment response, and the drug`s efficacy, potential for overuse, and adverse events. A non-oral route of administration and an antiemetic should be considered for severe nausea and vomiting(Silberstein 2004).

A Staged approach to migraine pharmacology (Peroutka 1996)

Migraine –Mild Stage

Features- occasional throbbing headaches. No major impairment of functioning.

Therapy- 1) mild analgesic

2) combination analgesic

3) anti-emetics depending on severity.

Migraine- Moderate Stage

Features-1) Moderate or severe headache.

2) Some impairment of functioning

3) Nausea common

Therapy-1)Combination analgesic.

2)Ergot alkaloid or sumatriptan


Migraine-Severe Stage

Features- 1) More than 3 severe headaches a month.

2) Significant functional impairment.

Therapies-1)Ergot alkaloids or sumatriptan

2)Prophylactic medications.


Drugs effective in the acute treatment of mild or moderate migraine (Peroutka 1996)

1) Mild analgesic:

a. Aspirin (300-600 mg every 4 hours)

b. Acetaminophen (500-1000 mg every 4-6 hours)

c. Ibuprofen (400?800 mg every 8 hours)

d. Naproxen sodium(500 mg stat, then 250 mg 6?8 hours)

2) Combination analgesics

a. Isometheptene with acetaminophen

b. Aspirin with butalbital

c. Aspirin with caffeine with butalbital

d. Acetaminophen, with butalbital

Drugs effective in the acute treatment of moderate or severe migraine

1) Orally or perrectal suppository

a. Ergotamine

b. Ergotanmine plus caffeine

2) Parenteral

a. Dihydroergotamine

3) Oral or subcutaneous

a. Sumatriptan

b. Nortriptan

c. Rizatriptan

d. Zolmitriptan

Prophylactic therapy (Peroutka 1996)

A general consensus among neurologist is to treat prophylactically of the patients having three or more migraine attacks per month if pain intensity is moderate to severe. A variety of agents is effective in the prophylactic treatment of migraine although none is effective greater than 60?70 percent of patients. Prophylactic medications should be given for a period of at least 6?12 weeks before being considered to be effective. If found to be effective the medication should be continued for 6 months and then discontinued to the high incidence of complete remission in migraine. If headache recurs after discontinuation of prophylactic therapy, the medication regimen should be reinstituted for another 6?months trial.

Drugs effective in prophylactic treatment of severe migraine (Peroutka 1996)

When the attacks of migraine occur weekly or several times a month or when they occur less often but are very prolonged and debilitating, a prophylactic program is appropriate.

Following drugs can be used in migraine prophylaxis.

1. Tricyclic antidepressant

a. Amitriptyline (10 ?100 mg at bedtime)

    1. Nortriptyline (25?75 mg at bedtime)
  1. Scrotonergic antagonist
    1. Methyserzide (4?8 mg daily)
    2. Cyproheptadine (4?16 mg daily)
    3. Pizotifen (0.5 to 3 mg daily)
  1. Selective serotonin reuptake inhibitor (SSRI)

a. Fluxetine (10?40 mg daily)

b. Paroxetine (10?60 mg daily)

  1. Beta?adrenergic antagonist

a. Propranolol (80?320 mg daily)

b. Timolol (20?60 mg daily)

c. Atenolol (50?100 mg daily)

d. Nadolol (40?80 mg daily)

    1. Metoprolol (100?450 mg dally)
  1. Monoamine oxidase inhibitor

a. Phenelzine (15 mg three times daily)

b. Isocarboxazid (10 mg four times daily)

  1. Anti-convulsants

a. Sodium valproate

b. Phenytoin

  1. Calcium channel blocker

a. Verapamil (80 mg tid/qid)

b. Nifedipine ( 90 – 360 mg daily in divided doses)

c. Diltiazem

d. Nimodipine

e. Flunarizine

  1. NSAIDs

a. Aspirin

b. Ibuprofen




Amitriptyline is the prototypical drug of the class- tricyclic antidepressants – so called because of the chracteristric three-ring nucleus (Potter and Hollister 2007).


Amitriptyline and most other tricyclic antidepressants are incompletely absorbed and undergo significant first-pass metabolism. As a result of high tissue protein binding and relatively high lipid solubility, volumes of distribution tends to be very large. Tricyclics are metabolized by two major routes: transformation of the tricyclc nucleus and alteration of the aliphatic side chain. Monodemethylation of tertiary amines leads to active metabolites such as desipramine and nortriptyline.

The pharmacokinetic parameters of amitriptyline are as follows: –

(i) Bioavailability 31 – 61%

(ii) Protein binding 82 – 96%

(iii) Plasma t ½ 31 – 46 hours

(iv) Active metabolite – Nortriptyline

(v) Volume of distribution 5 – 10 L/kg

(vi) Therapeutic plasma concentration 80 – 200 ng/dl. The range includes active metabolites

Amitriptyline as a prophylactic agent for migraine

Amitriptyline has been found to be effective for the prophylaxis of migraine, but it has no value in the treatment of acute migraine. This effect is independent of its anti-depressant actions. Amitriptyline is a potent blocker of the 5 – HT transporter and other transporters and also is an antagonist of multiple neurotransmitter receptors. However its mechanism of action in migraine prophylaxis is unknown (Katzung 2007).

Amitriptyline is used commonly in mixed headache cases (i.e., patients having symptoms of both migraine and muscle contraction headaches). Patients should be started on a 10 – or 25 mg dose at bed time, and the dose may be increased to 150 to 200 mg/day (Peroutka 1996).

Side effects. Side effects usually are related to the anticholinergic properties of the drug (i.e., dry mouth, dizziness, blurred vision, urinary retention, cardiac arrhythmia). In addition, sedation and weight gain occasionally are encountered and may limit patient compliance. If side effects occur, the dose should be halved. A 6 – to 12 – week’s trial is recommended before the drug is considered ineffective (Peroutka 1996).

Contraindications. Amitriptyline may predispose patients to cardiac arrhythmias and is therefore contraindicated in heart disease (Peroutka 1996).


Pizotifen is a benzocycloheptane based drug used as a medicine, primarily as a preventive to reduce the frequency of recurrent migraine headaches.


Bioavailability 78%

Protein binding 91%

Metabolism Glucuronidation (main route).N-glucuronide

Accounts for>50% of plasma and 60%-70% of

Urinary excreted drug

Half life 23 hour

Excretion 18% feces,55% urine (both as metabolites)

Mechanism of action

Pizotifen is a serotonin antagonist acting mainly at the 5-HT1,5-HT2A and 5HT2C receptors. It also has some activity as an antihistamine as well as some anticholinergic activity (Dixon et. al. 1977).


The main medical use for pizotifen is for the prevention of vascular headache including migraine and cluster headache. Pizotifen is one of a range of medications used for this purpose. While pizotifen is reasonably effective(Barnes 2004),its use is limited by side effects, principally drowsiness and weight gain, and it is usually not first choice for preventing migraines, instead being used as an alternative when other drugs have failed to be effective (Pierangeli et. al. 2006).

Other applications for which pizotifen may be used include as an antidepressant, or for the treatment of anxiety or social phobia (Standal 1977)

Adverse effects

Side effects include sedation, dry mouth, drowsiness, increased appetite and weight gain. Occasionally it may cause nausea dizziness. In rare cases, anxiety, aggression and depression may also occur (Crowder and Maclay 1984).


Pizotifen is contraindicated in patients who suffer from hypersensitivity to any of its components. It is also contraindicated in gastric outlet obstruction, pregnancy, angle-closure glaucoma and difficulty urinating.


Multiple clinical studies have shown that approximately 50% to 70% of patients derive some benefit from prophylactic propranolol therapy. Approximately one-third of the patients report greater than 50% reduction in the number of attacks with treatment(Peroutka 1996).Pharmacokinetic and pharmacodynamic parameters for propranolol

(1) Oral availability 1 – 26%

(2) Urinary excretion – 1%

(3) Bound in plasma – 87%

(4) Clearance – 50.4 L/h/70 kg

(5) Volume of distribution – 270L/70 kg

(6) Half –life – 3.9 hour

(7) Target concentrations – 20 ng /ml

A dose of 40 mg twice a day usually is begun with as much as 320 mg per day being given for at least 6 to 12 weeks before deciding that the patient is nonresponsive to therapy(Peroutka 1996).

The pathophysiological basis for the effectiveness of ß-adrenergic antagonist is not known. No single pharmacological property of this class of drugs can explain their apparent clinical efficacy. Antimigraine effects of these drugs do not correlate with their potency at ß – adrenergic receptors since not all ß – adrenergic receptor antagonists are effective antimigraine agents. The ability of certain ß – adrenergic antagonists to modulate serotonergic systems also has been postulated to contribute to their antimigraine efficacy. Alternatively, it has been suggested that only pure ß – adrenergic antagonists are effective agents in migraine therapy, whereas antagonist that display intrinsic sympathomimetic activity (i.e., partial agonist activity) may be less effective migraine prophylactic agents.

Side effects with ß – adrenergic receptor antagonists seldom are severe. However these drugs are contraindicated in asthma, advanced AV block, sinus bradycardia, and diabetes mellitus. Common side effects include lethargy, gastrointestinal upset, bradycardia and orthostatic hypotension, although these side effects rarely necessitate discontinuation of the drug. Exercise intolerance and potential for impotence do limit the acceptability of these drugs to males, particularly young males.


Type of Study

This was an intervention study.

Place of Study

This study was carried out in the Neurology outpatient department of Mymensingh Medical College Hospital, Mymensingh.

Study Period

This study was conducted from January 2006 to December 2007 for duration of two years. Initial 6months for literature review and preparation of protocol. Next one year for data collection and analysis, and the rest for report writing.

Sample size determination

. N =

No previous established data on response of migraine to amitriptyline, pizotifen or propranolol was found in Bangladesh. The most effective prophylactic agents available typically reduce the headache frequency by at least 50% in approximately 50% of patients (Boes et.al.2008).

So, for determining sample size we considered response rate of migraine to amitriptyline, pizotifen and propranolol = 50%.

Z = 1.96

p= 50

q= (100-p) = 50

d= 5

So, sample size = 384.

Sampling Technique : Purposive.

Due to time constraint and limitation of financial and logistic support total 110 patients were selected from the sample size, among them 8 patients were withdrawn due to non-cooperation. After duly taking informed written consent about aims and objectives of the study remaining 102 patients were divided into 3 groups (Group-I, Group-II , and Group-III) on alternate basis. Each group consisted of 34 patients. Cases of group-I were given tab. amitriptyline 25 mg/day (age group 19-50 years) and 12.5 mg/day (age group 11-18 years). Cases of group-II were given tab. pizotifen 1.5 mg (age group 19-50 years) and 0.5 mg bid (age group 11-18 years). Cases of group-III were given tab. propranolol 20 mg bid (age group 19-50 years) and 10 mg bid (age group 11-18 years). During the study period 04 patients from each group did not attend the follow-up schedule. Hence, they were dropped out and finally results of 30 cases from each group were compared.

Selection criteria

The patients were recruited from the outpatient department of Neurology of Mymensingh Medical College Hospital and selected as per inclusion and exclusion criteria:

Inclusion Criteria:

(1) Migraine without or with aura

a. Migraine without aura.

(i) Attacks lasting 4 – 72 hours (duration applies to untreated or unsuccessfully treated attacks)

(ii) At least two of the following four headache characteristics:

ü Unilateral

ü Pulsating

ü Moderate to severe (disturbing or precluding daily activities)

ü Aggravated by movement

(iii) At least one associated symptom:

ü Nausea or vomiting

ü Photophobia

ü Phonophobia

b. Migraine with aura

I. One or more transient focal neurological aura symptoms (referring to focal cortical or brainstem dysfunction)

II. Gradual development of aura symptoms over > 4 minutes or several symptoms in succession.

III. Aura symptoms last 4 – 60 minutes.

IV. Headache follows or accompanies aura within 60 minutes. (Adapted from criteria set by international headache society).

2) Patients aged 10 to 50 years were eligible for the study if they met the international headache society (IHS) diagnostic criteria for migraine with or without aura.

3) Patients had a history of migraine of at least 1 year and had between 3 and 8 attacks per month.

4) Patients were not on any prophylactic treatment of migraine for last one month.

5) Patients had at least three migraine attacks in the last month prior to trial.

6)Moderate (cannot work) to severe (must go to bed) headache(Hoque 2000).

Exclusion Criteria:

1) Headache with neurological deficit

2) Headache with major medical or psychiatric illness.

3) Headache with ear, nose, throat disease and ocular problem.

4) Patients with bronchial asthma.

5) Patients with heart failure.

The operational definition of moderate headache was the headache due to which the study subjects could not perform their daily routine activities. Severe headache was defined as the headache due to which the study subjects must had to go to bed in addition to their inability to perform daily routine activities (Hoque 2000).

Clinical Examination

Detailed history regarding headache with neurological deficit, age, sex, occupation, detailed history of headache (duration, frequency, quality, severity, localization, timing), known medical diseases were taken from each subject. Thorough general examination, nervous system and other systemic examinations were done. Fundoscopic examination and examination for focal neurological signs were carried out with special attention.


Study subjects requiring investigations to rule out possibility of disease which needed to be evaluated by investigations were excluded from the study.

Follow-up of the cases

After selection of the study subjects, they were prescribed with either amitriptyline or pizotifen or propranolol as preventive medication. 1000 mg (2 tablets) of paracetamol and 10 mg (1 tablet ) of domperidone were also prescribed as abortive therapy considering the severity of headache and associated nausea and vomiting. The following variables were used to determine the efficacy of the above mentioned drugs during the whole follow-up period-

(1) Number of attacks in previous one month when on regular treatment with one of the three drugs.

(2) Headache severity using visual analogue scale.

(3) Presence of nausea/vomiting.

(4) Number of acute headache medications used.

(5) Duration of each attack.

Patient`s frequency of headache attack, pain intensity (in a scale of 0 to 10), presence of nausea and vomiting and duration of each attack in the month before starting treatment, were recorded. The study subjects were requested to maintain a headache diary to note migraine attack date, pain intensity (1 to 10 scale), presence of nausea and/ or vomiting, number of acute headache medications used and duration of each headache attack. They were convinced to come for follow-up at an interval of 1 month for 6 months. In each visit all of the above mentioned variables were recorded. Any adverse effect of drug was also recorded. After 3 months’ of treatment 8 patients of amitriptyline group, 11 patients of pizotifen group and 10 patients of propranolol group showed no improvement. So these (total 29) patients were excluded from the study and the rest 61 patients were followed up for subsequent 3 months.


All relevant information from history, clinical examination, investigations and follow-up were recorded in a predesigned data collection sheet (appendix- I). Collected data were compiled and appropriate analyses were done by using computer based software, Statistical Package for Social Sciences (SPSS). Results were expressed as frequency, percentage mean ±SD. For statistical analysis one way ANOVA tests were done for comparing means of quantitative data and Chi-square tests were done for qualitative data. Paired t tests were done for comparing between pretreatment and post-treatment adverse effects of drugs within each of three groups. P value < 0.05 was considered statistically significant.


30 study subjects in amitriptyline group (group-I), 30 study subjects in pizotifen group (group-II) and 30 study subjects in propranolol group (group-III) completed the study.

Table-1: Distribution of study subjects by age

Years Amitriptyline Group Pizotifen Group Propranolol Group Total
Frequency Frequency Frequency Frequency
11-15 7 (7.8) 6(6.66) 4(4.44) 17(18.9)
16-20 7(7.8) 5(5.55) 7(7.8) 19(21.1)
21-25 6(6.66) 5(5.55) 3(3.33) 14(15.6)
26-30 5(5.55) 5(5.55) 6(6.66) 16(17.8)
31-35 2(2.22) 5(5.55) 6(6.66) 13(14.4)
36-40 1(1.11) 2(2.22) 4(4.44) 7(7.8)
41-45 2(2.22) 1(1.11) 0(0) 3(3.3)
46-50 0(0) 1(1.11) 0(0) 1(1.11)
Total 30(33.33) 3