• No results found

THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE

N/A
N/A
Protected

Academic year: 2022

Share "THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE "

Copied!
135
0
0

Loading.... (view fulltext now)

Full text

(1)

THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE

Dissertation submitted to THE TAMILNADU

DR. M.G.R. MEDICAL UNIVERSITY

In partial fulfillment of the regulations for the award of the degree of

M.D. (PHARMACOLOGY)

BRANCH - VI

Reg. No. 201716401

DEPARTMENT OF PHARMACOLOGY CHENGALPATTU MEDICAL COLLEGE

CHENGALPATTU - 603 001

MAY – 2020

(2)

This is to certify that this dissertation entitled, A RANDOMIZED CONTROLLED TRIAL TO STUDY THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE, submitted by Dr.N.CAROLINE DEVAKIRUBAI, in partial fulfillment for the award of the degree of M.D.(Pharmacology) by The Tamilnadu Dr.M.G.R.Medical University, Chennai is a bonafide record of the research work done by her, under the guidance of Dr. K.VIJAYARANI, M.D., Professor and HOD, Department of Pharmacology, Government Thiruvannamalai Medical College during the academic year 2017-20 in the Department of Pharmacology, Chengalpattu Medical College, Chengalpattu- 603 001.

Dr.K.Vijayarani, M.D., Professor and Guide,

Department Of Pharmacology, Govt. Thiruvannamalai Medical College.

Dr.S.Pauline Packiaseeli, M.D., Associate professor and HOD i/c, Department of Pharmacology, Chengalpattu Medical College.

Dr. G.Hariharan., M.S., M.Ch., DEAN

Chengalpattu Medical College &Hospital Chengalpattu - 603 001.

(3)

I solemnly declare that the dissertation entitled “A RANDOMIZED CONTROLLED TRIAL TO STUDY THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE” is done by me at Chengalpattu Medical College and hospital, Chengalpattu during the period of 2018-2019 under the guidance and supervision of Dr.K.VIJAYARANI, M.D., Professor and HOD, Department of Pharmacology, Government Thiruvannamalai Medical College. This dissertation is submitted to The Tamilnadu Dr.M.G.R.Medical University, Chennai towards the partial fulfilment of the requirements for the award of M.D. DEGREE IN PHARMACOLOGY.

Dr. N. CAROLINE DEVAKIRUBAI., MD Pharmacology Postgraduate Student, Department of Pharmacology,

Chengalpattu Medical College, Chengalpattu- 603001.

Place : Chengalpattu Date :

(4)

I express my sincere gratitude to Dean, Dr.G.Hariharan., M.S., M.Ch., Chengalpattu Medical College, for permitting me to undertake this research work as a part of my MD curriculum.

I would like to convey my gratitude to my guide Dr.K.Vijayarani, M.D., Professor and HOD, Department of Pharmacology, Government Thiruvannamalai Medical College for her unfailing guidance, sincere advice and constant support throughout the study.

I express my sincere thanks to Dr.S.Pauline Packiaseeli, M.D., Associate Professor and HOD i/c, Department of Pharmacology, Chengalpattu Medical College for her enduring encouragement and valuable comments in my writing.

I am very thankful to Dr.B.Sharmila, M.D., Dr.J.Komathi, M.D., former Associate Professors, Department of Pharmacology, Chengalpattu Medical College for their remarkable guidance, continuous suggestions and directions throughout the study.

I would like to convey my gratitude to my co-guide Dr.P.Chandrasekar M.D, D.M., Professor and Head, Department of Neurology, Chengalpattu Medical College, for permitting me to carry out this study in Neurology OPD of Chengalpattu Medical College.

I am very much grateful to all my Assistant Professors Dr.T.Ragupathy, M.D.,Dr.T.Siyamaladevi, M.D, Dr.B.Bhuvaneswari, M.D, Dr.R.Ranjini, M.D, Dr.A.Vinoth Kumar, M.D, Dr.S.A.Ayisha, M.D.,

(5)

M.Sc., Ph.D., Department of Pharmacology, Chengalpattu Medical College for their advice and encouragement.

I am very much grateful to my Assistant Professors Dr.Balaji M.D, D.M., and Dr Hariharan M.D, D.M., Department of Neurology for their guidance and encouragement.

I have great pleasure in thanking my brother Dr. A.Jenit Osborn M.D., for helping me in the statistical analysis. I thank my fellow postgraduates Dr.S.Sweetlin M.D., Dr.V.J Sharmi M.D, Dr.G.Amutha M.D, Dr.M.Punitha M.D., Dr.M.Firoze, Dr.Devipriya, Dr.V.C.Sangeetha, Dr.M.Sukanya, Dr.A.Kumutha, Dr.K.Hemalatha for their help and encouragement throughout this study.

I also extend my sincere thanks to all other staff members of this department for their wholehearted support. Finally I thank all my patients for they willingly cooperated to undertake and complete this study.

I sincerely thank the Almighty for His grace without which I could not have completed this work successfully. Last but not the least I thank my dear parents Mr. K. Nelson Tagore and Mrs. A. Boopathy, my husband Mr. A.

Johnson Antony, and my dear son Master. J. Benson Nathanael for their continuous encouragement, patience, valuable support and sincere prayers without which I could not have completed this work successfully.

I thank Mrs. D. Rajalakshmi for her efforts in bringing out the final print of the dissertation.

(6)
(7)

This is to certify that this dissertation work titled “A RANDOMIZED CONTROLLED TRIAL TO STUDY THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE” of the candidate DR.N.CAROLINE DEVAKIRUBAI., with registration Number 201716401 for the award of Degree of M.D in the branch of PHARMACOLOGY-BRANCH- VI. I personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 3% percentage of plagiarism in the dissertation.

Guide & Supervisor sign with Seal.

(8)

CHAPTER

NO. TITLE PAGE

NO.

1 INTRODUCTION 1

2 REVIEW OF LITERATURE 5

3 AIM AND OBJECTIVES 55

4 METHODOLOGY 55

5 RESULTS 60

6 DISCUSSION 88

7 CONCLUSION 95

8 BIBLIOGRAPHY 9 ANNEXURES

(9)

FIGURE

NO. TITLE PAGE

NO.

1 ICHD-3 Classification of Migraine 19

2 Management of Migraine 30

3 Chemical structure of Propranolol 41

4 Chemical structure of Amitriptyline 45

5 Chemical structure of sodium valproate 47

6 Chemical structure of pyridoxine 49

7 Study Flowchart 59

8 Distribution of the study participants 60

9 Age-wise distribution of the study participants 61 10 Mean age of the study participants in group A and B 62

11 Sex distribution 63

12 Type of migraine 64

13 Type of AURA 65

14 Associated symptoms with migraine 66

15 Site of headache 67

16 Location of headache 68

17 Family history of migraine 69

(10)

18 Prophylaxis of migraine 70 19 Baseline characteristics of migraine in group A and B 72 20 Comparison of mean frequency of migraine between

group A and B

74

21 Comparison of mean number of days with headache between group A and B

76

22 Comparison of mean severity of migraine between group A and B

78

23 Comparison of mean MIDAS score between group A and B

80

24 Comparison of baseline characteristics among those with AURA between group A and B

82

25 Comparison of mean frequency of migraine among MWA patients between group A and B

83

26 Comparison of mean number of days with headache among those with AURA between group A and B

84

27 Comparison of mean severity of migraine among those with AURA between group A and B

85

28 Comparison of mean MIDAS score among those with AURA between group A and B

86

29 Incidence of adverse events among group A and B 87

(11)

TABLE NO.

TITLE

PAGE NO.

1 Consensus guidelines to identify patient’s for prophylactic

therapy 40

2 Classification of drugs available for prophylactic therapy

based on evidence of efficacy 40

3 Distribution of study participant 60

4 Age distribution 61

5 Mean age distribution 62

6 Sex distribution 63

7 Type of migraine 64

8 Type of aura 65

9 Associated symptoms with migraine 66

10 Site of headache 67

11 Location of headache 68

12 Family history of migraine 69

13 Prophylaxis of migraine 70

14 Baseline characteristics of migraine in Group A and

Group B 71

15a Baseline and 3rd monthly mean frequency of migraine for

Group A 73

(12)

NO. NO.

15b Baseline and 3rd monthly mean frequency of migraine for

Group B 73

16 Baseline and 3rd monthly mean frequency of migraine

between Group A and Group B 74

17a

Baseline and 3rd monthly mean number of headache days

in group A 75

17b

Baseline and 3rd monthly mean number of headache days

in group B 75

18

Baseline and 3rd monthly mean number of headache days

between Group A and Group B 76

19a

Baseline and 3rd monthly mean severity of migraine in

group A 77

19b

Baseline and 3rd monthly mean severity of migraine in

group B 77

20 Baseline and 3rd monthly mean severity of migraine

between group A and Group B 78

21a Baseline and 3rd monthly mean MIDAS score for group A 79 21b Baseline and 3rd monthly mean MIDAS score for group B 79

22 Baseline and 3rd monthly mean MIDAS score between

group A and group B 80

23 Distribution of MWA patients in group A and B 81 24 Comparison of the baseline characteristics of MWA

patients in Group A and B 81

(13)

NO. NO.

25 Baseline and 3rd monthly mean frequency of migraine

among MWA patients between Group A and B 83 26 Baseline and 3rd monthly mean duration of attack among

MWA patients between Group A and B 84

27 Baseline and 3rd monthly mean severity of migraine

among MWA patients between Group A and B 85 28 Baseline and 3rd monthly mean MIDAS score among

MWA patients between Group A and B 86

29 Incidence of adverse events among group A and B 87

(14)

3ʹUTR - 3ʹ Untranslated Region

ACE - Angiotensin Converting Enzyme

AIWS - Alice In Wonderland Syndrome

CGAS - Candidate Gene Association Studies

CGRP - Calcitonin Gene Related Peptide

COX - Cyclooxygenase

CSD - Cortical Spreading Depression

DALYs - Disability-Adjusted Life Years

ESR1 - Estrogen Receptor 1gene

FHM - Familial Hemiplegic Migraine

FMRI - Functional Magnetic Resonance Imaging

GABA - Gamma Aminobutyric Acid

GBD - Global Burden of Disease

GWAS - Genome Wide Association Studies

Hcy - Homocysteine

HHcy - Hyperhomocysteinemia

ICHD 3 - The International Classification of Headache Disorder 3rd Edition

IHS - International Headache Society

(15)

MIDAS - Migraine Disability Assessment

MOH - Medication Overuse Headache

MTHFR - Methylenetetrahydrofolate Reductase

MWA - Migraine With Aura

MWOA - Migraine Without Aura

NSAIDs - Nonsteroidal Anti-Inflammatory Drugs PACAP - Pituitary Adenylate Cyclise – Activating

Polypeptide

PET - Positron Emission Tomography

PGR - Progesterone Receptor Gene

SHM - Sporadic Hemiplegic Migraine

SNPs - Single Nucleotide Polymorphisms

TCA - Tricyclic Antidepressant

TCC - Trigeminal Cervical Complex

TTH - Tension Type Headache

WHO - World Health Organization

YLDs - Years Lived With Disability

(16)

Title

A RANDOMIZED CONTROLLED TRIAL TO STUDY THE EFFECT OF PYRIDOXINE AS ADJUVANT IN PROPHYLAXIS OF MIGRAINE

Background

Migraine is a chronic, multifactorial, disabling, neurovascular headache disorder.Prophylactic treatment constitutes an important aspect of migraine management. In spite of the availability of a wide range of drugs, current therapies are effective only for a proportion of migraine sufferers.The present study is planned to assess the effect of pyridoxine as an adjuvant in the prophylaxis of migraine.

Aim

To study the effect of pyridoxine supplementation on the severity, duration and frequency of migraine attacks in patients on standard prophylaxis regimen for migraine in outpatient department of Neurology in a tertiary care hospital at Chengalpattu.

Methodology

After approval from Institutional Ethical Committee, 100 patients were recruited and randomised into either group A to receive standard prophylaxis or group B to receive Tab. Pyridoxine 80mg/day in addition to standard

(17)

duration of attack, severity and MIDAS score at 3, 6, and 9 months which was assessed using MIDAS questionnaire. Safety is assessed by recording adverse drug reactions reported during follow up.

Results

This study reiterates that, among the migraine patients with aura, pyridoxine supplementation led to significant reduction in the mean duration of attack (p=0.013 & 0.036), severity of migraine (p=0.043 & 0.031) and MIDAS score (p=0.020 & 0.012) at 3rd and 6th month respectively, but was not effective on the frequency of migraine. There was no significant difference observed among migraine without aura patients. There was no significant increase in the adverse event in group B.

Conclusion

This study confirms the efficacy of Pyridoxine supplementation in migraine with aura patients. Pyridoxine at a dose of 80mg/day was well tolerated.

KeyWords: Migraine, Pyridoxine, Migraine disability assessment score.

(18)

INTRODUCTION

Headache is one of the most common complaints in general practice. It is ubiquitous and prevalent in countries of all economic strata. International Headache Society defines headache as “Pain located in the head, above the orbitomeatal line and/or nuchal ridge”(1).

Headache disorders ranks as the sixth leading cause of years lived with disability (YLDs) worldwide(2). The International Classification of Headache Disorder 3rd Edition (ICHD-3) classifies headache disorders as primary and secondary headaches, neuropathies and facial pains and other headaches (3).

Primary headaches are disorders by themselves. They are caused by independent pathologic mechanisms and not caused by or attributed to another disorder. Examples include migraine, tension-type headache(TTH) and cluster headache(1) .

Secondary headaches are caused due to an underlying disorder though they may have characteristics of primary headache. Headaches attributed to bacterial meningitis, trauma or medication overuse headache (MOH) are few examples that falls under this category(1).

Neuropathic pain of head develops due to a lesion or any disease of the somatosensory nervous system(1). Neuralgias are characterized by pain in the region innervated by the affected nerve.

(19)

The most common type of headache disorders prevalent worldwide are migraine, TTH and MOH(4).

Migraine is a chronic debilitating neurological disorder which imposes a substantial burden on morbidity, loss of working days and economic stress on individual, family and society. Prevalence of migraine has been estimated to show increasing trend since 1990. Studies are being done to explore the various risk factors, aetiology, epidemiology, genetic role, pathogenesis, pharmacological and non pharmacological modalities of management of migraine, safety and percentage of response to those modalities.

Pharmacological management of migraine can be either abortive or prophylactic. Abortive therapy relieves the symptoms during acute attacks.

Prophylactic therapy is given for patients whose daily activities are significantly affected as a consequence of the increased frequency and severity of the disease.

Migraine prophylaxis includes lifestyle modification, avoidance of known trigger factors and medication. Arrays of drugs are available for the prophylactic management of migraine. Drugs with the best documented efficacy for prophylaxis are the beta blockers, flunarizine, sodium valproate, topiramate and amitriptyline. Second choice drugs with less efficacy and evidence are venlafaxine, gabapentin, naproxen, butterbur root, riboflavin and magnesium(5).

(20)

Few studies have suggested that non-pharmacological therapies like relaxation techniques, bio-feedback, cognitive behavioural therapy and acupuncture have some role in migraine prophylaxis(5). The choice of the prophylactic medication should be tailored by the physician bearing in mind the headache profile, patient’s need, co-morbid conditions, efficacy and adverse effects of the drug.

In spite of the availability of wide range treatment options, current therapies provide only around 50% relief in approximately 50% of migraine sufferers(5). This implies that newer therapeutic targets are required in order to reduce the disease burden. In the last few decades, several studies have identified a large number of genetic variants associated with migraine. One such gene that is most investigated in the pathogenesis of migraine is the methylene- tetrahydrofolate reductase (MTHFR) gene.

The MTHFR gene encodes for the MTHFR enzyme that catalyzes the reduction of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate which is needed for the conversion of homocysteine to methionine. Reduction in the MTHFR enzymatic activity due to point mutation in the gene leads to increase in serum homocysteine levels and is one of the genetic risk factor for migraine.

Hyperhomocysteinemia is caused by abnormal methionine biosynthesis due to deficiencies in folate, vitamin B12, and pyridoxine.

(21)

Previous studies have shown that pyridoxine administration improve vascular functions, a major aetiology in migraine attacks. Studies have mostly focused on pyridoxine, folate and cobalamin combination. Studies are scarce in assessing the effect of individual vitamins in migraine attacks and also in follow up after study period.

Hence the present study planned to assess the effect of pyridoxine individually as an adjuvant on the characteristics of migraine attacks while on regular prophylaxis for a period of 6 months and during follow up for 3 months after stopping pyridoxine.

(22)

REVIEW OF LITERATURE

Migraine is described as unilateral throbbing headache which is moderate or severe in intensity associated with nausea and vomiting usually lasting for 4 to 72 hours. The two major types of migraine are migraine without aura and migraine with aura.

HISTORY

The earliest documentation of migraine dates back to a papyrus (ancient medical textbook) dating as old as 3500 BC in the tomb of Thebes’s mentions that the king in the tomb had suffered all his life of a sickness of half head.

Migraine is described as a periodic syndrome in Mesopotamian poems in 3000 B.C(6). Hippocrates (460-377BC) described the visual aura in migraine and its relief through vomiting(7). He has mentioned that the hellebore family of plants has been be used to treat these patients. Aretaeus of Cappadocia, described a unilateral headache associated with nausea, vomiting, with headache-free intervals and called it as heterocrania(6).

Galen distinguished the features of migraine from other common headaches and used the term "hemicrania" (half-head) to describe it. John Fordyce published De Hemicrania in 1758 about his own left sided migraine attacks. He was the first to observe polyuria, prodromal depression and its link with menstruation. Fothergill was the first to draw the attention to diet as a triggering factor and identified chocolate as a precipitating factor(6).

(23)

There are references to a number of different classification systems for headaches with a rich history. The first recorded system that resembles the modern one was published by Thomas Willis, greatest forerunner of modern neurology, in De Cephalagia in 1672(6) .

EPIDEMIOLOGY Global disease burden

As per the Global burden of disease (GBD) studies 2016, migraine is the sixth most prevalent disease out of the 328 diseases estimated(8). Migraine has victimised 1.04 billion individuals across the globe. The global age standardised prevalence for migraine was 14.4% overall: 18.9% for women, and 9.8% for men. The age-standardised prevalence of migraine was highest in Italy and Nepal and lowest in China(9).

Migraine ranks second in causing disability globally at cause level 4. Over 16 years migraine has ascended the ranks of the top causes of YLDs worldwide, from 19th in GBD 2000 to 7th in GBD 2010 , 6th in GBD 2013 to the 2nd position in 2016(10).

Migraine has caused 45.1 million YLDs globally in 2016, an increase of 51.2% from the 29.8 million YLDs in 1990. The disease is burdensome in women between ages 15 and 49 years, causing 20.3 million YLDs. The age standardised YLD rates per 100 000 population for migraine were 598.7

(24)

globally. The age-standardised YLD rates were higher in women (777.6), than in men (422.3)(9) .

A peak in the prevalence and YLD rate occurred between ages 35 and 39 years. In both sexes, the percentages of YLDs in the age group 15–49 years were 8.2%. In children aged 5–14 years it contributed to 4.5%. The YLD percentage was 4.2% in individuals aged 50–69 years and 1.3% in the elderly (≥70 years).

The proportion of all DALYs for migraine was 1.9% for both sexes. DALYs was higher for women, around 2.7% compared to men which were 1.2%(9).

Migraine – prevalence in South East Asia and India

Epidemiological data from the cross sectional studies conducted by Lifting The Burden (LTB), a non profit organization in partnership with WHO revealed the 1 year prevalence of all headache disorder in India is about 64% out of which 25% was contributed by migraine. In Nepal the 1 year prevalence of migraine was 35%(11).

In India the estimated 1-day headache prevalence was 5.9% which shows that about 1.7% of the Indian population had headache at any moment. This contributes to a 3% daily loss in overall productivity at the population level(11).

The Tamil Nadu disease burden profile showed that migraine constitutes 2.3% of total DALYs of the state. Migraine ranked 14th in the leading cause of DALY in 2016 up from 23rd in 1990(12).

(25)

NEUROANATOMY OF MIGRAINE

The anatomical structures involved in migraine are extensively explored for several decades and yet to be revealed completely. The initiation of migraine may be due to a central or peripheral process(13). The important anatomical structures involved in migraine are

Trigemino-vascular pathway: The large cerebral vessels, pial vessels, large venous sinuses and dura mater are innervated by a plexus of largely unmyelinated fibres arising from the ophthalmic division of the trigeminal ganglion(14). These trigeminal fibres originate from the trigeminal ganglion that contain substance P and calcitonin gene-related peptide (CGRP), which are released when the trigeminal ganglion is stimulated(15).

Trigeminal cervical complex (TCC): The afferent fibres from the trigeminal ganglion before synapsing on second-order neurons in the TCC join with inputs from adjacent skin, pericranial and paraspinal muscle, and other C1-C2 innervated tissues. The trigeminal nucleus caudalis (TNC) and the dorsal horn of the upper cervical spinal cord (C1-C2) together constitute the TCC(16).

Brainstem, thalamus, hypothalamus and basal ganglia: The ascending fibres from the TCC transmit signals to various nuclei present in the brainstem, thalamus, hypothalamus and basal ganglia(16).

(26)

Cortex: Signals from the above nuclei project to multiple cortical areas that are involved in processing the cognitive, emotional, and sensory- discriminative aspects of the nociceptive signals. This give rise to the associated symptoms that are characteristic of the migraine attacks(16). PATHOPHYSIOLOGY OF MIGRAINE

Vascular theory

According to this theory the transiently induced ischemia is thought to be responsible for the aura of migraine. The subsequent vasodilatation causes mechanical depolarization of perivascular nociceptive nerves within the walls of engorged intra and extra cranial vessels resulted in headache(17). Later, studies showed that migraine is primarily due to neuronal dysfunction and vascular changes are a consequence of it.

Current proposed mechanisms underlying the various phases of migraine attack Premonitory phase - Hypothalamic activation

The premonitory phase of migraine commonly occurs hours to days before onset of headache during a migraine attack. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies of triggered and spontaneous migraine attacks show changes in the activity and connectivity of the hypothalamus in the hours preceding headache. Activations were noted in the posterolateral hypothalamus in addition to the midbrain tegmental area, periaqueductal gray, dorsal pons, and various cortical areas(18).

(27)

These changes in hypothalamic function may possibly account for polyuria, mood change, and change in appetite preceding headache. Increased activity in the occipital cortex in a PET study is correlated with light sensitivity, and that activation of the brainstem is related with nausea(19).

Aura - Initiation and propagation of cortical spreading depression (CSD) Aristides Leao, a neurophysiologist in 1944 first described CSD which is thought to be the pathophysiological basis of aura. CSD is characterized by a slowly (2-6 mm/min) propagating wave of depolarization in neuronal and glial cell membranes that is followed by inhibition of cortical activity for up to 30 minutes. This coincides with the initiation and progression of aura symptoms(16).

CSD is initiated by local increase in extracellular potassium (K+) that chronically depolarize neurons for approximately 30-50 seconds.(20) The initial accumulation of extracellular (K+) occurs as a consequence of repeated depolarization and repolarization of hyperexcitable neurons in the cerebral cortex, which further depolarizes the cells from which it was released(16). This large efflux of (K+) is associated with influx of sodium (Na+) and calcium (Ca2+), and release of glutamate(21).

The propagation of CSD is yet to be fully understood, but recent hypotheses suggest that the propagation is mediated via gap junctions between glial cells or neurons. This wave of spreading depression is associated with a wave of hyperaemia, followed by a prolonged phase of cortical oligemia(16). The

(28)

alterations in blood flow are secondary to decreased metabolic demand in abnormally functioning neurons rather than the underlying cause of symptoms of aura(17).

Headache phase

Previously it was believed that CSD initiates the activation of meningeal nociceptors. ATP, glutamate, K+, hydrogen ions, CGRP, and nitrous oxide that are released locally during a CSD are thought to activate the meningeal nociceptors. Evidence from animal studies also supports this assumption(16).

But majority of the migraine attacks are not preceded by aura. A prospective study on the time course of aura and headache symptoms, found that many patients reported migraine symptoms such as nausea, photophobia, phonophobia, and headache during the aura phase and few reported that headache started simultaneously with the aura. Therefore, it is now considered aura may be the result of an aberrant “brain state” which occurs in a genetically susceptible individual during a migraine attack and the physiological events occurring during the premonitory phase could be the primary cause of both trigeminovascular pathway activation and cortical neuronal/glial activity (16). Peripheral Sensitization -Trigeminovascular pathway activation

When nociceptive neurons that innervate the dura mater are stimulated they release vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38. This will

(29)

activate the trigeminovascular pathway. Once activated by endogenous mediators, the peripheral trigeminovascular neurons become sensitized to dural stimuli. So their threshold for response decreases and the magnitude of their response increases (16).

Peripheral sensitization is thought to be responsible for the characteristic throbbing pain of migraine, and the exacerbation of pain by bending over or coughing. This increased sensitivity to sensory stimulation is thought to be a consequence of hyperresponsiveness within primary afferent fibers and/or central neurons. The specific inflammatory mediators that promote activation and sensitization of peripheral trigeminovascular neurons remains to be fully understood. Quite a lot of animal studies implicate CGRP release in the initiation and maintenance of peripheral sensitization (16).

Central Sensitization

Sensitization of the central trigeminovascular neurons in the TCC and thalamic nuclei are responsible for cephalic and extra-cephalic allodynia.

Cephalic allodynia characterised by signs of scalp and cephalic muscle tenderness and an aversion to touch develops over 30-60 minutes and reaches a maximum around 120 minutes, results from sensitization in the spinal trigeminal nucleus. Thalamic sensitization which is responsible for extra-cephalic allodynia develops approximately after 2-4 hours (22). Cutaneous allodynia may be a risk factor for migraine progression. It may be due to repeated activation and

(30)

sensitization of the central trigeminovascular pathways, leading to persistent central sensitization, elevating the risk for developing chronic migraine(16).

GENETICS OF MIGRAINE

Molecular genetic studies have provided substantial insights into the molecular underpinnings of migraine. Studies among twins estimated a heritability of approximately 50% for migraine. The heritability for migraine with aura is significantly higher than for migraine without aura. Candidate gene association studies (CGAS), as well as genome-wide association studies (GWAS), have recognized a large number of genetic variants associated with migraine. These genes are involved in several neurological, vascular, or hormonal pathways (23).

Neuronal genes and migraine

Familial hemiplegic migraine (FHM), was the first identified single gene mutation associated with migraine. It is a rare form of migraine that is inherited as an autosomal dominant pattern. FHM is characterized by migraine attacks accompanied by a transient unilateral motor weakness (16).

Three types of FHM have been identified so far. FHM1is caused by mutations in CACNA1A on chromosome 19p13 that encodes for the α1 subunit of voltage-gated Ca2+ channels that controls the neurotransmitter release at synapses. FHM2 results from mutations in ATP1A2 on chromosome 1q23 which

(31)

encodes for the α2 subunit of Na+/K+-ATPase which is expressed in the glial cells of adults and aids reuptake of glutamate from the synaptic cleft (16).

Both FHM1 and FHM2 mutations leads to hyperexcitatory neurotransmission through the unregulated release or reduced reuptake of glutamate from the synaptic cleft. FHM3 is caused by mutation in SCN1A on chromosome 2q24 that encodes for the α1 subunit of voltage-gated Na+ channels which are expressed on inhibitory interneurons; FHM3 mutations causes unregulated firing of excitatory neurons (16).

Vascular genes and migraine

This category of genes includes those regulating blood pressure, expression of endothelial cells, vasoconstriction and vasodilatation. In this group of genes, the methylenetetrahydrofolate reductase (MTHFR), and the angiotensin-converting enzyme (ACE) genes are the most investigated in migraine pathogenesis. The vascular genes associated with migraine have been also shown to play a key role in elevating the risk of cardio- and cerebrovascular disorders. This is of particular relevance for MA, which has a considerable co morbidity with stroke (23).

Role of MTHFR gene in the pathogenesis of migraine

The MTHFR gene is located on chromosome 1p36.22 and consists of 11 exons. The gene encodes for a 656 amino acid multi-domain protein, the methylenetetrahydrofolate reductase enzyme that converts

(32)

5, 10 - methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5- methyltetrahydrofolate generated by this enzyme is necessary for initiation of the methionine cycle. Thus MTHFR protein plays an important regulatory role in the connection between folate and methionine cycles and is needed for the conversion of homocysteine to methionine (23).

Homocysteine (Hcy) is an essential amino acid that plays critical role in cell functions such as protein synthesis and neurotransmitter methylation. It is also a precursor to S-adenosyl methionine (SAM), which serves as the methyl donor for numerous methylation reactions. These reactions are involved in the transfer of methyl groups from a donor (e.g., SAM) to a recipient (e.g., DNA or a protein) (23).

Methylation results in altered function of the recipient molecule. The demethylated SAM then is further processed to homocysteine, which in turn is converted back into methionine either through a folate dependent mechanism or a folate-independent mechanism. The MTHFR enzyme has a unique function in that it regulates the availability of methyl groups for methylation reactions at the cost of purines and pyrimidine synthesis (23).

Folate is also necessary to drive this pathway. Lack of dietary folate and/or reduced MTHFR enzymatic activity can result in increased plasma level of homocysteine (24).

(33)

The clinical consequences of elevated plasma homocysteine levels includes endothelial cell injury, alterations in coagulant properties of blood, reduced flexibility of the vessels, spontaneous trigeminal cell firing, oxidative stress, DNA damage, activation of pro-apoptotic factors and activation of NMDA receptor (23).

Spontaneous trigeminal cell firing leading to inflammation in the meninges and dilation of the cerebral vessels is thought in part to cause the pain associated with migraine. Auto-oxidation of homocysteine resulting in formation of superoxide anions causes oxidative damage to the vascular endothelium can also increase the likelihood of migraine and other vascular disorders (24).

Genetic variants of MTHFR gene

A large number of variants of the MTHFR gene are described so for as a result of ample studies being carried out by the researchers. Few variants that are identified so far are,

 The first genetic variant, C677T in exon 4 is characterized by cytosine (C)

→ thymine (T) change at position 677, with an amino acid substitution in the catalytic domain of alanine 222 to valine (Ala222Val). The resulting protein is a thermolabile enzyme that is less active at higher temperatures.

Individuals carrying two copies of this variant (TT homozygous) showed higher homocysteine levels and lower serum folate levels compared to controls. Roughly 15% of European and North America Caucasians are

(34)

estimated to be homozygous for the thermolabile variant. This variant is associated with a large number of diseases, like venous thrombosis, cardio- and cerebrovascular diseases, migraine, depression, Alzheimer’s disease, Parkinson’s disease, and ovarian cancer (23).

 A second genetic variant, the A1298C in exon 8 at position 1298 is characterized by an adenine (A) → cytosine (C) substitution that substitutes a glutamate into an alanine amino acid (Glu429Ala). This variant results in lowering the MTHFR activity to a lesser degree than C677T polymorphism (23).

 Recently, in Norfolk Island, new genetic variants of MTHFR gene have been investigated through next-generation sequencing techniques. Three different single nucleotide polymorphisms (SNPs) in the MTHFR gene showed a significant association with migraine. The genetic variants were located in exon 11 (rs2274976), intron 7 (rs6696752) , and 3ʹ untranslated region (3ʹUTR) (rs4846048) (25).

 Another recent study in the Iranian population found that a different polymorphism (rs4846049) in 3′ UTR region is significantly associated with migraine (23).

(35)

Role of Angiotensin converting enzyme in migraine

ACE catalyzes the conversion of angiotensin I to angiotensin II, which acts as a potent vasoconstrictor. ACE also plays a role in the inactivation of bradykinin, a strong vasodilator, so the net effect is powerful vasoconstrictor effect on blood vessels. Genetic polymorphism due to insertion/deletion in the ACE gene poses a moderate risk for vascular diseases. It has also been implicated as a risk factor for migraine. Like the MTHFR gene, ACE seems to play an important role in the pathogenesis of MWA, rather than in MWOA.

Paterna et al first suggested a role for the ACE D/D genotype in migraine (24). Hormonal genes and migraine

A more credible explanation for the sex differences could be genetic effect on the migraine threshold, resulting in a higher threshold in men than in women. An increasing number of studies have explored genetic associations between the functionally important polymorphisms in estrogen receptor 1 (ESR1) gene, progesterone receptor gene (PGR) and migraine susceptibility (26).

Though there might be a genetic predisposition to migraine, additional endogenous or exogenous triggers in women are likely to account for the sex difference in migraine prevalence. Fluctuations in the hormone concentrations, mainly oestrogen, are considered to account for the higher prevalence ratio in women during the reproductive years (27) .

(36)

Figure 1: ICHD-3 Classification of Migraine

(37)

MIGRAINE WITHOUT AURA

Previously MWOA was described as common migraine or hemicrania simplex. Diagnostic criteria of MWOA includes (28)

A. “At least five attacks fulfilling criteria B-D

B. Headache attacks lasting for 4-72 hr (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics:

1. unilateral location 2. pulsating quality

3. moderate or severe pain intensity

4. aggravation by or causing avoidance of routine physical activity (eg walking or climbing stairs)

D. During headache at least one of the following:

1. Nausea and/or vomiting

2. Photophobia and phonophobia MIGRAINE WITH AURA

MWA is characterised by recurrent attacks of gradually developing unilateral fully-reversible visual, sensory or other central nervous system

(38)

symptoms lasting for few minutes that are usually followed by headache and associated migraine symptoms (29).

Classical migraine, ophthalmic, hemiparaesthetic, hemiplegic or aphasic migraine; migraine accompagnée and complicated migraine are the terms previously used to describe MWA. Diagnostic criteria of MWA includes: (29) a) “At least two attacks fulfilling criteria b and c

b) One or more of the following fully reversible aura symptoms:

1. Visual 2. Sensory

3. Speech and/or language 4. Motor

5. Brainstem 6. Retinal

c) At least three of the following six characteristics

1. At least one aura symptom spreads gradually over ≥5 minutes 2. Two or more aura symptoms occur in succession

3. Each individual aura symptom lasts 5-60 minutes

(39)

4. At least one aura symptom is unilateral (aphasia is considered as unilateral symptom)

5. At least one aura symptom is positive (scintillations and pins and needles are positive symptoms of aura)

6. The aura is accompanied, or followed within 60 minutes, by headache

Migraine with typical aura

Migraine with typical aura is further divided into

 Typical aura with headache

Characterised by aura accompanied or followed within 60 minutes by headache with or without characteristic feature of migraine (30).

 Typical aura without headache

Migraine with typical aura in which aura is neither accompanied nor followed by headache of any sort (31).

Migraine with brainstem aura

Previously was referred as basilar artery migraine / basilar type migraine / basilar migraine. Since basilar artery involvement is unlikely now it is called migraine with brainstem aura. It is characterised by migraine with aura symptoms originating from the brainstem. Diagnostic criteria includes: (32)

(40)

Attacks fulfilling the criteria for MWA and at least 2 of the following fully reversible brainstem symptoms with no motor or retinal symptoms.

 Dysarthria

 Tinnitus

 Vertigo

 Hypacusis

 Diplopia

 Ataxia not attributable to any sensory deficit

 Decreased level of consciousness (GCS≤13)

 No motor or retinal symptoms (32).

Hemiplegic migraine

Migraine patients who experience fully reversible motor symptoms in addition to typical aura are grouped under this category. The motor weakness generally last less than 72 hours but in few it may persist even for weeks (33). Hemiplegic migraine is further sub divided into

a) Familial hemiplegic migraine (FHM) b) Sporadic hemiplegic migraine (SHM)

(41)

Retinal migraine

Patients with repeated attacks of fully reversible monocular visual disturbances associated with migraine headache are diagnosed as retinal migraine. The visual phenomena include scintillations, scotomas or blindness which is confirmed during an attack by clinical visual field examination or the patient’s drawing the monocular field defect(34).

The visual disturbance should fulfil atleast 2 of the following:

i. Spreading gradually over ≥ 5 minutes ii. Lasting for 5 – 60 minutes

iii. Accompanied or followed by headache within 60 minutes (34) . CHRONIC MIGRAINE

Chronic migraine is described as headache occurring on 15 or more days per month for more than a period of 3 months, which on at least 8 attacks per month has the feature of migraine (35) .

TRIGGERS OF MIGRAINE

A migraine trigger is any factor that, on exposure or withdrawal, leads to the development of an acute migraine headache. Various external and internal stimuli can lead to migraine in susceptible individuals. Triggers may be categorized as behavioural, environmental, infectious, dietary, chemical, or

(42)

hormonal. Most common migraine triggers include stress, sleep, fatigue, fasting, physical exercise, hormonal changes (36).

Migraine attacks may be triggered by allergic reactions, bright lights, loud noises, and certain odours or perfumes, head trauma, physical or emotional stress, changes in sleep patterns, smoking, skipping meals, alcohol, menstrual cycle fluctuations, foods containing tyramine, monosodium glutamate (MSG) or nitrates, other foods such as chocolate, dairy products, and fermented or pickled foods (36) .

A study conducted by Park et al to identify various trigger factors of migraine using smartphone headache diary application (SHD) revealed that the probability of a headache was 57.7% for stress, 55.1% for sleep deprivation, 48.5% for fatigue, and 46.5% for any trigger. The headaches with trigger factors were more severe compared to those without trigger factors. Travelling, hormonal changes, noise, alcohol, overeating and stress increased the risk of migraines. Hormonal changes and noise increased the risk of migraine irrespective of preventive medication, whereas stress, overeating, alcohol, and travelling increased the risk of migraine in situations without preventive medication (36) .

One study in India found that for some migraineurs washing hair in a bath was a migraine trigger but the underlying scientific basis is not established(37) .

(43)

CLINICAL FEATURE OF MIGRAINE

The migraine attack is divided into 4 nonobligatory phases(38) 1. The premonitory phase

2. The aura

3. The headache phase 4. The postdrome The premonitory phase

The first detailed description of migrainous premonitory phase was given by Blau in 1980. This phase commonly occurs 2-48 hours before migraine attack(39) .

Common symptoms experienced during this phase include fatigue, food cravings, excessive yawning, muscle tenderness, polyuria, photophobia, nausea, altered sense of hearing or of smell, swelling or fluid retention, irritability, confusion, impaired speech or impaired memory and difficulty in reading(39) .

Premonitory symptoms and aura both develop gradually. But they can be distinguished based on two main characteristic features, namely the timing of the occurrence of these symptoms prior to the headache pain, and their clinical characteristics. An aura does not last more than 60 minutes, it is always related to

(44)

focal cortical activity, and cortical spreading depression represents its underlying pathophysiological mechanism (39) .

On the contrary, premonitory symptoms have a longer duration and they may not resolve prior to pain onset. And they are more likely to derive from different areas of the central nervous system (CNS) and they are characterized by general/behavioural features (39) .

Aura

Approximately one-third of the migraine attacks are preceded by aura.

Aura is a transient neurological symptom characterised by recurrent attacks of unilateral, fully reversible, visual, sensory or other CNS symptoms that usually develop gradually, evolve over at least 5 minutes and can last for up to 60 minutes. They are mostly be followed by headache and associated migraine symptoms. Sometime it’s not followed by headache (16) .

Visual aura is the most common type of aura, occurring in almost 90% of MWA patients followed by sensory aura. Systematic studies have revealed that many patients with visual aura occasionally have symptoms in the extremities and/or speech symptoms. On the other hand, patients with symptoms in the extremities and/or speech or language symptoms more or less always experience visual aura symptoms at least during some attacks (29).

(45)

When multiple auras occur during an attack, they usually follow one another in succession. The maximal acceptable duration of most aura symptoms is one hour, but motor symptoms may last up to 72 hours (29) .

Alice in Wonderland syndrome (AIWS), named for Lewis Carroll’s titular character, is a rare form of migraine aura, characterized by transient episodes of visual hallucinations and perceptual distortions, during which objects or body parts are perceived as altered in various ways (metamorphopsia), including enlargement (macropsia) or reduction (micropsia) in the perceived size of a form(40) .

The headache phase

Migraine headache is characterised by unilateral throbbing headache which is moderate or severe in intensity associated with nausea, vomiting, photophobia and phonophobia, usually lasting for 4 to 72 hours.

The postdrome phase

The postdrome is defined as the time between headache resolution and feeling completely back to normal. Headache resolution is defined as cessation of troublesome headache(38). Majority of migraineurs take hours to fully recover;

some may even take days. Most of the people describe postdrome as feeling “like a zombie” or “hung-over”(41). The symptoms of postdrome includes tiredness, difficulty in concentration, stiff neck, light sensitivity, somnolence, lowered mood levels, especially depression and pale face (38) .

(46)

CO MORBIDITIES OF MIGRAINE

The term co morbidity refers to the statistical association of two distinct diseases in the same individual at a rate higher than expected by chance (42). Many illnesses are reported to be co morbid with migraine and this stresses the clinical complexity of this headache disorder.

Co morbidity in migraine is important from several perspectives:

(1) Co-occurrence of the diseases can complicate the diagnosis, e.g., focal sign of migraine and stroke

(2) One disease can alarm the clinicians of the other diseases, e.g., migraine and restless legs syndrome (RLS)

(3) Helps in individualising the drug for that patient, e.g., tricyclic antidepressants for migraine patients with depressive disorders; and (4) Co morbidity of the illnesses can provide clues to the pathophysiology of

migraine (42).

Patients with MWA are at an increased risk of stroke, CVD and psychiatric disorders. Women with migraine are likely to have a increased risk of CVD, compared to men. The association between migraine and depression and panic disorder is bidirectional. Young adults or adolescents suffering from MWA have a higher suicide risk (42).

(47)

MANAGEMENT OF MIGRAINE

Figure 2: Management of Migraine Abortive therapy

The Goals of abortive therapy are:

 To treat the acute attack rapidly and consistently without recurrence

 Restore the patient’s ability to function normally

 Minimise the analgesic use and rescue medications

 To relieve the accompanying symptoms

 To give a cost-effective therapy

(48)

 Minimise the adverse effects(43).

Principles of acute therapy

 Educate the patient about migraine and its treatment option

 Initiate the treatment while the pain is mild and choose right drug, right dose and right route of administration

 Nonsteroidal anti-inflammatory drugs(NSAIDs) are the first line drug for mild to moderate intensity migraine. Triptans are the drug of choice for severe intensity migraine.

 Tailor the treatment according to the individual’s need.

 For patients who are awakened by moderate to severe attacks, or whose pain peaks rapidly (ie, within 30 min), and for those with nausea or vomiting during the premonitory period or early in the course of the attack non-oral route of administration (eg, nasal spray, injection, suppository) can improve the outcomes.

 Antiemetics should not be restricted only to patients with vomiting.

Even nausea should be treated appropriately

 Patients should be cautioned about medication overuse headache(44).

(49)

Drugs for abortive therapy can be classified as follows Specific acute medication

 5HT1B/1D receptor agonist (Triptans) :

Sumatriptan, Almotriptan, Eletriptan, Rizatriptan, Frovatriptan, Naratriptan, Zolmitriptan

 Ergot Alkaloids

Ergotamine tartarate, Dihydroegotamine.

Nonspecific acute medication

 Nonsteroidal anti-inflammatory drugs(NSAIDs)

Aspirin, Paracetamol , Ibuprofen, Naproxen , Diclofenac, Ketoprofen, Ketorolac

 Opioids

Butorphanol, Codeine, Meperidine, Methadone, Tramadol

 Antiemetics

Metoclopromide, Prochlorperazine, Domperidone 5-HT1B/1D Receptor Agonists

Triptans are considered to be the gold standard symptomatic treatment.

They are reserved for cases of migraine with severe intensity and used as a

(50)

second line drug when patients have inadequate response to simple analgesics.

Their potential mechanisms of actions are: cranial vasoconstriction, peripheral neuronal inhibition , and inhibition of transmission through second-order neurons of the trigeminocervical complex(45).

Oral triptans provide headache relief within 30 to 60 minutes except for naratriptan which has a slow onset of action . A meta-analysis showed that eletriptan 80 mg and rizatriptan 20 mg have higher 2-hour response rates than sumatriptan 100 mg and that naratriptan 2.5 mg and frovatriptan 2.5 mg have the lowest response rates. Recurrence rates are lowest with eletriptan at 2 hours.

Dissolving tablets (wafers) of rizatriptan 10 mg and zolmitriptan 2.5 mg can be used if oral intake exacerbates nausea(45).

Parenteral formulations can also be useful in patients with nausea or vomiting. sumatriptan and zolmitriptan are also available in the form of nasal sprays. The tolerability profile of rizatriptan, sumatriptan, zolmitriptan, and eletriptan appears to be similar(45).

Contraindications for the use of triptans include untreated arterial hypertension, coronary heart disease, Raynaud’s disease, history of ischaemic stroke, pregnancy, lactation, and severe liver or renal failure. Triptans should be taken less than 10 days per month to avoid the emergence of MOH(45).

(51)

Ergot Alkaloids

The ergotamines are agonist at 5HT1B/1D receptor like Triptans. These drugs are not preferred nowadays because of their poor receptor specificity and more side effects at therapeutically effective doses. Dihydroergotamine is used in some patients who have an inadequate response to triptans. It is available as a nasal spray and can also be injected subcutaneously or intramuscularly (46).

The main adverse effects include nausea, vomiting, paraesthesia, and ergotism. These drugs are contraindicated in cardiovascular and cerebrovascular diseases, Raynaud’s disease, arterial hypertension, renal failure, pregnancy and lactation (45).

NSAIDs

NSAIDs are the first choice for migraine with mild or moderate severity(45). They act by inhibiting cyclooxygenase(COX) enzyme. Aspirin is irreversible COX inhibitors while other NSAIDs are competitive and reversible inhibitor of COX. Paracetamol is effective if the attack is mild in severity and is an alternative when there is a contraindication for the use of NSAIDs (46) .

Ibuprofen and diclofenac potassium have a rapid onset of action as they are rapidly absorbed from the gastrointestinal tract. But their short half-life may make repeated dosing necessary for a single attack in some patients. Both ibuprofen and diclofenac potassium have special formulations with more rapid absorption and a more rapid onset of action. They are shown to have advantages

(52)

over their oral tablet counterparts. Solubilized ibuprofen 400 mg has shown a higher response rate for headache relief at 1 hour as compared to the corresponding standard ibuprofen tablet. With diclofenac potassium powder for oral solution (50 mg) analgesic effects were noted within 15 minutes and are superior to its tablet formulation (46) .

Aspirin also has a relatively rapid absorption and an intermediate half-life of 5-6 hours if active metabolites are included. Effervescent aspirin formulation has a faster absorption than regular tablets. On the other hand, naproxen sodium has slower absorption but a longer half-life but headache relief at 2 hours are lower than ibuprofen (46) .

Combinations of drugs

There is good evidence that combining sumatriptan 85mg with naproxen sodium 500mg provides a higher 2-hour headache relief rate than either drug alone. Patient taking this combination experienced a higher 24-hour sustained pain response (no more than mild pain and no rescue medication at 2 hours and for 24 hours post-dose) than either drug alone. Another study with frovatriptan 2.5mg and dexketoprofen also showed a higher pain free rate at 2 hours than with frovatriptan alone. So combining an NSAID with a triptan would be a good strategy for treating patients who do not respond well to a triptan alone (46) .

(53)

In case of unresponsiveness or contraindications to other medications, combination analgesics with opioids can be considered. Tramadol may be the preferred option in such cases. Combination analgesics with opioids including codeine should not be used routinely because of the poor evidence for their efficacy over that provided by NSAIDs (46) .

A post hoc analysis of a rizatriptan clinical trial found that recent opioid use was associated with a lower response rate to rizatriptan and has raised a concern that using opioids may make patients more refractory to other acute medications including the triptans. Use of barbiturate-containing analgesics and stronger opioids like morphine and butorphanol should be limited to exceptional cases because of the risk of addiction and medication overuse headache (46) . Antiemetics

Metoclopramide is the antiemetic with greatest evidence for efficacy in migraine. Prochlorperazine and domperidone can also be used. These drugs carry a risk of extrapyramidal adverse effects but are uncommon with intermittent use.

Patients must be cautioned about overuse of these medications (46) .

Treatment strategies recommended by American Academy of Family Physicians for abortive therapy

 The stratified approach: This is based on headache severity. Mild headaches are initially treated with NSAIDs, whereas more severe headaches are initially treated with a Triptan.

(54)

 “Step care across attacks” approach: The initial medication is chosen based on cost and adverse effect profile. If treatment is unsuccessful, a more potent medication is used for the subsequent attacks.

 “Step care within attacks” approach: Initially a simple analgesic is used, if necessary switches to more potent medications later in the same attack.

 A comparative trial revealed that stratified approach was more successful at relieving pain at two hours, but it resulted in more adverse effects. The

“step care within attacks” approach works best for patients with prolonged episodes or inconsistent symptom patterns (44) .

Prophylactic therapy

Goals of long term migraine prophylaxis are: (47)

 To reduce the frequency, severity and duration of attack

 To improve the responsiveness to abortive treatment

 To improve function and reduce disability

 To reduce medication overuse headache

 To reduce the overall cost associated with treatment of migraine

 To improve health- related quality of life(HRQoL)

(55)

Indications for prophylactic therapy

The following patients with migraine should be considered for prophylactic therapy:(47)

 Patient’s with attacks significantly interfering daily routines despite acute treatment

 Patient’s with frequent attacks (≥4 MHDs)

 Patient’s who have failed to respond to acute treatment or with contraindication to acute treatments

 Patient’s with medication overuse. It is defined as:

- 10 or more days per month for ergot derivatives, triptans, opioids, combination analgesics, and a combination of drugs from different classes that are not individually overused

- 15 or more days per month for nonopioid analgesics, acetaminophen, and nonsteroidal antiinflammatory drugs

 Adverse effects with acute treatments

 Patient preference

(56)

The American Headache Society 2018 guidelines for prophylactic therapy:(47)

1. To use evidence based preventive treatment

2. Start with a low dose and titrate slowly until target response develops or maximum dose is reached

3. Give an adequate trial period of atleast 8 weeks to optimize the possibility of a therapeutic response. Patients with partial response should be counselled that cumulative benefits may occur over 6 to 12 months of continued use

4. Optimize drug selection based on evidence for efficacy, comorbid condition of patient, concomitant medication, headache profile, tolerability and pregnancy or potential to become pregnant

5. Educate the patient the importance of adherence to the treatment

6. Explain the patient what the likely benefits of pharmacologic prophylaxis will be:

 50% reduction in the headache frequency

 Significant decrease in duration of attack as defined by patient

 Significant decrease in severity of attack as defined by patient

 Improved response to acute treatment

(57)

 Reduction in disability and improvements in functioning

 Improvements in the health related quality of life and reduction in psychological distress due to migraine

Table 1: Consensus guidelines to identify patient’s for prophylactic therapy(47)

Prophylactic

therapy Headache days/month Degree of disability (using MIDAS)

Offered

6 or more None

4 or more Some

3 or more Severe

Considered

4 or 5 None

3 Some

2 Moderate

Table 2: Classification of drugs available for prophylactic therapy based on evidence of efficacy (47)

Established efficacy Probably

effective Possibly effective Antiepileptic drugs:

Divalproex sodium, Valproate sodium,

Topiramate

Beta-blockers: Propranolol, Metoprolol, Timolol Triptans: Frovatriptan

Others:

OnabotulinumtoxinA

Antidepressants:

Amitriptyline, Venlafaxine Beta-blockers:

Atenolol, Nadolol

ACE inhibitors: Lisinopril Alpha-agonists: Clonidine,

Guanfacine Antiepileptic drugs:

Carbamazepine Beta-blockers: Nebivolol,

Pindolol Antihistamines:

Cyproheptadine Angiotensin receptor blockers: Candesartan

(58)

In addition to the above drugs herbal remedies like Feverfew(Tanacetum parthenium L.) , butterbur (Petasites hybridus) have shown some promising effect in migraine. Studies have shown that high dose Riboflavin(Vitamin B2) is effective in migraine prophylaxis.

STANDARD PROPHYLAXIS Propranolol:

Figure 3: Chemical structure of Propranolol

Propranolol was developed by Scottish physician and pharmacologist Sir James Whyte Black in 1958. It is a nonselective, competitive β adrenergic receptor antagonist with equal affinity to β1 and β2 receptors.

Pharmacological Action:

 Blockade of β1 receptors inhibit noradrenaline (NA) release and tyrosine hydroxylase activity, the rate-limiting step in NA synthesis

References

Related documents

Although a refined source apportionment study is needed to quantify the contribution of each source to the pollution level, road transport stands out as a key source of PM 2.5

INDEPENDENT MONITORING BOARD | RECOMMENDED ACTION.. Rationale: Repeatedly, in field surveys, from front-line polio workers, and in meeting after meeting, it has become clear that

With respect to other government schemes, only 3.7 per cent of waste workers said that they were enrolled in ICDS, out of which 50 per cent could access it after lockdown, 11 per

Of those who have used the internet to access information and advice about health, the most trustworthy sources are considered to be the NHS website (81 per cent), charity

Harmonization of requirements of national legislation on international road transport, including requirements for vehicles and road infrastructure ..... Promoting the implementation

Angola Benin Burkina Faso Burundi Central African Republic Chad Comoros Democratic Republic of the Congo Djibouti Eritrea Ethiopia Gambia Guinea Guinea-Bissau Haiti Lesotho

We are using ATLAS to study how the value of current changes in presence of high energy radiation in case of a Silicon p-n diode in its reverse bias condition and also the DC

Daystar Downloaded from www.worldscientific.com by INDIAN INSTITUTE OF ASTROPHYSICS BANGALORE on 02/02/21.. Re-use and distribution is strictly not permitted, except for Open