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View with images and charts A Report on Migraine 1. INTRODUCTION 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 betablockers, 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). RATIONALE OF THE STUDY 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. HYPOTHESIS Efficacy of amitriptyline, pizotifen and propranolol in prophylaxis of migraine is similar.


2. OBJECTIVES 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. 3. REVIEW OF LITERATURE 3.1. HISTORICAL BACKGROUND 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). 3.2 INCIDENCE AND EPIDEMIOLOGY 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). 3.3 NEUROANATOMY 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 piaarachnoid, 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 followsThe Primary Headaches: 1. Migraine. 2. Tension-type headache. 3. Cluster headache and other trigeminal-autonomic cephalalgias. 4. Other primary headache disorders. The Secondary Headaches: 5. Headache attributed to head and /or neck trauma. 6. Headache attributed to cranial and/or cervical vascular disorder. 7. Headache attributed to non- vascular, non- infectious intracranial disorder. 8. Headache attributed to a substance or its withdrawal.


9. Headache attributed to infection. 10. Headache attributed to disturbance of homeostasis. 11. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structures. 12. Headache attributed to psychiatric disorder. 13. Cranial neuralgias and central causes of facial pain. 14. 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 â&#x20AC;&#x201C; 4 2) Headache attacks lasting 4 â&#x20AC;&#x201C; 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) 3.5. PATHOGENESIS AND PATHOPHYSIOLOGY 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 â&#x20AC;&#x201C; 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 Îą-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). 3.6. CLINICAL FEATURES AND DIAGNOSIS MIGRAINE WITH OR WITHOUT AURA 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 AS A SYMPTOM 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). SIMPLIFIED DIAGNOSTIC CRITERIA FOR MIGRAINE WITH OR 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: a. Unilateral b. Pulsating c. Moderate to severe (disturbing or precluding daily activities) d. Aggravated by movement 3. At least one associated symptom: a. Nausea or vomiting


b. Photophobia c. 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 â&#x20AC;&#x201C; 60 minutes 4. Headache follows or accompanies aura within 60 minutes

MANAGEMENT OF MIGRAINE (Peroutka 1996) 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). TREATMENT OF MIGRAINE (Peroutka 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 â&#x20AC;&#x201C;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 3)Anti-emetic 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. 3)Anti-emetics.


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) b. Nortriptyline (25-75 mg at bedtime) 2. Scrotonergic antagonist a. Methyserzide (4-8 mg daily) b. Cyproheptadine (4-16 mg daily) c. Pizotifen (0.5 to 3 mg daily) 3. Selective serotonin reuptake inhibitor (SSRI) a. Fluxetine (10-40 mg daily) b. Paroxetine (10-60 mg daily) 4. 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) e. Metoprolol (100-450 mg dally) 5. Monoamine oxidase inhibitor a. Phenelzine (15 mg three times daily) b. Isocarboxazid (10 mg four times daily) 6. Anti-convulsants a. Sodium valproate b. Phenytoin 7. Calcium channel blocker


a. b. c. d. e.

Verapamil (80 mg tid/qid) Nifedipine ( 90 – 360 mg daily in divided doses) Diltiazem Nimodipine Flunarizine

8. NSAIDs a. Aspirin b. Ibuprofen 3.7 PHARMACOLOGY OF AMITRIPTYLINE, PIZOTIFEN AND PROPRANOLOL AMITRIPTYLINE Amitriptyline is the prototypical drug of the class- tricyclic antidepressants – so called because of the chracteristric three-ring nucleus (Potter and Hollister 2007). Pharmacokinetics: 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: Pizotifen is a benzocycloheptane based drug used as a medicine, primarily as a preventive to reduce the frequency of recurrent migraine headaches. Pharmacokinetics 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). Uses


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). Contraindications 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. PROPRANOLOL 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. 4. MATERIALS AND METHODS 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 z 2 × pq d2 No previous established data on response of migraine to amitriptyline, pizotifen or

.N=


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 noncooperation. 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) (ii)     (iii)   

Attacks lasting 4 – 72 hours (duration applies to untreated or unsuccessfully treated attacks) At least two of the following four headache characteristics: Unilateral Pulsating Moderate to severe (disturbing or precluding daily activities) Aggravated by movement At least one associated symptom: Nausea or vomiting Photophobia 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. Investigation 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 monthsâ&#x20AC;&#x2122; 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. DATA COLLECTION AND PROCESSING 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 ÂąSD. 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. 5. OBSERVATIONS AND RESULTS 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)

30(33.33)

30(33.33)

90(100)

# Figures within parentheses indicate percentage In our study, majority (>95%) of the study subjects were between 11 and 40 years of age.


Table-2: Distribution of study subjects by sex Sex

Amitriptyline Group

Pizotifen Group

Propranolol Group

Total

Frequency

Frequency

Frequency

Frequency

Male

9 (10)

13(14.44)

13(14.44)

35(38.9)

Femal e

21(23.33)

17(18.89)

17(18.89)

55(61.1)

Total

30(33.33)

30(33.33)

30(33.33)

90(100)

# Figures within parentheses indicate percentage. Total 90 subjects completed the study, of them 55 were female (61.1%) and the rest 35 were male (38.9%), which reflects higher prevalence of migraine in women. Table -3: Distribution of study subjects by occupation Occupation

Amitriptyline Group

Pizotifen Group

Propranolol Group

Total

Frequency

Frequency

Frequency

Frequenc y

Students

15(16.67)

12(13.33)

12(13.33)

39(43.3)

Housewives

7(7.8)

9(10.0)

7(7.8)

23(25.6)

Service Holder

3(3.33)

4(4.44)

7(7.8)

14(15.6)

Businessman

2(2.22)

3(3.33)

2(2.22)

7(7.8)

Others (e.g. 3(3.33) Rickshaw-puller, Day Labourer, Motor Mechanics)

2(2.22)

2(2.22)

7(7.8)

Total

30(33.33)

30(33.33)

90(100)

30(33.33)

# Figures within parentheses indicate percentage. Students and housewives occupied the largest number of study subjects (68.9%). Table -4: Distribution of study subjects by type of migraine.


Type of Amitriptyline Migrain Group e Frequency

Pizotifen Group

Propranolol Group

Total

Frequency

Frequency

Frequency

Commo n

26 (28.89)

21(23.33)

26(28.89)

73(81.1)

Classic

4(4.44)

9(10.0)

4(4.44)

17(18.9)

Total

30(33.33)

30(33.33)

30(33.33)

90(100)

#Figures within parentheses indicate percentage. Presenting features of the study subjects. Common migraine comprised 81.1% and classic migraine comprised 18.9%. Table -5: Base line statistics of disease duration and frequency and duration of headache. Disease duration, frequency Prophylactic and duration of headache drugs

Mean

Std. Deviation

Duration of disease in year

Amitriptyline

5.10

4.10

Pizotifen

4.73

3.78

Propranolol

5.20

2.81

per Amitriptyline

4.43

1.55

Pizotifen

4.20

1.65

Propranolol

4.73

1.31

13.27

9.40

16.37

13.97

17.13

10.84

Headache month

frequency

Duration of each headache Amitriptyline attack in hour Pizotifen Propranolol

Mean ± SD duration of migraine of amitriptyline group (group-I) was 5.10± 4.10 years, that of pizotifen group (group-II) was 4.73± 3.78 years and that of propranolol group (group-III) was 5.20± 2.81 years. Table-6: Pretreatment comparative statistics of duration of disease, headache frequency per month and duration of each headache attack among different groups (ANOVA test). Disease

duration. Study Groups

P value


Frequency and duration of headache. Duration of disease in Amitriptyline(5.10) years Amitriptyline(5.10) Pizotifen (4.73) Headache frequency per Amitriptyline (4.43) month Amitriptyline (4.43) Pizotifen (4.20) Duration of each headache Amitriptyline(13.27) attack in hour. Amitriptyline(13.27)

Pizotifen(4.73)

695

Propranolol(5.20)

.915

Propranolol(5.20)

.617

Pizotifen(4.20)

.551

Propranolol(4.73)

.443

Propranolol(4.73)

.174

Pizotifen(16.37)

.302

Propranolol(17.13 .199 )

Pizotifen(16.37)

Propranolol(17.13 .798 )

Difference in the duration of disease, headache frequency per month and duration of each headache attack among study groups was not statistically significant (P>0.05). Table-7: Base line statistics of headache characteristics. Headache characteristics

Prophylactic treatment Amitriptylin e

Pizotifen

Propranolol

Total

Headache quality

Throbbing

29

28

30

87

Compressing

1

2

0

3

Headache severity

Moderate

3

2

0

5

Severe

27

28

30

85

Headache localization

Bitemporal

6

5

5

16

Right temporal

12

13

10

35

Left temporal

9

8

12

29

Vertex

3

2

0

5

Generalized

0

2

3

5

Morning

8

6

11

25

No definite time

19

22

13

54

At noon

3

2

6

11

Headache timing

In our study, majority of the patients (87 out of 90) had throbbing type of headache. The table also shows that most of the patients (64 out of 90) had unilateral headache, either right


temporal or left temporal. Table-8: Descriptive statistics of headache frequency per month, frequency of domperidone and paracetamol used and duration of attack in first follow up (after one month) among different groups. Headache frequency, Study Groups duration. Frequency of paracetamol and domperidone used.

Mean

Std. Deviation

Headache month

per Amitriptyline

3.27

1.55

Pizotifen

3.07

1.48

Propranolol

3.03

1.00

3.80

2.44

3.67

1.69

4.07

2.39

2.60

1.83

2.43

1.77

Propranolol

2.70

1.51

Amitriptyline

7.40

5.88

Pizotifen

10.97

10.01

Propranolol

8.80

4.51

frequency

Frequency of paracetamol Amitriptyline used Pizotifen Propranolol Frequency of domperidone Amitriptyline used Pizotifen Duration of attack in hours

In first follow up i.e after one month`s treatment there was a decrease in headache frequency per month and in duration of each attack in comparison to the pretreatment status. Table-9: Comparative statistics of headache frequency per month, frequency of paracetamol and domperidone used, duration of each attack in the first follow up among different groups (ANOVA test) Frequency and duration of Study Groups headache. Frequency of paracetamol and domperidone used Headache frequency per Amitriptyline (3.27) month

P value

Pizotifen (3.07)

.921

Amitriptyline (3.27)

Propranolol(3.03)

.881

Pizotifen (3.07)

Propranolol(3.03)

1.000

Pizotifen (3.67)

.994

Frequency of paracetamol Amitriptyline (3.80)


used Frequency domperidone used

Amitriptyline (3.80)

Propranolol(4.07)

.953

Pizotifen (3.67)

Propranolol(4.07)

.860

Pizotifen (2.43)

.974

Amitriptyline (2.60)

Propranolol(2.70)

.994

Pizotifen (2.43)

Propranolol(2.70)

.906

Pizotifen (10.97)

.163

Propranolol(8.80)

.834

Propranolol(8.80)

.569

of Amitriptyline (2.60)

Duration of each Amitriptyline (7.40) headache attack in hour Amitriptyline (7.40) Pizotifen (10.97)

After one month`s treatment there was no significant difference regarding the decrease in headache frequency per month, number of tablets of paracetamol and domperidone used and duration of each attack among the study groups (P value>0.05). Table -10: Comparative statistics of severity of headache and presence and absence of nausea/vomiting in first follow up among different groups (Chi-square test) Severity of headache. Status of nausea/vomiting

Prophylactic Drugs Amitript yline

Pizotife n

Propran olol

Severity headache

21

20

19

10

11

7

5

7

23

25

23

of Moderate Severe

Presence of Absent nausea/vomitin Present g

9

Chidf Square

P value

.300

2

.861

.534

2

.766

After one month`s treatment there was no significant difference regarding the decrease in severity of headache and occurrence of nausea/vomiting among the study groups (P value>0.05). Table- 11: Descriptive statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in second follow up of different groups Frequency and duration of headache. Study groups Frequency of paracetamol and

Mean

Std. Deviation


domperdone used Headache frequency per month

Number of paracetamol used

Number of domperidone used

Duration of attack in hour

Amitriptyline

2.6538

1.69570

Pizotifen

2.3793

1.11528

Propranolol

2.5862

1.08619

Amitriptyline

2.8846

1.68112

Pizotifen

2.8621

1.61961

Propranolol

3.5862

2.66615

Amitriptyline

1.4000

1.91485

Pizotifen

1.8276

1.48970

Propranolol

1.9655

1.74198

Amitriptyline

5.5385

5.54964

Pizotifen

8.7241

10.03083

Propranolol

6.6552

5.06582

In second follow up i.e after two monthsâ&#x20AC;&#x2122; treatment there was a decrease in headache frequency per month, duration of each attack and frequency of paracetamol and domperidone used in comparison to status in the first follow up. Table-12: Comparative statistics of headache frequency per month, frequency of domperidone and paracetamol used and duration of attack in second follow up among different groups (ANOVA test) Frequency and duration of headache. Study Groups Frequency of paracetamol and domperidone used

P value

Headache frequency per month

Amitriptyline Pizotifen (2.6538) (2.3793)

.742

Amitriptyline Propranolol (2.6538) (2.5862)

.982

Pizotifen (2.3793)

.836

Frequency of paracetamol used

Propranolol (2.5862)

Amitriptyline Pizotifen (2.8846) (2.8621)

1.0000

Amitriptyline Propranolol (2.8846) (3.5862)

.568

Pizotifen (2.8621)

.521

Propranolol (3.5862)


Frequency of domperidone used

Amitriptyline Pizotifen (1.4000) (1.8276)

.660

Amitriptyline Propranolol (1.4000) (1.9655)

.485

Pizotifen (1.8276)

.954

Propranolol (1.9655)

Duration of each headache attack in Amitriptyline Pizotifen hour (5.5385) (8.7241)

.379

Amitriptyline Propranolol (5.5385) (6.6552)

.825

Pizotifen (8.7241)

.695

Propranolol (6.6552)

Comparative statistics shows no difference among the study groups (P value>0.05). Table-13: Comparative statistics of severity of headache and presence or absence of nausea/vomiting in second follow up among different groups (Chi-square test) Severity of headache. Status Prophylactic Drugs of nausea/vomiting. Amitriptyl Pizotife ine n Severity headache

of Mild

Propano lol

8

5

5

Moderate

14

15

15

Severe

8

10

10

11

7

14

19

23

16

Status of Absent nausea/vomitin Present g

Chidf Square

P value

1.331

4

.856

3.588

2

.166

Comparative statistics shows no difference among the study groups (P value>0.05). Table- 14: Descriptive statistics of headache frequency per month, frequency of domperidone and paracetamol used and duration of attack in third follow up among different groups Frequency and duration of headache. Study Groups Frequency of paracetamol and domperidone used.

Mean

Std. Deviation


Headache frequency per month

Frequency of paracetamol used

Frequency of domperidone used

Duration of attack in hour

Amitriptyline

2.40

1.80

Pizotifen

2.11

1.12

Propanolol

2.65

1.37

Amitriptyline

2.52

2.00

Pizotifen

2.56

1.67

Propranolol

3.83

2.96

Amitriptyline

1.25

2.15

Pizotifen

1.26

1.61

Propranolol

1.74

2.03

Amitriptyline

4.88

5.73

Pizotifen

7.94

10.76

Propranolol

5.89

5.70

In third follow up i.e after three monthsâ&#x20AC;&#x2122; treatment there was a decrease in headache frequency per month, duration of each attack and frequency of paracetamol and domperidone used in comparison to status in the second follow up. Table- 15: Comparative statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in third follow up among different groups (ANOVA test).

Frequency and duration of Study Groups headache. Frequency of paracetamol and domperidone used. Headache frequency per month

Amitriptyline (2.40) Amitriptyline (2.40) Pizotifen(2.11) Number of paracetamol used Amitriptyline (2.52) Amitriptyline (2.52) Pizotifen(2.56) Number of domperidone used Amitriptyline (1.25) Amitriptyline (1.25) Pizotifen(1.26) Duration of each headache attack Amitriptyline (hour) (4.88) Amitriptyline (4.88) Pizotifen(7.94)

P value

Pizotifen (2.11) Propranolol (2.65) Propranolol(2.65) Pizotifen (2.56) Propranolol (3.83) Propanolol(3.83) Pizotifen (1.26) Propranolol (1.74) Propranolol(1.74) Pizotifen (7.94) Propranolol (5.89) Propranolol(5.89)

.872 .929 .359 1.000 .232 .214 1.000 .811 .744 .494 .905 .779


Comparative statistics shows no difference among the study groups (P value>0.05). Table- 16: Comparative statistics of severity of headache and presence and absence of nausea/vomiting in third follow up among different groups (Chi-square test) Severity of headache. Prophylactic Drugs Status of Amitriptyl Pizotife nausea/vomiting ine n Severity of Mild headache Moderate Severe Status of Absent nausea/vomi Present ting

Propanolol

Chidf Square

P value

1.550

4

.818

1.944

2

.378

13

12

9

9

8

11

8

10

10

20

15

19

10

15

11

Comparative statistics shows no difference among the study groups (P value>0.05). Table-17: Descriptive statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in fourth follow up among different groups (n=61) Frequency and duration of Study Groups headache. Frequency of paracetamol and domperidone used.

Frequency

Mean

Std. Deviation

Number of paracetamol used

Amitriptyline

22

1.14

.89

Pizotifen

19

.61

.59

Propanolol

20

.70

1.08

Amitriptyline

22

.09

.29

Pizotifen

19

.16

.50

Propanolol

20

.45

.94

per Amitriptyline

22

1.14

.35

Pizotifen

19

1.11

.32

Propanolol

20

1.15

.49

Amitriptyline

22

1.68

1.70

Pizotifen

19

1.61

2.19

Number of domperidone used

Headache month

frequency

Duration of attack (hours)


Propanolol

20

1.48

2.16

In fourth follow up i.e after four monthsâ&#x20AC;&#x2122; treatment there was a decrease in headache frequency per month, duration of each attack and frequency of paracetamol and domperidone used in comparison to status in third follow up. Table-18: Comparative statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in fourth follow up among different groups (ANOVA test)

Frequency and duration of headache. Study Groups Frequency of paracetamol and domperidone used.

P value

Headache frequency per month

Amitriptyline Pizotifen (1.14) (1.11)

.992

Amitriptyline Propranolol (1.14) (1.15)

.999

Pizotifen(1.1 1) Number of paracetamol used

Amitriptyline Pizotifen (1.14) (.61)

.166

Amitriptyline Propranolol (1.14) (.70)

.303

Pizotifen(.61 ) Number of domperidone used

Propranolol( .978 1.15)

Propranolol( .982 .70)

Amitriptyline Pizotifen (.09) (.16)

.981

Amitriptyline Propranolol (.09) (.45)

.198

Pizotifen(.16 )

Propranolol( .394 .45)

Duration of each headache attack Amitriptyline Pizotifen (hour) (1.68) (1.61) Amitriptyline Propranolol (1.68) (1.48) Pizotifen(1.6 1)

.999 .982

Propranolol( .996 1.48)


Comparative statistics shows no difference among the study groups (P value>0.05). Table- 19: Comparative statistics of severity of headache and presence and absence of nausea/vomiting in fourth follow up among different groups (Chi-square test) Severity of headache. Status of nausea/ vomiting

Prophylectic Drugs Amitript yline

Pizotife n

Propanolo l

Severity headache

18

12

14

4

7

6

19

17

18

3

2

2

of Mild Moderate

Chidf Square

P value

1.833

2

.400

.161

2

.923

Severe Presence

of Absent

nausea/ vomiting

Present

Comparative statistics shows no difference among the study groups (P value>0.05). Table-20: Descriptive statistics of headache frequency per month, duration of attack ,frequency of paracetamol and domperidone used in fifth follow up among different groups (n=61) Frequency and duration of Study Groups headache. Frequency of paracetamol and domperidone used

Frequency

Mean

Std. Deviation

Headache frequency per Amitriptyline month Pizotifen

22

1.18

.50

19

1.00

.00

20

1.00

.00

22

1.18

1.15

19

.87

.23

20

.80

.25

22

1.00

.62

19

1.00

.47

20

.50

.51

of Amitriptyline

22

.18

.50

Pizotifen

19

.00

.00

Propranolol

20

.25

.44

Propranolol Duration of each headache Amitriptyline attack in hour Pizotifen Propranolol Frequency of paracetamol Amitriptyline used Pizotifen Propranolol Frequency domperidone used


In fifth follow up i.e. after five monthsâ&#x20AC;&#x2122; treatment there was a decrease in headache frequency per month, duration of each headache attack and frequency of paracetamol and domperidone used in comparison to status in the fourth follow up. Table- 21: Comparative statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in fifth follow up among different groups (ANOVA test) (n=61). Frequency and duration of Study Groups headache. Frequency of paracetamol and domperidone used. Headache month

frequency

per Amitriptyline (1.18)

P value

Pizotifen (1.00)

.165

Amitriptyline (1.18)

Propranolol (1.00)

.157

Pizotifen(1.00)

Propranolol(1.00)

1.000

Pizotifen (.87)

.422

Amitriptyline (1.18)

Propranolol (.80)

.245

Pizotifen(.87)

Propranolol(.80)

.987

Pizotifen (1.00)

1.000

Amitriptyline (1.00)

Propranolol (.50)

.012

Pizotifen(1.00)

Propranolol(.50)

.016

Pizotifen (.00)

.375

Amitriptyline (.18)

Propranolol (.25)

.923

Pizotifen(.00)

Propranolol(.25)

.148

Duration of each headache Amitriptyline attack in hour (1.18)

Frequency of paracetamol Amitriptyline used (1.00)

Frequency of domperidone Amitriptyline used (.18)

At the end of the 5th month it was observed that the use of Paracetamol as abortive therapy was more in case of amitriptyline in comparison to propranolol. Also it was observed in the same follow up that the use of paracetamol as abortive therapy was more in case of pizotifen in comparison to propranolol. Table- 22: Comparative statistics of severity of headache and presence and absence of


nausea/vomiting in fifth follow up among different groups (Chi-square test). Severity of headache. Status of nausea/vomiting

Prophylactic Drugs Amitript yline

Pizotife n

Severity headache

of Mild

20

Status nausea/ vomiting

of Absent

Moderate

Present

Propranolol

Chidf Square

P value

18

20

1.859

2

.395

2

1

0

22

18

20

2.247

2

.325

0

1

0

Comparative statistics shows no difference among the study groups (P value>0.05). Table- 23: Descriptives statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in sixth follow up among different groups (n=61) Frequency and duration Study Groups of headache. Frequency of paracetamol and domperidone used

Frequency

Mean

Std. Deviation

Headache frequency per Amitriptyline month Pizotifen

22

1.18

.50

19

1.00

.00

20

1.00

.00

22

1.18

1.15

19

.87

.23

20

.80

.25

22

.91

.43

19

.95

.40

20

.50

.51

of Amitriptyline

22

1.18

.50

Pizotifen

19

.87

.00

Propranolol

20

.80

.44

Propranolol Duration of each Amitriptyline headache attack in hour Pizotifen Propranolol Frequency of paracetamol Amitriptyline used Pizotifen Propranolol Frequency domperidone used

In sixth follow up i.e after six monthsâ&#x20AC;&#x2122; treatment there was a decrease in headache frequency


per month, duration of each headache attack and frequency of paracetamol and domperidone used in comparison to status in fifth follow up. Table- 24: Comparative statistics of headache frequency per month, frequency of paracetamol and domperidone used and duration of attack in sixth follow up among different groups (ANOVA test) Frequency and duration of Study Groups headache. Frequency of paracetamol and domperidone used. Headache month

frequency

per Amitriptyline (1.18)

P value

Pizotifen (1.00)

.165

Amitriptyline (1.18)

Propranolol (1.00)

.157

Pizotifen(1.00)

Propranolol(1.00 )

1.000

Pizotifen (.87)

.422

Amitriptyline (1.18)

Propranolol (.80)

.245

Pizotifen(.87)

Propranolol(.80)

.987

Pizotifen (.95)

.990

Amitriptyline (.91)

Propranolol (.50)

.014

Pizotifen(.95)

Propranolol(.50)

.009

Pizotifen (.00)

.375

Amitriptyline (.18)

Propranolol (.25)

.923

Pizotifen(.00)

Propranolol(.25)

.148

Duration of each headache Amitriptyline attack in hour (1.18)

Frequency of paracetamol Amitriptyline used (.91)

Frequency of domperidone Amitriptyline used (.18)

At the end of the 6th month it was observed that the use of paracetamol as abortive therapy was more in case of amitriptyline in comparison to propranolol. Also it was observed in the same follow up that the use of paracetamol as abortive therapy was more in case of pizotifen in comparison to propranolol.


Table- 25: Comparative statistics of severity of headache and presence and absence of nausea/vomiting in sixth follow up among different groups (Chi-square test) Severity of headache. Prophylactic Drugs Status of nausea/ Amitriptylin Pizotife vomiting e n Severity of headache

df

Propanolol

ChiSquare

P valu e

1.859

2

.395

2.247

2

.325

Mild

22

19

20

Moderate

0

0

0

22

18

20

0

1

0

Status of Absent nausea/ Present vomiting

Comparative statistics shows no difference among the study groups (P value>0.05). Table-26: Comparative statistics of improvement status of migraine at the end of the sixth follow-up among different groups (Chi-square test) Improvement status

Improveme Improve nt of d migraine Not improve d Total

Prophylactic Drugs Amitriptylin e

Pizotife n

Propranolol

ChiSquare

22

19

20

.712

8

11

10

30

30

30

df

P valu e

2

.700

Comparative statistics shows no difference among the study groups (P value>0.05). Table- 27: Comparison between pre-treatment body weight and end of follow-up body weight of the three treatment groups (Paired t test) Groups

Frequenc y

Amitriptyline 22

Body weight(kg) Initial(Mean±SD)

52.78±9.12

% change P value Final(Mean±SD) from initial to final(Mean) 54.63±8.89

+2.15

<0.01


Pizotifen

19

54.89±8.42

55.47±8.43

+1.10

<0.01

Propranolol

20

49.83±10.25

50.05±10.27

+0.50

>0.10

Change of body weight from before to after 6 months of migraine prophylactic treatment. In amitriptyline and pizotifen groups the change of body weight was statistically significant (P<0.01). But in propranolol group the change of body weight was not statistically significant (P>0.10). Table -28: Assessment of pulse rate of the three study groups before and after 6 months of preventive treatment.(Paired t test). Groups

Frequenc y

Initial pulse Final pulse % change P value rate(Mean±SD) rate(Mean±SD) from initial to final (Mean)

Amitriptyline 22

76.22±6.71

79.19±7.06

+3.47

<0.01

Pizotifen

19

76.89±5.69

77.43±6.08

+0.63

>0.10

Propranolol

20

81.20±6.09

71.60±3.98

-11.43

<0.001

Table-28 shows 11.43% change in pulse rate between pre- and post-treatment with propranolol and the change was significant (P<0.05). In amitriptyline group the change in pulse rate was also significant (P<0.01). But in pizotifen group it was not significant (P>0.10). 6. DISCUSSION The present study was a hospital-based intervention study, carried out to assess whether there is any difference in efficacy of amitriptyline with that of propranolol or with that of pizotifen in prophylaxis of migraine. In this study, majority (>95%) of the study subjects were between 11 and 40 years of age which is similar to the findings observed by Lipton (Lipton et. al. 2001). Mean ± SD age of patients of group-I (amitriptyline group) was 23.17 ± 9.28 years. Mean ± SD age of patients of group-II (pizotifen group) and group-III (propranolol group) were 25.50 ± 9.57 years and 26.20 ± 8.37 years respectively.. Females were 55(61.11%) and male were 35 (38.89%) of the study subjects, with a female to male ratio of 1.57: 1 (Table 2). The ratio observed by Lipton was 3:1 (approximately) (Lipton et. al. 2001). Difference in study might be due to small sample size. Students and housewives occupied the largest number of study subjects who were un-employed (Table:3). Lipton showed that migraine prevalence was inversely related with socioeconomic status


(Lipton et. al. 2001). Regarding types of migraine, 17 (18.9%)of study subjects were having classic migraine and 73 (81.1%) were having common migraine which is near to the result shown by Rasmussen (Table-4) (Rasmussen and Olesen 1992). Pretreatment headache-related disabilities had no significant difference among the three groups -duration of disease, frequency of headache per month and duration of each headache attack were statistically not significant (P>0.05, Table-6). These similarities enabled the study to have a valid comparative statistical analysis. Mean ± SD duration of migraine of amitriptyline group (group-I) was 5.10 ± 4.10 years, that of pizotifen group (group-II) was 4.73 ± 3.78 years and that of propranolol group (group-III) was 5.20 ± 2.81 years (Table-5). The difference in duration of migraine suffering among the three groups was not significant (P>0.05, Table-6). In group-I, mean headache frequency per month was 4.43 ± 1.55 at baseline which became 2.40 ± 1.80 after 3 months and 1.18 ± 0.50 after 6 months. In group-II, mean headache frequency per month was 4.20 ± 1.65 at baseline which became 2.11 ± 1.1 2 after 3 months and 1.0 ± 0.00 after 6 months. In group-III, mean headache frequency per month was 4.73 ± 1.31 at baseline which became 2.65 ± 1.37 after 3 months and 1.0 ± 0.00 after 6 months (Tables-5,14 & 23). Hence, improvement in headache frequency was observed after 6 months of treatment with amitriptyline, pizotifen and propranolol therapy. But, in comparative statistics there was no significant difference in the mean decrease in headache frequency among the three treatment groups (P value> 0.05) (Table:24). Regarding headache severity baseline statistics were as follows:In group-I, out of 30 patients 27 patients had severe headache and 03 had moderate headache. In group-II, out of 30 patients 28 patients had severe headache and 02 had moderate headache. In group-III, all 30 patients had severe headache. After 3 months of treatment the three groups showed the following results:In group-I out of 30 patients 13 patients had mild or no headache, 09 had moderate headache and 08 had severe headache. In group-II out of 30 patients 12 had mild or no headache, 08 had moderate headache and 10 had severe headache. In group-III out of 30 patients 09 had mild or no headache, 11 had moderate headache and 10 had severe headache. Comparative statistics using Chi-square test showed P value 0.818 i.e. not significant (Table-16). After 6 months of treatment, in group-I, 22 patients had mild or no headache, in group-II 19 patients had mild or no headache, in group-III 20 patients had mild or no headache. Comparative statistics using Chi-square test showed P value 0.395 i.e. not significant (Table25). There was no significant difference in the mean decrease in headache severity amongst the three treatment groups.


Regarding duration of each headache attack baseline statistics was as follows:-In group-I (amitriptyline group) mean ± SD duration of each headache attack was 13.27 ±9.40 hour. In group-II (pizotifen group) mean ± SD duration of each headache attack was 16.37 ± 13.97 hour and that of group-III (propranolol group) was 17.13 ± 10.84 hour. Comparative statistics among the three groups showed P value > 0.05 i.e. not significant (Table-6). After 3 months of treatment, mean ± SD duration of each headache attack in group-I was 4.88 ± 5.73 hour. In group-II and group-III it was 7.94 ±10.76 hour and 5.89 ± 5.70 hour respectively. Again comparative statistics among the three groups showed P value> 0.05, i.e. not significant (Table-14 and Table-15). After 6 months of treatment, it was observed that mean ± SD duration of each headache attack in groups I, II and III were 1.18 ± 1.15 hour, 0.87 ± 0.23 hour and 0.80 ± 0.25 hour respectively and P value was >0.05 i.e. not significant (Table:24). It is now obvious that all the three drugs are effective in reducing the duration of each headache attack but there is no significant difference in their efficacy. At the end of the 5th month it was observed that the use of paracetamol as abortive therapy was more in case of amitriptyline in comparison to propranolol. Also it was observed in the same follow-up that the use of paracetamol as abortive therapy was more in case of pizotifen in comparison to propranolol (P value< 0.05,Table-21). Similar picture was found in the 6 th follow-up visit regarding the use of paracetamol as abortive therapy when P values were less than 0.05, i.e. significant. In this regard, propranolol is superior to amitriptyline and pizotifen (Table-24). The present study comparing the efficacy of amitriptyline, pizotifen and propranolol showed comparable improvement in terms of headache frequency per month, duration of each headache attack and severity of headache. All drugs showed improvement and there was statistically no significant difference in improving the symptoms of migraine. At the end of the 6th follow-up it was found that in group-I 22 patients out of 30 improved. In group-II and in group-III 19 and 20 patients showed improvement. Comparative statistics showed no significant difference in improvement of number of patients of three treatment groups (Table26). In the section Results and Observation we have seen that all the three drugs amitriptyline, pizotifen and propranolol are effective in improving the symptoms of migraine, but there is no significant difference in their efficacy (P value >0.05). Ziegler and his group compared propranolol and amitriptyline. In comparing relative efficacy in migraine, both agents were evaluated for correlating improvement in headaches with improvement in anxiety and depression. This extensive study, which lasted for 40 weeks, involved crossover to the alternative agent. Thirty of 54 patients completed the study, and 12


reported at least a 50% reduction in headaches following propranolol treatment. Ten patients treated with amitriptyline had similar results. Good response to each agent was reported in 7 patients (Ziegler et. al. 1987). In Europe, pizotifen has become a standard of comparison for many antimigraine drugs. Velming and his colleagues (51) compared metoprolol in dosages 50 mg twice daily to pizotifen 0.5 mg three times daily, in a double-blind, crossover study. The frequency and severity of headaches and consumption of abortive medications were used as comparative indices. Although both agents produced significant decrease in headache frequency and severity as compared to the initial phase, neither drug was statistically superior to the other in prophylaxis. The study was completed by 31 patients (Diamond 1999). During the follow-up, 3 study subjects complained of dry mouth and 4 study subjects complained of somnolence in amitriptyline group. Weight gain and pulse rate increased significantly (P<0.05) in this group. None of the effect caused withdrawal of medication. In pizotifen group, 3 study subjects complained of mild lassitude and needed no withdrawal of medication. Weight gain was 1.10 percent higher than mean baseline value (P< 0.05). In propranolol group, 2 study subjects complained of vertigo and 3 complained of insomnia. Pulse reduced significantly (P< 0.05). None of the effect caused withdrawal of medication. 7. SUMMARY This intervention study was carried out in the Neurology Outpatient Department, Mymensingh Medical College Hospital, from January, 2006 to December, 2007. The objective of the study was to assess the difference in the efficacy of amitriptyline, pizotifen and propranolol in the prophylaxis of migraine. Thirty patients were selected for amitriptyline group (group-I). Equal number of patients were selected for pizotifen group (group-II) and propranolol group (group-III). The study subjects were selected purposively for each group. Mean ±SD age of the patients of group-I was 23.17 ± 9.28 years and that of group-II and group-III was 25.50 ± 9.57 years and 26.20 ± 8.37 years respectively. Out of 90 study subjects, 55 (61.1%) were female and 35 (38.9%) were male. Seventy-three (81.1%) of the patients were having common migraine and 17 (18.9%) of the patients were having classic migraine. Mean ± SD duration of suffering from migraine was 5.10 ± 4.10 years for amitriptyline group, 4.73 ± 3.78 years for pizotifen group and 5.20 ± 2.81 years for propranolol group. Pretreatment frequency of migraine attack per month were 4.43 ± 1.55 for amitriptyline group, 4.20 ± 1.65 for pizotifen group and 4.73 ± 1.31 for propranolol group. Before commencing the study 27 patients had severe headache and 3 had moderate headache of amitriptyline group, 28 patients had severe headache and 2 had moderate headache of


pizotifen group and all 30 patients had severe headache of propranolol group. Pretreatment mean ±SD duration of each headache attack was 13.27 ± 9.40 hour for amitriptyline group, 16.37 ± 13.97 hour for pizotifen group and 17.13 ± 10.84 hour for propranolol group. Before commencing the study all 90 patients had nausea and/or vomiting. 25 mg of amitriptyline at bedtime was given to study subjects aged 19 years and above and those who were below 19 years received 12.5mg. Pizotifen at a dose of 1.5 mg was given at bedtime to study subjects aged 19 years and above and 0.5 mg bid to those who were below 19 years. 40 mg of propranolol in two divided doses was given to study subjects aged 19 years and above and 20 mg in two divided was given to patients below 19 years. All the drugs were given orally. The study subjects were followed-up monthly for 6 months. Changes in headache frequency per month, headache severity and duration of each migraine attack were compared after 3 and 6 months of treatment. No significant difference was observed between the groups regarding headache frequency per month, headache severity and duration of each headache attack. But it was observed that tablet paracetamol used as abortive therapy was less frequent in case of propranolol group than that of amitriptyline and pizotifen groups. Some side-effects were observed in all 3 groups but were well-tolerated by the patients and needed no withdrawal of medication. 8. CONCLUSION This study was intended to compare the efficacy of the Tricyclic antidepressant drug Amitriptyline, Serotonin antagonist drug Pizotifen and the non-selective beta blocker drug Propranolol in the prophylactic treatment of patients with moderate to severe headache of migraine. All the three drugs helped in reducing migraine attack frequency per month, headache severity and duration of each headache attack. It was also observed that tablet paracetamol used as abortive therapy was less frequent in case of propranolol group than that of amitriptyline group and pizotifen group. All the drugs were well tolerated with minimum adverse effects. 9. RECOMMENDATION Observing the pros and cons of the present study, it can be stated that all the three drugs amitriptyline, pizotifen and propranolol are effective in the improvement of symptoms, reduction of severity and frequency of migraine attacks. An intensive research is, however, needed on the prophylactic management of migraine. With this view in mind, the following recommendation is put forward for consideration of further research to relevant authority. A community based randomized, multicentered, double-blind, placebo-controlled study may be conducted for prolonged period to observe the efficacy among amitriptyline, pizotifen and propranolol in the prevention of migraine.


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Appendix-III Visual analogue scale for rating the intensity and severity of pain of migraine headache (Stewart, Lipton & Celentano, 1999)

10 9 Intensity of Pain

8 7 6 5 4 3 2 1 0

1

2

3

4

5

6

Pain Scale

7

8

9

10


1= Just Noticeable 2= Very Weak 3= Weak 4= Mild 5= Moderate

6= Strong 7= Intense 8= Very Intense 9= Excruciating 10= Intolerable

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